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  • 1.
    Ahlström, Håkan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Feltelius, N
    Nyman, Rickard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Hällgren, Roger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Magnetic resonance imaging of sacroiliac joint inflammation1990In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 33, no 12, p. 1763-1769Article in journal (Refereed)
    Abstract [en]

    A consecutive series of 27 patients with symptoms compatible with sacroiliitis underwent magnetic resonance imaging (MRI) of the sacroiliac joints. The diagnostic sensitivity of MRI was similar to that of computed tomography or conventional radiography. However, MRI seems to have the potential of providing unique information about the disease process in sacroiliitis by demonstrating abnormalities in subchondral bone and periarticular bone marrow. The results of this study suggest that early inflammatory changes in sacroiliitis occur in the subchondral structures of the sacroiliac joints.

  • 2. Ahmed, Aisha S.
    et al.
    Li, Jian
    Ahmed, Mahmood
    Hua, Long
    Yakovleva, Tatiana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ossipov, Michael H.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Stark, André
    Attenuation of Pain and Inflammation in Adjuvant-Induced Arthritis by the Proteasome Inhibitor MG1322010In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 62, no 7, p. 2160-2169Article in journal (Refereed)
    Abstract [en]

    Objective. In rheumatoid arthritis (RA), pain and joint destruction are initiated and propagated by the production of proinflammatory mediators. Synthesis of these mediators is regulated by the transcription factor NF-kappa B, which is controlled by the ubiquitin proteasome system (UPS). The present study explored the effects of the proteasome inhibitor MG132 on inflammation, pain, joint destruction, and expression of sensory neuropeptides as markers of neuronal response in a rat model of arthritis. Methods. Arthritis was induced in rats by injection of heat-killed Mycobacterium butyricum. Arthritis severity was scored, and nociception was evaluated by mechanical pressure applied to the hind paw. Joint destruction was assessed by radiologic and histologic analyses. NF-kappa B DNA-binding activity was analyzed by electromobility shift assay, and changes in the expression of the p50 NF-kappa B subunit and the proinflammatory neuropeptides substance P (SP) and calcitonin generelated peptide (CGRP) were detected by immunohistochemistry. Results. Arthritic rats treated with MG132 demonstrated a marked reduction in inflammation, pain, and joint destruction. The elevated DNA-binding activity of the NF-kappa B/p50 homodimer and p50, as well as the neuronal expression of SP and CGRP, observed in the ankle joints of arthritic rats were normalized after treatment with MG132. Conclusion. In arthritic rats, inhibition of proteasome reduced the severity of arthritis and reversed the pain behavior associated with joint inflammation. These effects may be mediated through the inhibition of NF-kappa B activation and may possibly involve the peripheral nervous system. New generations of nontoxic proteasome inhibitors may represent a novel pharmacotherapy for RA.

  • 3. Akkoc, Nurullah
    et al.
    Sari, Ismail
    Akar, Servet
    Binicier, Omer
    Thomas, Mark G.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics.
    Weale, Michael E.
    Birlik, Merih
    Savran, Yusuf
    Onen, Fatos
    Bradman, Neil
    Plaster, Christopher A.
    Increased Prevalence of M694V in Patients With Ankylosing Spondylitis: Additional Evidence for a Link With Familial Mediterranean Fever2010In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 62, no 10, p. 3059-3063Article in journal (Refereed)
    Abstract [en]

    Objective. To assess whether there is a statistically significant difference in the frequency of common MEFV allele variants in patients with ankylosing spondylitis (AS) as compared with control patients with rheumatoid arthritis (RA) and with healthy control subjects. Methods. Sixty-two patients with AS, 50 healthy control subjects, and 46 patients with RA were assessed for the presence of MEFV variants. Exon 10 was analyzed by direct sequencing. E148Q was analyzed by restriction endonuclease enzyme digestion (REED) or by direct sequencing when REED analysis failed. Results. The allele frequency of all MEFV variants in the AS group was significantly higher than that in the pooled control group of healthy subjects plus RA patients (15.3% versus 6.8%; P = 0.021). M694V was the only variant that was significantly more common in the AS group than in the combined or individual control groups (P = 0.026 for AS patients versus healthy controls, P = 0.046 for AS patients versus RA patient controls, and P = 0.008 for AS patients versus healthy and RA patient control groups). The carriage rate of M694V was also significantly higher in the AS patient group than in the combined control group (odds ratio 7.0, P = 0.014). Neither M694V nor any other MEFV variant showed a correlation with most of the disease-related measures examined. Conclusion. We found an increased frequency of MEFV variants in AS patients as compared with healthy controls and with RA patient controls. This was primarily due to the presence of M694V. The roles of other exon 10 variants, as well as the relationship between the variant status and the severity and clinical course of the disease, need to be explored in further studies that include sufficiently large sample sizes.

  • 4. Alenius, Gerd-Marie
    et al.
    Husmark, Tomas
    Theander, Elke
    Larsson, Per
    Geijer, Mats
    Teleman, Annika
    Lindqvist, Ulla R. C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Rheumatoid Arthritis, a More Severe Disease Than Psoriatic Arthritis?: A Comparison Of Disease Activity In Patients With Psoriatic Arthritis and Rheumatoid Arthritis From The Swedish Early Psoriatic Arthritis Registry (SwePsA) and The Swedish Rheumatology Registry For Early Rheumatoid Arthritis (SRR)2013In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 65, no Suppl. 10, p. S150-S150Article in journal (Other academic)
  • 5. 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.
    Rutting, Maud
    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 Treatment?2013In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 65, no Suppl. 10, p. S719-S719Article in journal (Other academic)
  • 6. Arlestig, Lisbeth
    et al.
    Brink, Mikael
    Hansson, Monika
    Jakobsson, Per Johan
    Holmdahl, Rikard
    Mathsson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Klareskog, Lars
    Rantapaa-Dahlqvist, Solbritt M.
    Single Nucleotide Polymorphisms within the HLA-DRB1 Gene in Relation to Antibodies Against Citrullinated Peptides in Individuals Prior to the Development of Rheumatoid Arthritis2012In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 64, no S10, p. S180-S180Article in journal (Other academic)
  • 7. Askling, Johan
    et al.
    Fored, C. Michael
    Brandt, Lena
    Baecklund, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Bertilsson, Lennart
    Cöster, Lars
    Geborek, Pierre
    Jacobsson, Lennart T.
    Lindblad, Staffan
    Lysholm, Jörgen
    Rantapää-Dahlqvist, Solbritt
    Saxne, Tore
    Romanus, Victoria
    Klareskog, Lars
    Feltelius, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Risk and case characteristics of tuberculosis in rheumatoid arthritis associated with tumor necrosis factor antagonists in Sweden2005In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 52, no 7, p. 1986-1992Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    Because treatment with tumor necrosis factor (TNF) antagonists may increase the risk of tuberculosis (TB), and because knowledge of the risk of TB in rheumatoid arthritis (RA) not treated with biologics is scarce and of uncertain generalizability to low-risk populations, this study sought to determine the risk of TB among Swedish patients with RA.

    METHODS:

    Using data from Swedish nationwide and population-based registers and data from an ongoing monitoring program of TNF antagonists, the relative risks of TB in patients with RA (versus the general population) and of TB associated with TNF antagonists (versus RA patients not treated with biologics) were determined by comparing the incidence of hospitalization for TB in 3 RA cohorts and 2 general population cohorts from 1999 to 2001. We also reviewed the characteristics of all reported cases of TB in RA patients treated with TNF antagonists in Sweden and calculated the incidence of TB per type of TNF antagonist between 1999 and 2004.

    RESULTS:

    During 1999-2001, RA patients who were not treated with TNF antagonists were at increased risk of TB versus the general population (relative risk 2.0, 95% confidence interval [95% CI] 1.2-3.4). RA patients treated with TNF antagonists had a 4-fold increased risk of TB (relative risk 4.0, 95% CI 1.3-12) versus RA patients not treated with TNF antagonists. The reported TB cases during 1999-2004 in RA patients exposed to TNF antagonists (9 infliximab, 4 etanercept, 2 both) were predominantly pulmonary. TB occurred up to 3 years following the start of treatment.

    CONCLUSION:

    Irrespective of whether TNF antagonists are administered, Swedish patients with RA are at increased risk of TB. During 1999-2001, TNF antagonists were associated with an increased risk of TB, up to 4-fold in magnitude. This increased risk may persist over time during treatment and is related to both infliximab and etanercept.

