Genetic identification and functional validation of FcγRIV as key molecule in autoantibody-induced tissue injury.

Michael Kasperkiewicz, Falk Nimmerjahn, Sabina Wende, Misa Hirose, Hiroaki Iwata, Marcel F Jonkman, Unni Samavedam, Yask Gupta, Steffen Möller, Ellen Rentz, Lars Hellberg, Kathrin Kalies, Xinhua Yu, Enno Schmidt, Robert Häsler, Tamás Laskay, Jürgen Westermann, Jörg Köhl, Detlef Zillikens, Ralf J Ludwig
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Journal of pathology : a journal of the Pathological Society of Great Britain and Ireland
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Autoantibody-mediated diseases are clinically heterogeneous and often fail conventional therapeutic strategies. Gene expression profiling has helped to identify new molecular pathways in these diseases, although their potential as treatment targets largely remains to be functionally validated. Based on weighted gene co-expression network analysis, we determined the transcriptional network in experimental epidermolysis bullosa acquisita (EBA), a paradigm of an antibody-mediated organ-specific autoimmune disease characterized by autoantibodies directed against type VII collagen. We identified 33 distinct and differentially expressed modules, including Fcγ receptor (FcγR) IV and components of the neutrophil-associated enzyme system in autoantibody transfer-induced EBA. Validation experiments, including functional analysis, demonstrated that FcγRIV expression on neutrophils crucially contributes to autoantibody-induced tissue injury in the transfer model of EBA. Mice lacking the common γ-chain of activating FcγRs, deficient in FcγRIV or treated with FcγRIV function blocking antibody, but not mice deficient in FcγRI, FcγRIIB, FcγRIII or both FcγRI and FcγRIII, were effectively protected from EBA. Skin disease was restored in γ-chain-deficient mice locally reconstituted with neutrophils from wild-type, but not from γ-chain-deficient, mice. Our findings both genetically and functionally identify a novel disease-related molecule, FcγRIV, in an autoantibody-mediated disorder, which may be of importance for the development of novel targeted therapies.