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  • 1.
    Abdeldaim, Guma
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Bacteriology. Benghazi Univ, Fac Med, Dept Med Microbiol & Parasitol, Benghazi, Libya..
    Svensson, Erik
    Statens Serum Inst, Int Reference Lab Mycobacteriol, Copenhagen, Denmark..
    Blomberg, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Virology.
    Herrmann, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Bacteriology.
    Duplex detection of the Mycobacterium tuberculosis complex and medically important non-tuberculosis mycobacteria by real-time PCR based on the rnpB gene2016In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 124, no 11, p. 991-995Article in journal (Refereed)
    Abstract [en]

    A duplex real-time PCR based on the rnpB gene was developed for Mycobacterium spp. The assay was specific for the Mycobacterium tuberculosis complex (MTB) and also detected all 19 tested species of non-tuberculous mycobacteria (NTM). The assay was evaluated on 404 clinical samples: 290 respiratory samples and 114 from tissue and other nonrespiratory body sites. M. tuberculosis was detected by culture in 40 samples and in 30 samples by the assay. The MTB assay showed a sensitivity similar to Roche Cobas Amplicor MTB-PCR (Roche Molecular Systems, Pleasanton, CA, USA). There were only nine samples with non-tuberculous mycobacteria detected by culture. Six of them were detected by the PCR assay.

  • 2.
    Abdillahi, Suado M.
    et al.
    Lund Univ, Div Infect Med, Dept Clin Sci, Tornavagen 10, S-22184 Lund, Sweden.
    Maass, Tobias
    Univ Cologne, Fac Med, Ctr Biochem, Ctr Mol Med Cologne, D-50931 Cologne, Germany.
    Kasetty, Gopinath
    Lund Univ, Div Resp Med & Allergol, Dept Clin Sci, S-22184 Lund, Sweden.
    Strömstedt, Adam A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Farmakognosi.
    Baumgarten, Maria
    Lund Univ, Div Infect Med, Dept Clin Sci, Tornavagen 10, S-22184 Lund, Sweden.
    Tati, Ramesh
    Lund Univ, Div Infect Med, Dept Clin Sci, Tornavagen 10, S-22184 Lund, Sweden.
    Nordin, Sara L.
    Lund Univ, Div Infect Med, Dept Clin Sci, Tornavagen 10, S-22184 Lund, Sweden.
    Walse, Björn
    Sarom Biostruct AB, S-22363 Lund, Sweden.
    Wagener, Raimund
    Univ Cologne, Fac Med, Ctr Biochem, Ctr Mol Med Cologne, D-50931 Cologne, Germany.
    Schmidtchen, Artur
    Lund Univ, Div Dermatol & Venereol, Dept Clin Sci, S-22184 Lund, Sweden;Univ Copenhagen, Bispebjerg Hosp, Dept Biomed Sci, Copenhagen Wound Healing Ctr, DK-2400 Copenhagen, Denmark.
    Mörgelin, Matthias
    Lund Univ, Div Infect Med, Dept Clin Sci, Tornavagen 10, S-22184 Lund, Sweden;Colzyx AB, S-22381 Lund, Sweden.
    Collagen VI Contains Multiple Host Defense Peptides with Potent In Vivo Activity2018In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 201, no 3, p. 1007-1020Article in journal (Refereed)
    Abstract [en]

    Collagen VI is a ubiquitous extracellular matrix component that forms extensive microfibrillar networks in most connective tissues. In this study, we describe for the first time, to our knowledge, that the collagen VI von Willebrand factor type A like domains exhibit a broad-spectrum antimicrobial activity against Gram-positive and Gram-negative bacteria in human skin infections in vivo. In silico sequence and structural analysis of VWA domains revealed that they contain cationic and amphipathic peptide sequence motifs, which might explain the antimicrobial nature of collagen VI. In vitro and in vivo studies show that these peptides exhibited significant antibacterial activity against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa through membrane disruption. Our findings shed new light on the role of collagen VI derived peptides in innate host defense and provide templates for development of peptide-based antibacterial therapies.

  • 3.
    Abdulla, Maysaa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer Immunotherapy.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer Immunotherapy.
    Lindskog, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.
    Hollander, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer Immunotherapy.
    Expression of IDO1 and PD-L2 in Patients with Benign Lymphadenopathies and Association with Autoimmune Diseases2023In: Biomolecules, E-ISSN 2218-273X, Vol. 13, no 2, article id 240Article in journal (Refereed)
    Abstract [en]

    The expression patterns of IDO1 and PD-L2 have not been thoroughly investigated in benign lymphadenopathies. The aim with this study was to elucidate how IDO1 and PD-L2 are expressed in benign lymphadenopathies in patients with autoimmune diseases (AD) compared to patients without AD. Formalin-fixed paraffin-embedded lymph nodes from 22 patients with AD and 57 patients without AD were immunohistochemically stained to detect IDO1 and PD-L2. The material was previously stained with EBER in situ hybridization to detect cells harboring the Epstein-Barr virus (EBV). IDO1 and PD-L2 were generally expressed by leukocytes to low degrees, while follicular IDO1+ cells were very rare. IDO1+ cells in single germinal centers were detected in five patients, and there was a high co-occurrence of follicular EBV+ cells in these cases (three of five patients). There were also significant correlations between interfollicular EBV+ cells and interfollicular IDO1+ cells (Spearman rho = 0.32, p = 0.004) and follicular IDO1+ cells (Spearman rho = 0.34, p = 0.004). High or low amounts of IDO1+ or PD-L2+ cells were not statistically significantly associated with patients with AD. However, the lymphadenopathy with the highest amount of interfollicular IDO1+ cells, which was also the only lymphadenopathy in which endothelial cells expressed IDO1, was in a patient with sarcoidosis. This study further supports that the EBV induces the expression of IDO1 and our findings should be recognized by future studies on IDO1 and PD-L2 in inflammatory and malignant conditions.

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  • 4.
    Abolhassani, Hassan
    et al.
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden.;Univ Tehran Med Sci, Res Ctr Immunodeficiencies, Pediat Ctr Excellence, Childrens Med Ctr, Tehran, Iran..
    Delavari, Samaneh
    Univ Tehran Med Sci, Res Ctr Immunodeficiencies, Pediat Ctr Excellence, Childrens Med Ctr, Tehran, Iran..
    Landegren, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Karolinska Inst, Ctr Mol Med, Dept Med Solna, Stockholm, Sweden..
    Shokri, Sima
    Iran Univ Med Sci, Hazrat e Rasool Gen Hosp, Sch Med, Dept Pediat, Tehran, Iran..
    Bastard, Paul
    Rockefeller Univ, Rockefeller Branch, St Giles Lab Human Genet Infect Dis, New York, NY 10021 USA.;Necker Hosp Sick Children, Necker Branch, Lab Human Genet Infect Dis, Inst Natl Sante & Rech Med U1163, Paris, France.;Univ Paris, Imagine Inst, Paris, France..
    Du, Likun
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden..
    Zuo, Fanglei
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden..
    Hajebi, Reza
    Univ Tehran Med Sci, Dept Gen Surg, Sch Med, Sina Hosp, Tehran, Iran..
    Abolnezhadian, Farhad
    Ahvaz Jundishapur Univ Med Sci, Dept Pediat, Abuzar Childrens Hosp, Ahvaz, Iran..
    Iranparast, Sara
    Ahvaz Jundishapur Univ Med Sci, Fac Med Sci, Dept Immunol, Ahvaz, Iran..
    Modaresi, Mohammadreza
    Univ Tehran Med Sci, Childrens Med Ctr, Pediat Ctr Excellence, Div Pediat Pulm Dis, Tehran, Iran..
    Vosughimotlagh, Ahmad
    North Khorasan Univ Med Sci, Dept Pediat, Bojnurd, Iran..
    Salami, Fereshte
    Univ Tehran Med Sci, Res Ctr Immunodeficiencies, Pediat Ctr Excellence, Childrens Med Ctr, Tehran, Iran..
    Aranda-Guillen, Maribel
    Karolinska Inst, Ctr Mol Med, Dept Med Solna, Stockholm, Sweden..
    Cobat, Aurelie
    Necker Hosp Sick Children, Necker Branch, Lab Human Genet Infect Dis, Inst Natl Sante & Rech Med U1163, Paris, France.;Univ Paris, Imagine Inst, Paris, France..
    Marcotte, Harold
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden..
    Zhang, Shen-Ying
    Rockefeller Univ, Rockefeller Branch, St Giles Lab Human Genet Infect Dis, New York, NY 10021 USA.;Necker Hosp Sick Children, Necker Branch, Lab Human Genet Infect Dis, Inst Natl Sante & Rech Med U1163, Paris, France.;Univ Paris, Imagine Inst, Paris, France..
    Zhang, Qian
    Rockefeller Univ, Rockefeller Branch, St Giles Lab Human Genet Infect Dis, New York, NY 10021 USA.;Necker Hosp Sick Children, Necker Branch, Lab Human Genet Infect Dis, Inst Natl Sante & Rech Med U1163, Paris, France..
    Rezaei, Nima
    Univ Tehran Med Sci, Res Ctr Immunodeficiencies, Pediat Ctr Excellence, Childrens Med Ctr, Tehran, Iran..
    Casanova, Jean-Laurent
    Rockefeller Univ, Rockefeller Branch, St Giles Lab Human Genet Infect Dis, New York, NY 10021 USA.;Necker Hosp Sick Children, Necker Branch, Lab Human Genet Infect Dis, Inst Natl Sante & Rech Med U1163, Paris, France.;Univ Paris, Imagine Inst, Paris, France.;Howard Hughes Med Inst, New York, NY USA..
    Kämpe, Olle
    Karolinska Inst, Ctr Mol Med, Dept Med Solna, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, Stockholm, Sweden..
    Hammarström, Lennart
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden..
    Pan-Hammarström, Qiang
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden..
    Genetic and immunologic evaluation of children with inborn errors of immunity and severe or critical COVID-192022In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 150, no 5, p. 1059-1073Article in journal (Refereed)
    Abstract [en]

    Background: Most severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals are asymptomatic or only exhibit mild disease. In about 10% of cases, the infection leads to hypoxemic pneumonia, although it is much more rare in children. Objective: We evaluated 31 young patients aged 0.5 to 19 years who had preexisting inborn errors of immunity (IEI) but lacked a molecular diagnosis and were later diagnosed with coronavirus disease 2019 (COVID-19) complications. Methods: Genetic evaluation by whole-exome sequencing was performed in all patients. SARS-CoV-2-specific antibodies, autoantibodies against type I IFN (IFN-I), and inflammatory factors in plasma were measured. We also reviewed COVID-19 disease severity/outcome in reported IEI patients. Results: A potential genetic cause of the IEI was identified in 28 patients (90.3%), including mutations that may affect IFN signaling, T- and B-cell function, the inflammasome, and the complement system. From tested patients 65.5% had detectable virus-specific antibodies, and 6.8% had autoantibodies neutralizing IFN-I. Five patients (16.1%) fulfilled the diagnostic criteria of multisystem inflammatory syndrome in children. Eleven patients (35.4%) died of COVID-19 complications. All together, at least 381 IEI children with COVID-19 have been reported in the literature to date. Although many patients with asymptomatic or mild disease may not have been reported, severe presentation of COVID-19 was observed in 23.6% of the published cases, and the mortality rate was 8.7%. Conclusions: Young patients with preexisting IEI may have higher mortality than children without IEI when infected with SARS-CoV-2. Elucidating the genetic basis of IEI patients with severe/critical COVID-19 may help to develop better strategies for prevention and treatment of severe COVID-19 disease and complications in pediatric patients.

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  • 5.
    Abolhassani, Hassan
    et al.
    Karolinska Inst, Dept Biosci & Nutr, S-14183 Huddinge Stockholm, Sweden.;Univ Tehran Med Sci, Res Ctr Immunodeficiencies, Pediat Ctr Excellence, Childrens Med Ctr, Tehran, Iran..
    Landegren, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Karolinska Inst, Ctr Mol Med, Dept Med, Stockholm, Sweden..
    Bastard, Paul
    Rockefeller Univ, St Giles Lab Human Genet Infect Dis, Rockefeller Branch, 1230 York Ave, New York, NY 10021 USA.;Necker Hosp Sick Children, Inst Natl Sante & Rech Med U1163, Necker Branch, Lab Human Genet Infect Dis, Paris, France.;Univ Paris, Imagine Inst, Paris, France..
    Materna, Marie
    Necker Hosp Sick Children, Inst Natl Sante & Rech Med U1163, Necker Branch, Lab Human Genet Infect Dis, Paris, France.;Univ Paris, Imagine Inst, Paris, France..
    Modaresi, Mohammadreza
    Univ Tehran Med Sci, Childrens Med Ctr, Pediat Ctr Excellence, Div Pediat Pulm Dis, Tehran, Iran..
    Du, Likun
    Karolinska Inst, Dept Biosci & Nutr, S-14183 Huddinge Stockholm, Sweden..
    Aranda-Guillen, Maribel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sardh, Fabian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Karolinska Inst, Ctr Mol Med, Dept Med, Stockholm, Sweden..
    Zuo, Fanglei
    Karolinska Inst, Dept Biosci & Nutr, S-14183 Huddinge Stockholm, Sweden..
    Zhang, Peng
    Rockefeller Univ, St Giles Lab Human Genet Infect Dis, Rockefeller Branch, 1230 York Ave, New York, NY 10021 USA..
    Marcotte, Harold
    Karolinska Univ Hosp Huddinge, Dept Lab Med, Div Clin Immunol, Karolinska Inst, Stockholm, Sweden..
    Marr, Nico
    Sidra Med, Dept Human Immunol, Doha, Qatar.;Hamad Bin Khalifa Univ, Coll Hlth & Life Sci, Doha, Qatar..
    Khan, Taushif
    Sidra Med, Dept Human Immunol, Doha, Qatar..
    Ata, Manar
    Sidra Med, Dept Human Immunol, Doha, Qatar..
    Al-Ali, Fatima
    Sidra Med, Dept Human Immunol, Doha, Qatar..
    Pescarmona, Remi
    Univ Lyon, Univ Claude Bernard, Ctr Int Rech Infectiol,ENS Lyon, Ctr Natl Rech Sci,Inserm,U1111,UMR5308,Lyon 1, Lyon, France.;Hosp Civils Lyon, Ctr Hosp Lyon Sud, Lab Immunol, Pierre Benite, France..
    Belot, Alexandre
    Univ Lyon, Univ Claude Bernard, Ctr Int Rech Infectiol,ENS Lyon, Ctr Natl Rech Sci,Inserm,U1111,UMR5308,Lyon 1, Lyon, France.;Hosp Civils Lyon, Mere Enfant, Hop Femme, Paediat Nephrol Rheumatol Dermatol, Bron, France.;Natl Reference Ctr Rheumat & Autoimmune & Syst Di, Lyon, France..
    Beziat, Vivien
    Necker Hosp Sick Children, Inst Natl Sante & Rech Med U1163, Necker Branch, Lab Human Genet Infect Dis, Paris, France.;Univ Paris, Imagine Inst, Paris, France..
    Zhang, Qian
    Rockefeller Univ, St Giles Lab Human Genet Infect Dis, Rockefeller Branch, 1230 York Ave, New York, NY 10021 USA.;Necker Hosp Sick Children, Inst Natl Sante & Rech Med U1163, Necker Branch, Lab Human Genet Infect Dis, Paris, France..
    Casanova, Jean-Laurent
    Rockefeller Univ, St Giles Lab Human Genet Infect Dis, Rockefeller Branch, 1230 York Ave, New York, NY 10021 USA.;Necker Hosp Sick Children, Inst Natl Sante & Rech Med U1163, Necker Branch, Lab Human Genet Infect Dis, Paris, France.;Univ Paris, Imagine Inst, Paris, France.;Howard Hughes Med Inst, New York, NY USA..
    Kämpe, Olle
    Karolinska Inst, Ctr Mol Med, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, Stockholm, Sweden..
    Zhang, Shen-Ying
    Rockefeller Univ, St Giles Lab Human Genet Infect Dis, Rockefeller Branch, 1230 York Ave, New York, NY 10021 USA.;Necker Hosp Sick Children, Inst Natl Sante & Rech Med U1163, Necker Branch, Lab Human Genet Infect Dis, Paris, France.;Univ Paris, Imagine Inst, Paris, France..
    Hammarström, Lennart
    Karolinska Inst, Dept Biosci & Nutr, S-14183 Huddinge Stockholm, Sweden..
    Pan-Hammarström, Qiang
    Karolinska Inst, Dept Biosci & Nutr, S-14183 Huddinge Stockholm, Sweden..
    Inherited IFNAR1 Deficiency in a Child with Both Critical COVID-19 Pneumonia and Multisystem Inflammatory Syndrome2022In: Journal of Clinical Immunology, ISSN 0271-9142, E-ISSN 1573-2592, Vol. 42, no 3, p. 471-483Article in journal (Refereed)
    Abstract [en]

    Background Inborn errors of immunity (IEI) and autoantibodies to type I interferons (IFNs) underlie critical COVID-19 pneumonia in at least 15% of the patients, while the causes of multisystem inflammatory syndrome in children (MIS-C) remain elusive. Objectives To detect causal genetic variants in very rare cases with concomitant critical COVID-19 pneumonia and MIS-C. Methods Whole exome sequencing was performed, and the impact of candidate gene variants was investigated. Plasma levels of cytokines, specific antibodies against the virus, and autoantibodies against type I IFNs were also measured. Results We report a 3-year-old child who died on day 56 of SARS-CoV-2 infection with an unusual clinical presentation, combining both critical COVID-19 pneumonia and MIS-C. We identified a large, homozygous loss-of-function deletion in IFNAR1, underlying autosomal recessive IFNAR1 deficiency. Conclusions Our findings confirm that impaired type I IFN immunity can underlie critical COVID-19 pneumonia, while suggesting that it can also unexpectedly underlie concomitant MIS-C. Our report further raises the possibility that inherited or acquired dysregulation of type I IFN immunity might contribute to MIS-C in other patients.

