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  • 1.
    Bulfone-Paus, Silvia
    et al.
    Univ Manchester, Div Musculoskeletal & Dermatol Sci, Fac Biol Med & Hlth, Manchester, Lancs, England..
    Nilsson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Karolinska Inst, Dept Med, Immunol & Allergy Unit, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden.
    Draber, Petr
    Acad Sci Czech Republ, Inst Mol Genet, Dept Signal Transduct, Prague, Czech Republic..
    Blank, Ulrich
    INSERM, U1149, Ctr Rech Inflammat, Paris, France.;CNRS, ERL8252, Paris, France.;Univ Paris Diderot, Sorbonne Paris Cite, Fac Med, Site Xavier Bichat,Inflamex Lab Excellence, Paris, France..
    Levi-Schaffer, Francesca
    Hebrew Univ Jerusalem, Inst Drug Res, Sch Pharm, Fac Med,Pharmacol & Expt Therapeut Unit, Jerusalem, Israel..
    Positive and Negative Signals in Mast Cell Activation2017In: Trends in immunology, ISSN 1471-4906, E-ISSN 1471-4981, Vol. 38, no 9, p. 657-667Article, review/survey (Refereed)
    Abstract [en]

    Mast cells are powerful immune modulators of the tissue microenvironment. Within seconds of activation, these cells release a variety of preformed biologically active products, followed by a wave of mediator synthesis and secretion. Increasing evidence suggests that an intricate network of inhibitory and activating receptors, specific signaling pathways, and adaptor proteins governs mast cell responsiveness to stimuli. Here, we discuss the biological and clinical relevance of negative and positive signaling modalities that control mast cell activation, with an emphasis on novel Fc epsilon RI regulators, immunoglobulin E (IgE)-independent pathways [e.g., Mas-related G protein-coupled receptor X2 (MRGPRX2)], tetraspanins, and the CD300 family of inhibitory and activating receptors.

  • 2.
    Dahlin, Joakim S.
    et al.
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Stockholm, Sweden..
    Ekoff, Maria
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Stockholm, Sweden..
    Grootens, Jennine
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Stockholm, Sweden..
    Löf, Liza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Hagberg, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ungerstedt, Johanna S.
    Karolinska Inst, Dept Med Huddinge, Stockholm, Sweden.;Karolinska Univ Hosp, Hematol Ctr, Stockholm, Sweden..
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Nilsson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Karolinska Univ Hosp, Karolinska Inst, Dept Med, Stockholm, Sweden.
    KIT signaling is dispensable for human mast cell progenitor development2017In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 130, no 16, p. 1785-1794Article in journal (Refereed)
    Abstract [en]

    Human hematopoietic progenitors are generally assumed to require stem cell factor (SCF) and KIT signaling during differentiation for the formation of mast cells. Imatinib treatment, which inhibits KIT signaling, depletes mast cells in vivo. Furthermore, the absence of SCF or imatinib treatment prevents progenitors from developing into mast cells in vitro. However, these observations do not mean that mast cell progenitors require SCF and KIT signaling throughout differentiation. Here, we demonstrate that circulating mast cell progenitors are present in patients undergoing imatinib treatment. In addition, we show that mast cell progenitors from peripheral blood survive, mature, and proliferate without SCF and KIT signaling in vitro. Contrary to the prevailing consensus, our results show that SCF and KIT signaling are dispensable for early mast cell development.