  • 8. Askling, Johan
    et al.
    van Vollenhoven, Ronald F.
    Granath, Fredrik
    Raaschou, Pauline
    Fored, C. Michael
    Baecklund, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Dackhammar, Christina
    Feltelius, Nils
    Cöster, Lars
    Geborek, Pierre
    Jacobsson, Lennart T.
    Lindblad, Staffan
    Rantapää-Dahlqvist, Solbritt
    Saxne, Tore
    Klareskog, Lars
    Cancer risk in patients with rheumatoid arthritis treated with anti-tumor necrosis factor alpha therapies: does the risk change with the time since start of treatment?2009In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 60, no 11, p. 3180-3189Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    To determine the short-term and medium-term risks of cancer in patients receiving anti-tumor necrosis factor alpha (anti-TNFalpha) therapies that have proven effective in the treatment of chronic inflammatory conditions.

    METHODS:

    By linking together data from the Swedish Biologics Register, Swedish registers of RA, and the Swedish Cancer Register, we identified and analyzed for cancer occurrence a national cohort of 6,366 patients with RA who first started anti-TNF therapy between January 1999 and July 2006. As comparators, we used a national biologics-naive RA cohort (n = 61,160), a cohort of RA patients newly starting methotrexate (n = 5,989), a cohort of RA patients newly starting disease-modifying antirheumatic drug combination therapy (n = 1,838), and the general population of Sweden. Relative risks (RRs) were estimated using Cox regression analyses, examining overall RR as well as RR by time since the first start of anti-TNF therapy, by the duration of active anti-TNF therapy, and by the anti-TNF agent received.

    RESULTS:

    During 25,693 person-years of followup in 6,366 patients newly starting anti-TNF, 240 first cancers occurred, yielding an RR of 1.00 (95% confidence interval 0.86-1.15) versus the biologics-naive RA cohort, and similar RRs versus the other 2 RA comparators. RRs did not increase with increasing time since the start of anti-TNF therapy, nor with the cumulative duration of active anti-TNF therapy. During the first year following the first treatment start, but not thereafter, dissimilar cancer risks for adalimumab, etanercept, and infliximab were observed.

    CONCLUSION:

    During the first 6 years after the start of anti-TNF therapy in routine care, no overall elevation of cancer risk and no increase with followup time were observed.

  • 9.
    Baecklund, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Backlin, Carin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Iliadou, Anastasia
    Granath, Fredrik
    Ekbom, Anders
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Feltelius, Nils
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Klareskog, Lars
    Askling, Johan
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Characteristics of diffuse large B cell lymphomas in rheumatoid arthritis2006In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 54, no 12, p. 3774-3781Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    Patients with rheumatoid arthritis (RA) are at increased risk of malignant lymphomas, with a correlation between RA disease severity and lymphoma risk, most pronounced for diffuse large B cell lymphomas (DLBCLs), which also constitute the majority of RA-associated lymphomas. DLBCLs can be further subdivided into germinal center (GC)-like and non-GC-like subtypes, with different cellular origins and prognoses. This study was undertaken to investigate whether RA displays a specific association with any of the DLBCL subtypes.

    METHODS:

    We identified 139 patients with DLBCLs within a population-based case-control study of 378 RA patients with lymphoma. The DLBCLs were examined for CD10, Bcl-6, and interferon regulatory factor 4 expression patterns, subclassified into GC and non-GC subtypes, and then correlated with clinical parameters.

    RESULTS:

    We found a statistically significant predominance of the non-GC subtype (97 patients; 70% of all DLBCLs). These patients more often had an advanced stage of lymphoma at diagnosis and had a worse 5-year overall survival rate (16% versus 33%) compared with patients with the GC subtype. There was a strong association with RA disease activity in both subtypes, with >70% of the GC and non-GC cases occurring in RA patients with the highest overall disease activity scores.

    CONCLUSION: These findings suggest that severe RA is particularly associated with the non-GC subtype of DLBCL, and indicate a critical role of activated peripheral B cells as the cells of origin in these lymphomas.

  • 10.
    Baecklund, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Iliadou, Anastasia
    Askling, Johan
    Ekbom, Anders
    Backlin, Carin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Granath, Fredrik
    Catrina, Anca Irinel
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Feltelius, Nils
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Klareskog, Lars
    Association of chronic inflammation, not its treatment, with increased lymphoma risk in rheumatoid arthritis2006In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 54, no 3, p. 692-701Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    Chronic inflammatory conditions such as rheumatoid arthritis (RA) have been associated with malignant lymphomas. This study was undertaken to investigate which patients are at highest risk, and whether antirheumatic treatment is hazardous or protective.

    METHODS:

    We performed a matched case-control study of 378 consecutive Swedish RA patients in whom malignant lymphoma occurred between 1964 and 1995 (from a population-based RA cohort of 74,651 RA patients), and 378 controls. Information on disease characteristics and treatment from onset of RA until lymphoma diagnosis was abstracted from medical records. Lymphoma specimens were reclassified and tested for Epstein-Barr virus (EBV). Relative risks (odds ratios [ORs]) for lymphomas (by subtype) associated with deciles of cumulative disease activity were assessed, as were ORs associated with drug treatments.

    RESULTS:

    The relative risks of lymphoma were only modestly elevated up to the seventh decile of cumulative disease activity. Thereafter, the relative risk increased dramatically (OR ninth decile 9.4 [95% confidence interval 3.1-28.0], OR tenth decile 61.6 [95% confidence interval 21.0-181.0]). Most lymphomas (48%) were of the diffuse large B cell type, but other lymphoma subtypes also displayed an association with cumulative disease activity. Standard nonbiologic treatments did not increase lymphoma risk. EBV was present in 12% of lymphomas.

    CONCLUSION:

    Risk of lymphoma is substantially increased in a subset of patients with RA, those with very severe disease. High inflammatory activity, rather than its treatment, is a major risk determinant.

  • 11. Balboni, Imelda
    et al.
    Niewold, Timothy B
    Morgan, Gabrielle
    Limb, Cindy
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Utz, Paul J
    Pachman, Lauren M
    Brief Report: Interferon-α Induction and Detection of Anti-Ro, Anti-La, Anti-Sm, and Anti-RNP Autoantibodies by Autoantigen Microarray Analysis in Juvenile Dermatomyositis2013In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 65, no 9, p. 2424-2429Article in journal (Refereed)
    Abstract [en]

    Objective:

    To evaluate serum interferon- (IFN) activity in the context of autoantibody profiles in patients with juvenile dermatomyositis (JDM). 

    Methods:

    Sera from 36 patients with JDM were analyzed. Autoantibody profiles were determined by probing microarrays, which were fabricated with approximate to 80 distinct autoantigens, with serum and a Cy3-conjugated secondary antibody. Arrays were scanned and analyzed to determine antigen reactivity. Serum IFN activity was measured using a functional reporter cell assay. Sera were assayed alone or in combination with cellular material released from necrotic U937 cells to stimulate peripheral blood mononuclear cells from healthy donors in vitro, and IFN production in culture was measured by a dissociation-enhanced lanthanide fluoroimmunoassay (DELFIA). 

    Results:

    Reactivity against at least 1 of 41 autoantigens on the microarray, including Ro 52, Ro 60, La, Sm, and RNP, was observed in 75% of the serum samples from patients with JDM. IFN activity was detected in 7 samples by reporter cell assay. The reporter cell assay showed a significant association of reactivity against Ro, La, Sm, and proliferating cell nuclear antigen with serum IFN activity (P = 0.005). Significance Analysis of Microarrays (SAM) identified increased reactivity against Sm, RNP, Ro 52, U1-C, and Mi-2 in these sera. Sixteen samples induced IFN production as measured by DELFIA, and there was a significant association of reactivity against Ro, La, Sm, and RNP with the induction of IFN by serum and necrotic cell material (P = 0.034). SAM identified increased reactivity against Ro 60 in these sera. 

    Conclusion:

    These data support the hypothesis that nucleic acid-associated autoantibodies, including the Ro/La and Sm/RNP complexes, may stimulate the production of active IFN in children with JDM.

  • 12. Bengtsson, Anders A
    et al.
    Sturfelt, Gunnar
    Lood, Christian
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    van Vollenhoven, Ronald F
    Axelsson, Bengt
    Sparre, Birgitta
    Tuvesson, Helén
    Wallén Öhman, Marie
    Leanderson, Tomas
    Pharmacokinetics, tolerability, and preliminary efficacy of ABR-215757, a new quinoline-3-carboxamide derivative, in murine and human SLE2012In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 64, no 5, p. 1579-1588Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To assess the efficacy of ABR-215757, a new immunomodulatory small molecule in a murine SLE model, to evaluate the pharmacokinetics and tolerability in SLE patients at doses predicted to be efficacious and safe, and to determine the maximum tolerated dose (MTD).

    METHODS: The efficacy of ABR-215757 was studied in lupus prone MRLlpr/lpr mice and compared with established SLE treatments. Dose response data of ABR-215757 were together with pharmacokinetic data used to calculate effective and safe clinical doses. The pharmacokinetics and tolerance of ABR-215757 were evaluated in a Phase Ib double-blind, placebo controlled, dose-escalation study where cohorts of SLE patients received daily oral treatment for 12 weeks.