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    FULLTEXT01
  • 6.
    Abolhassani, Hassan
    et al.
    Karolinska Inst, Dept Biosci & Nutr, S-14183 Huddinge, Sweden.;Univ Tehran Med Sci, Res Ctr Immunodeficiencies, Pediat Ctr Excellence, Childrens Med Ctr, Tehran, Iran.
    Vosughimotlagh, Ahmad
    North Khorasan Univ Med Sci, Dept Pediat, Bojnurd, Iran.
    Asano, Takaki
    Rockefeller Univ, Rockefeller Branch, St Giles Lab Human Genet Infect Dis, 1230 York Ave, New York, NY 10021 USA.
    Landegren, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism. Karolinska Inst, Ctr Mol Med, Dept Med Solna, Stockholm, Sweden.
    Boisson, Bertrand
    Rockefeller Univ, Rockefeller Branch, St Giles Lab Human Genet Infect Dis, 1230 York Ave, New York, NY 10021 USA.;Necker Hosp Sick Children, Necker Branch, Lab Human Genet Infect Dis, INSERM U1163, Paris, France.;Univ Paris, Imagine Inst, Paris, France.
    Delavari, Samaneh
    Univ Tehran Med Sci, Res Ctr Immunodeficiencies, Pediat Ctr Excellence, Childrens Med Ctr, Tehran, Iran.
    Bastard, Paul
    Necker Hosp Sick Children, Necker Branch, Lab Human Genet Infect Dis, INSERM U1163, Paris, France.;Univ Paris, Imagine Inst, Paris, France.
    Aranda-Guillen, Maribel
    Karolinska Inst, Ctr Mol Med, Dept Med Solna, Stockholm, Sweden.
    Wang, Yating
    Karolinska Inst, Dept Biosci & Nutr, S-14183 Huddinge, Sweden.
    Zuo, Fanglei
    Karolinska Inst, Dept Biosci & Nutr, S-14183 Huddinge, Sweden.
    Sardh, Fabian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Karolinska Inst, Ctr Mol Med, Dept Med Solna, Stockholm, Sweden..
    Marcotte, Harold
    Karolinska Inst, Dept Lab Med, Stockholm, Sweden.;Karolinska Univ, Hosp Huddinge, Stockholm, Sweden.
    Du, Likun
    Karolinska Inst, Dept Biosci & Nutr, S-14183 Huddinge, Sweden.
    Zhang, Shen-Ying
    Rockefeller Univ, Rockefeller Branch, St Giles Lab Human Genet Infect Dis, 1230 York Ave, New York, NY 10021 USA.
    Zhang, Qian
    Rockefeller Univ, Rockefeller Branch, St Giles Lab Human Genet Infect Dis, 1230 York Ave, New York, NY 10021 USA.
    Rezaei, Nima
    Univ Tehran Med Sci, Res Ctr Immunodeficiencies, Pediat Ctr Excellence, Childrens Med Ctr, Tehran, Iran.
    Kampe, Olle
    Karolinska Inst, Ctr Mol Med, Dept Med Solna, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, Stockholm, Sweden.
    Casanova, Jean-Laurent
    Rockefeller Univ, Rockefeller Branch, St Giles Lab Human Genet Infect Dis, 1230 York Ave, New York, NY 10021 USA.;Necker Hosp Sick Children, Necker Branch, Lab Human Genet Infect Dis, INSERM U1163, Paris, France.;Univ Paris, Imagine Inst, Paris, France.;Howard Hughes Med Inst, New York, NY USA.
    Hammarstrom, Lennart
    Karolinska Inst, Dept Biosci & Nutr, S-14183 Huddinge, Sweden.
    Pan-Hammarstrom, Qiang
    Karolinska Inst, Dept Biosci & Nutr, S-14183 Huddinge, Sweden.
    X-Linked TLR7 Deficiency Underlies Critical COVID-19 Pneumonia in a Male Patient with Ataxia-Telangiectasia2022In: Journal of Clinical Immunology, ISSN 0271-9142, E-ISSN 1573-2592, Vol. 42, no 1, p. 1-9Article in journal (Refereed)
    Abstract [en]

    Background Coronavirus disease 2019 (COVID-19) exhibits a wide spectrum of clinical manifestations, ranging from asymptomatic to critical conditions. Understanding the mechanism underlying life-threatening COVID-19 is instrumental for disease prevention and treatment in individuals with a high risk.

    Objectives We aimed to identify the genetic cause for critical COVID-19 pneumonia in a patient with a preexisting inborn error of immunity (IEI).

    Methods Serum levels of specific antibodies against the virus and autoantibodies against type I interferons (IFNs) were measured. Whole exome sequencing was performed, and the impacts of candidate gene variants were investigated. We also evaluated 247 ataxia-telangiectasia (A-T) patients in the Iranian IEI registry.

    Results We report a 7-year-old Iranian boy with a preexisting hyper IgM syndrome who developed critical COVID-19 pneumonia. IgM only specific COVID-19 immune response was detected but no autoantibodies against type I IFN were observed. A homozygous deleterious mutation in the ATM gene was identified, which together with his antibody deficiency, radiosensitivity, and neurological signs, established a diagnosis of A-T. Among the 247 A-T patients evaluated, 36 had SARS-CoV-2 infection, but all had mild symptoms or were asymptomatic except the index patient. A hemizygous deleterious mutation in the TLR7 gene was subsequently identified in the patient.

    Conclusions We report a unique IEI patient with combined ATM and TLR7 deficiencies. The two genetic defects underlie A-T and critical COVID-19 in this patient, respectively.

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    FULLTEXT01
  • 7.
    Adamson, L.
    et al.
    Karolinska Inst, Dept Pathol & Oncol, Stockholm, Sweden..
    Andersson, B.
    Gothenburg Univ, Immunol, Gothenburg, Sweden..
    Kiessling, R.
    Karolinska Inst, Dept Pathol & Oncol, Stockholm, Sweden..
    Nasman-Glaser, B.
    Karolinska Inst, Dept Pathol & Oncol, Stockholm, Sweden..
    Karlsson-Parra, Alex
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    GMP-production of an allogenic DC-based cancer vaccine (INTUVAX) for treatment of patients with metastatic kidney-or primary liver cancer. Comparison of two production platforms for DC-generation2016In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 46, p. 946-947Article in journal (Other academic)
  • 8.
    Adler, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Initiation of alternative pathway of complement, and development of novel liposomal coatings2023Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The complement system is a central part of the innate immune system, and is an essential part in recognizing and clearing non/altered-self surfaces in the body. This thesis comprises of projects in which the initiation of the alternative pathway (AP) of complement in the fluid phase as well on various artificial and lipid surfaces has been studied. We have also synthesized and evaluated polymer-lipids as liposome coatings to suppress innate immune activation with focus on complement regulation.

    In paper I we investigated how “C3b-like” C3(H2O) is in regards to form an initial fluid phase AP C3 convertase. Even though C3(H2O) could form a C3 convertase, it was much slower in comparison to the convertase generated by C3b. 

    In paper II the contact activation of C3 on various artificial and lipid surfaces as a potential targeted AP activation pathway was explored. C3 bound selectively to lipid surfaces with negatively charged phospholipids and cholesterol, activated platelets and apoptotic cells. Thus, AP was initiated without prior proteolytic cleavage of C3 nor by preformed C3(H2O) on specific surfaces in a selective manner.

    In paper III and IV, synthetic phosphatidylcholine inspired polymer-lipids consisting of poly(2-methacryloyloxyethyl phosphorylcholine)-conjugated lipids (PMPC-lipids) with different degrees of MPC polymerization were synthesized. The protein adsorption, with focus on complement proteins onto the PMPC-lipids were evaluated, indicating that PMPC-lipids with a longer polymer chain are better to suppress protein adsorption. 

    In paper V fragmented heparin-conjugated (fHep) lipids were investigated for their potential ability to recruit complement regulators to a lipid bilayer surface for complement regulation. This study indicated that fHep-liposomes could recruit the main fluid phase regulator of the AP, factor H, as well as the coagulation regulator antithrombin from human plasma. 

    To conclude, the results from this thesis indicates that C3(H2O) in the fluid phase is a poor initiator of the AP, however contact activated C3 could be targeting activation pathway for the AP. We could also successfully synthesize PMPC-lipids and fHep-lipids for protein suppression and potential complement regulation on coated liposomes. 

    List of papers
    1. Assessment of the Role of C3(H2O) in the Alternative Pathway
    Open this publication in new window or tab >>Assessment of the Role of C3(H2O) in the Alternative Pathway
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    2020 (English)In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 11, article id 530Article in journal (Refereed) Published
    Abstract [en]

    In this study we investigate the hydrolysis of C3 to C3(H2O) and its ability to initiate activation via the alternative pathway (AP) of the complement system. The internal thioester bond within C3 is hydrolyzed by water in plasma because of its inherent lability. This results in the formation of non-proteolytically activated C3(H2O) which is believed have C3b-like properties and be able to form an active initial fluid phase C3 convertase together with Factor B (FB). The generation of C3(H2O) occurs at a low but constant rate in blood, but the formation can be greatly accelerated by the interaction with various surfaces or nucleophilic and chaotropic agents. In order to more specifically elucidate the relevance of the C3(H2O) for AP activation, formation was induced in solution by repeated freeze/thawing, methylamine or KCSN treatment and named C3(x) where the x can be any of the reactive nucleophilic or chaotropic agents. Isolation and characterization of C3(x) showed that it exists in several forms with varying attributes, where some have more C3b-like properties and can be cleaved by Factor I in the presence of Factor H. However, in common for all these variants is that they are less active partners in initial formation of the AP convertase compared with the corresponding activity of C3b. These observations support the idea that formation of C3(x) in the fluid phase is not a strong initiator of the AP. It is rather likely that the AP mainly acts as an amplification mechanism of complement activation that is triggered by deposition of target-bound C3b molecules generated by other means.

    Place, publisher, year, edition, pages
    FRONTIERS MEDIA SA, 2020
    Keywords
    complement, C3, C3(H2O), C3b, alternative pathway, C3 convertase
    National Category
    Immunology
    Identifiers
    urn:nbn:se:uu:diva-410958 (URN)10.3389/fimmu.2020.00530 (DOI)000526750400001 ()32296436 (PubMedID)
    Funder
    Swedish Research Council, 2016-2075-5.1Swedish Research Council, 2016-04519
    Available from: 2020-05-28 Created: 2020-05-28 Last updated: 2024-01-17Bibliographically approved
    2. A targeted binding and activation of native C3 without proteolytic cleavage induced by contact with biosurfaces
    Open this publication in new window or tab >>A targeted binding and activation of native C3 without proteolytic cleavage induced by contact with biosurfaces
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    (English)Manuscript (preprint) (Other academic)
    Keywords
    complement, alternative pathway, contact activated C3, thioester, biosurfaces
    National Category
    Immunology in the medical area
    Research subject
    Immunology; Immunology
    Identifiers
    urn:nbn:se:uu:diva-499228 (URN)
    Available from: 2023-03-24 Created: 2023-03-24 Last updated: 2023-03-28
    3. Synthesis of poly(2-methacryloyloxyethyl phosphorylcholine)-conjugated lipids and their characterization and surface properties of modified liposomes for protein interactions
    Open this publication in new window or tab >>Synthesis of poly(2-methacryloyloxyethyl phosphorylcholine)-conjugated lipids and their characterization and surface properties of modified liposomes for protein interactions
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    2021 (English)In: Biomaterials Science, ISSN 2047-4830, E-ISSN 2047-4849, Vol. 9, no 17, p. 5854-5867Article in journal (Refereed) Published
    Abstract [en]

    Poly(ethylene glycol) (PEG) is frequently used for liposomal surface modification. However, as PEGylated liposomes are cleared rapidly from circulation upon repeated injections, substitutes of PEG are being sought. We focused on a water-soluble polymer composed of 2-methacryloyloxyethyl phosphorylcholine (MPC) units, and synthesized poly(MPC) (PMPC)-conjugated lipid (PMPC-lipid) with degrees of MPC polymerization ranging from 10 to 100 (calculated molecular weight: 3 to 30 kDa). In addition, lipids with three different alkyl chains, myristoyl, palmitoyl, and stearoyl, were applied for liposomal surface coating. We studied the interactions of PMPC-lipids with plasma albumin, human complement protein C3 and fibrinogen using a quartz crystal microbalance with energy dissipation, and found that adsorption of albumin, C3 and fibrinogen could be suppressed by coating with PMPC-lipids. In particular, the effect was more pronounced for PMPC chains with higher molecular weight. We evaluated the size, polydispersity index, surface charge, and membrane fluidity of the PMPC-lipid-modified liposomes. We found that the effect of the coating on the dispersion stability was maintained over a long period (98 days). Furthermore, we also demonstrated that the anti-PEG antibody did not interact with PMPC-lipids. Thus, our findings suggest that PMPC-lipids can be used for liposomal coating.

    Place, publisher, year, edition, pages
    Royal Society of ChemistryRoyal Society of Chemistry (RSC), 2021
    National Category
    Physical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-469709 (URN)10.1039/d1bm00570g (DOI)000674760600001 ()34286724 (PubMedID)
    Funder
    Swedish Research Council, 2018-04199Swedish Research Council, 2016-2075-5.1Swedish Research Council, 2016-04519The Swedish Foundation for International Cooperation in Research and Higher Education (STINT)VinnovaEU, Horizon 2020
    Available from: 2022-03-14 Created: 2022-03-14 Last updated: 2024-01-15Bibliographically approved
    4. Effect of liposome surface modification with water-soluble phospholipid polymer chain-conjugated lipids on interaction with human plasma proteins
    Open this publication in new window or tab >>Effect of liposome surface modification with water-soluble phospholipid polymer chain-conjugated lipids on interaction with human plasma proteins
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    2022 (English)In: Journal of materials chemistry. B, ISSN 2050-750X, E-ISSN 2050-7518, Vol. 10, no 14, p. 2512-2522Article in journal (Refereed) Published
    Abstract [en]

    Alternative liposome surface coatings for PEGylation to evade the immune system, particularly the complement system, have garnered significant interest. We previously reported poly(2-methacryloyloxyethyl phosphorylcholine) (MPC)-based lipids (PMPC-lipids) and investigated the surface modification of liposomes. In this study, we synthesize PMPC-lipids with polymerization degrees of 10 (MPC10-lipid), 20 (MPC20-lipid), 50 (MPC50-lipid), and 100 (MPC100-lipid), and coated liposomes with 1, 5, or 10 mol% PMPC-lipids (PMPC-liposomes). Non-modified and PEGylated liposomes are used as controls. We investigate the liposome size, surface charge, polydispersity index, and adsorption of plasma proteins to the liposomes post incubation in human plasma containing N,N,N ',N '-ethylenediamine tetraacetic acid (EDTA) or lepirudin by some methods such as sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE), western blotting, and automated capillary western blot, with emphasis on the binding of complement protein C3. It is shown that the coating of liposome PMPC-lipids can suppress protein adsorption more effectively with an increase in the molecular weight and molar ratio (1-10 mol%). Apolipoprotein A-I is detected on PMPC-liposomes with a higher molecular weight and higher molar ratio of PMPC-lipids, whereas alpha(2)-macroglobulin is detected on non-modified, PEGylated, and PMPC-liposomes with a shorter polymer chain. In addition, a correlation is shown among the PMPC molecular weight, molar ratio, and C3 binding. The MPC10-lipid cannot inhibit C3 binding efficiently, whereas surface modifications with 10 mol% MPC20-lipid and 5 mol% and 10 mol% MPC50-lipid suppress both total protein and C3 binding. Hence, liposome modification with PMPC-lipids can be a possible strategy for avoiding complement activation.

    Place, publisher, year, edition, pages
    Royal Society of Chemistry (RSC), 2022
    National Category
    Physical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-478350 (URN)10.1039/d1tb01485d (DOI)000704923100001 ()34617092 (PubMedID)
    Funder
    Swedish Research Council, 2018-04199Swedish Research Council, 2016-2075-5.1Swedish Research Council, 2016-04519EU, Horizon 2020Vinnova
    Available from: 2022-06-23 Created: 2022-06-23 Last updated: 2023-03-28Bibliographically approved
    5. Regulation of the innate immune system by fragmented heparin-conjugated lipids on lipid bilayered membranes in vitro
    Open this publication in new window or tab >>Regulation of the innate immune system by fragmented heparin-conjugated lipids on lipid bilayered membranes in vitro
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    2023 (English)In: Journal of materials chemistry. B, ISSN 2050-750X, E-ISSN 2050-7518, Vol. 11, no 46, p. 11121-11134Article in journal (Refereed) Published
    Abstract [en]

    Surface modification with heparin is a powerful biomaterial coating strategy that protects against innate immunity activation since heparin is a part of the proteoglycan heparan sulfate on cell surfaces in the body. We studied the heparinization of cellular and material surfaces via lipid conjugation to a heparin-binding peptide. In the present study, we synthesized fragmented heparin (fHep)-conjugated phospholipids and studied their regulation of the innate immune system on a lipid bilayered surface using liposomes. Liposomes have versatile applications, such as drug-delivery systems, due to their ability to carry a wide range of molecules. Owing to their morphological similarity to cell membranes, they can also be used to mimic a simple cell-membrane to study protein–lipid interactions. We investigated the interaction of complement-regulators, factor H and C4b-binding protein (C4BP), as well as the coagulation inhibitor antithrombin (AT), with fHep-lipids on the liposomal surface. Herein, we studied the ability of fHep-lipids to recruit factor H, C4BP, and AT using a quartz crystal microbalance with dissipation monitoring. With dynamic light scattering, we demonstrated that liposomes could be modified with fHep-lipids and were stable up to 60 days at 4 °C. Using a capillary western blot-based method (Wes), we showed that fHep-liposomes could recruit factor H in a model system using purified proteins and assist in the degradation of the active complement protein C3b to iC3b. Furthermore, we found that fHep-liposomes could recruit factor H and AT from human plasma. Therefore, the use of fHep-lipids could be a potential coating for liposomes and cell surfaces to regulate the immune system on the lipid surface.

    Place, publisher, year, edition, pages
    Royal Society of Chemistry, 2023
    National Category
    Immunology in the medical area Biochemistry and Molecular Biology Materials Chemistry
    Identifiers
    urn:nbn:se:uu:diva-499229 (URN)10.1039/D3TB01721D (DOI)001103685900001 ()37953734 (PubMedID)
    Funder
    The Swedish Foundation for International Cooperation in Research and Higher Education (STINT)Swedish Research Council, 2018-04199EU, Horizon 2020Vinnova
    Note

    Title in the list of papers of Anna Adler's thesis: Regulation of innate immune system by fragmented heparin-conjugated lipids on lipid bilayer membranes

    Available from: 2023-03-24 Created: 2023-03-24 Last updated: 2024-02-08Bibliographically approved
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  • 9.
    Adler, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Fritsch, Marlene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Fromell, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Leneweit, Gero
    Carl Gustav Carus-Institute, Association for the Promotion of Cancer Therapy, Niefern-Öschelbronn, Germany.
    Ekdahl, Kristina N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Linnaeus Center of Biomaterials Chemistry, Linnaeus University, SE-391 82 Kalmar, Sweden.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Teramura, Yuji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Cellular and Molecular Biotechnology Research Institute (CMB), National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba Central Fifth, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8565, Japan; Master's/Doctoral Program in Life Science Innovation (T-LSI), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan.
    Regulation of the innate immune system by fragmented heparin-conjugated lipids on lipid bilayered membranes in vitro2023In: Journal of materials chemistry. B, ISSN 2050-750X, E-ISSN 2050-7518, Vol. 11, no 46, p. 11121-11134Article in journal (Refereed)
    Abstract [en]

    Surface modification with heparin is a powerful biomaterial coating strategy that protects against innate immunity activation since heparin is a part of the proteoglycan heparan sulfate on cell surfaces in the body. We studied the heparinization of cellular and material surfaces via lipid conjugation to a heparin-binding peptide. In the present study, we synthesized fragmented heparin (fHep)-conjugated phospholipids and studied their regulation of the innate immune system on a lipid bilayered surface using liposomes. Liposomes have versatile applications, such as drug-delivery systems, due to their ability to carry a wide range of molecules. Owing to their morphological similarity to cell membranes, they can also be used to mimic a simple cell-membrane to study protein–lipid interactions. We investigated the interaction of complement-regulators, factor H and C4b-binding protein (C4BP), as well as the coagulation inhibitor antithrombin (AT), with fHep-lipids on the liposomal surface. Herein, we studied the ability of fHep-lipids to recruit factor H, C4BP, and AT using a quartz crystal microbalance with dissipation monitoring. With dynamic light scattering, we demonstrated that liposomes could be modified with fHep-lipids and were stable up to 60 days at 4 °C. Using a capillary western blot-based method (Wes), we showed that fHep-liposomes could recruit factor H in a model system using purified proteins and assist in the degradation of the active complement protein C3b to iC3b. Furthermore, we found that fHep-liposomes could recruit factor H and AT from human plasma. Therefore, the use of fHep-lipids could be a potential coating for liposomes and cell surfaces to regulate the immune system on the lipid surface.

