| First Author | Kasperkiewicz M | Year | 2012 |
| Journal | J Pathol | Volume | 228 |
| Issue | 1 | Pages | 8-19 |
| PubMed ID | 22430937 | Mgi Jnum | J:186784 |
| Mgi Id | MGI:5433243 | Doi | 10.1002/path.4023 |
| Citation | Kasperkiewicz M, et al. (2012) Genetic identification and functional validation of FcgammaRIV as key molecule in autoantibody-induced tissue injury. J Pathol 228(1):8-19 |
| abstractText | 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 Fcgamma receptor (FcgammaR) IV and components of the neutrophil-associated enzyme system in autoantibody transfer-induced EBA. Validation experiments, including functional analysis, demonstrated that FcgammaRIV expression on neutrophils crucially contributes to autoantibody-induced tissue injury in the transfer model of EBA. Mice lacking the common gamma-chain of activating FcgammaRs, deficient in FcgammaRIV or treated with FcgammaRIV function blocking antibody, but not mice deficient in FcgammaRI, FcgammaRIIB, FcgammaRIII or both FcgammaRI and FcgammaRIII, were effectively protected from EBA. Skin disease was restored in gamma-chain-deficient mice locally reconstituted with neutrophils from wild-type, but not from gamma-chain-deficient, mice. Our findings both genetically and functionally identify a novel disease-related molecule, FcgammaRIV, in an autoantibody-mediated disorder, which may be of importance for the development of novel targeted therapies. Copyright (c) 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. |