    RESULTS: Disease inhibition in MRLlpr/lpr mice, comparable to that of prednisolone and mycophenolate mofetil, was obtained with ABR-215757. Prominent effects on disease manifestations, serological markers and a steroid sparing effect were seen for ABR-215757. The pharmacokinetic properties in SLE patients were linear and well suitable for once daily oral treatment. The majority of the adverse events (AEs) were mild or moderate and transient. The most frequent AEs were arthralgia and myalgia, reported at the highest (4.5 and 6 mg/day) dose levels. At 4.5 mg and higher some AEs of severe intensity and serious adverse events (SAEs) were reported.

    CONCLUSION: ABR-215757 effectively inhibited disease and had a steroid sparing effect in experimental lupus. Clinical doses up to 3 mg/day, dose levels predicted from pre-clinical studies to be efficacious and safe, were well tolerated in the SLE patients. The MTD was concluded to be 4.5 mg/day.

  • 13.
    Berggren, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Alexsson, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Alm, Gunnar V.
    Syvanen, Ann-Christine
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Variation of Interferon-Alpha Production in Healthy Individuals and Association with Autoimmune Susceptibility Genes2012In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 64, no S10, p. S961-S961Article in journal (Other academic)
  • 14.
    Berggren, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hagberg, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Weber, Gert
    Alm, Gunnar V
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    B lymphocytes enhance the interferon-α production by plasmacytoid dendritic cells2012In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 64, no 10, p. 3409-3419Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    Type I interferon (IFN) system and B cells are activated in many autoimmune diseases, e.g. systemic lupus erythematosus (SLE). IFNα produced by plasmacytoid dendritic cells (pDC) stimulate several B cell functions, including autoantibody production. However, not much is known how B cells influence the pDC function. We therefore investigated the regulatory effect of B cells on IFNα production by pDC.

    METHODS:

    PDC and B cells from healthy blood donor PBMC were stimulated with RNA-containing immune complexes (RNA-IC) consisting of U1 snRNP and IgG from SLE patients, herpes simplex virus (HSV) or oligonucleotide ODN2216, alone or in co-cultures. IFNα, several other cytokines and pDC or B cell-associated surface molecules were analyzed by immunoassays or flow cytometry.

    RESULTS:

    B cells enhanced the IFNα production by pDC up to 47-fold, and the effect was most pronounced for pDC stimulated with RNA-IC. Anti-CD31 antibody reduced the RNA-IC-induced IFNα production by 80%, but not when ODN2216 was used as IFN-inducer. Supernatants from ODN2216-stimulated B cells promoted IFNα production by pDC, while supernatants from RNA-IC-stimulated B cells did not.

    CONCLUSION:

    Our results reveal a novel B cell function, enhancing the type I IFN production by pDC. Since B cells are activated by type I IFN, this pDC-B cell cross-talk might be of fundamental importance in the etiopathogenesis of SLE, and contribute to a chronic immune activation in SLE and other systemic rheumatic diseases.

  • 15.
    Blomberg, Stina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Eloranta, Maija-Leena
    Magnusson, Mattias
    Alm, Gunnar V.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Expression of the markers BDCA-2 and BDCA-4 and production of interferon-alpha by plasmacytoid dendritic cells in systemic lupus erythematosus2003In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 48, no 9, p. 2524-32Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To study the expression of blood dendritic cell antigen 2 (BDCA-2) and BDCA-4 molecules by plasmacytoid dendritic cells (PDCs) in the blood of patients with systemic lupus erythematosus (SLE), and to study PDC production of interferon-alpha (IFN alpha) and its inhibition by anti-BDCA-2 and anti-BDCA-4 antibodies. METHODS: Peripheral blood mononuclear cells (PBMCs) from SLE patients (SLE PBMCs) and from healthy controls were induced to produce IFN alpha in vitro by SLE serum containing an endogenous IFN alpha-inducing factor (SLE-IIF) or by herpes simplex virus type 1 (HSV-1). The frequencies and numbers of BDCA-2-, BDCA-3-, and BDCA-4-expressing cells were analyzed by flow cytometry, and the effects of anti-BDCA-2 and anti-BDCA-4 monoclonal antibodies (mAb) on IFN alpha production were investigated. RESULTS: IFN alpha production by SLE PBMCs induced by SLE-IIF or HSV-1 was decreased compared with that of healthy control PBMCs (P = 0.002 and P = 0.0007, respectively). The proportions of BDCA-2- and BDCA-3-expressing cells in SLE PBMCs were reduced compared with those in PBMCs from healthy controls (P = 0.01 and P = 0.004, respectively). IFN alpha producers in culture, especially among SLE PBMCs, displayed reduced BDCA-2 expression and constituted only a minority of the BDCA-2-positive cells, at least in healthy control PBMCs (median 18%). IFN alpha production by both SLE and healthy control PBMCs stimulated by SLE-IIF or HSV-1 was markedly reduced by anti-BDCA-2 mAb (median 81-98% inhibition). Anti-BDCA-4 mAb only partially inhibited SLE-IIF-induced IFN alpha production. CONCLUSION: SLE patients had a reduced number of BDCA-2-expressing PDCs, also termed natural IFN alpha-producing cells, and their IFN alpha production could be inhibited by anti-BDCA-2/4 mAb. Such mAb may be a therapeutic option for inhibiting the ongoing IFN alpha production in SLE patients.

  • 16. Brink, Mikael
    et al.
    Hansson, Monika
    Mathsson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Jakobsson, Per-Johan
    Holmdahl, Rikard
    Hallmans, Goran
    Stenlund, Hans
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Klareskog, Lars
    Rantapaa-Dahlqvist, Solbritt
    Multiplex Analyses of Antibodies Against Citrullinated Peptides in Individuals Prior to Development of Rheumatoid Arthritis2013In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 65, no 4, p. 899-910Article in journal (Refereed)
    Abstract [en]

    Objective The presence of antibodies against cyclic citrullinated peptides has been demonstrated to precede the onset of symptoms of rheumatoid arthritis (RA) by several years. The aim of this study was to analyze antibodies against 10 citrullinated autoantigen-derived peptides for reactivity before the onset of RA symptoms. Methods A casecontrol study was conducted within the Medical Biobank of Northern Sweden. The study was performed in 409 individuals, 386 of whom donated 717 blood samples before the onset of symptoms of RA (pre-patients). The median period of time predating the onset of RA was 7.4 years. A total of 1,305 population-based control subjects were also studied. Antibodies to 10 citrullinated peptides, fibrinogen 573 (Fib573), Fib591, Fib3652, Fib72, Fib74, -enolase (citrullinated -enolase peptide 1 [CEP-1]), triple-helical type II collagen peptide C1 (citC1III), filaggrin, vimentin 217 (Vim217), and Vim6075, were analyzed using a microarray system. Results The fluorescence intensity of antibodies against Fib3652, Fib74, CEP-1, citC1III, and filaggrin was significantly increased in pre-patients compared with controls (P < 0.001). The levels of the earliest-detectable antibodies (Fib591 and Vim6075) fluctuated over time, with only a slight increase after the onset of disease. The frequency of antibodies against Fib3652, CEP-1, and filaggrin increased gradually, reaching the highest levels before symptom onset. The frequency of a cluster of antibodies, citC1III, Fib573, and Fib74, increased only slightly before the onset of symptoms but increased prominently after disease onset. The odds ratio for the development of RA in individuals expressing both CEP-1 and Fib3652 antibodies (using data from samples obtained <3.35 years predating symptom onset) was 40.4 (95% confidence interval 19.882.3) compared with having either antibody alone. Conclusion Development of an immune response toward citrullinated peptides is initially restricted but expands with time to induce a more specific response, with levels, particularly those of antibodies against CEP-1, Fib3652, and filaggrin, increasing during the predating time period closer to the onset of symptoms.

  • 17.
    Båve, Ullvi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lövgren, Tanja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Cajander, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Eloranta, Maija-Leena
    Alm, Gunnar V.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Activation of the type I interferon system in primary Sjögren's syndrome: a possible etiopathogenic mechanism2005In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 52, no 4, p. 1185-1195Article in journal (Refereed)
    Abstract [en]

    Objective

    The etiopathogenesis of primary Sjögren's syndrome (SS) is largely unknown. In other autoimmune diseases, type I interferon (IFN) may play a pivotal role by triggering and sustaining the disease process. We therefore aimed to determine whether patients with primary SS had an activated type I IFN system.

    Methods

    Salivary gland biopsy specimens and sera from patients with primary SS were investigated for the occurrence of IFNα-producing cells and measurable IFNα levels, respectively. The ability of primary SS sera together with apoptotic or necrotic cells to induce IFNα production in normal peripheral blood mononuclear cells was examined. The IFNα inducer was characterized, and IFNα-producing cells were identified. Clinical data were correlated with the IFNα-inducing capacity of primary SS sera.

