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      Allelic and copy-number variations of FcγRs affect granulocyte function and susceptibility for autoimmune blistering diseases.

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          Abstract

          Low-affinity Fcγ receptors (FcγR) bridge innate and adaptive immune responses. In many autoimmune diseases, these receptors act as key mediators of the pathogenic effects of autoantibodies. Genes encoding FcγR exhibit frequent variations in sequence and gene copy number that influence their functional properties. FcγR variations also affect the susceptibility to systemic autoimmunity, e.g. systemic lupus erythematosus and rheumatoid arthritis. This raises the question whether FcγR variations are also associated with organ-specific autoimmunity, particularly autoantibody-mediated diseases, such as subepidermal autoimmune blistering diseases (AIBD). A multitude of evidence suggests a pathogenic role of neutrophil granulocyte interaction with autoantibodies via FcγR. In a two-stage study, we analyzed whether the FcγR genotype affects neutrophil function and mRNA expression, and consequently, bullous pemphigoid (BP) disease risk. We compared this to findings in pemphigus vulgaris/foliaceus (PV/PF), two Fc-independent AIBDs. Our results indicate that both allele and copy number variation of FcγR genes affect FcγR mRNA expression and reactive oxygen species (ROS) release by granulocytes. Susceptibility of BP was associated with FcγR genotypes that led to a decreased ROS release by neutrophils, indicating an unexpected protective role for these cells. BP and PV/PF differed substantially regarding the FcγR genotype association patterns, pointing towards different disease etiologies.

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          Author and article information

          Journal
          J. Autoimmun.
          Journal of autoimmunity
          Elsevier BV
          1095-9157
          0896-8411
          Jul 2015
          : 61
          Affiliations
          [1 ] Department of Dermatology, Allergology and Venereology, University of Lübeck, Lübeck, Germany; Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany. Electronic address: Andreas.Recke@uksh.de.
          [2 ] Department of Experimental Hematology, Sanquin Research Institute, Amsterdam, The Netherlands.
          [3 ] Department of Dermatology, Allergology and Venereology, University of Lübeck, Lübeck, Germany; Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.
          [4 ] Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.
          [5 ] Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck, Germany; Zentrum für Klinische Studien, Universität zu Lübeck, Lübeck, Germany.
          [6 ] Department of Dermatology, Allergology and Venereology, University of Lübeck, Lübeck, Germany.
          [7 ] Department of Transfusion Medicine, University of Lübeck, Lübeck, Germany.
          [8 ] Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany.
          [9 ] Institute of Epidemiology, Christian-Albrechts-University, Kiel, Germany; popgen Biobank, Christian-Albrechts-University, Kiel, Germany.
          [10 ] Department of Dermatology, Allergology and Venereology, Christian-Albrechts-University, Kiel, Germany.
          [11 ] Department of Dermatology, Allergology and Venereology, University Hospital Würzburg, Würzburg, Germany.
          [12 ] Department of Dermatology and Allergology, Ludwig Maximilian University, Munich, Germany.
          [13 ] Department of Dermatology and Allergology, Philipp University of Marburg, Marburg, Germany.
          [14 ] Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.
          [15 ] Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany. Electronic address: Saleh.Ibrahim@uksh.de.
          Article
          S0896-8411(15)00070-0
          10.1016/j.jaut.2015.05.004
          26032265
          dcd59399-edfc-43ec-80b4-c60f91d63352
          History

          Autoimmune blistering dermatoses,Functional genetics,Joint copy number and allelic variation,Neutrophils,Reactive oxygen species,Autoantibodies,Fcγ receptors

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