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  • 10.
    Adler, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Manivel, Vivek Anand
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Fromell, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Teramura, Yuji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Cellular & Mol Biotechnol Res Inst CMB, Natl Inst Adv Ind Sci andTechnol AIST, Tsukuba, Japan..
    Nilsson Ekdahl, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Linnaeus Univ, Linnaeus Ctr Biomat Chem, Kalmar, Sweden..
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    A Robust Method to Store Complement C3 With Superior Ability to Maintain the Native Structure and Function of the Protein2022In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 13, article id 891994Article in journal (Refereed)
    Abstract [en]

    Complement components have a reputation to be very labile. One of the reasons for this is the spontaneous hydrolysis of the internal thioester that is found in both C3 and C4 (but not in C5). Despite the fact that approximate to 20,000 papers have been published on human C3 there is still no reliable method to store the protein without generating C3(H2O), a fact that may have affected studies of the conformation and function of C3, including recent studies on intracellular C3(H2O). The aim of this work was to define the conditions for storage of native C3 and to introduce a robust method that makes C3 almost resistant to the generation of C3(H2O). Here, we precipitated native C3 at the isoelectric point in low ionic strength buffer before freezing the protein at -80 degrees C. The formation of C3(H2O) was determined using cation exchange chromatography and the hemolytic activity of the different C3 preparations was determined using a hemolytic assay for the classical pathway. We show that freezing native C3 in the precipitated form is the best method to avoid loss of function and generation of C3(H2O). By contrast, the most efficient way to consistently generate C3(H2O) was to incubate native C3 in a buffer at pH 11.0. We conclude that we have defined the optimal storage conditions for storing and maintaining the function of native C3 without generating C3(H2O) and also the conditions for consistently generating C3(H2O).

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  • 11. Adriaensen, Wim
    et al.
    Dorlo, Thomas P C
    Netherlands Cancer Institute.
    Vanham, Guido
    Kestens, Luc
    Kaye, Paul M
    van Griensven, Johan
    Immunomodulatory Therapy of Visceral Leishmaniasis in Human Immunodeficiency Virus-Coinfected Patients.2017In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 8, p. 1943-, article id 1943Article in journal (Refereed)
    Abstract [en]

    Patients with visceral leishmaniasis (VL)-human immunodeficiency virus (HIV) coinfection experience increased drug toxicity and treatment failure rates compared to VL patients, with more frequent VL relapse and death. In the era of VL elimination strategies, HIV coinfection is progressively becoming a key challenge, because HIV-coinfected patients respond poorly to conventional VL treatment and play an important role in parasite transmission. With limited chemotherapeutic options and a paucity of novel anti-parasitic drugs, new interventions that target host immunity may offer an effective alternative. In this review, we first summarize current views on how VL immunopathology is significantly affected by HIV coinfection. We then review current clinical and promising preclinical immunomodulatory interventions in the field of VL and discuss how these may operate in the context of a concurrent HIV infection. Caveats are formulated as these interventions may unpredictably impact the delicate balance between boosting of beneficial VL-specific responses and deleterious immune activation/hyperinflammation, activation of latent provirus or increased HIV-susceptibility of target cells. Evidence is lacking to prioritize a target molecule and a more detailed account of the immunological status induced by the coinfection as well as surrogate markers of cure and protection are still required. We do, however, argue that virologically suppressed VL patients with a recovered immune system, in whom effective antiretroviral therapy alone is not able to restore protective immunity, can be considered a relevant target group for an immunomodulatory intervention. Finally, we provide perspectives on the translation of novel theories on synergistic immune cell cross-talk into an effective treatment strategy for VL-HIV-coinfected patients.

  • 12. Agardh, D
    et al.
    Dahlbom, I
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Daniels, T
    Lörinc, E
    Ivarsson, SÅ
    Lernmark, Å
    Hansson, Tony
    Department of Rheumatology, Karolinska Institute.
    Autoantibodies Against Soluble and Immobilized Human Recombinant Tissue Transglutaminase in Children with Celiac Disease.2005In: J Pediatr Gastroenterol Nutr., Vol. 41, no 3, p. 322-327Article in journal (Refereed)
  • 13.
    Ahl, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Eriksson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sedin, John
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Seignez, Cedric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Schwan, Emil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Kreuger, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Christoffersson, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Turning Up the Heat: Local Temperature Control During in vivo Imaging of Immune Cells2019In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 10, article id 2036Article in journal (Refereed)
    Abstract [en]

    Intravital imaging is an invaluable tool for studying the expanding range of immune cell functions. Only in vivo can the complex and dynamic behavior of leukocytes and their interactions with their natural microenvironment be observed and quantified. While the capabilities of high-speed, high-resolution confocal and multiphoton microscopes are well-documented and steadily improving, other crucial hardware required for intravital imaging is often developed in-house and less commonly published in detail. In this report, we describe a low-cost, multipurpose, and tissue-stabilizing in vivo imaging platform that enables sensing and regulation of local tissue temperature. The effect of tissue temperature on local blood flow and leukocyte migration is demonstrated in muscle and skin. Two different models of vacuum windows are described in this report, however, the design of the vacuum window can easily be adapted to fit different organs and tissues.

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  • 14.
    Ahmed, Aisha S.
    et al.
    Karolinska Inst, Dept Clin Neurosci, Nobel Vag 9, S-17177 Stockholm, Sweden.
    Gedin, Per
    Lowenstromska Hosp, Ortho Ctr Stockholm, S-19489 Upplands Vasby, Sweden.
    Hugo, Anders
    Lowenstromska Hosp, Ortho Ctr Stockholm, S-19489 Upplands Vasby, Sweden.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kanar, Alkass
    Karolinska Inst, Dept Oncol Pathol, S-17177 Stockholm, Sweden;Swedish Natl Board Forens Med, S-17165 Solna, Sweden.
    Hart, David A.
    Univ Calgary, McCaig Inst Bone & Joint Hlth, Calgary, AB T2N 1N4, Canada.
    Druid, Henrik
    Karolinska Inst, Dept Oncol Pathol, S-17177 Stockholm, Sweden;Swedish Natl Board Forens Med, S-17165 Solna, Sweden.
    Svensson, Camilla
    Karolinska Inst, Dept Physiol & Pharmacol, S-17177 Stockholm, Sweden.
    Kosek, Eva
    Karolinska Inst, Dept Clin Neurosci, Nobel Vag 9, S-17177 Stockholm, Sweden;Stockholm Spine Ctr, Lowenstromska Hosp, S-19489 Upplands Vasby, Sweden.
    Activation of NF-kappa B in Synovium versus Cartilage from Patients with Advanced Knee Osteoarthritis: A Potential Contributor to Inflammatory Aspects of Disease Progression2018In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 201, no 7, p. 1918-1927Article in journal (Refereed)
    Abstract [en]

    The aim was to assess the activation and association of the NF-kappa B system across synovial membrane (SM) and articular cartilage (AC) in patients with knee osteoarthritis (OA) and ascertain its potential effects on catabolic mediator expression in advanced OA. SM and AC were obtained from 40 OA patients undergoing total knee arthroplasty and from 19 postmortem control subjects. NF-kappa B subunit RelA in nuclear and cytosolic fractions and NF-kappa B1-DNA binding in nuclear extracts was assessed by ELISA, whereas NFKB1, RELA, IL-8, IL-6, and MMP3 gene expression were analyzed by reverse transcriptase-quantitative PCR in tissues. We observed higher SM nuclear RelA protein levels and upregulated NF-kappa B1-DNA binding in OA patients compared with postmortem controls. However, in AC, lower nuclear RelA levels were observed compared with cytosolic extracts in patients. Nuclear RelA levels correlated positively with NF-kappa B1-DNA binding in SM and AC in patients. SM RELA and MMP3 mRNA levels were upregulated, whereas IL-8 and IL-6 as well as AC RELA were downregulated in patients compared with controls. In SM, nuclear RelA levels correlated positively with MMP3 gene expression in patients. A negative correlation was observed between SM nuclear RelA levels and AC NF-kappa B1-DNA binding, and SM nuclear NF-kappa B1-DNA binding correlated negatively with AC MMP3 and NFKB1 mRNA levels in patients. These findings highlight NF-kappa B-triggered cross-talk and feedback mechanisms between SM and AC in OA. Further, our findings strongly support a role for an activated NF-kappa B system in the transcriptional mechanism of inflammatory processes, especially in SM of patients with advanced OA.

  • 15. Akeus, Paulina
    et al.
    Langenes, Veronica
    von Mentzer, Astrid
    Yrlid, Ulf
    Sjoling, Asa
    Saksena, Pushpa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Raghavan, Sukanya
    Quiding-Jarbrink, Marianne
    Altered chemokine production and accumulation of regulatory T cells in intestinal adenomas of APC(Min/+) mice2014In: Cancer Immunology and Immunotherapy, ISSN 0340-7004, E-ISSN 1432-0851, Vol. 63, no 8, p. 807-819Article in journal (Refereed)
    Abstract [en]

    Tumor progression in the colon moves from aberrant crypt foci to adenomatous polyps to invasive carcinomas. The composition of the tumor-infiltrating leukocyte population affects the ability of the immune system to fight the tumor. T cell infiltration into colorectal adenocarcinomas, particularly T helper 1 (Th1) type T cells as well as increased regulatory T cell (Treg) frequencies, is correlated with improved prognosis. However, whether Th1 cells and Tregs are already present at the adenoma stage is not known. In this study, the APC(Min/+) mouse model of intestinal adenomatous polyposis was used to investigate tumor-associated lymphocyte subsets and the mechanisms of their accumulation into gastrointestinal adenomas. Compared to unaffected tissue, adenomas accumulated CD4(+)FoxP3(+) putative Treg in parallel with lower frequencies of conventional T cells and B cells. The accumulation of Treg was also observed in human adenomatous polyps. Despite high Treg numbers, the function of conventional T cells present in the APC(Min/+) adenomas was not different from those in the unaffected tissue. Adenomas displayed an altered chemokine balance, with higher CCL17 and lower CXCL11 and CCL25 expression than in the unaffected tissue. In parallel, CXCR3(+) Tregs were largely absent from adenomas. The data indicate that already in early stages of tumor development, the balance of lymphocyte-recruiting chemokines is altered possibly contributing to the observed shift toward higher frequencies of Treg.

  • 16.
    Akula, Srinivas
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology and Immunology. Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, Box 7011, SE-75007 Uppsala, Sweden..
    Lara, Sandra
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology and Immunology.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hellman, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology and Immunology.
    Quantitative Analysis of the Transcriptome of Two Commonly Used Human Monocytic Cell Lines-THP-1 and Mono Mac 6-Reveals Their Arrest during Early Monocyte/Neutrophil Differentiation2022In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 23, no 10, article id 5818Article in journal (Refereed)
    Abstract [en]

    Cell lines of monocyte/macrophage origin are often used as model systems to study monocyte/macrophage biology. A relevant question is how similar these cell lines are to their in vivo counterparts? To address this issue, we performed a detailed analysis of the transcriptome of two commonly used human monocyte/macrophage cell lines, Mono Mac 6 and THP-1. Both of these cell lines originate from leukemic cells with myelo-monocytic characteristics. We found that both Mono Mac 6 and THP-1 represent cells of very immature origin. Their transcriptomes show more similarities to immature neutrophils than cells of the monocyte/macrophage lineage. They express significant levels of N-elastase, proteinase 3, cathepsin G, and azurocidin but very low levels of CD14, ficolin, and complement factor P. All major MHC class II genes are also expressed at low levels. They show high levels of lysozyme and low levels of one of the immunoglobulin Fc receptors, FCGRIIA, which is characteristic of both neutrophils and monocytes. THP-1, but not Mono Mac 6, also expresses the high-affinity receptor for IgG, FCGRIA. Both cell lines lack the expression of the connective tissue components fibronectin, proteoglycan 4, and syndecan 3, which are characteristics of tissue macrophages but are absent in blood monocytes, indicating that they originate from bone marrow precursors and not yolk sac-derived hematopoietic cells. Both of these cell lines seem, therefore, to represent cells arrested during early myelo-monocytic development, at a branch point between neutrophil and monocyte differentiation. Their very immature phenotype indicates that great care should be taken when using these cell lines as models for normal monocyte/macrophage biology.

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  • 17.
    Akula, Srinivas
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Paivandy, Aida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Fu, Zhirong
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Thorpe, Michael
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Pejler, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, SE-75007 Uppsala, Sweden.
    Hellman, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Quantitative In-Depth Analysis of the Mouse Mast Cell Transcriptome Reveals Organ-Specific Mast Cell Heterogeneity2020In: CELLS, E-ISSN 2073-4409, Vol. 9, no 1, article id 211Article in journal (Refereed)
    Abstract [en]

    Mast cells (MCs) are primarily resident hematopoietic tissue cells that are localized at external and internal surfaces of the body where they act in the first line of defense. MCs are found in all studied vertebrates and have also been identified in tunicates, an early chordate. To obtain a detailed insight into the biology of MCs, here we analyzed the transcriptome of MCs from different mouse organs by RNA-seq and PCR-based transcriptomics. We show that MCs at different tissue locations differ substantially in their levels of transcripts coding for the most abundant MC granule proteins, even within the connective tissue type, or mucosal MC niches. We also demonstrate that transcript levels for the major granule proteins, including the various MC-restricted proteases and the heparin core protein, can be several orders of magnitude higher than those coding for various surface receptors and enzymes involved in protease activation, as well as enzymes involved in the synthesis of heparin, histamine, leukotrienes, and prostaglandins. Interestingly, our analyses revealed an almost complete absence in MCs of transcripts coding for cytokines at baseline conditions, indicating that cytokines are primarily produced by activated MCs. Bone marrow-derived MCs (BMMCs) are often used as equivalents of tissue MCs. Here, we show that these cells differ substantially from tissue MCs with regard to their transcriptome. Notably, they showed a transcriptome indicative of relatively immature cells, both with respect to the expression of granule proteases and of various enzymes involved in the processing/synthesis of granule compounds, indicating that care should be taken when extrapolating findings from BMMCs to the in vivo function of tissue-resident MCs. Furthermore, the latter finding indicates that the development of fully mature tissue-resident MCs requires a cytokine milieu beyond what is needed for in vitro differentiation of BMMCs. Altogether, this study provides a comprehensive quantitative view of the transcriptome profile of MCs resident at different tissue locations that builds nicely on previous studies of both the mouse and human transcriptome, and form a solid base for future evolutionary studies of the role of MCs in vertebrate immunity.

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  • 18.
    Akula, Srinivas
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology and Immunology. Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, Box 7011, SE-75007 Uppsala, Sweden..
    Tripathi, Shiva Raj
    Charite Univ Med Berlin, Inst Allergol, Hindenburgdamm 30, D-12203 Berlin, Germany.;Freie Univ Berlinand, Hindenburgdamm 30, D-12203 Berlin, Germany.;Humboldt Univ, Hindenburgdamm 30, D-12203 Berlin, Germany.;Fraunhofer Inst Translat Med & Pharmacol ITMP, Immunol & Allergol IA, Hindenburgdamm 30, D-12203 Berlin, Germany..
    Franke, Kristin
    Charite Univ Med Berlin, Inst Allergol, Hindenburgdamm 30, D-12203 Berlin, Germany.;Freie Univ Berlinand, Hindenburgdamm 30, D-12203 Berlin, Germany.;Humboldt Univ, Hindenburgdamm 30, D-12203 Berlin, Germany.;Fraunhofer Inst Translat Med & Pharmacol ITMP, Immunol & Allergol IA, Hindenburgdamm 30, D-12203 Berlin, Germany..
    Wernersson, Sara
    Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, Box 7011, SE-75007 Uppsala, Sweden..
    Babina, Magda
    Charite Univ Med Berlin, Inst Allergol, Hindenburgdamm 30, D-12203 Berlin, Germany.;Fraunhofer Inst Translat Med & Pharmacol ITMP, Immunol & Allergol IA, Hindenburgdamm 30, D-12203 Berlin, Germany..
    Hellman, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology and Immunology.
    Cultures of Human Skin Mast Cells, an Attractive In Vitro Model for Studies of Human Mast Cell Biology2024In: Cells, E-ISSN 2073-4409, Vol. 13, no 1, article id 98Article in journal (Refereed)
    Abstract [en]

    Studies of mast cell biology are dependent on relevant and validated in vitro models. Here, we present detailed information concerning the phenotype of both freshly isolated human skin mast cells (MCs) and of in vitro cultures of these cells that were obtained by analyzing their total transcriptome. Transcript levels of MC-related granule proteins and transcription factors were found to be remarkably stable over a 3-week culture period. Relatively modest changes were also seen for important cell surface receptors including the high-affinity receptor for IgE, FCER1A, the low-affinity receptor for IgG, FCGR2A, and the receptor for stem cell factor, KIT. FCGR2A was the only Fc receptor for IgG expressed by these cells. The IgE receptor increased by 2-5-fold and an approximately 10-fold reduction in the expression of FCGR2A was observed most likely due to the cytokines, SCF and IL-4, used for expanding the cells. Comparisons of the present transcriptome against previously reported transcriptomes of mouse peritoneal MCs and mouse bone marrow-derived MCs (BMMCs) revealed both similarities and major differences. Strikingly, cathepsin G was the most highly expressed granule protease in human skin MCs, in contrast to the almost total absence of this protease in both mouse MCs. Transcript levels for the majority of cell surface receptors were also very low compared to the granule proteases in both mouse and human MCs, with a difference of almost two orders of magnitude. An almost total absence of T-cell granzymes was observed in human skin MCs, indicating that granzymes have no or only a minor role in human MC biology. Ex vivo skin MCs expressed high levels of selective immediate early genes and transcripts of heat shock proteins. In validation experiments, we determined that this expression was an inherent property of the cells and not the result of the isolation process. Three to four weeks in culture results in an induction of cell growth-related genes accompanying their expansion by 6-10-fold, which increases the number of cells for in vitro experiments. Collectively, we show that cultured human skin MCs resemble their ex vivo equivalents in many respects and are a more relevant in vitro model compared to mouse BMMCs for studies of MC biology, in particular human MC biology.

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  • 19.
    Alanazi, Sultan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Melo, Fabio Rabelo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pejler, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Tryptase Regulates the Epigenetic Modification of Core Histones in Mast Cell Leukemia Cells2021In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 12, article id 804408Article in journal (Refereed)
    Abstract [en]

    Mast cells are immune cells that store large amounts of mast cell-restricted proteases in their secretory granules, including tryptase, chymase, and carboxypeptidase A3. In mouse mast cells, it has been shown that tryptase, in addition to its canonical location in secretory granules, can be found in the nuclear compartment where it can impact core histones. Here we asked whether tryptase can execute core histone processing in human mast cell leukemia cells and whether tryptase thereby can affect the epigenetic modification of core histones. Our findings reveal that triggering of cell death in HMC-1 mast cell leukemia cells is associated with extensive cleavage of core histone 3 (H3) and more restricted cleavage of H2B. Tryptase inhibition caused a complete blockade of such processing. Our data also show that HMC-1 cell death was associated with a major reduction of several epigenetic histone marks, including H3 lysine-4-mono-methylation (H3K4me1), H3K9me2, H3 serine-10-phosphorylation (H3S10p), and H2B lysine-16-acetylation (H2BK16ac), and that tryptase inhibition reverses the effect of cell death on these epigenetic marks. Further, we show that tryptase is present in the nucleus of both viable and dying mast cell leukemia cells. In line with a role for tryptase in regulating nuclear events, tryptase inhibition caused an increased proliferation of the mast cell leukemia cells. Altogether, the present study emphasizes a novel principle for how epigenetic modification of core histones is regulated and provides novel insight into the biological function of human mast cell tryptase.