  • 3.
    Grootens, Jennine
    et al.
    Karolinska Inst, Dept Med Solna, S-17164 Stockholm, Sweden;Karolinska Univ Hosp, S-17164 Stockholm, Sweden.
    Ungerstedt, Johanna S.
    Karolinska Inst, Dept Med Huddinge, S-14186 Stockholm, Sweden;Karolinska Univ Hosp, Hematol Ctr, S-17176 Stockholm, Sweden.
    Ekoff, Maria
    Karolinska Inst, Dept Med Solna, S-17164 Stockholm, Sweden;Karolinska Univ Hosp, S-17164 Stockholm, Sweden.
    Rönnberg, Elin
    Karolinska Inst, Dept Med Solna, S-17164 Stockholm, Sweden;Karolinska Univ Hosp, S-17164 Stockholm, Sweden.
    Klimkowska, Monika
    Karolinska Univ Hosp Huddinge, Dept Clin Pathol & Cytol, S-14186 Stockholm, Sweden.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Arock, Michel
    Ecole Normale Super, Mol & Cellular Oncol, F-94235 Cachan, France;Hop La Pitie Salpetriere, Clin Hematol Lab, F-75013 Paris, France.
    Söderlund, Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Mattsson, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Nilsson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Karolinska Inst, Dept Med Solna, S-17164 Stockholm, Sweden;Karolinska Univ Hosp, S-17164 Stockholm, Sweden.
    Dahlin, Joakim S.
    Karolinska Inst, Dept Med Solna, S-17164 Stockholm, Sweden;Karolinska Univ Hosp, S-17164 Stockholm, Sweden.
    Single-cell analysis reveals the KIT D816V mutation in haematopoietic stem and progenitor cells in systemic mastocytosis2019In: EBioMedicine, E-ISSN 2352-3964, Vol. 43, p. 150-158Article in journal (Refereed)
    Abstract [en]

    Background: Systemic mastocytosis (SM) is a haematological disease characterised by organ infiltration by neoplastic mast cells. Almost all SM patients have a mutation in the gene encoding the tyrosine kinase receptor KIT causing a D816V substitution and autoactivation of the receptor. Mast cells and CD34(+) haematopoietic progenitors can carry the mutation: however, in which progenitor cell subset the mutation arises is unknown. We aimed to investigate the distribution of the D816V mutation in single mast cells and single haematopoietic stem and progenitor cells.

    Methods: Fluorescence-activated single-cell index sorting and KIT D816V mutation assessment were applied to analyse mast cells and >10,000 CD34(+) bone marrow progenitors across 10 haematopoietic progenitor subsets. In vitro assays verified cell-forming potential.

    Findings: We found that in SM 60-99% of the mast cells harboured the KIT D816V mutation. Despite increased frequencies of mast cells in SM patients compared with control subjects, the haematopoietic progenitor subset frequencies were comparable. Nevertheless, the mutation could be detected throughout the haematopoietic landscape of SM patients, from haematopoietic stem cells to more lineage-primed progenitors. In addition, we demonstrate that Fc epsilon RI+ bone marrow progenitors exhibit mast cell-forming potential, and we describe aberrant CD45RA expression on SM mast cells for the first time.

    Interpretation: The KIT D816V mutation arises in early haematopoietic stem and progenitor cells and the mutation frequency is approaching 100% in mature mast cells, which express the aberrant marker CD45RA.

  • 4.
    Grootens, Jennine
    et al.
    Karolinska Inst, Dept Med Solna, Immunol & Allergy Unit, Stockholm, Sweden;Karolinska Univ Hosp, Stockholm, Sweden.
    Ungerstedt, Johanna S.
    Karolinska Inst, Dept Med Huddinge, Stockholm, Sweden;Karolinska Univ Hosp, Hematol Ctr, Stockholm, Sweden.
    Nilsson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Karolinska Inst, Dept Med Solna, Immunol & Allergy Unit, Stockholm, Sweden;Karolinska Univ Hosp, Stockholm, Sweden.
    Dahlin, Joakim S.
    Karolinska Inst, Dept Med Solna, Immunol & Allergy Unit, Stockholm, Sweden;Karolinska Univ Hosp, Stockholm, Sweden.
    Deciphering the differentiation trajectory from hematopoietic stem cells to mast cells2018In: BLOOD ADVANCES, ISSN 2473-9529, Vol. 2, no 17, p. 2273-2281Article, review/survey (Refereed)
    Abstract [en]

    Hematopoietic stem cells differentiate into all types of blood cells, including peripheral tissue-resident mast cells. The early mast cell differentiation takes place in the bone marrow, after which the progenitor cells enter the circulation and mature once reaching their target organ. Early results from single-cell culture experiments and colony-forming assays have produced the classic hierarchical tree model of hematopoiesis. The introduction of high-throughput, single-cell RNA sequencing is now revolutionizing our understanding of the differentiation process, questioning the classic tree-based models. By integrating the results from early cell culture experiments with single-cell transcriptomics, we present a differentiation landscape model of hematopoiesis and discuss it with focus on mast cells. The review also describes how the hematologic neoplasm systemic mastocytosis can be used to model human hematopoiesis using naturally occurring cell barcoding by means of the common KIT D816V mutation.