    Results

    Numerous IFNα-producing cells were detected in salivary gland biopsy specimens, despite low serum IFNα levels. Autoantibodies to RNA-binding proteins, combined with material released by necrotic or late apoptotic cells, were potent inducers of IFNα production in plasmacytoid dendritic cells (PDCs). This appeared to be attributable to RNA-containing immune complexes triggering PDCs by means of RNA and interaction with Fcγ receptor IIa. The IFNα-inducing capacity of sera was associated with positive results of a labial salivary gland biopsy (focus score ≥1) and with dermatologic, hematologic, and pulmonary manifestations.

    Conclusion

    Patients with primary SS have an activated type I IFN system. Although virus may initiate the production of IFN, the continued IFNα synthesis is caused by RNA-containing immune complexes that activate PDCs to prolong IFNα production at the tissue level. This IFNα promotes the autoimmune process by a vicious circle–like mechanism, with increased autoantibody production and formation of more endogenous IFNα inducers.

  • 18. Cerqueira, Catia
    et al.
    Ossipova, Elena
    Hansson, Monika
    Mathsson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Klareskog, Lars
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Jakobsson, Per Johan
    Neutralization Of Anti-Citrullinated Protein Antibodies - a Way To Go?2013In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 65, no Suppl. 10, p. S391-S392Article in journal (Other academic)
  • 19. Chatzidionysiou, Katerina
    et al.
    Turesson, Carl
    Teleman, Annika
    Knight, Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Lindqvist, Elisabet
    Larsson, Per
    Coster, Lars
    Rydberg, Barbro
    van Vollenhoven, Ronald F.
    Heimburger, Mikael
    A Multicenter, Randomized, Controlled, Open-Label Pilot Study of the Feasibility of Discontinuation of Adalimumab in Rheumatoid Arthritis Patients in Stable Clinical Remission2012In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 64, no S10, p. S336-S336Article in journal (Other academic)
  • 20. Chung, Sharon A
    et al.
    Tian, Chao
    Taylor, Kimberly E
    Lee, Annette T
    Ortmann, Ward A
    Hom, Geoffrey
    Graham, Robert R
    Nititham, Joanne
    Kelly, Jennifer A
    Morrisey, Jean
    Wu, Hui
    Yin, Hong
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Alarcón-Riquelme, Marta E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Tsao, Betty P
    Harley, John B
    Gaffney, Patrick M
    Moser, Kathy L
    Manzi, Susan
    Petri, Michelle
    Gregersen, Peter K
    Langefeld, Carl D
    Behrens, Timothy W
    Seldin, Michael F
    Criswell, Lindsey A
    European population substructure is associated with mucocutaneous manifestations and autoantibody production in systemic lupus erythematosus2009In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 60, no 8, p. 2448-2456Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To determine whether genetic substructure in European-derived populations is associated with specific manifestations of systemic lupus erythematosus (SLE), including mucocutaneous phenotypes, autoantibody production, and renal disease. METHODS: SLE patients of European descent (n=1,754) from 8 case collections were genotyped for >1,400 ancestry informative markers that define a north-south gradient of European substructure. Using the Structure program, each SLE patient was characterized in terms of percent Northern (versus percent Southern) European ancestry based on these genetic markers. Nonparametric methods, including tests for trend, were used to identify associations between Northern European ancestry and specific SLE manifestations. RESULTS: In multivariate analyses, increasing levels of Northern European ancestry were significantly associated with photosensitivity (Ptrend=0.0021, odds ratio for highest quartile of Northern European ancestry versus lowest quartile [ORhigh-low] 1.64, 95% confidence interval [95% CI] 1.13-2.35) and discoid rash (Ptrend=0.014, ORhigh-low 1.93, 95% CI 0.98-3.83). In contrast, increasing levels of Northern European ancestry had a protective effect against the production of anticardiolipin autoantibodies (Ptrend=1.6x10(-4), ORhigh-low 0.46, 95% CI 0.30-0.69) and anti-double-stranded DNA autoantibodies (Ptrend=0.017, ORhigh-low 0.67, 95% CI 0.46-0.96). CONCLUSION: This study demonstrates that specific SLE manifestations vary according to Northern versus Southern European ancestry. Thus, genetic ancestry may contribute to the clinical heterogeneity and variation in disease outcomes among SLE patients of European descent. Moreover, these results suggest that genetic studies of SLE subphenotypes will need to carefully address issues of population substructure based on genetic ancestry.

  • 21.
    Classen, Jean-Francois
    et al.
    de Duve Institute, Universite´ Catholique de Louvain, Brussels, Belgium.
    Henrohn, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Rorsman, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lennartsson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Lauwerys, Bernard R.
    Saint-Luc University Hospital, Universite´ Catholique de Louvain, Brussels, Belgium.
    Wikström, Gerhard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rorsman, Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Lenglez, Sandrine
    de Duve Institute, Universite´ Catholique de Louvain, Brussels, Belgium.
    Franck-Larsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Tomasi, Jean-Paul
    Saint-Luc University Hospital, Universite´ Catholique de Louvain, Brussels, Belgium.
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Vanthuyne, Marie
    Saint-Luc University Hospital, Universite´ Catholique de Louvain, Brussels, Belgium.
    Houssiau, Frédéric A.
    Saint-Luc University Hospital, Universite´ Catholique de Louvain, Brussels, Belgium.
    Demoulin, Jean-Baptiste
    de Duve Institute, Universite´ Catholique de Louvain, Brussels, Belgium.
    Lack of evidence of stimulatory autoantibodies to platelet-derived growth factor receptor in patients with systemic sclerosis2009In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 60, no 4, p. 1137-1144Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Systemic sclerosis (SSc) is a severe connective tissue disease of unknown etiology, characterized by fibrosis of the skin and multiple internal organs. Recent findings suggested that the disease is driven by stimulatory autoantibodies to platelet-derived growth factor receptor (PDGFR), which stimulate the production of reactive oxygen species (ROS) and collagen by fibroblasts. These results opened novel avenues of research into the diagnosis and treatment of SSc. The present study was undertaken to confirm the presence of anti-PDGFR antibodies in patients with SSc. METHODS: Immunoglobulins from 37 patients with SSc were purified by protein A/G chromatography. PDGFR activation was tested using 4 different sensitive bioassays, i.e., cell proliferation, ROS production, signal transduction, and receptor phosphorylation; the latter was also tested in a separate population of 7 patients with SSc from a different research center. RESULTS: Purified IgG samples from patients with SSc were positive when tested for antinuclear autoantibodies, but did not specifically activate PDGFRalpha or PDGFRbeta in any of the tests. Cell stimulation with PDGF itself consistently produced a strong signal. CONCLUSION: The present results raise questions regarding the existence of agonistic autoantibodies to PDGFR in SSc.

  • 22. de Jong, T. D.
    et al.
    Vosslamber, Saskia
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Gelderman, Kyra
    von Blomberg, Mary
    Bultink, Irene
    Voskuyl, Alexandre
    Verweij, Cornelis L.
    On the Origin of the Type I Interferon Signature in Rheumatoid Arthritis2012In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 64, no S10, p. S770-S771Article in journal (Other academic)
  • 23.
    Dobritzsch, Doreen
    et al.
    Karolinska Institutet.
    Lindh, Ingrid
    Uysal, Hüseyin
    Nandakumar, Kutty S
    Burkhardt, Harald
    Schneider, Gunter
    Holmdahl, Rikard
    Crystal structure of an arthritogenic anticollagen immune complex2011In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 63, no 12, p. 3740-3748Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: In rheumatoid arthritis, joint inflammation and cartilage destruction are mediated by autoantibodies directed to various self antigens. Type II collagen (CII)-specific antibodies are likely to play a role in this process and have been shown to induce experimental arthritis in susceptible animals. The purpose of this study was to reveal how arthritogenic autoantibodies recognize native CII in its triple-helical conformation.

    METHODS: Site-directed mutagenesis and crystallographic studies were performed to reveal crucial contact points between the CII antibody and the triple-helical CII peptide.

    RESULTS: The crystal structure of a pathogenic autoantibody bound to a major triple-helical epitope present on CII was determined, allowing a first and detailed description of the interactions within an arthritogenic complex that is frequently occurring in both mice and humans with autoimmune arthritis. The crystal structure emphasizes the role of arginine residues located in a commonly recognized motif on CII and reveals that germline-encoded elements are involved in the interaction with the epitope.

    CONCLUSION: The crystal structure of an arthritogenic antibody binding a triple-helical epitope on CII indicates a crucial role of germline-encoded and arginine residues as the target structures.

  • 24. Ekdahl, K N
    et al.
    Rönnblom, L
    Sturfelt, G
    Nilsson, B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Increased phosphate content in complement component C3, fibrinogen, vitronectin, and other plasma proteins in systemic lupus erythematosus: covariation with platelet activation and possible association with thrombosis.1997In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 40, no 12, p. 2178-2186Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate whether extracellular phosphorylation of plasma proteins takes place in vivo in patients with systemic lupus erythematosus (SLE), to determine possible correlations between phosphate levels and clinical and/or laboratory parameters, and to identify individual phosphorylated plasma proteins.

