Distinct impact of IgG subclass on autoantibody pathogenicity in different IgG4-mediated diseases

• Published in: eLife 2022-08, Vol.11
• Main Authors: Bi, Yanxia, Su, Jian, Zhou, Shengru, Zhao, Yingjie, Zhang, Yan, Zhang, Huihui, Liu, Mingdong, Zhou, Aiwu, Xu, Jianrong, Pan, Meng, Zhao, Yiming, Li, Fubin
• Format: Article
• Language: English
• Subjects: ADAMTS13; autoantibody; desmoglein 1; Fc-FcγR interaction; IgG4; Immunology and Inflammation
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.76223

IgG4 is the least potent human IgG subclass for the FcγR-mediated antibody effector function. Paradoxically, IgG4 is also the dominant IgG subclass of pathogenic autoantibodies in IgG4-mediated diseases. Here, we show that the IgG subclass and Fc-FcγR interaction have a distinct impact on the pathogenic function of autoantibodies in different IgG4-mediated diseases in mouse models. While IgG4 and its weak Fc-FcγR interaction have an ameliorative role in the pathogenicity of anti-ADAMTS13 autoantibodies isolated from thrombotic thrombocytopenic purpura (TTP) patients, they have an unexpected exacerbating effect on anti-Dsg1 autoantibody pathogenicity in pemphigus foliaceus (PF) models. Strikingly, a non-pathogenic 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 complexes, which is harmful in TTP, but beneficial in PF and may provide new therapeutic opportunity.