  • 5. Gülen, T
    et al.
    Möller Westerberg, C
    Lyberg, K
    Ekoff, M
    Kolmert, J
    Bood, J
    Öhd, J
    James, A
    Dahlén, S-E
    Nilsson, G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Department of Medicine, Clinical Immunology and Allergy Research Unit, Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, Sweden; Mastocytosis Centre Karolinska, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden; Centre for Allergy research (CfA), Karolinska Institutet, Stockholm, Sweden .
    Dahlén, B
    Assessment of in vivo mast cell reactivity in patients with systemic mastocytosis.2017In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 47, no 7, p. 909-917Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Patients with systemic mastocytosis (SM) have clinical signs of mast cell (MC) activation and increased levels of MC mediators. It is unclear whether the increased mediator levels are caused by increased numbers of tissue MCs, or whether these cells in affected individuals have a hyperactive phenotype.

    OBJECTIVE: To determine reactivity of the skin and the airways to directly acting mediators and indirectly acting mast cell secretagogues in subjects with SM.

    METHODS: were measured, as well as ex vivo basophil histamine release.

    RESULTS: Mast cell mediators in the blood and urine were significantly higher in patients with SM than in HC and A controls. Responsiveness to local activation of skin MCs (by morphine) and airway MCs (by mannitol) was similar in SM and HC groups. Likewise, end-organ responsiveness in the skin to histamine, and in the airways to methacholine, was similar in all three subject groups. There was no evidence of increased basophil reactivity in SM patients.

    CONCLUSIONS AND CLINICAL RELEVANCE: Mast cells in the skin and airways of subjects with SM do not exhibit hyper-reactivity towards the MC-activating stimuli morphine and mannitol, respectively. Therefore, the highly elevated baseline levels of MC mediators in SM are most likely due to increased MC numbers, rather than altered MC responsiveness. The underlying mechanisms could involve leakage of MC mediators, or dysfunctions in mediator synthesis, storage and release. One clinical implication of our study is that there is no contraindication to perform skin tests using morphine in subjects with mastocytosis.

  • 6.
    Halova, Ivana
    et al.
    Czech Acad Sci, Inst Mol Genet, Dept Signal Transduct, Prague, Czech Republic.
    Rönnberg, Elin
    Karolinska Univ Hosp, Karolinska Inst & Clin Immunol & Transfus Med, Dept Med, Immunol & Allergy Unit, Stockholm, Sweden.
    Draberova, Lubica
    Czech Acad Sci, Inst Mol Genet, Dept Signal Transduct, Prague, Czech Republic.
    Vliagoftis, Harissios
    Karolinska Univ Hosp, Karolinska Inst & Clin Immunol & Transfus Med, Dept Med, Immunol & Allergy Unit, Stockholm, Sweden; Univ Alberta, Alberta Resp Ctr, Edmonton, AB, Canada; Univ Alberta, Dept Med, Edmonton, AB, Canada.
    Nilsson, Gunnar P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Immunology and Allergy Unit, Department of Medicine, Karolinska Institutet and Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden.
    Draber, Petr
    Czech Acad Sci, Inst Mol Genet, Dept Signal Transduct, Prague, Czech Republic.
    Changing the threshold-Signals and mechanisms of mast cell priming2018In: Immunological Reviews, ISSN 0105-2896, E-ISSN 1600-065X, Vol. 282, no 1, p. 73-86Article in journal (Refereed)
    Abstract [en]