    METHODS: Sera from SLE patients were analyzed for total amounts of protein-bound phosphate by a colorimetric technique, and for levels of beta-thromboglobulin by radioimmunoassay. In addition, the ability of these sera to activate platelets, resulting in the release of protein kinase, was tested using an assay in which platelet-rich plasma from healthy blood donors was incubated with sera or immune complexes from SLE patients. In this assay, [gamma-32P]ATP was added, and 32P-labeled C3 was quantified. Phosphate in individual proteins was detected by Western blot analysis.

    RESULTS: 32P-labeled, activated platelets were able to phosphorylate exogenously added proteins, without the addition of ATP or cations. Platelet-rich plasma from healthy blood donors became activated by sera or by polyethylene glycol-precipitated immune complexes from patients with SLE, which led to the extracellular phosphorylation of plasma proteins, exemplified in the C3 assay. The phosphate content in plasma proteins was increased in SLE patients with previous thrombosis. The degree of phosphorylation increased up to 3-fold in serial samples obtained from 2 SLE patients during periods of disease exacerbation. Substantial phosphate increases were seen in C3 and fibrinogen. The changes were linked to platelet activation because of the observed covariation with the levels of beta-thromboglobulin.

    CONCLUSION: In SLE patients, the phosphate content in plasma proteins (including C3 and fibrinogen) increases due to platelet activation.

  • 25.
    Eloranta, Maija-Leena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Alm, Gunnar V
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Disease Mechanisms in RheumatologyTools and Pathways: Plasmacytoid Dendritic Cells and Their Role in AutoimmuneRheumatic Diseases2013In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 65, no 4, p. 853-863Article in journal (Refereed)
  • 26.
    Eloranta, Maija-Leena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Helmers, Sevim Barbasso
    Ulfgren, Ann-Kristin
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Alm, Gunnar V.
    SLU.
    Lundberg, Ingrid E.
    A possible mechanism for endogenous activation of the type I interferon system in myositis patients with anti-Jo-1 or anti-Ro 52/anti-Ro 60 autoantibodies2007In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 56, no 9, p. 3112-3124Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate type I interferon (IFN) system activation and its correlation with autoantibodies and organ manifestations in polymyositis (PM), dermatomyositis (DM), and inclusion body myositis. METHODS: Sera from 30 patients and 16 healthy controls, or purified IgG, were combined with material released from necrotized cells to stimulate IFNalpha production by peripheral blood mononuclear cells (PBMCs) from healthy blood donors. Muscle biopsy specimens from 25 patients and 7 healthy controls were investigated for blood dendritic cell antigen 2 (BDCA-2)-positive plasmacytoid dendritic cells (PDCs) and IFNalpha/beta-inducible myxovirus resistance 1 (MX-1) protein. RESULTS: Sera from 13 patients who were positive for anti-Jo-1 or anti-Ro 52/anti-Ro 60 autoantibodies induced IFNalpha production in PBMCs when combined with necrotic cell material. In addition, IgG prepared from anti-Jo-1-positive PM sera induced IFNalpha with necrotic material, but not when the latter was treated with RNase. BDCA-2 expression in PDCs in muscle tissue was increased in PM patients with anti-Jo-1 autoantibodies, while MX-1 staining in capillaries was increased in DM patients, compared with healthy individuals. IFNalpha-inducing capacity correlated with interstitial lung disease, while MX-1 expression in the capillaries correlated with DM. CONCLUSION: Immune complexes containing anti-Jo-1 or anti-Ro 52/anti-Ro 60 autoantibodies and RNA may act as endogenous IFNalpha inducers that activate IFNalpha production in PDCs. These PDCs could be of importance for inducing myositis, whereas in DM patients without autoantibodies the presence of MX-1 protein in capillaries suggests another cellular IFNalpha source and induction mechanism. Consequently, the type I IFN system may be of importance in both PM and DM, but via different pathways.

  • 27.
    Eloranta, Maija-Leena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lövgren, Tanja
    Uppsala University.
    Finke, Doreen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Mathsson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Kastner, Berthold
    Alm, Gunnar V.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Regulation of the interferon-alpha production induced by RNA-containing immune complexes in plasmacytoid dendritic cells2009In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 60, no 8, p. 2418-2427Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Interferon-alpha (IFNalpha) is produced in several autoimmune diseases, including systemic lupus erythematosus (SLE), and may be important in their pathogenesis. We undertook this study to investigate how IFNalpha production induced by RNA-containing immune complexes (ICs) in plasmacytoid dendritic cells (PDCs) is regulated. METHODS: Normal PDCs purified from peripheral blood mononuclear cells (PBMCs) were cocultivated with other cell populations isolated from healthy individuals or SLE patients. IFNalpha production was induced by RNA-containing ICs, which consisted of anti-RNP autoantibodies and U1 small nuclear RNP particles, and the effects of prostaglandin E2 (PGE2), reactive oxygen species (ROS), or the cytokines IFNalpha2b, granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-10 (IL-10), or tumor necrosis factor alpha (TNFalpha) were explored. RESULTS: Monocytes inhibited IFNalpha production by PDCs in PBMC cultures, while natural killer (NK) cells were stimulatory. The monocytes had little effect on IFNalpha production by pure PDCs but inhibited its stimulation by NK cells. Monocytes from SLE patients were less inhibitory. Exposure of PBMCs or PDCs to IFNalpha2b/GM-CSF increased their IFNalpha production. RNA-containing ICs caused production of ROS, PGE2, and TNFalpha, especially in monocytes. These mediators and IL-10 suppressed IFNalpha production in PBMC cultures, with ROS and PGE2 also inhibiting IFNalpha production by purified PDCs. Inhibition by all of these agents, except for ROS, was abolished by IFNalpha2b/GM-CSF. The inhibitory effect of monocytes was significantly counteracted by the ROS scavengers serotonin and catalase. CONCLUSION: IFNalpha production induced by RNA-containing ICs in PDCs is regulated by a network of interactions between monocytes, NK cells, and PDCs, involving several pro- and antiinflammatory molecules. This should be considered when designing and applying new therapies.

  • 28.
    Eloranta, Maija-Leena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Dual role of CpG-stimulated B cells in the regulation of dendritic cells: comment on the article by Berggren et al Reply2013In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 65, no 8, p. 2216-Article in journal (Other academic)
  • 29. Enocsson, Helena
    et al.
    Sjöwall, Christopher
    Skogh, Thomas
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wetterö, Jonas
    Interferon-alpha Mediates Suppression of C-Reactive Protein Explanation for Muted C-Reactive Protein Response in Lupus Flares?2009In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 60, no 12, p. 3755-3760Article in journal (Refereed)
    Abstract [en]

    Objective. C-reactive protein (CRP) is synthesized by hepatocytes in response to interleukin-6 (IL-6) during inflammation. Despite raised IL-6 levels and extensive systemic inflammation, serum CRP levels remain low during most viral infections and disease flares of systemic lupus erythematosus (SLE). Because both viral infections and SLE are characterized by high levels of interferon-alpha (IFN alpha), the aim of this study was to determine whether this cytokine can inhibit the induction of CRP. Methods. The interference of all 12 IFN alpha subtypes with CRP promoter activity induced by IL-6 and IL-1 beta was studied in a CRP promoter- and luciferase reporter-transfected human hepatoma cell line, Hep-G2. CRIP secretion by primary human hepatocytes was analyzed by enzyme-linked immunosorbent assay. Results. CRP promoter activity was inhibited by all single IFN alpha subtypes, as well as by 2 different mixtures of biologically relevant IFN alpha subtypes. The most prominent effect was seen using a leukocyte-produced mixture of IFN alpha (56% inhibition at 1,000 IU/ml). The inhibitory effect of IFN alpha was confirmed in primary human hepatocytes. CRP promoter inhibition was dose dependent and mediated via the type I IFN receptor. Transferrin production and Hep-G2 proliferation/viability were not affected by IFN alpha. Conclusion. The current study demonstrates that IFN alpha is an inhibitor of CRP promoter activity and CRP secretion. This finding concords with previous observations of up-regulated IFN alpha and a muted CRP response during SLE disease flares. Given the fundamental role of both IFN alpha and CRP in the immune response, our results are of importance for understanding the pathogenesis of SLE and may also contribute to understanding the differences in the CRP response between viral and bacterial infections.

