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

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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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Yanxia Bi

Shanghai Institute of Immunology, Shanghai Jiao Tong University, Shanghai, China

Competing interests
Yanxia Bi, A patent application based on the study has been submitted (Chinese patent application number: 202011408005.X), and Fubin Li, Yanxia Bi, Yan Zhang, and Huihui Zhang are listed as inventors..
Jian Su

Jiangsu Institute of Hematology, First Affiliated Hospital of Soochow University, Suzhou, China

Competing interests
No competing interests declared.
Shengru Zhou

Department of Dermatology, Shanghai Jiao Tong University, Shanghai, China

Competing interests
No competing interests declared.
Yingjie Zhao

Shanghai Institute of Immunology, Shanghai Jiao Tong University, Shanghai, China

Competing interests
No competing interests declared.
Yan Zhang

Shanghai Institute of Immunology, Shanghai Jiao Tong University, Shanghai, China

Competing interests
Yan Zhang, A patent application based on the study has been submitted (Chinese patent application number: 202011408005.X), and Fubin Li, Yanxia Bi, Yan Zhang, and Huihui Zhang are listed as inventors..
Huihui Zhang

Shanghai Institute of Immunology, Shanghai Jiao Tong University, Shanghai, China

Competing interests
Huihui Zhang, A patent application based on the study has been submitted (Chinese patent application number: 202011408005.X), and Fubin Li, Yanxia Bi, Yan Zhang, and Huihui Zhang are listed as inventors..
Mingdong Liu

Shanghai Institute of Immunology, Shanghai Jiao Tong University, Shanghai, China

Competing interests
No competing interests declared.
Aiwu Zhou

Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, Shanghai, China

Competing interests
No competing interests declared.
Jianrong Xu

Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, Shanghai, China

Competing interests
No competing interests declared.
Meng Pan

Department of Dermatology, Shanghai Jiao Tong University, Shanghai, China

For correspondence
pm10633@rjh.com.cn

Competing interests
No competing interests declared.
Yiming Zhao

Jiangsu Institute of Hematology, First Affiliated Hospital of Soochow University, Suzhou, China

For correspondence
zhaoyimingbox@163.com

Competing interests
No competing interests declared.
Fubin Li

Shanghai Institute of Immunology, Shanghai Jiao Tong University, Shanghai, China

For correspondence
fubin.li@sjtu.edu.cn

Competing interests
Fubin Li, A patent application based on the study has been submitted (Chinese patent application number: 202011408005.X), and Fubin Li, Yanxia Bi, Yan Zhang, and Huihui Zhang are listed as inventors..

"This ORCID iD identifies the author of this article:" 0000-0001-6268-3378

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

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.