Distinct impact of IgG subclass on autoantibody pathogenicity in different IgG4-mediated diseases
Abstract
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.
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All data and materials generated or analyzed during this study are either included in this manuscript (Figures and supplementary information) or available upon reasonable request.
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Funding
National Natural Science Foundation of China (31422020)
- Fubin Li
National Natural Science Foundation of China (31870924)
- Fubin Li
National Natural Science Foundation of China (81873431)
- Yiming Zhao
Jiangsu Provincial Natural Science Foundation (BK20181164.)
- Yiming Zhao
Shanghai Sailing Program (16YF1409700)
- Yan Zhang
Shanghai Municipal Natural Science Foundation project (15ZR1436400)
- Huihui Zhang
Shanghai Young Oriental scholar program 2015
- Huihui Zhang
Innovative research team of high-level local universities in Shanghai (SSMU-2DCX20180100)
- Yan Zhang
- Huihui Zhang
- Fubin Li
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All mice were bred and maintained under specific pathogen-free (SPF) conditions, and all animal experiments were performed under the institutional guidelines of the Shanghai Jiao Tong University School of Medicine Institutional Animal Care and Use Committee (Protocol Registry Number: A-2015-014).
Human subjects: Ethical approval was obtained from the Ethics Committees in The Rui Jin Hospital of Shanghai Jiao Tong University School of Medicine and The First Affiliated Hospital of Soochow University, respectively. All PF and TTP patients and healthy volunteers signed informed consent.
Copyright
© 2022, Bi et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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