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  • 20.
    Albrecht, Inka
    et al.
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Wick, Cecilia
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Hallgren, Asa
    Karolinska Inst, Dept Med Solna, Expt Endocrinol, SE-17176 Stockholm, Sweden..
    Tjarnlund, Anna
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Nagaraju, Kanneboyina
    Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC 20010 USA..
    Andrade, Felipe
    Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA..
    Thompson, Kathryn
    Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC 20010 USA..
    Coley, William
    Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC 20010 USA..
    Phadke, Aditi
    Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC 20010 USA..
    Diaz-Gallo, Lina-Marcela
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Bottai, Matteo
    Karolinska Inst, Inst Environm Med, Unit Biostat, SE-17176 Stockholm, Sweden..
    Nennesmo, Inger
    Karolinska Inst, Dept Lab Med, SE-17176 Stockholm, Sweden..
    Chemin, Karine
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Herrath, Jessica
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Johansson, Karin
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Wikberg, Anders
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Ytterberg, A. Jimmy
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden.;Karolinska Inst, Dept Med Biochem & Biophys, SE-17176 Stockholm, Sweden..
    Zubarev, Roman A.
    Karolinska Inst, Dept Med Biochem & Biophys, SE-17176 Stockholm, Sweden..
    Danielsson, Olof
    Linkoping Univ, Fac Hlth Sci, Dept Clin & Expt Med, Div Neurol, Linkoping, Sweden..
    Krystufkova, Olga
    Charles Univ Prague, Fac Med 1, Inst Rheumatol, Prague, Czech Republic.;Charles Univ Prague, Fac Med 1, Dept Rheumatol, Prague, Czech Republic..
    Vencovsky, Jiri
    Charles Univ Prague, Fac Med 1, Inst Rheumatol, Prague, Czech Republic.;Charles Univ Prague, Fac Med 1, Dept Rheumatol, Prague, Czech Republic..
    Landegren, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Karolinska Inst, Dept Med Solna, Expt Endocrinol, SE-17176 Stockholm, Sweden..
    Wahren-Herlenius, Marie
    Karolinska Inst, Dept Med Solna, Expt Rheumatol Unit, SE-17176 Stockholm, Sweden..
    Padyukov, Leonid
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Karolinska Inst, Dept Med Solna, Expt Endocrinol, SE-17176 Stockholm, Sweden..
    Lundberg, Ingrid E.
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Development of autoantibodies against muscle-specific FHL1 in severe inflammatory myopathies2015In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 125, no 12, p. 4612-4624Article in journal (Refereed)
    Abstract [en]

    Mutations of the gene encoding four-and-a-half LIM domain 1 (FHL1) are the causative factor of several X-linked hereditary myopathies that are collectively termed FHL1-related myopathies. These disorders are characterized by severe muscle dysfunction and damage. Here, we have shown that patients with idiopathic inflammatory myopathies (IIMs) develop autoimmunity to FHL1, which is a muscle-specific protein. Anti-FHL1 autoantibodies were detected in 25% of IIM patients, while patients with other autoimmune diseases or muscular dystrophies were largely anti-FHL1 negative. Anti-FHL1 reactivity was predictive for muscle atrophy, dysphagia, pronounced muscle fiber damage, and vasculitis. FHL1 showed an altered expression pattern, with focal accumulation in the muscle fibers of autoantibody-positive patients compared with a homogeneous expression in anti-FHL1-negative patients and healthy controls. We determined that FHL1 is a target of the cytotoxic protease granzyme B, indicating that the generation of FHL1 fragments may initiate FHL1 autoimmunity. Moreover, immunization of myositis-prone mice with FHL1 aggravated muscle weakness and increased mortality, suggesting a direct link between anti-FHL1 responses and muscle damage. Together, our findings provide evidence that FHL1 may be involved in the pathogenesis not only of genetic FHL1-related myopathies but also of autoimmune IIM. Importantly, these results indicate that anti-FHL1 autoantibodies in peripheral blood have promising potential as a biomarker to identify a subset of severe IIM.

  • 21.
    Ali, Arwa
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer Immunotherapy.
    Gao, Menghan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Iskantar, Alexandros
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wang, Hai
    Chinese Acad Sci, CAS Ctr Excellence Nanosci, Natl Ctr Nanosci & Technol, Key Lab Biomed Effects Nanomat & Nanosafety, Beijing, Peoples R China.;Univ Chinese Acad Sci, Beijing, Peoples R China..
    Karlsson-Parra, Alex
    Mendus AB, Stockholm, Sweden..
    Yu, Di
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Jin, Chuan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Proinflammatory allogeneic dendritic cells enhance the therapeutic efficacy of systemic anti-4-1BB treatment2023In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 14, article id 1146413Article in journal (Refereed)
    Abstract [en]

    As an immune adjuvant, proinflammatory allogeneic dendritic cells (AlloDCs) have demonstrated promising immune-priming effects in several preclinical and clinical studies. The effector cells, including NK cells and T cells are widely acknowledged as pivotal factors in the effectiveness of cancer immunotherapy due to their ability to selectively identify and eradicate malignant cells. 4-1BB, as a costimulatory receptor, plays a significant role in the stimulation of effector cell activation. This study evaluated the anti-tumor effects when combining intratumoral administration of the immune-adjuvant AlloDCs with systemic a4-1BB treatment directly acting on effector cells. In both the CT-26 murine colon carcinoma model and B16 murine melanoma model, AlloDCs demonstrated a significant enhancement in the therapeutic efficacy of a4-1BB antibody. This enhancement was observed through the delayed growth of tumors and prolonged survival. Analysis of the tumor microenvironment (TME) in the combined-treatment group revealed an immune-inflamed TME characterized by increased infiltration of activated endogenous DCs and IFN?(+) CD8(+) T cells, showing reduced signs of exhaustion. Furthermore, there was an augmented presence of tissue-resident memory (T-RM) CD8(+) T cells (CD103(+)CD49a(+)CD69(+)). The combination treatment also led to increased infiltration of CD39(+)CD103(+) tumor-specific CD8(+) T cells and neoantigen-specific T cells into the tumor. Additionally, the combined treatment resulted in a less immunosuppressive TME, indicated by decreased infiltration of myeloid-derived suppressor cells and Tregs. These findings suggest that the combination of intratumoral AlloDCs administration with systemic agonistic a4-1BB treatment can generate a synergistic anti-tumor response, thereby warranting further investigation through clinical studies.

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  • 22.
    Alim, Abdul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine. Public Health and Caring Sciences.
    Mechanisms in Tendon Healing: Pain, Biomarkers and the Role of Mast Cells2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Tendon injuries and tendinopathy are common disorders, but the underlying mechanisms are not well understood. The overall aim of this thesis was to better understand the mechanisms underlying tendon healing, pain, and inflammation.

    The aim of the first study was to assess biomarkers of tendon healing, including procollagen type I (PINP) and type III (PIIINP) in relation to patient outcome in 65 patients with Achilles tendon rupture (ATR). At two weeks post-ATR, PINP and PIIINP-levels were quantified using microdialysis followed by ELISA. At one-year post-ATR patient outcome was assessed using the validated Achilles tendon Total Rupture Score. We found that higher ratio of PINP and PIIINP to total protein were significantly associated with less pain but more fatigue in the affected limb.

    In the second study, we applied Intermittent Pneumatic Compression (IPC) therapy for two weeks to stimulate tendon healing. The patients received either adjuvant IPC treatment or treatment-as-usual in a plaster cast without IPC. We observed that IPC therapy significantly increased PINP levels in the injured tendon, suggesting enhanced healing response.

    In our third study, we investigated healing response and the role of mast cells (MCs) in-vivo using an ATR rat model. Three weeks postoperatively, we demonstrated an increased number of MCs and a higher proportion of degranulated MCs in the injured tendon compared to the control. We further established that MCs in the injured tendon were positive for the glutamate receptor NMDAR1.

    In our final study, we assessed the effect of glutamate stimulation on in-vitro-derived mouse bone marrow MCs. Mast cell degranulation was quantified through β-hexosaminidase release, immunofluorescence was used to quantify NMDARs at the protein level, and RT-qPCR/microarray was used to study the expression of NMDARs and associated genes. Glutamate induced a robust upregulation of glutamate receptors of both ionotropic and metabotropic type, both at the mRNA and at protein level. NMDAR1 co-localized with glutamate in the membrane of MCs, thereby confirming an interaction between glutamate and its receptor. Glutamate also induced expression of pro-inflammatory compounds such as IL-6 and CCL2 and transcription factors such as Egr2, Egr3 and FosB. Moreover, the NMDA-channel blocker MK-801 completely abrogated the response of MCs to glutamate, supporting a functional glutamate–glutamate receptor axis in MCs.

    Together, findings presented in this dissertation reveal possible mechanisms of tendon healing in relation to pain and function, and establish a novel principle for how immune cells can communicate with nerve cells after ATR.

    List of papers
    1. Procollagen markers in microdialysate can predict patient outcome after Achilles tendon rupture.
    Open this publication in new window or tab >>Procollagen markers in microdialysate can predict patient outcome after Achilles tendon rupture.
    2016 (English)In: BMJ open sport & exercise medicine, ISSN 2055-7647, Vol. 2, no 1, article id e000114Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVE: Patients who sustain acute Achilles tendon rupture (ATR) exhibit variable and mostly impaired long-term functional, and patient-reported outcomes. However, there exists a lack of early predictive markers of long-term outcomes to facilitate the development of improved treatment methods. The aim of this study was to assess markers of tendon callus production in patients with ATR in terms of outcome, pain, and fatigue.

    STUDY DESIGN AND SETTING: Prospective cohort study; level of evidence 2. Outpatient orthopaedic/sports medicine department.

    PATIENTS: A total of 65 patients (57 men, 8 women; mean age 41±7 years) with ATR were prospectively assessed.

    ASSESSMENTS: Markers of tendon callus production, procollagen type I N-terminal propeptide (PINP) and procollagen type III N-terminal propeptide (PIIINP), were assessed 2 weeks postoperatively using microdialysis followed by enzymatic quantification. Normalised procollagen levels (n-PINP and n-PIIINP) were calculated as the ratio of procollagen to total protein content. Pain and fatigue were assessed at 1 year using reliable questionnaires Achilles tendon Total Rupture Score (ATRS).

    RESULTS: Patients exhibited fatigue (77.6%) and pain (44.1%) to some extent. Higher levels of n-PINP (R=0.38, p=0.016) and n-PIIINP (R=0.33, p=0.046) were significantly associated with less pain in the limb. Increased concentrations of PINP (R=-0.47, p=0.002) and PIIINP (R=-0.37, p=0.024) were related to more self-reported fatigue in the leg. The results were corroborated by multiple linear regression analyses.

    CONCLUSIONS: Assessment of procollagen markers in early tendon healing can predict long-term patient-reported outcomes after ATR. These novel findings suggest that procollagen markers could be used to facilitate the development of improved treatment methods in patients who sustain ATR.

    TRIAL REGISTRATION NUMBERS: NCT01317160: Results. NCT02318472: Pre-results.

    Place, publisher, year, edition, pages
    London, UK: , 2016
    Keywords
    Achilles, Chronic, Collagen, Injuries, Tendon
    National Category
    Orthopaedics
    Research subject
    Orthopaedics
    Identifiers
    urn:nbn:se:uu:diva-395018 (URN)10.1136/bmjsem-2016-000114 (DOI)27900179 (PubMedID)
    Available from: 2019-10-11 Created: 2019-10-11 Last updated: 2020-02-19Bibliographically approved
    2. Achilles tendon rupture healing is enhanced by intermittent pneumatic compression upregulating collagen type I synthesis
    Open this publication in new window or tab >>Achilles tendon rupture healing is enhanced by intermittent pneumatic compression upregulating collagen type I synthesis
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    2018 (English)In: Knee Surgery, Sports Traumatology, Arthroscopy, ISSN 0942-2056, E-ISSN 1433-7347, Vol. 26, no 7, p. 2021-2029Article in journal (Refereed) Published
    Abstract [en]

    PURPOSE AND HYPOTHESIS: Adjuvant intermittent pneumatic compression (IPC) during leg immobilization following Achilles tendon rupture (ATR) has been shown to reduce the risk of deep venous thrombosis. The purpose of this study was to investigate whether IPC can also promote tendon healing.

    METHODS: One hundred and fifty patients with surgical repair of acute ATR were post-operatively leg immobilized and prospectively randomized. Patients were allocated for 2 weeks of either adjuvant IPC treatment (n = 74) or treatment-as-usual (n = 74) in a plaster cast without IPC. The IPC group received 6 h daily bilateral calf IPC applied under an orthosis on the injured side. At 2 weeks post-operatively, tendon healing was assessed using microdialysis followed by enzymatic quantification of tendon callus production, procollagen type I (PINP) and type III (PIIINP) N-terminal propeptide, and total protein content. 14 IPC and 19 cast patients (control group) consented to undergo microdialysis. During weeks 3-6, all subjects were leg-immobilized in an orthosis without IPC. At 3 and 12 months, patient-reported outcome was assessed using reliable questionnaires (ATRS and EQ-5D). At 12 months, functional outcome was measured using the validated heel-rise test.

    RESULTS: At 2 weeks post-rupture, the IPC-treated patients exhibited 69% higher levels of PINP in the ruptured Achilles tendon (AT) compared to the control group (p = 0.001). Interestingly, the IPC-treated contralateral, intact AT also demonstrated 49% higher concentrations of PINP compared to the non-treated intact AT of the plaster cast group (p = 0.002). There were no adverse events observed associated with IPC. At 3 and 12 months, no significant (n.s.) differences between the two treatments were observed using patient-reported and functional outcome measures.

    CONCLUSIONS: Adjuvant IPC during limb immobilization in patients with ATR seems to effectively enhance the early healing response by upregulation of collagen type I synthesis, without any adverse effects. Whether prolonged IPC application during the whole immobilization period can also lead to improved long-term clinical healing response should be further investigated. The healing process during leg immobilization in patients with Achilles tendon rupture can be improved through adjuvant IPC therapy, which additionally prevents deep venous thrombosis.

    LEVEL OF EVIDENCE: Randomized controlled trial, Level I.

    Keywords
    Achilles tendon rupture, Intermittent pneumatic compression devices, Microdialysis, Procollagen, Regeneration
    National Category
    Surgery
    Identifiers
    urn:nbn:se:uu:diva-395017 (URN)10.1007/s00167-017-4621-8 (DOI)28668970 (PubMedID)
    Available from: 2019-10-11 Created: 2019-10-11 Last updated: 2020-02-19Bibliographically approved
    3. Increased mast cell degranulation and co-localization of mast cells with the NMDA receptor-1 during healing after Achilles tendon rupture
    Open this publication in new window or tab >>Increased mast cell degranulation and co-localization of mast cells with the NMDA receptor-1 during healing after Achilles tendon rupture
    Show others...
    2017 (English)In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 370, no 3, p. 451-460Article in journal (Refereed) Published
    Abstract [en]

    The role of inflammation and the mechanism of tendon healing after rupture has historically been a matter of controversy. The purpose of the present study is to investigate the role of mast cells and their relation to the NMDA receptor-1 (a glutamate receptor) during healing after Achilles tendon rupture. Eight female Sprague Dawley rats had their right Achilles tendon transected. Three weeks after rupture, histological quantification of mast cell numbers and their state of degranulation was assessed by histochemistry. Co-localization of mast cell tryptase (a mast cell marker) and NMDA receptor-1 was determined by immunofluorescence. The intact left Achilles tendon was used as control. An increased number of mast cells and a higher proportion of degranulated mast cells were found in the healing Achilles tendon compared to the intact. In addition, increased co-localization of mast cell tryptase and NMDA receptor-1 was seen in the areas of myotendinous junction, mid-tendon proper and bone tendon junction of the healing versus the intact tendon. These findings introduce a possible role for mast cells in the healing phase after Achilles tendon rupture.

    Place, publisher, year, edition, pages
    Berlin Heidelberg: , 2017
    Keywords
    Achilles tendon healing, Mast cells, NMDA, Rats, Tryptase
    National Category
    Cell and Molecular Biology
    Research subject
    Orthopaedics; Immunology
    Identifiers
    urn:nbn:se:uu:diva-395522 (URN)10.1007/s00441-017-2684-y (DOI)000416358400010 ()28975451 (PubMedID)
    Available from: 2019-10-20 Created: 2019-10-20 Last updated: 2020-02-06Bibliographically approved
    4. Glutamate triggers the expression of functional ionotropic and metabotropic glutamate receptors in mast cells
    Open this publication in new window or tab >>Glutamate triggers the expression of functional ionotropic and metabotropic glutamate receptors in mast cells
    Show others...
    2021 (English)In: Cellular & Molecular Immunology, ISSN 1672-7681, E-ISSN 2042-0226, Vol. 18, no 10, p. 2383-2392Article in journal (Refereed) Published
    Abstract [en]

    Mast cells are emerging as players in the communication between peripheral nerve endings and cells of the immune system. However, it is not clear the mechanism by which mast cells communicate with peripheral nerves. We previously found that mast cells located within healing tendons can express glutamate receptors, raising the possibility that mast cells may be sensitive to glutamate signaling. To evaluate this hypothesis, we stimulated primary mast cells with glutamate and showed that glutamate induced the profound upregulation of a panel of glutamate receptors of both the ionotropic type (NMDAR1, NMDAR2A, and NMDAR2B) and the metabotropic type (mGluR2 and mGluR7) at both the mRNA and protein levels. The binding of glutamate to glutamate receptors on the mast cell surface was confirmed. Further, glutamate had extensive effects on gene expression in the mast cells, including the upregulation of pro-inflammatory components such as IL-6 and CCL2. Glutamate also induced the upregulation of transcription factors, including Egr2, Egr3 and, in particular, FosB. The extensive induction of FosB was confirmed by immunofluorescence assessment. Glutamate receptor antagonists abrogated the responses of the mast cells to glutamate, supporting the supposition of a functional glutamate-glutamate receptor axis in mast cells. Finally, we provide in vivo evidence supporting a functional glutamate-glutamate receptor axis in the mast cells of injured tendons. Together, these findings establish glutamate as an effector of mast cell function, thereby introducing a novel principle for how cells in the immune system can communicate with nerve cells.