    Mast cells play a key role in allergy and other inflammatory diseases involving engagement of multivalent antigen with IgE bound to high-affinity IgE receptors (FcεRIs). Aggregation of FcεRIs on mast cells initiates a cascade of signaling events that eventually lead to degranulation, secretion of leukotrienes and prostaglandins, and cytokine and chemokine production contributing to the inflammatory response. Exposure to pro-inflammatory cytokines, chemokines, bacterial and viral products, as well as some other biological products and drugs, induces mast cell transition from the basal state into a primed one, which leads to enhanced response to IgE-antigen complexes. Mast cell priming changes the threshold for antigen-mediated activation by various mechanisms, depending on the priming agent used, which alone usually do not induce mast cell degranulation. In this review, we describe the priming processes induced in mast cells by various cytokines (stem cell factor, interleukins-4, -6 and -33), chemokines, other agents acting through G protein-coupled receptors (adenosine, prostaglandin E2, sphingosine-1-phosphate, and β-2-adrenergic receptor agonists), toll-like receptors, and various drugs affecting the cytoskeleton. We will review the current knowledge about the molecular mechanisms behind priming of mast cells leading to degranulation and cytokine production and discuss the biological effects of mast cell priming induced by several cytokines.

  • 7. Lyberg, Katarina
    et al.
    Ali, Hani Abdulkadir
    Grootens, Jennine
    Kjellander, Matilda
    Tirfing, Malin
    Arock, Michel
    Hägglund, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Nilsson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Ungerstedt, Johanna
    Histone deacetylase inhibitor SAHA mediates mast cell death and epigenetic silencing of constitutively active D816V KIT in systemic mastocytosis.2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 6, p. 9647-9659Article in journal (Refereed)
    Abstract [en]

    Systemic mastocytosis (SM) is a clonal bone marrow disorder, where therapeutical options are limited. Over 90% of the patients carry the D816V point mutation in the KIT receptor that renders this receptor constitutively active. We assessed the sensitivity of primary mast cells (MC) and mast cell lines HMC1.2 (D816V mutated), ROSA (KIT WT) and ROSA (KIT D816V) cells to histone deacetylase inhibitor (HDACi) treatment. We found that of four HDACi, suberoyl anilide hydroxamic acid (SAHA) was the most effective in killing mutated MC. SAHA downregulated KIT, followed by major MC apoptosis. Primary SM patient MC cultured ex vivo were even more sensitive to SAHA than HMC1.2 cells, whereas primary MC from healthy subjects were less affected. There was a correlation between cell death and SM disease severity, where cell death was more pronounced in the case of aggressive SM, with almost 100% cell death among MC from the mast cell leukemia patient. Additionally, ROSA (KIT D816V) was more affected by HDACi than ROSA (KIT WT) cells. Using ChIP qPCR, we found that the level of active chromatin mark H3K18ac/H3 decreased significantly in the KIT region. This epigenetic silencing was seen only in the KIT region and not in control genes upstream and downstream of KIT, indicating that the downregulation of KIT is exerted by specific epigenetic silencing. In conclusion, KIT D816V mutation sensitized MC to HDACi mediated killing, and SAHA may be of value as specific treatment for SM, although the specific mechanism of action requires further investigation.