  • 30. Feng, Di
    et al.
    Stone, Rivka C.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sangster-Guity, Niquiche
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sigurdsson, Snaevar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wang, Chuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Alm, Gunnar
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Barnes, Betsy J.
    Genetic variants and disease-associated factors contribute to enhanced interferon regulatory factor 5 expression in blood cells of patients with systemic lupus erythematosus2010In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 62, no 2, p. 562-573Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Genetic variants of the interferon (IFN) regulatory factor 5 gene (IRF5) are associated with susceptibility to systemic lupus erythematosus (SLE). The contribution of these variants to IRF-5 expression in primary blood cells of SLE patients has not been addressed, nor has the role of type I IFNs. The aim of this study was to determine the association between increased IRF-5 expression and the IRF5 risk haplotype in SLE patients. METHODS: IRF-5 transcript and protein levels in 44 Swedish patients with SLE and 16 healthy controls were measured by quantitative real-time polymerase chain reaction, minigene assay, and flow cytometry. Single-nucleotide polymorphisms rs2004640, rs10954213, and rs10488631 and the CGGGG insertion/deletion were genotyped in these patients. Genotypes of these polymorphisms defined both a common risk haplotype and a common protective haplotype. RESULTS: IRF-5 expression and alternative splicing were significantly up-regulated in SLE patients compared with healthy donors. Enhanced transcript and protein levels were associated with the risk haplotype of IRF5; rs10488631 displayed the only significant independent association that correlated with increased transcription from the noncoding first exon 1C. Minigene experiments demonstrated an important role for rs2004640 and the CGGGG insertion/deletion, along with type I IFNs, in regulating IRF5 expression. CONCLUSION: This study provides the first formal proof that IRF-5 expression and alternative splicing are significantly up-regulated in primary blood cells of patients with SLE. Furthermore, the risk haplotype is associated with enhanced IRF-5 transcript and protein expression in patients with SLE.

  • 31. Fredi, Micaela
    et al.
    Tincani, Angela
    Yin, Hong
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Delgado-Vega, Angélica M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Borghi, Maria Orietta
    Meroni, Pier-Luigi
    Alarcón-Riquelme, Marta E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    IRF5 is associated with primary antiphospholipid syndrome, but is not a major risk factor2010In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 62, no 4, p. 1201-1202Article in journal (Refereed)
  • 32. Guo, Jian Ping
    et al.
    Bäckdahl, Liselotte
    Marta, Monica
    Mathsson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Lorentzen, Johnny C.
    Profound and paradoxical impact on arthritis and autoimmunity of the rat antigen-presenting lectin-like receptor complex2008In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 58, no 5, p. 1343-1353Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The antigen-presenting lectin-like receptor complex (APLEC) was recently identified as a genetic determinant for arthritis susceptibility. We undertook this study to define mechanisms underlying the impact of APLEC on arthritis, to determine whether sex effects occur, and to determine whether APLEC influences different types of arthritis and phenotypes other than susceptibility. METHODS: Arthritis-susceptible DA rats were compared with sex-matched congenic rats in which APLEC alleles were substituted with alleles from arthritis-resistant PVG rats. Six different arthritogenic agents were injected at the base of the tail: Freund's incomplete adjuvant, pristane, squalene, killed mycobacteria, yeast beta-glucan, or rat type II collagen (CII). Arthritis was visually scored, body weight was measured, and anti-CII IgG and cytokine messenger RNA (mRNA) levels were determined by enzyme-linked immunosorbent assay and reverse transcription-polymerase chain reaction, respectively. RESULTS: In 5 models of rheumatoid arthritis (RA), congenic rats deviated profoundly from DA rats by having reduced arthritis susceptibility, delayed onset, decreased severity, and/or reduced body weight loss. Paradoxical opposite genetic effects were noted, including a more severe disease course in congenic males in pristane-induced arthritis and decreased clinical signs in collagen-induced arthritis despite increased autoantibody levels. Interestingly, the anti-CII IgG isotype profile was skewed in congenic rats, and markedly reduced lymph node mRNA levels for interleukin-17 suggested that the cytokine profile of autoreactive T helper cells was also skewed in a less pathogenic direction. CONCLUSION: Rat APLEC regulates autoimmunity and multiple phenotypes in several types of arthritis. However, delineating the genetic impact may require stratification for sex or mode of arthritis induction. This pathogenetic complexity should be considered when evaluating APLEC in inflammatory and autoimmune diseases, including RA.

  • 33. Gustafsson, Johanna
    et al.
    Jensen-Urstad, Kerstin
    Herlitz-Lindberg, Marie
    Moller, Sonia
    Pettersson, Susanne
    Gunnarsson, Iva
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Svenungsson, Elisabet
    Atherosclerosis In Systemic Lupus Erythematosus (SLE) and Controls, -An Analysis Of SLE Subgroups2013In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 65, no Suppl. 10, p. S1243-S1243Article in journal (Other academic)
  • 34.
    Hagberg, Niklas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Theorell, Jakob
    Alm, Gunnar V.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Bryceson, Yenan
    Ronnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Systemic Lupus Erythematosus Immune Complexes Upregulate the Expression of CD319 and CD229 On Plasmacytoid Dendritic Cells2012In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 64, no s10, p. S368-S369Article in journal (Other academic)
  • 35. Hellgren, Karin
    et al.
    Baecklund, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Smedby, Karin E.
    Backlin, Carin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Askling, Johan
    Rheumatoid Arthritis and Risks of Malignant Lymphoma: Are Risks Still Increased?2012In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 64, no S10, p. S525-S526Article in journal (Other academic)
  • 36. Hellgren, Karin
    et al.
    Smedby, Karin E.
    Feltelius, Nils
    Baecklund, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Askling, Johan
    Do rheumatoid arthritis and lymphoma share risk factors?: A comparison of lymphoma and cancer risks before and after diagnosis of rheumatoid arthritis2010In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 62, no 5, p. 1252-1258Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Patients with rheumatoid arthritis (RA), in particular those with the most severe disease, are at increased risk of malignant lymphoma. Whether this increase is entirely consequential to the RA disease and/or its treatment or reflective of shared susceptibility to the two diseases remains unclear. To resolve this, we assessed whether patients with RA are at increased risk of lymphoma or of other cancers, already before diagnosis of RA, and if the relative risk increases with time since RA diagnosis.

    METHODS: 6,745 patients with incident RA (ACR criteria, symptom duration < 1 year) registered in the Swedish Early RA register from 1997 through 2006 were identified. For each patient, five general population controls were randomly matched by gender, age, marital status and residence (n=33,657). All individuals were linked to the nationwide Swedish Cancer Register 1958-2006. Relative risks (RR) of lymphoma and cancer overall before and after the diagnosis of RA were estimated using conditional logistic and Cox regression, respectively.

    RESULTS: Before diagnosis of RA, no increased risk of lymphoma (RR= 0.67, 95% CI 0.37-1.23) or other cancers (RR= 0.78, 95% CI 0.70-0.88) was observed. During the first ten years following diagnosis of RA, the overall RR of lymphoma was 1.75 (95 % CI 1.04-2.96).

    CONCLUSION: Overall, a history of cancer, lymphoma included, does not increase the risk of subsequent RA development. Shared susceptibility for RA and lymphoma may thus be of limited importance. By contrast increased lymphoma risks were observed already within the first decade following RA diagnosis.

  • 37. Helmers, Sevim Barbasso
    et al.
    Englund, P
    Engström, M
    Åhlin, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Fathi, M
    Janciauskiene, S
    Heimbürger, M
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Lundberg, IE
    Sera from anti-Jo-1-positive patients with polymyositis and interstitial lung disease induce expression of intercellular adhesion molecule 1 in human lung endothelial cells2009In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 60, no 8, p. 2524-2530Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate whether sera or purified IgG from patients with polymyositis (PM) and patients with dermatomyositis (DM), with or without interstitial lung disease (ILD), can activate endothelial cells (ECs). METHODS: Patients' sera were selected based on the presence or absence of anti-Jo-1, anti-SSA, or anti-U1 small nuclear RNP autoantibodies. The presence of autoantibodies was determined by line blot assays. Cultured human microvascular ECs derived from lung tissue (HMVEC-L) were incubated with sera or purified IgG from 22 patients with PM, 7 patients with DM, and 10 healthy individuals as controls. Assessment of intercellular adhesion molecule 1 (ICAM-1) expression was conducted by immunofluorescence (n=22) and by cell-based enzyme-linked immunosorbent assay (ELISA) (n=20). Serum levels of soluble ICAM-1 (sICAM-1) were determined by ELISA. RESULTS: Sera from PM patients with ILD who were positive for anti-Jo-1 autoantibodies had a significantly stronger effect on the expression of ICAM-1 by HMVEC-L in comparison with sera from healthy controls and patients with other autoantibodies. Purified IgG did not induce ICAM-1 expression. Higher serum levels of sICAM-1 were found in patients with myositis compared with healthy controls. CONCLUSION: EC activation with ICAM-1 expression could contribute to the multiorgan involvement, including the development of myositis and ILD, in patients carrying anti-Jo-1 autoantibodies. The EC-activating factors are not the autoantibodies themselves, but might be systemic factors associated with these autoantibodies.