    Place, publisher, year, edition, pages
    Springer Nature, 2021
    Keywords
    Glutamate, Glutamate receptors, Mast cells, NMDA receptors, Tryptase
    National Category
    Immunology in the medical area
    Identifiers
    urn:nbn:se:uu:diva-434116 (URN)10.1038/s41423-020-0421-z (DOI)000527501500001 ()32313211 (PubMedID)
    Funder
    AFA InsuranceSwedish Research CouncilSwedish Cancer SocietyThe Swedish Heart and Lung AssociationKnut and Alice Wallenberg Foundation
    Available from: 2021-02-05 Created: 2021-02-05 Last updated: 2023-07-14Bibliographically approved
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  • 23.
    Alim, Abdul
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Grujic, Mirjana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ackerman, Paul W
    Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
    Kristiansson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Eliasson, Pernilla
    Department of Orthopedics and Sports Medicine, Linköping University, Linköping, Sweden.
    Peterson, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Pejler, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Glutamate triggers the expression of functional ionotropic and metabotropic glutamate receptors in mast cells2021In: Cellular & Molecular Immunology, ISSN 1672-7681, E-ISSN 2042-0226, Vol. 18, no 10, p. 2383-2392Article in journal (Refereed)
    Abstract [en]

    Mast cells are emerging as players in the communication between peripheral nerve endings and cells of the immune system. However, it is not clear the mechanism by which mast cells communicate with peripheral nerves. We previously found that mast cells located within healing tendons can express glutamate receptors, raising the possibility that mast cells may be sensitive to glutamate signaling. To evaluate this hypothesis, we stimulated primary mast cells with glutamate and showed that glutamate induced the profound upregulation of a panel of glutamate receptors of both the ionotropic type (NMDAR1, NMDAR2A, and NMDAR2B) and the metabotropic type (mGluR2 and mGluR7) at both the mRNA and protein levels. The binding of glutamate to glutamate receptors on the mast cell surface was confirmed. Further, glutamate had extensive effects on gene expression in the mast cells, including the upregulation of pro-inflammatory components such as IL-6 and CCL2. Glutamate also induced the upregulation of transcription factors, including Egr2, Egr3 and, in particular, FosB. The extensive induction of FosB was confirmed by immunofluorescence assessment. Glutamate receptor antagonists abrogated the responses of the mast cells to glutamate, supporting the supposition of a functional glutamate-glutamate receptor axis in mast cells. Finally, we provide in vivo evidence supporting a functional glutamate-glutamate receptor axis in the mast cells of injured tendons. Together, these findings establish glutamate as an effector of mast cell function, thereby introducing a novel principle for how cells in the immune system can communicate with nerve cells.

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  • 24.
    Allam, Venkata
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Univ Technol Sydney, Fac Hlth, Grad Sch Hlth, Sydney, NSW, Australia..
    Pavlidis, Stelios
    Imperial Coll London, Data Sci Inst, London, England.;Janssen Res & Dev, Computat Sci, High Wycombe, England..
    Liu, Gang
    Centenary Inst, Ctr Inflammat, Sydney, NSW, Australia.;Univ Technol Sydney, Sydney, NSW, Australia..
    Kermani, Nazanin Zounemat
    Imperial Coll London, Data Sci Inst, London, England..
    Simpson, Jennifer
    QIMR Berghofer Med Res Inst, Resp Immunol, Brisbane, Qld, Australia..
    To, Joyce
    Univ Technol Sydney, Fac Sci, Sch Life Sci, Sydney, NSW, Australia..
    Donnelly, Sheila
    Univ Technol Sydney, Fac Sci, Sch Life Sci, Sydney, NSW, Australia..
    Guo, Yi-Ke
    Imperial Coll London, Data Sci Inst, London, England..
    Hansbro, Philip M.
    Centenary Inst, Ctr Inflammat, Sydney, NSW, Australia.;Univ Technol Sydney, Sydney, NSW, Australia..
    Phipps, Simon
    QIMR Berghofer Med Res Inst, Resp Immunol, Brisbane, Qld, Australia..
    Morand, Eric F.
    Monash Univ, Ctr Inflammatory Dis, Melbourne, Vic, Australia..
    Djukanovic, Ratko
    Univ Southampton, Fac Med, NIHR Southampton Biomed Res Ctr, Clin & Expt Sci, Southampton, England..
    Sterk, Peter
    Univ Amsterdam, Amsterdam Univ Med Ctr, Dept Resp Med, Amsterdam, Netherlands..
    Chung, Kian Fan
    Imperial Coll London, Natl Heart & Lung Inst, Airways Dis, London, England..
    Adcock, Ian
    Imperial Coll London, Natl Heart & Lung Inst, Airways Dis, London, England..
    Harris, James
    Monash Univ, Ctr Inflammatory Dis, Melbourne, Vic, Australia..
    Sukkar, Maria B.
    Univ Technol Sydney, Fac Hlth, Grad Sch Hlth, Sydney, NSW, Australia..
    Macrophage migration inhibitory factor promotes glucocorticoid resistance of neutrophilic inflammation in a murine model of severe asthma2023In: Thorax, ISSN 0040-6376, E-ISSN 1468-3296, Vol. 78, no 7, p. 661-673Article in journal (Refereed)
    Abstract [en]

    Background: Severe neutrophilic asthma is resistant to treatment with glucocorticoids. The immunomodulatory protein macrophage migration inhibitory factor (MIF) promotes neutrophil recruitment to the lung and antagonises responses to glucocorticoids. We hypothesised that MIF promotes glucocorticoid resistance of neutrophilic inflammation in severe asthma.

    Methods: We examined whether sputum MIF protein correlated with clinical and molecular characteristics of severe neutrophilic asthma in the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort. We also investigated whether MIF regulates neutrophilic inflammation and glucocorticoid responsiveness in a murine model of severe asthma in vivo.

    Results: MIF protein levels positively correlated with the number of exacerbations in the previous year, sputum neutrophils and oral corticosteroid use across all U-BIOPRED subjects. Further analysis of MIF protein expression according to U-BIOPRED-defined transcriptomic-associated clusters (TACs) revealed increased MIF protein and a corresponding decrease in annexin-A1 protein in TAC2, which is most closely associated with airway neutrophilia and NLRP3 inflammasome activation. In a murine model of severe asthma, treatment with the MIF antagonist ISO-1 significantly inhibited neutrophilic inflammation and increased glucocorticoid responsiveness. Coimmunoprecipitation studies using lung tissue lysates demonstrated that MIF directly interacts with and cleaves annexin-A1, potentially reducing its biological activity.

    Conclusion: Our data suggest that MIF promotes glucocorticoid-resistance of neutrophilic inflammation by reducing the biological activity of annexin-A1, a potent glucocorticoid-regulated protein that inhibits neutrophil accumulation at sites of inflammation. This represents a previously unrecognised role for MIF in the regulation of inflammation and points to MIF as a potential therapeutic target for the management of severe neutrophilic asthma.

  • 25.
    Allam, Venkata
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala Univ, Dept Med Biochem & Microbiol, Uppsala, Sweden.;Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, Uppsala, Sweden..
    Waern, Ida
    Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, Uppsala, Sweden..
    Taha, Sowsan
    Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, Uppsala, Sweden..
    Akula, Srinivas
    Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, Uppsala, Sweden..
    Wernersson, Sara
    Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, Uppsala, Sweden..
    Pejler, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala Univ, Dept Med Biochem & Microbiol, Uppsala, Sweden..
    Nafamostat has anti-asthmatic effects associated with suppressed pro-inflammatory gene expression, eosinophil infiltration and airway hyperreactivity2023In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 14, article id 1136780Article in journal (Refereed)
    Abstract [en]

    IntroductionAsthma is characterized by an imbalance between proteases and their inhibitors. Hence, an attractive therapeutic option could be to interfere with asthma-associated proteases. Here we exploited this option by assessing the impact of nafamostat, a serine protease inhibitor known to neutralize mast cell tryptase. MethodsNafamostat was administered in a mouse model for asthma based on sensitization by house dust mite (HDM) extract, followed by the assessment of effects on airway hyperreactivity, inflammatory parameters and gene expression. ResultsWe show that nafamostat efficiently suppressed the airway hyperreactivity in HDM-sensitized mice. This was accompanied by reduced infiltration of eosinophils and lymphocytes to the airways, and by lower levels of pro-inflammatory compounds within the airway lumen. Further, nafamostat had a dampening impact on goblet cell hyperplasia and smooth muscle layer thickening in the lungs of HDM-sensitized animals. To obtain deeper insight into the underlying mechanisms, a transcriptomic analysis was conducted. This revealed, as expected, that the HDM sensitization caused an upregulated expression of numerous pro-inflammatory genes. Further, the transcriptomic analysis showed that nafamostat suppressed the levels of multiple pro-inflammatory genes, with a particular impact on genes related to asthma. DiscussionTaken together, this study provides extensive insight into the ameliorating effect of nafamostat on experimental asthma, and our findings can thereby provide a basis for the further evaluation of nafamostat as a potential therapeutic agent in human asthma.

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  • 26.
    Almazan, Nerea Martin
    et al.
    Karolinska Inst, Dept Med, Unit Microbial Pathogenesis, S-17164 Stockholm, Sweden.;Karolinska Univ Hosp, Dept Neurol, S-17176 Stockholm, Sweden.;Karolinska Inst, Dept Lab Med, Div Pathol, S-14186 Stockholm, Sweden..
    Rahbar, Afsar
    Karolinska Inst, Dept Med, Unit Microbial Pathogenesis, S-17164 Stockholm, Sweden.;Karolinska Univ Hosp, Dept Neurol, S-17176 Stockholm, Sweden..
    Carlsson, Marcus
    Lund Univ, Ctr Math Sci, S-22362 Lund, Sweden..
    Hoffman, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine. Uppsala Univ, Zoonosis Sci Ctr ZSC, Dept Med Biochem & Microbiol IMBIM, S-1477 Uppsala, Sweden..
    Kolstad, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala Univ, Zoonosis Sci Ctr ZSC, Dept Med Biochem & Microbiol IMBIM, S-1477 Uppsala, Sweden..
    Rönnberg, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala Univ, Zoonosis Sci Ctr ZSC, Dept Med Biochem & Microbiol IMBIM, S-1477 Uppsala, Sweden..
    Pantalone, Mattia Russel
    Karolinska Inst, Dept Med, Unit Microbial Pathogenesis, S-17164 Stockholm, Sweden.;Karolinska Univ Hosp, Dept Neurol, S-17176 Stockholm, Sweden..
    Fuchs, Ilona Lewensohn
    Karolinska Inst, Dept Lab Med, Div Clin Microbiol, S-14186 Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Microbiol, S-14186 Stockholm, Sweden..
    Naucler, Anna
    Karolinska Inst, Dept Med, Unit Microbial Pathogenesis, S-17164 Stockholm, Sweden..
    Ohlin, Mats
    Lund Univ, Dept Immunotechnol, S-22362 Lund, Sweden.;Lund Univ, SciLifeLab Human Antibody Therapeut Infrastruct Un, S-22362 Lund, Sweden..
    Sacharczuk, Mariusz
    Med Univ Warsaw, Fac Pharm, Ctr Preclin Res & Technol, Dept Pharmacodynam,Lab Med Div, Banacha 1B, PL-02091 Warsaw, Poland.;Polish Acad Sci, Inst Genet & Anim Biotechnol, Dept Expt Genom, Postepu 36A, PL-05552 Magdalenka, Poland..
    Religa, Piotr
    Karolinska Inst, Dept Med, Unit Microbial Pathogenesis, S-17164 Stockholm, Sweden.;Karolinska Univ Hosp, Dept Neurol, S-17176 Stockholm, Sweden.;Polish Acad Sci, Inst Genet & Anim Biotechnol, Dept Expt Genom, Postepu 36A, PL-05552 Magdalenka, Poland..
    Amer, Stefan
    Familjelakarna Saltsjdbaden, S-13334 Saltsjdbaden, Sweden..
    Molnar, Christian
    Familjelakarna Saltsjdbaden, S-13334 Saltsjdbaden, Sweden.;Karolinska Inst, Dept Neurobiol Care Sci & Soc, NVS, S-17177 Stockholm, Sweden..
    Lundkvist, Ake
    Susrud, Andres
    Immunor AS, N-0349 Oslo, Norway..
    Sorensen, Birger
    Immunor AS, N-0349 Oslo, Norway..
    Soderberg-Naucler, Cecilia
    Karolinska Inst, Dept Med, Unit Microbial Pathogenesis, S-17164 Stockholm, Sweden.;Karolinska Univ Hosp, Dept Neurol, S-17176 Stockholm, Sweden.;Univ Turku, Inst Biomed, Unit Infect & Immunol, MediCity Res Lab, FI-20014 Turku, Finland..
    Influenza-A mediated pre-existing immunity levels to SARS-CoV-2 could predict early COVID-19 outbreak dynamics2023In: iScience, E-ISSN 2589-0042, Vol. 26, no 12, article id 108441Article in journal (Refereed)
    Abstract [en]

    Susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections is highly variable and could be mediated by a cross-protective pre-immunity. We identified 14 cross-reactive peptides between SARS-CoV-2 and influenza A H1N1, H3N2, and human herpesvirus (HHV)-6A/B with potential relevance. The H1N1 peptide NGVEGF was identical to a peptide in the most critical receptor binding motif in SARS-CoV-2 spike protein that interacts with the angiotensin converting enzyme 2 receptor. About 62%-73% of COVID-19-negative blood donors in Stockholm had antibodies to this peptide in the early pre-vaccination phase of the pandemic. Seasonal flu vaccination enhanced neutralizing capacity to SARS-CoV-2 and T cell immunity to this peptide. Mathematical modeling taking the estimated pre -immunity levels to flu into account could fully predict pre-Omicron SARS-CoV-2 outbreaks in Stockholm and India. This cross-immunity provides mechanistic explanations to the epidemiological observation that influenza vaccination protected people against early SARS-CoV-2 infections and implies that flu-mediated cross-protective immunity significantly dampened the first SARS-CoV-2 outbreaks.

  • 27.
    Al-Shamkhi, Nasrin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Dahlen, S. E.
    Karolinska Inst, Inst Environm Med, Expt Asthma & Allergy Res Unit, Stockholm, Sweden..
    Hedlin, G.
    Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden..
    Middelveld, R.
    Karolinska Inst, Inst Environm Med, Expt Asthma & Allergy Res Unit, Stockholm, Sweden..
    Bjerg, A.
    Univ Gothenburg, Krefting Res Ctr, Dept Internal Med & Clin Nutr, Gothenburg, Sweden..
    Ekerljung, L.
    Univ Gothenburg, Krefting Res Ctr, Dept Internal Med & Clin Nutr, Gothenburg, Sweden..
    Olin, A. C.
    Univ Gothenburg, Sect Occupat & Environm Med, Dept Publ Hlth & Community Med, Inst Med,Sahlgrenska Acad, Gothenburg, Sweden..
    Sommar, J.
    Umea Univ, Dept Publ Hlth & Clin Med Occupat & Environm Med, Umea, Sweden..
    Forsberg, B.
    Umea Univ, Dept Publ Hlth & Clin Med Occupat & Environm Med, Umea, Sweden..
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Important non-disease-related determinants of exhaled nitric oxide levels in mild asthma - results from the Swedish GA(2)LEN study2016In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 46, no 9, p. 1185-1193Article in journal (Refereed)
    Abstract [en]

    Background Fractional exhaled nitric oxide (FeNO) has a potential clinical role in asthma management. Constitutive factors such as age, height and gender, as well as individual characteristics, such as IgE sensitization and smoking, affect the levels of FeNO in population-based studies. However, their effect on FeNO in subjects with asthma has been scarcely studied. Objective To study the effects on FeNO of these commonly regarded determinants, as demonstrated in healthy subjects, as well as menarche age and parental smoking, in a population of asthmatics. Material and Methods Fractional exhaled nitric oxide was measured in 557 subjects with asthma from the Swedish GA(2)LEN study. Allergic sensitization was assessed by skin prick tests to most common aeroallergens. Upper airway comorbidities, smoking habits, smoking exposure during childhood and hormonal status (for women) were questionnaire-assessed. Results Male gender (P < 0.001), greater height (P < 0.001) and sensitization to both perennial allergens and pollen (P < 0.001) are related to higher FeNO levels. Current smoking (P < 0.001) and having both parents smoking during childhood, vs. having neither (P < 0.001) or only one parent smoking (P = 0.002), are related to lower FeNO. Women with menarche between 9 and 11 years of age had lower FeNO than those with menarche between 12 and 14 years of age (P = 0.03) or 15 and 17 years of age (P = 0.003). Conclusions and Clinical relevance Interpreting FeNO levels in clinical practice is complex, and constitutional determinants, as well as smoking and IgE sensitisation, are of importance in asthmatic subjects and should be accounted for when interpreting FeNO levels. Furthermore, menarche age and parental smoking during childhood and their effects on lowering FeNO deserve further studies.

  • 28.
    Alvarado-Vazquez, P. Abigail
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mast cells and their progenitors in respiratory diseases: Understanding their connection to lung function and airway inflammation2023Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Mast cells are rare immune cells involved in allergic diseases, including asthma. These cells are derived from mast cell progenitors (MCps) that migrate to the peripheral tissues via the blood in response to allergic or non-allergic stimuli. The main purpose of this thesis was to investigate the role of mast cells and MCps in the lung function decline observed in mouse models of airway inflammation. We also investigated the MCp frequency during natural allergen exposure using patient samples. 

    Our aim in paper I was to investigate the effect of age and weight on lung function parameters in naïve mice using a pulmonary function test (PFT). We showed that age and weight positively correlated with lung function and successfully used the PFT to monitor asthma outcomes and distinguish between treated and untreated experimental asthma.

    In paper II, we investigated the specificity of a basophil-deficient mouse model that relies on the deletion of the mast cell protease 8 (mMCP-8), a classical basophil marker. We found that lung mast cells expressed mMCP-8, and deleting this protease reduced lung mast cells in mice with allergic airway inflammation.

    Mast cells express ST2 and thus can be activated by interleukin-33 (IL-33). Hence, in paper III, we used Cpa3cre/+ mast cell-deficient mice to investigate the role of mast cells in airway inflammation induced by intranasal IL-33 administration. We identified a new mechanism in which mast cells participate in T-cells mobilization into the alveolar space via the CXCL1/CXCR2 axis. 

    We have previously described increased circulating MCps in subjects with reduced lung function. However, if and how MCps change upon allergen exposure is unknown. Therefore, in paper IV, we investigated the frequency of blood MCps in birch pollen-sensitized asthma patients in and out of the birch pollen season. We demonstrated that in allergic asthma patients, circulating MCps were increased during natural pollen exposure and were associated with more asthma symptoms and less asthma control.

    This thesis involves both basic and translational research and provides new insights into the role of mast cells and their progenitors in type 2 inflammation.

    List of papers
    1. Use of spirometry-like measurements to monitor house dust mite-induced experimental asthma in mice
    Open this publication in new window or tab >>Use of spirometry-like measurements to monitor house dust mite-induced experimental asthma in mice
    2021 (English)In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 76, no 7, p. 2204-2207Article in journal, Letter (Other academic) Published
    Abstract [en]

    Weight and age correlated positively with FEV 0.1 and PEF among other lung function parameters in naïve mice. Lung function parameters decline in a model of experimental asthma induced by intranasal HDM administrations. Systemic injections of dexamethasone improved lung function, decreased mast cell populations and BAL levels of mast cell protease-1 in the HDM model.