  • 8.
    Maric, Jovana
    et al.
    Med Univ Graz, Otto Loewi Res Ctr, Pharmacol Sect, Graz, Austria;BioTechMed, Graz, Austria;Karolinska Inst, Dept Med Huddinge, Ctr Infect Med, Stockholm, Sweden.
    Ravindran, Avinash
    Karolinska Inst, Dept Med, Immunol & Allergy Unit, Solna, Sweden;Karolinska Univ Hosp, Clin Immunol & Transfus Med, Stockholm, Sweden.
    Mazzurana, Luca
    Karolinska Inst, Dept Med Huddinge, Ctr Infect Med, Stockholm, Sweden.
    Van Acker, Aline
    Karolinska Inst, Dept Med Huddinge, Ctr Infect Med, Stockholm, Sweden.
    Rao, Anna
    Karolinska Inst, Dept Med Huddinge, Ctr Infect Med, Stockholm, Sweden.
    Kokkinou, Efthymia
    Karolinska Inst, Dept Med Huddinge, Ctr Infect Med, Stockholm, Sweden.
    Ekoff, Maria
    Karolinska Inst, Dept Med, Immunol & Allergy Unit, Solna, Sweden;Karolinska Univ Hosp, Clin Immunol & Transfus Med, Stockholm, Sweden.
    Thomas, Dominique
    Goethe Univ Frankfurt, Inst Clin Pharmacol, Pharmazentrum Frankfurt ZAFES, Frankfurt, Germany.
    Fauland, Alexander
    Karolinska Inst, Dept Med Biochem & Biophys, Div Physiol Chem 2, Stockholm, Sweden.
    Nilsson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Karolinska Inst, Dept Med, Immunol & Allergy Unit, Solna, Sweden;Karolinska Univ Hosp, Clin Immunol & Transfus Med, Stockholm, Sweden.
    Wheelock, Craig E.
    Karolinska Inst, Dept Med Biochem & Biophys, Div Physiol Chem 2, Stockholm, Sweden.
    Dahlen, Sven-Erik
    Karolinska Inst, Inst Environm Med, Expt Asthma & Allergy Res, Stockholm, Sweden.
    Ferreiros, Nerea
    Goethe Univ Frankfurt, Inst Clin Pharmacol, Pharmazentrum Frankfurt ZAFES, Frankfurt, Germany.
    Geisslinger, Gerd
    Goethe Univ Frankfurt, Inst Clin Pharmacol, Pharmazentrum Frankfurt ZAFES, Frankfurt, Germany;Fraunhofer Inst Mol Biol & Appl Ecol IME, Project Grp Translat Med & Pharmacol TMP, Frankfurt, Germany.
    Friberg, Danielle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery. Karolinska Inst, Dept Clin Sci Intervent & Technol, CLINTEC, Stockholm, Sweden.
    Heinemann, Akos
    Med Univ Graz, Otto Loewi Res Ctr, Pharmacol Sect, Graz, Austria;BioTechMed, Graz, Austria.
    Konya, Viktoria
    Med Univ Graz, Otto Loewi Res Ctr, Pharmacol Sect, Graz, Austria;BioTechMed, Graz, Austria;Karolinska Inst, Dept Med Huddinge, Ctr Infect Med, Stockholm, Sweden.
    Mjosberg, Jenny
    Karolinska Inst, Dept Med Huddinge, Ctr Infect Med, Stockholm, Sweden;Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.
    Cytokine-induced endogenous production of prostaglandin D-2 is essential for human group 2 innate lymphoid cell activation2019In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 143, no 6, p. 2202-2214.e5Article in journal (Refereed)
    Abstract [en]

    Objective: We set out to examine PG production in human ILC2s and the implications of such endogenous production on ILC2 function. Methods: The effects of the COX-1/2 inhibitor flurbiprofen, the hematopoietic prostaglandin D2 synthase (HPGDS) inhibitor KMN698, and the CRTH2 antagonist CAY10471 on human ILC2s were determined by assessing receptor and transcription factor expression, cytokine production, and gene expression with flow cytometry, ELISA, and quantitative RT-PCR, respectively. Concentrations of lipid mediators were measured by using liquid chromatography-tandem mass spectrometry and ELISA. Results: We show that ILC2s constitutively express HPGDS and upregulate COX-2 upon IL-2, IL-25, and IL-33 plus thymic stromal lymphopoietin stimulation. Consequently, PGD2 and its metabolites can be detected in ILC2 supernatants. We reveal that endogenously produced PGD2 is essential in cytokine-induced ILC2 activation because blocking of the COX-1/2 or HPGDS enzymes or the CRTH2 receptor abolishes ILC2 responses. Conclusion: PGD2 produced by ILC2s is, in a paracrine/autocrine manner, essential in cytokine-induced ILC2 activation. Hence we provide the detailed mechanism behind how CRTH2 antagonists represent promising therapeutic tools for allergic diseases by controlling ILC2 function.