  • 38.
    Johansson, C
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Svenungsson, E
    Sturfelt, G
    Lundberg, I
    Truedsson, L
    Gunnarsson, I
    Lofstrom, B
    Frostegard, J
    Klareskog, L
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Alarcon-Riquelme, Marta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    A family-based association study of the IL10 and Bcl2 genes in swedish patients with SLE1999In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 42, no S9, p. S308-S308Article in journal (Other academic)
  • 39. Jonsen, Andreas
    et al.
    Bengtsson, Anders A.
    Bengtsson, Christine
    Gunnarsson, Iva
    Gustafsson, Johanna
    Hjalte, Frida
    Leonard, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Pettersson, Susanne
    Dahlqvist, Solbritt Rantapaa
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Sjowall, Christopher
    Carlsson, Katarina Steen
    Svenungsson, Elisabet
    Willim, Minna
    Nived, Ola
    Direct and Indirect Costs For Patients With Systemic Lupus Erythematosus In National Cohorts In Sweden2013In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 65, no Suppl. 10, p. S752-S752Article in journal (Other academic)
  • 40. Joshua, Vijay
    et al.
    Reynisdottir, Gudrun
    Ytterberg, Jimmy
    Engstrom, Marianne
    Eklund, Anders
    Skold, Magnus
    Jakobsson, Per-Johan
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Malmstrom, Vivianne
    Klareskog, Lars
    Grunewald, Johan
    Catrina, Anca I.
    Characterization Of Lung Inflammation and Identification Of Shared Citrullinated Targets In The Lungs and Joints Of Early RA2013In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 65, no Suppl. 10, p. S1039-S1039Article in journal (Other academic)
  • 41. Joshua, Vijay
    et al.
    Schobers, Loes
    Israelsson, Lena
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Hansson, Monika
    Catrina, Anca I.
    Pruijn, Ger J. M.
    Malmstrom, Vivianne
    B-Cell Responses To De Novo Identified Citrullinated Fibrinogen Peptides Are Associated With PTPN22 Risk Allele2013In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 65, no Suppl. 10, p. S392-S392Article in journal (Other academic)
  • 42. Kirwan, John R
    et al.
    Hickey, Sarah H
    Hällgren, Roger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Mielants, Herman
    Björck, Ewa
    Persson, Tore
    Wollheim, Frank A
    The effect of therapeutic glucocorticoids on the adrenal response in a randomized controlled trial in patients with rheumatoid arthritis2006In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 54, no 5, p. 1415-1421Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To measure the effect of low-dose systemic glucocorticoid treatment on the adrenal response to adrenocorticotropic hormone (ACTH) in patients with rheumatoid arthritis (RA). METHODS: Patients with RA who took part in a randomized double-blind placebo-controlled trial of budesonide (3 mg/day and 9 mg/day) and prednisolone (7.5 mg/day) underwent a short (60-minute) test with injection of ACTH (tetracosactide hexaacetate) at baseline and the day after completing the 3-month treatment program. Plasma cortisol measurements at baseline and 3 months were compared within and between the treatment groups. Individual patients were classified as normal responders to ACTH or as abnormal responders if changes were >2 SD below the pretreatment value in the entire group of study patients. RESULTS: Short tests with ACTH injection were performed on 139 patients before beginning the study medication and on 134 patients after cessation of the medication. There were no changes in the placebo group. Mean plasma cortisol levels following treatment were reduced in all active treatment groups. In addition, mean values were significantly reduced for the 30-minute and 60-minute responses to ACTH. The maximum reduction (35%) occurred in the prednisolone group at 60 minutes. Following treatment, 34% of patients taking budesonide 9 mg and 46% of those taking prednisolone 7.5 mg failed to reach the normal maximum cortisol response to ACTH. Four patients failed to achieve the normal percentage increase in cortisol levels, but only 1 patient failed to meet both criteria. CONCLUSION: Low doses of a glucocorticoid resulted in depression of baseline and ACTH-stimulated cortisol levels after 12 weeks of therapy. Although the responsiveness of the hypothalamic-pituitary-adrenal axis in individual patients generally remained within the normal range, these changes should be investigated further.

  • 43.
    Knight, Ann
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sandin, Sven
    Askling, Johan
    Risks and relative risks of Wegener's granulomatosis among close relatives of patients with the disease2008In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 58, no 1, p. 302-7Article in journal (Other academic)
    Abstract [en]

    OBJECTIVE: The etiology of Wegener's granulomatosis (WG) supposedly involves interplay between genetic susceptibility and environmental triggers. However, little is known about whether WG actually clusters in families. Information on the degree of familial aggregation in WG is of clinical relevance, because patients with WG often want to know whether their diagnosis puts their closest relatives at increased risk of the disease. The aim of this study was to investigate the risk of WG in relatives of patients with WG. METHODS: Using Swedish nationwide registers on morbidity, family structure, and vital status, we compared the occurrence of WG (register-based plus chart review) among 6,670 first-degree relatives and 428 spouses of 1,944 Swedish patients with WG with the occurrence among 68,994 first-degree relatives and 4,812 spouses of 19,655 control subjects from the general population. Relative risks were estimated using the Cox proportional hazards regression model. RESULTS: Two of the 6,670 first-degree relatives of patients with WG and 13 of the 68,994 first-degree relatives of their population controls had WG, resulting in a relative risk of 1.56 (95% confidence interval 0.35-6.90). None of the 428 spouses of patients had WG. CONCLUSION: In absolute terms, the occurrence of WG among close biologic and nonbiologic relatives of patients with WG is low. In terms of relative risk, our results provide strong evidence against a pronounced increase in familial risk such as that noted for systemic lupus erythematosus, irritable bowel disease, and multiple sclerosis but are compatible with familial aggregation of a magnitude similar to that for rheumatoid arthritis.

  • 44. Kokkonen, Heidi
    et al.
    Brink, Mikael
    Hansson, Monika
    Mathsson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lassen, Ewa
    Jakobsson, Per Johan
    Holmdahl, Rikard
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Klareskog, Lars
    Rantapaa-Dahlqvist, Solbritt M.
    Interaction of Antibodies Against Citrullinated Peptides with HLA Shared Epitope, PTPN22 1858T Variant, and Smoking in Individuals Prior to and After the Development of Rheumatoid Arthritis2012In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 64, no 10, p. S190-S190Article in journal (Other academic)
  • 45.
    Kozyrev, Sergey
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Lewén, Susanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Linga Reddy, M. V. Prasad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Alarcón-Riquelme, Marta E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Structural insertion/deletion variation in IRF5 is associated with a risk haplotype and defines the precise IRF5 isoforms expressed in systemic lupus erythematosus2007In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 56, no 4, p. 1234-1241Article in journal (Refereed)
    Abstract [en]

    Objective. To determine whether specific isoforms of IRF5 are transcribed in patients with systemic lupus erythematosus (SLE) who have risk genotypes in the exon 1B donor splice site at single-nucleotide polymorphism (SNP) no. rs2004640. Methods. Peripheral blood mononuclear cells were obtained from SLE patients and healthy controls from Argentina, Spain, and Germany and from trio families from Spain and Denmark. A reporter assay was used to investigate the role of SNP no. rs2004640. IRF5 expression in relation to the genotypes of functional SNPs was analyzed using quantitative polymerase chain reaction. Sequencing and genotyping of the IRF5 gene was performed. Results. Sequencing of complementary DNA from individuals with different genotypes showed 4 basic isoforms transcribed from all 5′-untranslated regions (5′-UTRs), suggesting no preferential isoform transcription based on rs2004640 genotypes. Analysis of translation efficiency showed that exon 1A was the most efficient in initiating protein synthesis. We identified a novel polymorphic insertion/deletion that defines the pattern of expression of isoforms of IRF5. The insertion consists of 4 repeats in exon 6 affecting the protein interaction domain. The insertion segregates in the risk haplotype with the high expression allele of a poly(A) site SNP no. rs10954213 and the exon 1B donor splice allele of the 5′-UTR SNP no. rs2004640. The poly(A) polymorphism correlated with levels of IRF5 in cells stimulated with interferon-α. The SNP most strongly associated with SLE was SNP no. rs2070197 (P = 5.2 × 10 -11), which is a proxy of the risk haplotype, but does not appear to be functional. Conclusion. None of the functional variants investigated in this study is strongly associated with SLE, with the exception of the exon 1B donor splice site, and its functional importance appears to be small. Our results suggest that there may be other functional polymorphisms, yet to be identified, in IRF5. We did not observe evidence of epistatic interaction between the functional SNPs.