    Place, publisher, year, edition, pages
    John Wiley & SonsWiley, 2021
    Keywords
    asthma, house dust mite, lung function, mast cells, mouse model
    National Category
    Immunology in the medical area Respiratory Medicine and Allergy
    Identifiers
    urn:nbn:se:uu:diva-436863 (URN)10.1111/all.14681 (DOI)000599069300001 ()33263946 (PubMedID)
    Available from: 2021-03-03 Created: 2021-03-03 Last updated: 2024-01-15Bibliographically approved
    2. Depletion of Mcpt8‐expressing cells reduces lung mast cells in mice with experimental asthma
    Open this publication in new window or tab >>Depletion of Mcpt8‐expressing cells reduces lung mast cells in mice with experimental asthma
    2022 (English)In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 78, no 5, p. 1363-1366Article in journal, Letter (Refereed) Published
    Place, publisher, year, edition, pages
    John Wiley & Sons, 2022
    National Category
    Immunology in the medical area
    Identifiers
    urn:nbn:se:uu:diva-500049 (URN)10.1111/all.15596 (DOI)000897515900001 ()
    Funder
    Agnes and Mac Rudberg FoundationSwedish Heart Lung Foundation, 20200625Knut and Alice Wallenberg FoundationSwedish Research Council, 2016‐00803
    Available from: 2023-04-11 Created: 2023-04-11 Last updated: 2023-10-06Bibliographically approved
    3. Mast cell-derived CXCL1 promotes bronchoalveolar CXCR2+ T-cells in mice with IL-33-induced airway inflammation
    Open this publication in new window or tab >>Mast cell-derived CXCL1 promotes bronchoalveolar CXCR2+ T-cells in mice with IL-33-induced airway inflammation
    (English)Manuscript (preprint) (Other academic)
    National Category
    Immunology in the medical area Respiratory Medicine and Allergy
    Identifiers
    urn:nbn:se:uu:diva-500052 (URN)
    Available from: 2023-04-11 Created: 2023-04-11 Last updated: 2023-04-12
    4. ­­Circulating mast cell progenitors increase in frequency during natural birch pollen exposure in allergic asthma patients
    Open this publication in new window or tab >>­­Circulating mast cell progenitors increase in frequency during natural birch pollen exposure in allergic asthma patients
    Show others...
    2023 (English)In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 78, no 11, p. 2959-2968Article in journal (Refereed) Published
    Abstract [en]

    Background: Mast cells (MCs) develop from a rare population of peripheral blood circulating MC progenitors (MCps). Here, we investigated whether the frequency of circulating MCps is altered in asthma patients sensitized to birch pollen during pollen season, compared to out of season.

    Methods: Asthma patients were examined during birch pollen season in late April to early June (May), and out of season in November–January. Spirometry measurements, asthma and allergy-related symptoms, asthma control questionnaire (ACQ), and asthma control test (ACT) scores were assessed at both time points. The MCp frequency was determined by flow cytometry in ficoll-separated blood samples from patients with positive birch pollen-specific IgE, and analyzed in relation to basic and disease parameters.

    Results: The frequency of MCps per liter of blood was higher in May than in November (p = .004), particularly in women (p = .009). Patients that reported moderate to severe asthma symptoms (<.0001), nose or eye symptoms (p = .02; p = .01), or reduced asthma control (higher ACQ, p = .01) had higher MCp frequency in May than those that did not report this. These associations remained significant after adjusting for sex and BMI. The change in asthma control to a lower ACT score in May correlated with an increase in MCp frequency in May (p = .006, rho = 0.46).

    Conclusions: The data suggest that the frequency of MCps increases in symptomatic patients with allergic asthma. Our results unravel a link between asthma symptoms and circulating MCps, and bring new insight into the impact of natural allergen exposure on the expansion of MCs.

    Place, publisher, year, edition, pages
    John Wiley & Sons, 2023
    National Category
    Immunology in the medical area Respiratory Medicine and Allergy
    Identifiers
    urn:nbn:se:uu:diva-500050 (URN)10.1111/all.15860 (DOI)001110105400022 ()37615432 (PubMedID)
    Funder
    Swedish Asthma and Allergy AssociationSwedish Heart Lung Foundation, 20200625Swedish Heart Lung Foundation, 20170479Cancer and Allergy FoundationKnut and Alice Wallenberg Foundation, 2017.0022Consul Berghs FoundationSwedish Association for Allergology (SFFA)Swedish Research Council, 2016-00803
    Available from: 2023-04-11 Created: 2023-04-11 Last updated: 2024-01-16Bibliographically approved
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  • 29. Alvarado-Vazquez, P. Abigail
    et al.
    Mendez-Enriquez, Erika
    Pähn, Lisa
    Hallgren, Jenny
    Mast cell-derived CXCL1 promotes bronchoalveolar CXCR2+ T-cells in mice with IL-33-induced airway inflammationManuscript (preprint) (Other academic)
  • 30.
    Alvarado-Vazquez, Perla Abigail
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Cardenas, Eduardo I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Division of Lung and Airway Research Institute of Environmental Medicine, Karolinska Institutet Stockholm Sweden.
    Das, Avijit
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hallgren, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Depletion of Mcpt8‐expressing cells reduces lung mast cells in mice with experimental asthma2022In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 78, no 5, p. 1363-1366Article in journal (Refereed)
    Download full text (pdf)
    fulltext
  • 31.
    Alvarado-Vazquez, Perla Abigail
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mendez-Enriquez, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hallgren, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Use of spirometry-like measurements to monitor house dust mite-induced experimental asthma in mice2021In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 76, no 7, p. 2204-2207Article in journal (Other academic)
    Abstract [en]

    Weight and age correlated positively with FEV 0.1 and PEF among other lung function parameters in naïve mice. Lung function parameters decline in a model of experimental asthma induced by intranasal HDM administrations. Systemic injections of dexamethasone improved lung function, decreased mast cell populations and BAL levels of mast cell protease-1 in the HDM model.

    Download full text (pdf)
    fulltext
  • 32.
    Alvarado-Vazquez, Perla Abigail
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mendez-Enriquez, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Salomonsson, Maya
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Waern, Ida
    Department of Anatomy, Physiology and Biochemistry, Swedish University of Agriculture.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Wernersson, Sara
    Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Hallgren, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    ­­Circulating mast cell progenitors increase in frequency during natural birch pollen exposure in allergic asthma patients2023In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 78, no 11, p. 2959-2968Article in journal (Refereed)
    Abstract [en]

    Background: Mast cells (MCs) develop from a rare population of peripheral blood circulating MC progenitors (MCps). Here, we investigated whether the frequency of circulating MCps is altered in asthma patients sensitized to birch pollen during pollen season, compared to out of season.

    Methods: Asthma patients were examined during birch pollen season in late April to early June (May), and out of season in November–January. Spirometry measurements, asthma and allergy-related symptoms, asthma control questionnaire (ACQ), and asthma control test (ACT) scores were assessed at both time points. The MCp frequency was determined by flow cytometry in ficoll-separated blood samples from patients with positive birch pollen-specific IgE, and analyzed in relation to basic and disease parameters.

    Results: The frequency of MCps per liter of blood was higher in May than in November (p = .004), particularly in women (p = .009). Patients that reported moderate to severe asthma symptoms (<.0001), nose or eye symptoms (p = .02; p = .01), or reduced asthma control (higher ACQ, p = .01) had higher MCp frequency in May than those that did not report this. These associations remained significant after adjusting for sex and BMI. The change in asthma control to a lower ACT score in May correlated with an increase in MCp frequency in May (p = .006, rho = 0.46).

    Conclusions: The data suggest that the frequency of MCps increases in symptomatic patients with allergic asthma. Our results unravel a link between asthma symptoms and circulating MCps, and bring new insight into the impact of natural allergen exposure on the expansion of MCs.

    Download full text (pdf)
    fulltext
  • 33. Amaral, A F S
    et al.
    Minelli, C
    Guerra, S
    Wjst, M
    Probst-Hensch, N
    Pin, I
    Svanes, C
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Heinrich, J
    Jarvis, D L
    The locus C11orf30 increases susceptibility to poly-sensitization2015In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 70, no 3, p. 328-333Article in journal (Refereed)
    Abstract [en]

    A number of genetic variants have been associated with allergic sensitization, but whether these are allergen specific or increase susceptibility to poly-sensitization is unknown. Using data from the large multicentre population-based European Community Respiratory Health Survey, we assessed the association between 10 loci and specific IgE and skin prick tests to individual allergens and poly-sensitization. We found that the 10 loci associate with sensitization to different allergens in a nonspecific manner and that one in particular, C11orf30-rs2155219, doubles the risk of poly-sensitization (specific IgE/4 allergens: OR = 1.81, 95% CI 0.80-4.24; skin prick test/4+ allergens: OR = 2.27, 95% CI 1.34-3.95). The association of rs2155219 with higher levels of expression of C11orf30, which may be involved in transcription repression of interferon-stimulated genes, and its association with sensitization to multiple allergens suggest that this locus is highly relevant for atopy.

  • 34.
    Amaral, Andre F. S.
    et al.
    Univ London Imperial Coll Sci Technol & Med, Resp Epidemiol Occupat Med & Publ Hlth, Natl Heart & Lung Inst, Emmanuel Kaye Bldg,1B Manresa Rd, London SW3 6LR, England..
    Newson, Roger B.
    Univ London Imperial Coll Sci Technol & Med, Resp Epidemiol Occupat Med & Publ Hlth, Natl Heart & Lung Inst, Emmanuel Kaye Bldg,1B Manresa Rd, London SW3 6LR, England.;Univ London Imperial Coll Sci Technol & Med, Dept Primary Care & Publ Hlth, Sch Publ Hlth, London, England..
    Abramson, Michael J.
    Monash Univ, Sch Publ Hlth & Prevent Med, Melbourne, Vic 3004, Australia..
    Anto, Josep M.
    Ctr Res Environm Epidemiol CREAL, Barcelona, Spain.;IMIM Hosp del Mar, Med Res Inst, Barcelona, Spain.;UPF, Barcelona, Spain.;CIBERESP, Madrid, Spain..
    Bono, Roberto
    Univ Turin, Dept Publ Hlth & Pediat, Turin, Italy..
    Corsico, Angelo G.
    Univ Pavia, Div Resp Dis, IRCCS Policlin San Matteo Fdn, Via Palestro 3, I-27100 Pavia, Italy..
    de Marco, Roberto
    Univ Verona, Unit Epidemiol & Med Stat, Dept Publ Hlth & Community Med, I-37100 Verona, Italy..
    Demoly, Pascal
    CHU Montpellier, Dept Pulmonol, Div Allergy, Arnaud de Villeneuve Hosp, Paris, France.;INSERM, EPAR Team, UMR S 1136, Paris, France..
    Forsberg, Bertil
    Umea Univ, Div Occupat & Environm Med, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Gislason, Thorarinn
    Univ Iceland, Fac Med, Reykjavik, Iceland.;Natl Univ Hosp Iceland, Landspitali, Dept Resp Med & Sleep, Reykjavik, Iceland..
    Heinrich, Joachim
    Helmholtz Zentrum, Inst Epidemiol 1, Munich, Germany.;Univ Munich, Inst & Outpatient Clin Occupat Social & Environm, Inner City Clin, Univ Hosp Munich, Munich, Germany..
    Huerta, Ismael
    Dept Hlth Asturias, Directorate Gen Publ Hlth, Epidemiol Surveillance Sect, Oviedo, Spain..
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Jogi, Rain
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research. Tartu Univ Hosp, Lung Clin, Tartu, Estonia..
    Kim, Jeong-Lim
    Univ Gothenburg, Dept Publich Hlth & Community Med, Sahlgrenska Acad, Gothenburg, Sweden..
    Maldonado, Jose
    Univ Hosp Huelva, Unit Clin Management Pneumol & Allergy, Huelva, Spain..
    Rovira, Jesus Martinez-Moratalla
    Univ Hosp Albacete, Unit Pneumol, Albacete, Spain..
    Neukirch, Catherine
    INSERM, UMR1152, Paris, France.;Univ Paris 07, UMR1152, Paris, France..
    Nowak, Dennis
    Univ Munich, Inst & Outpatient Clin Occupat Social & Environm, Inner City Clin, Univ Hosp Munich, Munich, Germany.;German Ctr Lung Res, Munich, Germany..
    Pin, Isabelle
    CHU Grenoble, Pole Couple Enfants, Pediat, F-38043 Grenoble, France.;Inst Albert Bonniot, INSERM, U823, Grenoble, France.;Univ Grenoble 1, Grenoble, France..
    Probst-Hensch, Nicole
    Swiss Trop & Publ Hlth Inst, Basel, Switzerland.;Univ Basel, Basel, Switzerland..
    Raherison-Semjen, Chantal
    Bordeaux Univ, Inst Publ Hlth & Epidemiol, INSERM, U897, Bordeaux, France..
    Svanes, Cecilie
    Univ Bergen, Ctr Int Hlth, Bergen, Norway.;Haukeland Hosp, Dept Occupat Med, N-5021 Bergen, Norway..
    Landa, Isabel Urrutia
    Galdakao Hosp, Dept Pneumol, Bizkaia, Spain..
    van Ree, Ronald
    Univ Amsterdam, Acad Med Ctr, Dept Expt Immunol, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands.;Univ Amsterdam, Acad Med Ctr, Dept Otorhinolaryngol, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands..
    Versteeg, Serge A.
    Univ Amsterdam, Acad Med Ctr, Dept Expt Immunol, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands..
    Weyler, Joost
    Univ Antwerp, Epidemiol & Social Med, B-2020 Antwerp, Belgium.;Univ Antwerp, StatUA Stat Ctr, B-2020 Antwerp, Belgium..
    Zock, Jan-Paul
    Ctr Res Environm Epidemiol CREAL, Barcelona, Spain.;UPF, Barcelona, Spain.;CIBERESP, Madrid, Spain..
    Burney, Peter G. J.
    Univ London Imperial Coll Sci Technol & Med, Resp Epidemiol Occupat Med & Publ Hlth, Natl Heart & Lung Inst, Emmanuel Kaye Bldg,1B Manresa Rd, London SW3 6LR, England..
    Jarvis, Deborah L.
    Univ London Imperial Coll Sci Technol & Med, Resp Epidemiol Occupat Med & Publ Hlth, Natl Heart & Lung Inst, Emmanuel Kaye Bldg,1B Manresa Rd, London SW3 6LR, England..
    Changes in IgE sensitization and total IgE levels over 20 years of follow-up2016In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 137, no 6, p. 1788-1795Article in journal (Refereed)
    Abstract [en]

    Background: Cross-sectional studies have reported a lower prevalence of sensitization in older adults, but few longitudinal studies have examined whether this is an aging or a year-of-birth cohort effect. Objective: We sought to assess changes in sensitization and total IgE levels in a cohort of European adults as they aged over a 20-year period. Methods: Levels of serum specific IgE to common aeroallergens (house dust mite, cat, and grass) and total IgE levels were measured in 3206 adults from 25 centers in the European Community Respiratory Health Survey on 3 occasions over 20 years. Changes in sensitization and total IgE levels were analyzed by using regression analysis corrected for potential differences in laboratory equipment and by using inverse sampling probability weights to account for nonresponse. Results: Over the 20-year follow-up, the prevalence of sensitization to at least 1 of the 3 allergens decreased from 29.4% to 24.8% (-4.6%; 95% CI, -7.0% to -2.1%). The prevalence of sensitization to house dust mite (-4.3%; 95% CI, -6.0% to -2.6%) and cat (-2.1%; 95% CI, -3.6% to -0.7%) decreased more than sensitization to grass (-0.6%; 95% CI, -2.5% to 1.3%). Age-specific prevalence of sensitization to house dust mite and cat did not differ between year-of-birth cohorts, but sensitization to grass was most prevalent in the most recent ones. Overall, total IgE levels decreased significantly (geometric mean ratio, 0.63; 95% CI, 0.58-0.68) at all ages in all year-of-birth cohorts. Conclusion: Aging was associated with lower levels of sensitization, especially to house dust mite and cat, after the age of 20 years.

  • 35.
    Amin, Kawa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    H Rasool, Aram
    Hattem, Ali
    AM Al-Karboly, Taha
    E Taher, Taher
    Bystrom, Jonas
    Autoantibody profiles in autoimmune hepatitis and chronic hepatitis C identifies similarities in patients with severe disease2017In: World Journal of Gastroenterology, ISSN 1007-9327, E-ISSN 2219-2840, Vol. 23, no 8, p. 1345-1352Article in journal (Refereed)
    Abstract [en]

    AIM: To determine how the auto-antibodies (Abs) profilesoverlap in chronic hepatitis C infection (CHC) andautoimmune hepatitis (AIH) and correlate to liverdisease.METHODS: Levels of antinuclear Ab, smooth muscle antibody (SMA)and liver/kidney microsomal-1 (LKM-1) Ab and markersof liver damage were determined in the sera of 50 patients with CHC infection, 20 AIH patients and 20healthy controls using enzyme linked immunosorbentassay and other immune assays. RESULTS: We found that AIH patients had more severe liverdisease as determined by elevation of total IgG,alkaline phosphatase, total serum bilirubin and serumtransaminases and significantly higher prevalence ofthe three non-organ-specific autoantibodies (auto-Abs)than CHC patients. Antinuclear Ab, SMA and LKM-1 Abwere also present in 36% of CHC patients and relatedto disease severity. CHC cases positive for auto-Abswere directly comparable to AIH in respect of mostmarkers of liver damage and total IgG. These caseshad longer disease duration compared with auto-Abnegative cases, but there was no difference in gender,age or viral load. KLM-1+ Ab CHC cases showed bestoverlap with AIH. CONCLUSION: Auto-Ab levels in CHC may be important markers ofdisease severity and positive cases have a diseasesimilar to AIH. Auto-Abs might have a pathogenic roleas indicated by elevated markers of liver damage.Future studies will unravel any novel associationsbetween these two diseases, whether genetic or other.

  • 36.
    Amin, Kawa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology. Clin Chem & Asthma Res Ctr, Uppsala, Sweden.;Univ Hosp, Uppsala, Sweden..
    Janson, C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Byström, J.
    Queen Mary Univ London, Barts & London, Harvey Res Inst, Expt Med & Rheumatol William, London, England..
    Role of Eosinophil Granulocytes in Allergic Airway Inflammation Endotypes2016In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 84, no 2, p. 75-85Article, review/survey (Refereed)
    Abstract [en]

    Eosinophil granulocytes are intriguing members of the innate immunity system that have been considered important defenders during parasitic diseases as well as culprits during allergy-associated inflammatory diseases. Novel studies have, however, found new homoeostasis-maintaining roles for the cell. Recent clinical trials blocking different Th2 cytokines have uncovered that asthma is heterogeneous entity and forms different characteristic endotypes. Although eosinophils are present in allergic asthma with early onset, the cells may not be essential for the pathology. The cells are, however, likely disease causing in asthma with a late onset, which is often associated with chronic rhinosinusitis. Assessment of eosinophilia, fraction exhaled nitric oxide (FeNO) and periostin are markers that have emerged useful in assessing and monitoring asthma severity and endotype. Current scientific knowledge suggests that eosinophils are recruited by the inflammatory environment, activated by the innate interleukin (IL)-33 and prevented from apoptosis by both lymphocytes and innate immune cells such as type two innate immune cells. Eosinophils contain four specific granule proteins that exhibit an array of toxic and immune-modulatory activates. The granule proteins can be released by different mechanisms. Additionally, eosinophils contain a number of inflammatory cytokines and lipid mediators as well as radical oxygen species that might contribute to the disease both by the recruitment of other cells and the direct damage to supporting cells, leading to exacerbations and tissue fibrosis. This review aimed to outline current knowledge how eosinophils are recruited, activated and mediate damage to tissues and therapies used to control the cells.