  • 9.
    Nilsson, Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Karolinska Univ Hosp, Karolinska Inst, Dept Med, Stockholm, Sweden.
    Dahlin, Joakim S.
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Stockholm, Sweden.
    New insights into the origin of mast cells2019In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 74, no 4, p. 844-845Article in journal (Refereed)
  • 10.
    Ravindran, Avinash
    et al.
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Immunol & Allergy Unit, Stockholm, Sweden.
    Rönnberg, Elin
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Immunol & Allergy Unit, Stockholm, Sweden.
    Dahlin, Joakim S.
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Immunol & Allergy Unit, Stockholm, Sweden.
    Mazzurana, Luca
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Huddinge, Ctr Infect Med, Stockholm, Sweden.
    Säfholm, Jesper
    Karolinska Inst, Inst Environm Med, Unit Expt Asthma & Allergy Res, Ctr Allergy Res, Stockholm, Sweden.
    Orre, Ann-Charlotte
    Karolinska Univ Hosp, Karolinska Inst, Dept Mol Med & Surg, Thorac Surg, Stockholm, Sweden.
    Al-Ameri, Mamdoh
    Karolinska Univ Hosp, Karolinska Inst, Dept Mol Med & Surg, Thorac Surg, Stockholm, Sweden.
    Peachell, Peter
    Univ Sheffield, Royal Hallamshire Hosp, Acad Unit Resp Med, Sheffield, S Yorkshire, England.
    Adner, Mikael
    Karolinska Inst, Inst Environm Med, Unit Expt Asthma & Allergy Res, Ctr Allergy Res, Stockholm, Sweden.
    Dahlen, Sven-Erik
    Karolinska Inst, Inst Environm Med, Unit Expt Asthma & Allergy Res, Ctr Allergy Res, Stockholm, Sweden.
    Mjösberg, Jenny
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Huddinge, Ctr Infect Med, Stockholm, Sweden;Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.
    Nilsson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Immunol & Allergy Unit, Stockholm, Sweden.
    An Optimized Protocol for the Isolation and Functional Analysis of Human Lung Mast Cells2018In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, article id 2193Article in journal (Refereed)
    Abstract [en]

    Background: Mast cells are tissue-resident inflammatory cells defined by their high granularity and surface expression of the high-affinity IgE receptor, Fc + RI, and CD117/KIT, the receptor for stem cell factor (SCF). There is a considerable heterogeneity among mast cells, both phenotypically and functionally. Human mast cells are generally divided into two main subtypes based on their protease content; the mucosa-associated MCT (tryptase positive and chymase negative mast cell) and the connective tissue associated-residing MCTC (tryptase and chymase positive mast cell). Human lung mast cells exhibit heterogeneity in terms of cellular size, expression of cell surface receptors, and secreted mediators. However, knowledge about human lung mast cell heterogeneity is restricted to studies using immunohistochemistry or purified mast cells. Whereas the former is limited by the number of cellular markers that can be analyzed simultaneously, the latter suffers from issues related to cell yield.

    Aim: To develop a protocol that enables isolation of human lung mast cells at high yields for analysis of functional properties and detailed analysis using single-cell based analyses of protein (flow cytometry) or RNA (RNA-sequencing) expression.

    Methods: Mast cells were isolated from human lung tissue by a sequential combination of washing, enzymatic digestion, mechanical disruption, and density centrifugation using Percoll (WEMP). As a comparison, we also isolated mast cells using a conventional enzyme-based protocol. The isolated cells were analyzed by flow cytometry.

    Results: We observed a significant increase in the yield of total human lung CD45(+) immune cells and an even more pronounced increase in the yield of CD117(+) mast cells with the WEMP protocol in comparison to the conventional protocols. In contrast, the frequency of the rare lymphocyte subset innate lymphoid cells group 2 (ILC2) did not differ between the two methods.

    Conclusion: The described WEMP protocol results in a significant increase in the yield of human lung mast cells compared to a conventional protocol. Additionally, the WEMP protocol enables simultaneous isolation of different immune cell populations such as lymphocytes, monocytes, and granulocytes while retaining their surface marker expression that can be used for advanced single-cell analyses including multi-color flow cytometry and RNA-sequencing.

