The Impact Of IgG Subclass On The Pathogenicity Of Autoantibody

Immunoglobulin G4(IgG4)is considered the least potent human IgG isotype for mediating antibody effector function through Fc-FcγR interaction and has been shown to be anti-inflammatory in the context of prolonged inflammation and allergic responses.Paradoxically,IgG4 is also the dominant IgG isotype of pathogenic autoantibodies in IgG4-mediated autoimmune diseases.Here we investigated the impact of IgG isotype and Fc-FcγR interaction on the pathogenicity of such IgG4 autoantibodies and found their distinct impact on IgG4 autoantibodies isolated from different IgG4-mediated diseases.In anti-ADAMTS13(abbreviation of “a disintegrin and metalloproteinase with thrombospondin type 1 motif,member 13”)autoantibodies isolated from thrombotic thrombocytopenic purpura(TTP)patient,the IgG4 isotype is protective in mouse models when compared with IgG1,likely due to its weak FcγR-mediated depletion of ADAMTS13,as reduced FcγR-binding and FcγR-deficiency both attenuate the inhibitory effect of anti-ADAMTS13 autoantibodies.This is clinically supported by the observed correlation between the reduction of human ADAMTS13 activity and protein,and the levels of IgG1,not IgG4 autoantibodies in TTP patients.In contrast,Fc-FcγR interaction is protective in anti-Dsg1(abbreviation of “desmoglein1”)autoantibodies isolated from pemphigus foliaceus(PF)patient.The protective role of Fc-FcγR interaction in Dsg1-autoantibody-induced pemphigus pathogenesis is supported by the exacerbated skin lesions observed in FcγR-deficient mice,and the attenuated skin lesions and accelerated recovery in mice treated with an anti-Dsg1 antibody variant optimized for FcγR-mediated effector function.Strikingly,a nonpathogenic anti-Dsg1 antibody variant optimized for FcγR-mediated effector function can attenuate the skin lesions induced by pathogenic anti-Dsg1 antibodies by promoting the clearance of dead keratinocytes.These studies suggest that IgG effector function contributes to the clearance of autoantibody-Ag complex,which is deleterious in the TTP model(although no TTP-like sympotoms),but beneficial in PF and may provide new therapeutic opportunity.Our study further suggests that the choice of IgG4 isotype in anti-ADAMTS13 autoantibodies represents a protective mechanism that human has evolved to reduce autoantibody pathogenicity,which is,however,not a wise one in the case of PF,where it seems to exacerbate the pathogenicity of autoantibodies.