  • 37.
    Anania, Jessica C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Westin, Annika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Adler, Jeremy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    A Novel Image Analysis Approach Reveals a Role for Complement Receptors 1 and 2 in Follicular Dendritic Cell Organization in Germinal Centers2021In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 12, article id 655753Article in journal (Refereed)
    Abstract [en]

    Follicular dendritic cells (FDCs) are rare and enigmatic cells that mainly reside in germinal centers (GCs). They are capable of capturing immune complexes, via their Fc (FcRs) and complement receptors (CRs) and storing them for long periods in non-degradative vesicles. Presentation of ICs on FDCs to B cells is believed to drive affinity maturation. CR1 and CR2 are expressed on B cells and FDCs. Cr2 knock out (KO) mice, lacking both receptors, have impaired antibody and GC responses. Utilizing a novel ImageJ macro to analyze confocal fluorescence microscopy images of spleen sections, we here investigate how FDCs in wild type (WT) and Cr2 KO mice behave during the first two weeks after immunization with sheep red blood cells (SRBC). Mice were immunized with SRBC i.v. and spleen and serum samples harvested at various time points. As expected, antibody and GC responses in Cr2 KO mice were impaired in comparison to WT mice. Fewer FDCs were identified in Cr2 KO mice, and these exhibited differential localization and organization in comparison to WT mice. WT FDCs were primarily located within GCs at the light zone/dark zone border. FDCs from WT but not Cr2 KO mice were actively dispersed in GCs, i.e. tended to move away from each other, presumably to increase their surface area for B cell interaction. FDCs from Cr2 KO mice were more often found on follicles outside of the GCs and those within the GCs were closer to the periphery in comparison to WT FDCs. Expression of CR1 and CR2, Fc gamma RIIB, and Fc mu R increased in FDCs from WT mice during the course of immunization. The results suggest that decreased ability to capture ICs by FDCs lacking CR1 and CR2 may not be the only explanation for the impaired GC and antibody responses in Cr2 KO mice. Poor FDC organization in GCs and failure to increase receptor expression after immunization may further contribute to the inefficient immune responses observed.

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    FULLTEXT01
  • 38.
    Anania, Jessica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Westin, Annika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    IgG Suppresses Antibody Responses to Sheep Red Blood Cells in Double Knock-Out Mice Lacking Complement Factor C3 and Activating Fc gamma-Receptors2020In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 11, article id 1404Article in journal (Refereed)
    Abstract [en]

    Antigen-specific IgG antibodies, passively administered together with erythrocytes, prevent antibody responses against the erythrocytes. The mechanism behind the suppressive ability of IgG has been the subject of intensive studies, yet there is no consensus as to how it works. An important question is whether the Fc-region of IgG is required. Several laboratories have shown that IgG suppresses equally well in wildtype mice and mice lacking the inhibitory Fc gamma IIB, activating Fc gamma Rs (Fc gamma RI, III, and IV), or complement factor C3. These observations consistently suggest that IgG-mediated suppression does not rely on Fc-mediated antibody functions. However, it was recently shown that anti-KEL sera failed to suppress antibody responses to KEL-expressing transgenic mouse erythrocytes in double knock-out mice lacking both activating Fc gamma Rs and C3. Yet, in the same study, antibody-mediated suppression worked well in each single knock-out strain. This unexpected observation suggested Fc-dependence of IgG-mediated suppression and prompted us to investigate the issue in the classical experimental model using sheep red blood cells (SRBC) as antigen. SRBC alone or IgG anti-SRBC together with SRBC was administered to wildtype and double knock-out mice lacking C3 and activating Fc gamma Rs. IgG efficiently suppressed the IgM and IgG anti-SRBC responses in both mouse strains, thus supporting previous observations that suppression in this model is Fc-independent.

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    FULLTEXT01
  • 39.
    Andersen, M.
    et al.
    North Denmark Reg Hosp, Dept Rheumatol, Bispensgade 37, DK-9800 Hjorring, Denmark.;Aalborg Univ, Dept Hlth Sci & Technol, Aalborg, Denmark..
    Nagaev, I.
    Umea Univ, Dept Clin Microbiol, Div Clin Immunol, Umea, Sweden..
    Meyer, M. K.
    Aalborg Univ, Dept Hlth Sci & Technol, Aalborg, Denmark.;North Denmark Reg Hosp, Ctr Clin Sci, Hjorring, Denmark..
    Nagaeva, O.
    Umea Univ, Dept Clin Microbiol, Div Clin Immunol, Umea, Sweden..
    Wikberg, Jarl E. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Mincheva-Nilsson, L.
    Umea Univ, Dept Clin Microbiol, Div Clin Immunol, Umea, Sweden..
    Andersen, G. N.
    North Denmark Reg Hosp, Dept Rheumatol, Bispensgade 37, DK-9800 Hjorring, Denmark.;Aalborg Univ, Dept Clin Med, Aalborg, Denmark..
    Melanocortin 2, 3 and 4 Receptor Gene Expressions are Downregulated in CD8(+) T Cytotoxic Lymphocytes and CD19(+) B Lymphocytes in Rheumatoid Arthritis Responding to TNF-alfa Inhibition2017In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 86, no 1, p. 31-39Article in journal (Refereed)
    Abstract [en]

    Melanocortin signalling in leucocyte subsets elicits anti-inflammatory and immune tolerance inducing effects in animal experimental inflammation. In man, however, the effects of melanocortin signalling in inflammatory conditions have scarcely been examined. We explored the differential reactions of melanocortin 1-5 receptors (MC1-5R) gene expressions in pathogenetic leucocyte subsets in rheumatoid arthritis (RA) to treatment with TNF- inhibitor adalimumab. Seven patients with active RA donated blood at start and at 3-month treatment. CD4(+) T helper (h) lymphocytes (ly), CD8(+) T cytotoxic (c) ly, CD19(+) B ly and CD14(+) monocytes were isolated, using immunomagnetic beads, total RNA extracted and reverse transcription quantitative polymerase chain reaction (RT-qPCR) performed. Fold changes in MC1-5R, Th1-, inflammatory- and regulatory cytokine gene expressions were assessed for correlation. Six patients responded to adalimumab treatment, while one patient was non-responder. In all lymphocyte subtypes, MC1-5R gene expressions decreased in responders and increased in the non-responder. In responders, decrease in MC2R, MC3R and MC4R gene expressions in CD8(+) Tc and CD19(+) B ly was significant. Fold change in MC1-5R and IFN gene expressions correlated significantly in CD8(+) Tc ly, while fold change in MC1R, MC3R and MC5R and IL-1 gene expressions correlated significantly in CD4(+) Th ly. Our results show regulation of MC2R, MC3R and MC4R gene expressions in CD8(+) Tc ly and CD19(+) B ly. The correlations between fold change in different MCRs and disease driving cytokine gene expressions in CD8(+) Tc ly and CD4(+) Th ly point at a central immune modulating function of the melanocortin system in RA.

  • 40. Andersson, Cecilia
    et al.
    Henriksson, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Magnusson, Karl-Eric
    Nilsson, Mats
    Mirazimi, Ali
    In situ rolling circle amplification detection of Crimean Congo hemorrhagic fever virus (CCHFV) complementary and viral RNA2012In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 426, no 2, p. 87-92Article in journal (Refereed)
    Abstract [en]

    Crimean Congo hemorrhagic fever virus (CCHFV) is a human pathogen that causes a severe disease with high fatality rate for which there is currently no specific treatment. Knowledge regarding its replication cycle is also highly limited. In this study we developed an in situ technique for studying the different stages during the replication of CCHFV. By integrating reverse transcription, padlock probes, and rolling circle amplification, we were able to detect and differentiate between viral RNA (vRNA) and complementary RNA (cRNA) molecules, and to detect viral protein within the same cell. These data demonstrate that CCHFV nucleocapsid protein (NP) is detectable already at 6 hours post infection in vRNA- and cRNA-positive cells. Confocal microscopy showed that cRNA is enriched and co-localized to a large extent with NP in the perinuclear area, while vRNA has a more random distribution in the cytoplasm with only some co-localize with NP. However, vRNA and cRNA did not appear to co-localize directly. 

  • 41.
    Andersson, Jonas
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Complement Activation Triggered by Biomaterial Surfaces: Mechanisms and Regulation2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Today there are a vast number of medical devices in temporary or permanent contact with human tissues. Blood-biomaterial contact is known to trigger the complement system and results in generation of fluid phase anaphylatoxins C3a and C5a, and surface-bound C3b and iC3b. All these products together are able to attract and activate leukocytes and trigger release of inflammatory mediators leading to a systemic inflammation indirectly causing hemostatic problems and even organ failure. The aim of this study was to identify how complement is triggered on a biomaterial surface and to find ways to regulate this activation.

    The finding that complement activation on biomaterials can be divided into initiation and amplification will facilitate regulation of complement activation biomaterial surfaces. This concept is also compatible with the two techniques to regulate complement activation on a surface.

    List of papers
    1. Complement activation on a model biomaterial surface: Binding of C3b via the alternative pathway amplification loop to plasma proteins adsorbed to the surface
    Open this publication in new window or tab >>Complement activation on a model biomaterial surface: Binding of C3b via the alternative pathway amplification loop to plasma proteins adsorbed to the surface
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-90375 (URN)
    Available from: 2003-04-24 Created: 2003-04-24 Last updated: 2010-01-13Bibliographically approved
    2. C3 Adsorbed to a Polymer Surface Can Form an Initiating Alternative Pathway Convertase
    Open this publication in new window or tab >>C3 Adsorbed to a Polymer Surface Can Form an Initiating Alternative Pathway Convertase
    Show others...
    2002 In: Journal of Immunology, ISSN 0022-1767, Vol. 168, no 11, p. 5786-5791Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-90376 (URN)
    Available from: 2003-04-24 Created: 2003-04-24Bibliographically approved
    3. Binding of a model regulator of complement activation (RCA) to a biomaterial surface: surface-bound factor H inhibits complement activation
    Open this publication in new window or tab >>Binding of a model regulator of complement activation (RCA) to a biomaterial surface: surface-bound factor H inhibits complement activation
    Show others...
    2001 In: Biomaterials, ISSN 0142-9612, Vol. 22, no 17, p. 2435-2443Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-90377 (URN)
    Available from: 2003-04-24 Created: 2003-04-24Bibliographically approved
    4. Optimal heparin surface concentration and antithrombin binding capacity as evaluated with human non-anticoagulated blood in vitro
    Open this publication in new window or tab >>Optimal heparin surface concentration and antithrombin binding capacity as evaluated with human non-anticoagulated blood in vitro
    Show others...
    2003 (English)In: Journal of Biomedical Materials Research, ISSN 0021-9304, E-ISSN 1097-4636, Vol. 67, no 2, p. 458-466Article in journal (Refereed) Published
    Abstract [en]

    Contact between blood and a biomaterial surface takes place in many applications and is known to activate the coagulation and complement systems. Heparin surface coatings have been shown to reduce blood activation upon contact with artificial surfaces. To establish the optimal heparin surface concentration, blood was incubated in a tubing loop model at 37 degrees C. The tubing was coated with different surface concentrations of heparin and rotated at three different velocities. We demonstrate that the blood compatibility of a surface with regard to coagulation, complement, and platelet activation can be improved by increasing the heparin surface concentration in the 6-12 pmol antithrombin/cm2 concentration interval. The binding of factor H is not influenced by the increased heparin surface concentration, suggesting that this factor is not the primary regulator of complement on heparin surfaces. In addition, the heparin coating has no effect on the complement activation that occurs on gas surfaces in extracorporeal circuits.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-90378 (URN)10.1002/jbm.a.10104 (DOI)14566786 (PubMedID)
    Available from: 2003-04-24 Created: 2003-04-24 Last updated: 2017-12-14Bibliographically approved
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    FULLTEXT01
  • 42.
    Andersson, Maria
    et al.
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden.;Karolinska Univ Hosp Solna, Dept Hematol, Stockholm, Sweden..
    Wu, Jinghua
    Karolinska Inst, Ctr Infect Med, Dept Med Huddinge, Stockholm, Sweden..
    Wullimann, David
    Karolinska Inst, Ctr Infect Med, Dept Med Huddinge, Stockholm, Sweden..
    Gao, Yu
    Karolinska Inst, Ctr Infect Med, Dept Med Huddinge, Stockholm, Sweden..
    Åberg, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Muschiol, Sandra
    Karolinska Univ Hosp, Dept Clin Microbiol, Stockholm, Sweden.;Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    Healy, Katie
    Karolinska Univ Hosp, Dept Clin Microbiol, Stockholm, Sweden..
    Naud, Sabrina
    Karolinska Inst, Dept Dent Med, Huddinge, Sweden..
    Bogdanovic, Gordana
    Karolinska Univ Hosp, Dept Clin Microbiol, Stockholm, Sweden.;Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    Palma, Marzia
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden.;Karolinska Univ Hosp Solna, Dept Hematol, Stockholm, Sweden..
    Mellstedt, Hakan
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Chen, Puran
    Karolinska Inst, Ctr Infect Med, Dept Med Huddinge, Stockholm, Sweden..
    Ljunggren, Hans-Gustaf
    Karolinska Inst, Ctr Infect Med, Dept Med Huddinge, Stockholm, Sweden..
    Hansson, Lotta
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden.;Karolinska Univ Hosp Solna, Dept Hematol, Stockholm, Sweden..
    Sallberg Chen, Margaret
    Karolinska Inst, Dept Dent Med, Huddinge, Sweden..
    Buggert, Marcus
    Karolinska Inst, Ctr Infect Med, Dept Med Huddinge, Stockholm, Sweden..
    Ingelman-Sundberg, Hanna M.
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden.;Karolinska Univ Hosp Solna, Dept Oncol, Stockholm, Sweden.;Karolinska Univ, Hosp Solna, Dept Oncol, SE-17176 Stockholm, Sweden..
    Osterborg, Anders
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden.;Karolinska Univ Hosp Solna, Dept Hematol, Stockholm, Sweden..
    Local and Systemic Immunity During Five Vaccinations Against SARS-CoV-2 in Zanubrutinib-Treated Patients With Chronic Lymphocytic Leukemia2023In: Journal of Hematology, ISSN 1927-1212, Vol. 12, no 4, p. 170-175Article in journal (Refereed)
    Abstract [en]

    Background: Patients with chronic lymphocytic leukemia (CLL) are vulnerable to coronavirus disease 2019 (COVID-19) and are at risk of inferior response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination, especially if treated with the first-generation Bruton’s tyrosine kinase inhibitor (BTKi) ibrutinib. We aimed to evaluate the impact of the third-generation BTKi, zanubrutinib, on systemic and mucosal response to SARS-CoV-2 vaccination.

    Methods: Nine patients with CLL with ongoing zanubrutinib therapy were included and donated blood and saliva during SARS-CoV-2 vaccination, before vaccine doses 3 and 5 and 2 - 3 weeks after doses 3, 4, and 5. Ibrutinib-treated control patients (n = 7) and healthy aged-matched controls (n = 7) gave blood 2 - 3 weeks after vaccine dose 5. We quantified reactivity and neutralization capacity of SARS-CoV-2-specific IgG and IgA antibodies (Abs) in both serum and saliva, and reactivity of T cells activated with viral peptides.

    Results: Both zanubrutinib- and ibrutinib-treated patients had significantly, up to 1,000-fold, lower total spike-specific Ab levels after dose 5 compared to healthy controls (P < 0.01). Spike-IgG levels in serum from zanubrutinib-treated patients correlated well to neutralization capacity (r = 0.68; P < 0.0001) and were thus functional. Mucosal immunity (specific IgA in serum and saliva) was practically absent in zanubrutinib-treated patients even after five vaccine doses, whereas healthy controls had significantly higher levels (tested in serum after vaccine dose 5) (P < 0.05). In contrast, T-cell reactivity against SARS-CoV-2 peptides was equally high in zanubrutinib- and ibrutinib-treated patients as in healthy control donors.

    Conclusions: In our small cohort of zanubrutinib-treated CLL patients, we conclude that up to five doses of SARS-CoV-2 vaccination induced no detectable IgA mucosal immunity, which likely will impair the primary barrier defence against the infection. Systemic IgG responses were also impaired, whereas T-cell responses were normal. Further and larger studies are needed to evaluate the impact of these findings on disease protection.

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  • 43.
    Andersson, Sofia E. M.
    et al.
    Univ Gothenburg, Sahlgrenska Acad, Dept Rheumatol & Inflammat Res, Inst Med, Box 480, S-40530 Gothenburg, Sweden..
    Lange, Elvira
    Univ Gothenburg, Ctr Person Ctr Care, Gothenburg, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Hlth & Rehabil, Gothenburg, Sweden..
    Kucharski, Daniel
    Univ Gothenburg, Sahlgrenska Acad, Dept Rheumatol & Inflammat Res, Inst Med, Box 480, S-40530 Gothenburg, Sweden..
    Svedlund, Sara
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Mol & Clin Med, Gothenburg, Sweden..
    Önnheim, Karin
    Univ Gothenburg, Sahlgrenska Acad, Dept Rheumatol & Inflammat Res, Inst Med, Box 480, S-40530 Gothenburg, Sweden..
    Bergquist, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Josefsson, Elisabet
    Univ Gothenburg, Sahlgrenska Acad, Dept Rheumatol & Inflammat Res, Inst Med, Box 480, S-40530 Gothenburg, Sweden..
    Lord, Janet M.
    Univ Birmingham, MRC ARUK Ctr Musculoskeletal Ageing Res, Inst Inflammat & Ageing, Birmingham, W Midlands, England..
    Mårtensson, Inga-Lill
    Univ Gothenburg, Sahlgrenska Acad, Dept Rheumatol & Inflammat Res, Inst Med, Box 480, S-40530 Gothenburg, Sweden..
    Mannerkorpi, Kaisa
    Univ Gothenburg, Ctr Person Ctr Care, Gothenburg, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Hlth & Rehabil, Gothenburg, Sweden..
    Gjertsson, Inger
    Univ Gothenburg, Sahlgrenska Acad, Dept Rheumatol & Inflammat Res, Inst Med, Box 480, S-40530 Gothenburg, Sweden.;Univ Gothenburg, Ctr Person Ctr Care, Gothenburg, Sweden..
    Moderate- to high intensity aerobic and resistance exercise reduces peripheral blood regulatory cell populations in older adults with rheumatoid arthritis2020In: Immunity & Ageing, E-ISSN 1742-4933, Vol. 17, article id 12Article in journal (Refereed)
    Abstract [en]

    Objective: Exercise can improve immune health and is beneficial for physical function in patients with rheumatoid arthritis (RA), but the immunological mechanisms are largely unknown. We evaluated the effect of moderate- to high intensity exercise with person-centred guidance on cells of the immune system, with focus on regulatory cell populations, in older adults with RA.

    Methods: Older adults (>= 65 years) with RA were randomized to either 20-weeks of moderate - to high intensity aerobic and resistance exercise (n = 24) or to an active control group performing home-based exercise of light intensity (n = 25). Aerobic capacity, muscle strength, DAS28 and CRP were evaluated. Blood samples were collected at baseline and after 20 weeks. The frequency of immune cells defined as adaptive regulatory populations, CD4 + Foxp3 + CD25 + CD127- T regulatory cells (Tregs) and CD19 + CD24hiCD38hi B regulatory cells (Bregs) as well as HLA-DR-/lowCD33 + CD11b + myeloid derived suppressor cells (MDSCs), were assessed using flow cytometry.

    Results: After 20 weeks of moderate- to high intensity exercise, aerobic capacity and muscle strength were significantly improved but there were no significant changes in Disease Activity Score 28 (DAS28) or CRP. The frequency of Tregs and Bregs decreased significantly in the intervention group, but not in the active control group. The exercise intervention had no effect on MDSCs. The reduction in regulatory T cells in the intervention group was most pronounced in the female patients.