  • 11.
    Rönnberg, Elin
    et al.
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Immunol & Allergy Unit, Solna, Sweden.
    Ghaib, Avan
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Immunol & Allergy Unit, Solna, Sweden;Univ Sulaimani, Coll Med, Dept Microbiol, Sulaimani, Iraq.
    Ceriol, Carlos
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Immunol & Allergy Unit, Solna, Sweden.
    Enoksson, Mattias
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Immunol & Allergy Unit, Solna, Sweden.
    Arock, Michel
    CNRS, UMR 8113, Ecole Normale Super Cachan, Mol & Cellular Oncol,LBPA, Cachan, France;Grp Hosp Pitie Salpetriere, Lab Cent Hematol, Paris, France.
    Säfholm, Jesper
    Karolinska Inst, Inst Environm Med, Unit Asthma & Allergy Res, Solna, Sweden.
    Orre, Ann-Charlotte
    Al-Ameri, Mamdoh
    Adner, Mikael
    Dahlen, Sven-Erik
    Ekoff, Maria
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Immunol & Allergy Unit, Solna, Sweden.
    Nilsson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Immunol & Allergy Unit, Solna, Sweden.
    Divergent Effects of Acute and Prolonged Interleukin 33 Exposure on Mast Cell IgE-Mediated Functions2019In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 1361Article in journal (Refereed)
    Abstract [en]

    Background: Epithelial cytokines, including IL-33 and Thymic stromal lymphopoietin (TSLP), have attracted interest because of their roles in chronic allergic inflammation-related conditions such as asthma. Mast cells are one of the major targets of IL-33, to which they respond by secreting cytokines. Most studies performed thus far have investigated the acute effects of IL-33 on mast cells. In the current study, we investigated how acute vs. prolonged exposure of mast cells to IL-33 and TSLP affects mediator synthesis and IgE-mediated activation.

    Methods: Human lung mast cells (HLMCs), cord blood-derived mast cells (CBMCs), and the ROSA mast cell line were used for this study. Receptor expression and the levels of mediators were measured after treatment with IL-33 and/or TSLP.

    Results: IL-33 induced the release of cytokines. Prolonged exposure to IL-33 increased while TSLP reduced intracellular levels of tryptase. Acute IL-33 treatment strongly potentiated IgE-mediated activation. In contrast, 4 days of exposure to IL-33 decreased IgE-mediated activation, an effect that was accompanied by a reduction in Fc epsilon RI expression.

    Conclusion: We show that IL-33 plays dual roles in mast cells, in which its acute effects include cytokine release and the potentiation of IgE-mediated degranulation, whereas prolonged exposure to IL-33 reduces IgE-mediated activation. We conclude that mast cells act quickly in response to the alarmin IL-33 to initiate an acute inflammatory response, whereas extended exposure to IL-33 during prolonged inflammation reduces IgE-mediated responses. This negative feedback effect suggests the presence of a novel regulatory pathway that modulates IgE-mediated human mast cell responses.

  • 12. Sjöberg, L C
    et al.
    Nilsson, A Zoltowska
    Lei, Y
    Gregory, J A
    Adner, M
    Nilsson, G P
    Immunology and Allergy Unit, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden; Centre for Allergy Research, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Interleukin 33 exacerbates antigen driven airway hyperresponsiveness, inflammation and remodeling in a mouse model of asthma2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, no 1, article id 4219Article in journal (Refereed)
    Abstract [en]

    Interleukin 33 (IL-33) represents a potential link between the airway epithelium and induction of Th2-type inflammatory responses associated with the development of asthma. This study investigated the potential of IL-33 to exacerbate antigen driven asthma responses. An ovalbumin (OVA) asthma model was used in which sensitized C57BL/6 mice were exposed to IL-33 before each OVA challenge. IL-33 given to sensitized mice acted synergistically with antigen and aggravated airway inflammation, hyperresponsiveness and remodeling compared with mice that were only OVA sensitized and challenged and mice that were only exposed to IL-33. Elevated levels of local and systemic mast cell protease mMCP-1, as well as antigen-specific IgE production, were observed following IL-33 administration to sensitized mice. Similarly, exposing OVA-sensitized mice to IL-33 increased the Th2 cytokine levels, including IL-4, IL-5 and IL-13. Furthermore, IL-33 and OVA administration to OVA-sensitized mice increased ILC2s in the lung, suggesting a role for ILC2s in IL-33-mediated exacerbation of OVA-induced airway responses. Collectively, these findings show that IL-33 aggravates important features of antigen-driven asthma, which may have implications for asthma exacerbations.