  • 46.
    Kristjánsdóttir, Helga
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Medical Genetics.
    Saevarsdottir, Saedis
    Gröndal, Gerdur
    Alcarcón-Riquelme, Marta E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Elendsson, Kristjan
    Valdimarsson, Helgi
    Steinsson, Kristjan
    Association of three systemic lupus erythematosus susceptibility factors, PD-1.3A, C4AQ0, and low levels of mannan-binding lectin, with autoimmune manifestations in Icelandic multicase systemic lupus erythematosus families2008In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 58, no 12, p. 3865-3872Article in journal (Refereed)
    Abstract [en]

    Objective: To study autoimmune diseases and autoantibodies in Icelandic multicase systemic lupus erythematosus (SLE) families and to determine the association of 3 SLE susceptibility factors, PD-1.3A, C4AQ0, and low levels of mannan-binding lectin (MBL), with autoimmune disease in this population.

    Methods: Eight SLE multicase families were studied, comprising a total of 124 family members (23 patients with SLE and 101 relatives). The diagnosis of an autoimmune disease was established and autoantibodies were measured in each family. In addition, PD-1.3A alleles were genotyped, and C4AQ0 allotypes were established by electrophoresis and haplotype analysis. Low levels of MBL were determined using enzyme-linked immunosorbent assay and variant-allele genotyping.

    Results: In the SLE multicase families there was a high frequency of other autoimmune diseases (32.2%) and a high frequency of autoantibodies (53.2%). Of all family members, 59.7% were determined to have SLE, other autoimmune diseases, antinuclear antibodies, and/or other autoantibodies. The families showed genetic heterogeneity for PD-1.3A, C4AQ0, and low MBL levels; the frequency of each factor ranged from 0% to 85%. The frequencies of PD-1.3A and C4AQ0 were significantly increased in patients with SLE, relatives with other autoimmune diseases, and non-autoimmune disease relatives compared with controls. In the 7 families whose members had low levels of MBL, this factor was significantly associated with SLE, but the frequency of low MBL was decreased in relatives with other autoimmune diseases as compared with non-autoimmune disease relatives and controls. There were indications of an additive effect, and 91% of patients with SLE, 78% of relatives with other autoimmune diseases, and 75% of non-autoimmune disease relatives carried at least 1 of the 3 factors.

    Conclusion: These results demonstrate a high frequency of autoimmune diseases and autoantibodies in SLE multicase families. PD-1.3A and C4AQ0 are part of a predisposing genetic background. Other genetic and/or environmental factors are necessary for disease expression, demonstrated by a high frequency of PD-1.3A and C4AQ0 in non-autoimmune disease relatives. Low MBL levels may be one such contributing factor. The results of this study provide an example of epistatic genetic effects and overlapping genetics in autoimmune diseases.

  • 47.
    Kristjánsdóttir, Helga
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Medical Genetics.
    Steinsson, Kristjan
    Gunnarsson, Iva
    Gröndal, Gerdur
    Erlendsson, Kristjan
    Alarcón-Riquelme, Marta E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Medical Genetics.
    Lower expression levels of the programmed death 1 receptor on CD4+CD25+ T cells and correlation with the PD-1.3A genotype in patients with systemic lupus erythematosus2010In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 62, no 6, p. 1702-1711Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE.: A genetic polymorphism, PD1.3A, in the PDCD1 gene encoding the co-inhibitory immunoreceptor PD-1, has been associated with SLE. The aim of the study was to assess PD-1 receptor expression in SLE patients, relatives and controls and correlate with PD-1.3A. METHODS.: Icelandic and Swedish SLE patients, relatives and controls were studied. PBMCs were stimulated with alphaCD3/CD28 and PD-1 expression analyzed by flow cytometry. PD-1.3A/G genotyping was performed by PCR-RFLP. RESULTS: I. PD-1 expression on PBMCs was induced after stimulation, by 2.1-fold in SLE patients, 3.1-fold in relatives and 5.1-fold in controls.II. The frequency of PD-1+ cells was significantly lower in SLE patients compared to relatives and controls. PD-1 expression on PD-1+ cells was significantly lower in SLE patients and relatives.III. PD-1 expression on CD4+CD25+ T cells was significantly lower in SLE patients and relatives.IV. PD-1 expression was significantly higher on CD25(high) compared to CD25(intermediate) and (low) cells.V. PD-1 expression on CD25(high) and CD25(intermediate) cells was significantly lower in SLE patients compared to controls.VI. PD-1 was expressed on both FoxP3- and FoxP3+ cells.VII. Lower PD-1 expression was significantly correlated with the PD-1.3A/G genotype. CONCLUSION.: The study demonstrates significantly lower PD-1 receptor expression in SLE patients and relatives and a significant correlation of lower PD-1 expression with the PD-1.3A allele. We conclude that PD-1.3A may be contributory to abnormalities in PD-1 receptor expression on CD4+CD25+ T-cells in SLE, providing support for an important role for the PD-1 pathway in SLE and possibly other autoimmune diseases.

  • 48. Laki, Judit
    et al.
    Lundstrom, Emeli
    Snir, Omri
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ganji, Izabella
    Catrina, Anca I.
    Bengtsson, Camilla
    Saevarsdottir, Saedis
    Wick, Marius C.
    Alfredsson, Lars
    Klareskog, Lars
    Padyukov, Leonid
    Very high levels of anti-citrullinated protein antibodies are associated with HLA-DRB1*15 non-shared epitope allele in patients with rheumatoid arthritis2012In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 64, no 7, p. 2078-2084Article in journal (Refereed)
    Abstract [en]

    Objective Production of anticitrullinated protein antibodies (ACPAs) is an important biomarker for rheumatoid arthritis (RA). We undertook this study to determine whether genetic factors (HLADRB1 alleles) are associated with extreme ACPA levels in individuals with ACPA-positive RA, and to ascertain whether there are any phenotypic characteristics associated with these subgroups of RA. Methods HLADRB1 allelic groups were genotyped in 1,073 ACPA-positive RA patients from the Swedish Epidemiological Investigation of Rheumatoid Arthritis study. We found that 283 patients (26.4%) had high ACPA levels (defined as >1,500 units/ml using the Euro-Diagnostica anti-CCP2 test), while the rest of the patients had moderate ACPA levels and served as the comparison group. A replication group consisted of 235 RA patients. Results No significant differences in baseline disease activity were observed between patients with high and those with moderate ACPA levels. However, the HLADRB1*15 allele was associated with high ACPA levels (P = 0.0002). A similar trend was detected in HLADRB1*15positive patients in the replication cohort, with meta-analysis of the discovery and replication cohorts demonstrating an overall effect of HLADRB1*15 on development of high ACPA levels in both the discovery and replication cohorts (P < 0.0001 by Mantel-Haenszel test with a fixed-effects model). Conclusion Our data indicate that HLADRB1*15 may promote the production of high ACPA levels. Due to the high value of ACPA level scores in the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for RA, the presence of HLADRB1*15 may, at least in part, contribute to fulfilling the criteria for RA. This illustrates the complex nature of the genetic regulation of ACPA levels. Additional mechanistic studies of the regulation of ACPAs and ACPA-positive RA are pending.

  • 49. Lessard, Christopher J.
    et al.
    Li, He
    Adrianto, Indra
    Ice, John A.
    Dozmorov, Mikhail G.
    Jonsson, Roland
    Rischmueller, Maureen
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Mariette, Xavier
    Miceli-Richard, Corinne
    Wahren-Herlenius, Marie
    Witte, Torsten
    Brennan, Michael T.
    Omdal, Roald
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Gaffney, Patrick M.
    Ng, Wan-Fai
    Rhodus, Nelson L.
    Segal, Barbara M.
    Wren, Jonathan D.
    Scofield, R. Hal
    Anaya, Juan-Manuel
    Harley, John B.
    Montgomery, Courtney G.
    Sivils, Kathy L.
    Complex Functional Effects Within The HLA Contribute To Sjogren's Syndrome Pathogenesis and May Influence Both Transcriptional Regulation and Peptide Binding2013In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 65, no Suppl. 10, p. S1184-S1185Article in journal (Other academic)
  • 50. Liu, Ke
    et al.
    Kaufman, Kenneth M.
    James, Judith A.
    Jonsson, Roland
    Kurien, Biji T.
    Mariette, Xavier
    Merrill, Joan T.
    Omdal, Roald
    Rischmueller, Maureen
    Vyse, Timothy J.
    Wahren-Herlenius, Marie
    Witte, Torsten
    Lessard, Christopher J.
    Zimmerman, Sarah L.
    Thompson, Susan D.
    Hirschfield, Gideon
    Xie, Gang
    Montgomery, Courtney G.
    Ng, Wan-Fai
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Gaffney, Patrick M.
    Siminovitch, Katherine A.
    Sivils, Kathy L.
    Scofield, R. Hal
    Sex Bias In Autoimmune Diseases: Increased Risk Of 47,XXX In Systemic Lupus Erythematosus (SLE) and Sjogren's Syndrome (SS) Supports The Gene Dose Hypothesis2013In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 65, no Suppl. 10, p. S379-S379Article in journal (Other academic)
12 1 - 50 of 90
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