    Conclusion: Moderate- to high intensity exercise in older adults with RA led to a decreased proportion of Tregs and Bregs, but that was not associated with increased disease activity or increased inflammation.

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  • 44.
    Andrén, Maria
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    The Role of Fc Gamma Receptors in Experimental Arthritis2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Induction of collagen-induced arthritis (CIA), an animal model for human rheumatoid arthritis, is dependent on anti-collagen type II (CII) antibodies. The effector mechanism by which autoantibodies contribute to inflammatory reactions in autoimmune diseases is not well understood. In this thesis I have studied the effector pathways used by IgG anti-CII antibodies to initiate arthritis, namely the IgG Fc receptors (FcγRs) and the complement system. We have found that FcγRIII is crucial for development of CIA, as CII-immunized mice lacking this receptor do not develop arthritis and IgG1 and IgG2b anti-CII antibodies require FcγRIII to trigger arthritis when transferred to naïve mice. The antibody-mediated arthritis was further enhanced in mice deficient in the inhibitory FcγRIIB, indicating that FcγRIIB regulates the activation of FcγRIII. Furthermore, we demonstrate that FcγRIII exist as three distinct haplotypes in mice, FcγRIII:H, FcγRIII:V and FcγRIII:T. Mice expressing the FcγRIII:H haplotype are more susceptible to CIA than mice expressing the FcγRIII:V haplotype, indicating that certain FcγRIII haplotype predisposes for CIA. We also show that the most likely FcγRIII-expressing effector cell in CIA is the macrophage, since FcγRIII-expressing macrophages exclusively can induce arthritis in FcγRIII-deficient mice challenged for CIA.

    The complement system was also investigated in development of CIA. We found that this effector pathway is also necessary for onset of arthritis, as CIA was inhibited by treatment with anti-complement factor 5 (C5) antibodies. C5-deficient mice could neither develop CIA unless provided with C5-containing sera.

    Taken together, the work presented in this thesis indicates that FcγRs and the complement system are crucial for the induction of experimental arthritis. These findings are important for understanding the mechanisms behind rheumatoid arthritis and blocking of these effector pathways may in the future be used as treatment of rheumatoid arthritis.

    List of papers
    1. Expression of FcγRIII is required for development of collagen-induced arthritis
    Open this publication in new window or tab >>Expression of FcγRIII is required for development of collagen-induced arthritis
    Show others...
    2002 In: European Journal of Immunology, Vol. 32, p. 2915-2922Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-92480 (URN)
    Available from: 2005-01-14 Created: 2005-01-14Bibliographically approved
    2. FcγRIII-expressing macrophages are essential for the development of collagen-induced arthritis
    Open this publication in new window or tab >>FcγRIII-expressing macrophages are essential for the development of collagen-induced arthritis
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-92481 (URN)
    Available from: 2005-01-14 Created: 2005-01-14 Last updated: 2010-01-13Bibliographically approved
    3. Induction of arthritis by single monoclonal IgG anti-collagen type II antibodies and enhancement of arthritis in mice lacking inhibitory FcγRIIB
    Open this publication in new window or tab >>Induction of arthritis by single monoclonal IgG anti-collagen type II antibodies and enhancement of arthritis in mice lacking inhibitory FcγRIIB
    Show others...
    2003 In: European Journal of Immunology, Vol. 33, p. 2269-2277Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-92482 (URN)
    Available from: 2005-01-14 Created: 2005-01-14Bibliographically approved
    4. IgG Fc receptor polymorphisms and C5 influence susceptibility to collagen-induced arthritis
    Open this publication in new window or tab >>IgG Fc receptor polymorphisms and C5 influence susceptibility to collagen-induced arthritis
    Article in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-92483 (URN)
    Available from: 2005-01-14 Created: 2005-01-14Bibliographically approved
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  • 45.
    Aoun, Mike
    et al.
    Karolinska Inst, Dept Med Biochem & Biophys, Div Med Inflammat Res, Solna, Sweden..
    Coelho, Ana
    Karolinska Inst, Dept Med Biochem & Biophys, Div Med Inflammat Res, Solna, Sweden..
    Kraemer, Alexander
    Karolinska Inst, Dept Med Biochem & Biophys, Div Med Inflammat Res, Solna, Sweden..
    Saxena, Amit
    Karolinska Inst, Dept Med Biochem & Biophys, Div Med Inflammat Res, Solna, Sweden..
    Sabatier, Pierre
    Karolinska Inst, Dept Med Biochem & Biophys, Div Physiol Chem 1, Solna, Sweden..
    Beusch, Christian Michel
    Karolinska Inst, Dept Med Biochem & Biophys, Div Physiol Chem 1, Solna, Sweden..
    Loennblom, Erik
    Karolinska Inst, Dept Med Biochem & Biophys, Div Med Inflammat Res, Solna, Sweden..
    Geng, Manman
    Xian JiaotongUniv, Precis Med Inst, Affiliated Hosp 2, Xian, Peoples R China..
    Do, Nhu-Nguyen
    Karolinska Inst, Dept Med Biochem & Biophys, Div Med Inflammat Res, Solna, Sweden.;Fraunhofer Inst Translat Med & Pharmacol, Frankfurt, Germany.;Fraunhofer Cluster Excellence Immune Mediated Dis, Frankfurt, Germany..
    Xu, Zhongwei
    Karolinska Inst, Dept Med Biochem & Biophys, Div Med Inflammat Res, Solna, Sweden..
    Zhang, Jingdian
    Karolinska Inst, Max Planck Inst Biol Ageing, Karolinska Inst Lab, Solna, Sweden.;Karolinska Inst, Dept Med Biochem & Biophys, Div Mol Metab, Solna, Sweden..
    He, Yibo
    Karolinska Inst, Dept Med Biochem & Biophys, Div Med Inflammat Res, Solna, Sweden..
    Romero Castillo, Laura
    Karolinska Inst, Dept Med Biochem & Biophys, Div Med Inflammat Res, Solna, Sweden..
    Abolhassani, Hassan
    Karolinska Univ Hosp, Karolinska Inst, Dept Biosci & Nutr, Div Clin Immunol, Neo Bldg, Solna, Sweden..
    Xu, Bingze
    Karolinska Inst, Dept Med Biochem & Biophys, Div Med Inflammat Res, Solna, Sweden..
    Viljanen, Johan V.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Rorbach, Joanna
    Karolinska Inst, Max Planck Inst Biol Ageing, Karolinska Inst Lab, Solna, Sweden.;Karolinska Inst, Dept Med Biochem & Biophys, Div Mol Metab, Solna, Sweden..
    Fernandez Lahore, Gonzalo
    Karolinska Inst, Dept Med Biochem & Biophys, Div Med Inflammat Res, Solna, Sweden..
    Gjertsson, Inger
    Univ Gothenburg, Dept Rheumatol & Inflammat Res, Gothenburg, Sweden..
    Kastbom, Alf
    Linköping Univ, Dept Biomed & Clin Sci, Div Inflammat & Infect, Linköping, Sweden..
    Sjoewall, Christopher
    Linköping Univ, Dept Biomed & Clin Sci, Div Inflammat & Infect, Linköping, Sweden..
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Zubarev, Roman A.
    Karolinska Inst, Dept Med Biochem & Biophys, Div Physiol Chem 1, Solna, Sweden.;IM Sechenov First Moscow State Med Univ, Dept Pharmacol & Technol Chem, Moscow, Russia..
    Burkhardt, Harald
    Fraunhofer Inst Translat Med & Pharmacol, Frankfurt, Germany.;Fraunhofer Cluster Excellence Immune Mediated Dis, Frankfurt, Germany.;Goethe Univ, Univ Hosp Frankfurt, Div Rheumatol, Frankfurt am Main, Germany..
    Holmdahl, Rikard
    Karolinska Inst, Dept Med Biochem & Biophys, Div Med Inflammat Res, Solna, Sweden.;Xian JiaotongUniv, Precis Med Inst, Affiliated Hosp 2, Xian, Peoples R China..
    Antigen-presenting autoreactive B cells activate regulatory T cells and suppress autoimmune arthritis in mice2023In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 220, no 11, article id e20230101Article in journal (Refereed)
    Abstract [en]

    B cells undergo several rounds of selection to eliminate potentially pathogenic autoreactive clones, but in contrast to T cells, evidence of positive selection of autoreactive B cells remains moot. Using unique tetramers, we traced natural autoreactive B cells (C1-B) specific for a defined triple-helical epitope on collagen type-II (COL2), constituting a sizeable fraction of the physiological B cell repertoire in mice, rats, and humans. Adoptive transfer of C1-B suppressed arthritis independently of IL10, separating them from IL10-secreting regulatory B cells. Single-cell sequencing revealed an antigen processing and presentation signature, including induced expression of CD72 and CCR7 as surface markers. C1-B presented COL2 to T cells and induced the expansion of regulatory T cells in a contact-dependent manner. CD72 blockade impeded this effect suggesting a new downstream suppressor mechanism that regulates antigen-specific T cell tolerization. Thus, our results indicate that autoreactive antigen-specific naive B cells tolerize infiltrating T cells against self-antigens to impede the development of tissue-specific autoimmune inflammation.

  • 46.
    Arasa, Jorge
    et al.
    Swiss Fed Inst Technol, Inst Pharmaceut Sci, Zurich, Switzerland..
    Collado-Diaz, Victor
    Swiss Fed Inst Technol, Inst Pharmaceut Sci, Zurich, Switzerland..
    Kritikos, Ioannis
    Swiss Fed Inst Technol, Inst Pharmaceut Sci, Zurich, Switzerland..
    Medina-Sanchez, Jessica Danielly
    Swiss Fed Inst Technol, Inst Pharmaceut Sci, Zurich, Switzerland..
    Friess, Mona Carina
    Swiss Fed Inst Technol, Inst Pharmaceut Sci, Zurich, Switzerland..
    Sigmund, Elena Caroline
    Swiss Fed Inst Technol, Inst Pharmaceut Sci, Zurich, Switzerland..
    Schineis, Philipp
    Swiss Fed Inst Technol, Inst Pharmaceut Sci, Zurich, Switzerland..
    Hunter, Morgan Campbell
    Swiss Fed Inst Technol, Inst Pharmaceut Sci, Zurich, Switzerland..
    Tacconi, Carlotta
    Swiss Fed Inst Technol, Inst Pharmaceut Sci, Zurich, Switzerland..
    Paterson, Neil
    Max Planck Inst Immunobiol & Epigenet, Freiburg, Germany.;Univ Freiburg, Fac Biol, Freiburg, Germany.;Int Max Planck Res Sch Immunobiol Epigenet & Meta, Freiburg, Germany..
    Nagasawa, Takashi
    Osaka Univ, Grad Sch Frontier Biosci, Lab Stem Cell Biol & Dev Immunol, Osaka, Japan.;Osaka Univ, Grad Sch Med, Osaka, Japan..
    Kiefer, Friedemann
    Max Planck Inst Mol Biomed, Munster, Germany.;Westfalische Wilhelms Univ Munster, European Inst Mol Imaging, Munster, Germany..
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Detmar, Michael
    Swiss Fed Inst Technol, Inst Pharmaceut Sci, Zurich, Switzerland..
    Moser, Markus
    Max Planck Inst Biochem, Martinsried, Germany.;Tech Univ Munich, Inst Expt Hematol, Munich, Germany..
    Laemmermann, Tim
    Max Planck Inst Immunobiol & Epigenet, Freiburg, Germany..
    Halin, Cornelia
    Swiss Fed Inst Technol, Inst Pharmaceut Sci, Zurich, Switzerland..
    Upregulation of VCAM-1 in lymphatic collectors supports dendritic cell entry and rapid migration to lymph nodes in inflammation2021In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 218, no 7, article id e20201413Article in journal (Refereed)
    Abstract [en]

    Dendritic cell (DC) migration to draining lymph nodes (dLNs) is a slow process that is believed to begin with DCs approaching and entering into afferent lymphatic capillaries. From capillaries, DCs slowly crawl into lymphatic collectors, where lymph flow induced by collector contraction supports DC detachment and thereafter rapid, passive transport to dLNs. Performing a transcriptomics analysis of dermal endothelial cells, we found that inflammation induces the degradation of the basement membrane (BM) surrounding lymphatic collectors and preferential up-regulation of the DC trafficking molecule VCAM-1 in collectors. In crawl-in experiments performed in ear skin explants, DCs entered collectors in a CCR7- and beta 1 integrin-dependent manner. In vivo, loss of beta 1-integrins in DCs or of VCAM-1 in lymphatic collectors had the greatest impact on DC migration to dLNs at early time points when migration kinetics favor the accumulation of rapidly migrating collector DCs rather than slower capillary DCs. Taken together, our findings identify collector entry as a critical mechanism enabling rapid DC migration to dLNs in inflammation.

  • 47.
    Ardesjö Lundgren, Brita
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rorsman, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Portela-Gomes, Guida M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Ekdahl, Kristina Nilsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Ekwall, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Identification of complement C3 as an autoantigen in inflammatory bowel disease2010In: European Journal of Gastroenterology and Hepathology, ISSN 0954-691X, E-ISSN 1473-5687, Vol. 22, no 4, p. 429-436Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Autoantibodies against goblet cells in the gastrointestinal mucosa have been described in patients with inflammatory bowel disease (IBD) but a corresponding autoantigen has not yet been identified. The aim of this study was to identify such an antigen. METHODS: First, 10 candidate autoantigens were discarded based on double stainings of appendiceal sections and a mucin-producing cell line (HT29-mtx). Second, an appendiceal cDNA library was immunoscreened with IBD sera. RESULTS: Three out of 48 positive clones were identified as complement C3. Using immunoprecipitation of in vitro transcribed and translated C3, seven of 17 primary sclerosing cholangitis patient sera, 15 of 65 IBD sera, and none out of 54 sera from healthy blood donors showed C3 immunoreactivity. The results were confirmed using western blot and an enzyme-linked immunosorbent assay with alternative sources of C3 protein. CONCLUSION: In conclusion, we have identified complement C3 as a potential autoantigen in IBD and primary sclerosing cholangitis.

  • 48. Arkema, Elizabeth V
    et al.
    Jonsson, Jerker
    Baecklund, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Bruchfeld, Judith
    Feltelius, Nils
    Askling, Johan
    Are patients with rheumatoid arthritis still at an increased risk of tuberculosis and what is the role of biological treatments?2015In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 74, no 6, p. 1212-1217Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To estimate the risk of tuberculosis (TB) in patients with rheumatoid arthritis (RA) both with and without exposure to biological therapy and to directly compare the risks between therapies.

    METHODS: Data from the Swedish National Population Registers, Tuberculosis Register and the Swedish Biologics Register were used to conduct a prospective population-based national cohort study (2002-2011). We estimated the rate of incident TB in the general population and in a cohort of biological-naïve and biological-exposed patients diagnosed with RA. Cox models were used to estimate HRs with particular attention to risks by calendar and follow-up time and individual biologics.

    RESULTS: Compared to the general population, RA patients not exposed to biologicals had a fourfold increased risk of TB (HR 4.2; 95% CI 2.7 to 6.7), which did not decline over calendar time. In contrast, the risk of TB in the biological-exposed RA population decreased since 2002 compared with biological-naïve; from HR=7.9 (95% CI 3.3 to 18.9) in 2002-2006 to HR=2.4 (95% CI 0.9 to 6.1) in 2007-2011. The HRs for most recent exposure to adalimumab and infliximab compared with etanercept were 3.1 (95% CI 0.8 to 12.5) and 2.7 (95% CI 0.7 to 10.9), respectively, and the HR for etanercept compared with biological-naïve RA was 1.7 (95% CI 0.6 to 4.6).

    CONCLUSIONS: In the past decade, the risk of TB has decreased among biological-exposed RA patients but remains higher than in biological-naïve RA patients. Most cases of TB in RA occur in biological-naïve RA patients, underscoring the elevated risk also in these patients.

  • 49.
    Arnberg, Filip K.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, National Center for Disaster Psychiatry. Stockholm Univ, Stress Res Inst, S-10691 Stockholm, Sweden..
    Lekander, Mats
    Stockholm Univ, Stress Res Inst, S-10691 Stockholm, Sweden.;Karolinska Inst, Osher Ctr Integrat Med, Stockholm, Sweden..
    Morey, Jennifer N.
    Univ Kentucky, Dept Psychol, 125 Kastle Hall, Lexington, KY 40506 USA..
    Segerstrom, Suzanne C.
    Univ Kentucky, Dept Psychol, 125 Kastle Hall, Lexington, KY 40506 USA..
    Self-rated health and interleukin-6: Longitudinal relationships in older adults2016In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 54, p. 226-232Article in journal (Refereed)
    Abstract [en]

    Background: Both self-rated health (SRH) and inflammation are implicated in chronic diseases and premature mortality. Better SRH is associated with lower proinflammatory cytokines, but there is little evidence about whether this relationship is more stable or dynamic. Objective: To study the between- and within-person associations between SRH and IL-6. Methods: Older adults (N = 131; M-age = 75 years) rated their health and provided blood samples for analysis of IL-6 at separate occasions every 6 months over a period up to 5 years. Age, sex, BMI, neuroticism, and statin use were examined as covariates in multilevel models. Results: In bivariate models, better SRH, lower BMI, younger age, and female sex correlated with lower IL-6. In multilevel models, stable SRH (between-person differences; p < .001) but not dynamic SRH (within-person changes; p = .93) correlated with IL-6. The stable relationship persisted with demographic and health covariates in the model. Conclusions: Better stable SRH but not dynamic SRH was robustly associated with lower IL-6 among older adults, lending support to previous cross-sectional findings on the relation between inflammatory markers and SRH. The findings suggest that trait-like mechanisms, rather than changes over a time scale of 6-month waves, govern this association. To further investigate the mechanisms behind the SRH-IL-6 association, studies with different measurement frequencies, higher within-person variability, and experimental approaches are warranted.

  • 50.
    Arroz-Madeira, Silvia
    et al.
    Univ Lausanne, Dept Oncol, Lausanne, Switzerland.;Ludwig Inst Canc Res Lausanne, Lausanne, Switzerland..
    Bekkhus, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ulvmar, Maria H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Petrova, Tatiana V.
    Univ Lausanne, Dept Oncol, Ch Boveresses 155, CH-1066 Epalinges, Switzerland.;Univ Lausanne, Dept Oncol, Lausanne, Switzerland.;Ludwig Inst Canc Res Lausanne, Lausanne, Switzerland..
    Lessons of Vascular Specialization From Secondary Lymphoid Organ Lymphatic Endothelial Cells2023In: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 132, no 9, p. 1203-1225Article, review/survey (Refereed)
    Abstract [en]

    Secondary lymphoid organs, such as lymph nodes, harbor highly specialized and compartmentalized niches. These niches are optimized to facilitate the encounter of naive lymphocytes with antigens and antigen-presenting cells, enabling optimal generation of adaptive immune responses. Lymphatic vessels of lymphoid organs are uniquely specialized to perform a staggering variety of tasks. These include antigen presentation, directing the trafficking of immune cells but also modulating immune cell activation and providing factors for their survival. Recent studies have provided insights into the molecular basis of such specialization, opening avenues for better understanding the mechanisms of immune-vascular interactions and their applications. Such knowledge is essential for designing better treatments for human diseases given the central role of the immune system in infection, aging, tissue regeneration and repair. In addition, principles established in studies of lymphoid organ lymphatic vessel functions and organization may be applied to guide our understanding of specialization of vascular beds in other organs.

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