  • 13.
    Söderberg, O
    et al.
    Uppsala University.
    Christiansen, I
    Nilsson, G
    Uppsala University.
    Carlsson, M
    Nilsson, K
    Uppsala University.
    Interleukin-15 + thioredoxin induce DNA synthesis in B-chronic lymphocytic leukemia cells but not in normal B cells.1997In: Leukemia, ISSN 0887-6924, Vol. 11, no 8, p. 1298-304Article in journal (Other scientific)
  • 14.
    Wennstig, A. K.
    et al.
    Umea Univ, Sundsvall Hosp, Dept Oncol, Dept Surg & Perioperat Sci Surg, Sundsvall, Sweden..
    Garmo, H.
    Kings Coll London, Sch Canc & Pharmaceut Sci, TOUR, London, England.;Reg Canc Ctr, SE-75185 Uppsala, Sweden..
    Isacsson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Gagliardi, G.
    Karolinska Univ Hosp, Dept Med Radiat Phys & Nucl Med, SE-17176 Stockholm, Sweden..
    Rintela, N.
    Karolinska Univ Hosp, Dept Med Radiat Phys & Nucl Med, SE-17176 Stockholm, Sweden..
    Lagerqvist, B.
    Uppsala Univ, Dept Med Sci, SE-75185 Uppsala, Sweden..
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Kings Coll London, Sch Canc & Pharmaceut Sci, TOUR, London, England..
    Blomqvist, C.
    Orebro Univ, Univ Hosp, Dept Oncol, SE-70182 Orebro, Sweden..
    Sund, M.
    Umea Univ, Dept Surg & Perioperat Sci Surg, SE-90185 Umea, Sweden..
    Nilsson, G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    The relationship between radiation doses to coronary arteries and later intervention requiring coronary stenosis in breast cancer2018In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 92, p. S61-S62Article in journal (Other academic)
  • 15. Zoltowska Nilsson, Anna Maria
    et al.
    Lei, Ying
    Adner, Mikael
    Nilsson, G P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Immunology and Allergy Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden; Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden .
    Mast cell dependent IL-33/ST2 signaling is protective against the development of airway hyperresponsiveness in a house dust mite mouse model of asthma2018In: American Journal of Physiology - Lung cellular and Molecular Physiology, ISSN 1040-0605, E-ISSN 1522-1504, Vol. 314, no 3, p. L484-L492Article in journal (Refereed)
    Abstract [en]

    Interleukin-33 (IL-33) and its receptor ST2 have been influentially associated to the pathophysiology of asthma. Due to the divergent roles of IL-33 in regulating mast cell functions, there is a need to further characterize IL-33/ST2-dependent mast cell responses and their significance in the context of asthma. This study aimed to investigate how IL-33/ST2-dependent mast cell responses contribute to the development of airway hyperresponsiveness (AHR) and airway inflammation in a mouse model of house dust mite (HDM) induced asthma. Mast cell deficient C57BL/6-KitW-sh (Wsh) mice engrafted with either wild-type (Wsh+MC-WT) or ST2 deficient bone marrow derived mast cells (Wsh+MC-ST2KO) were exposed to HDM delivered intranasally. An exacerbated development of AHR in response to HDM was seen in Wsh+MC-ST2KO compared to Wsh+MC-WT mice. The contribution of this IL-33/ST2-dependent mast cell response to AHR seems to reside within the smaller airways in the peripheral parts of the lung, as suggested by the isolated yet marked effect on tissue resistance. Considering the absence of a parallel increase in cellular inflammation in BALF and lung, the aggravated AHR in Wsh+MC-ST2KO mice, seems to be independent of cellular inflammation. We observed an association between the elevated AHR and reduced PGE2 levels in bronchoalveolar lavage fluid. Due to the protective properties of PGE2 in airway responses, it is conceivable that IL-33/ST2-dependent mast cell induction of PGE2 could be responsible for the dampening effect on AHR. In conclusion, we reveal that IL-33/ST2-dependent mast cell responses can have a protective, rather than causative role in the development of AHR.

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