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

  1. Yanxia Bi
  2. Jian Su
  3. Shengru Zhou
  4. Yingjie Zhao
  5. Yan Zhang
  6. Huihui Zhang
  7. Mingdong Liu
  8. Aiwu Zhou
  9. Jianrong Xu
  10. Meng Pan  Is a corresponding author
  11. Yiming Zhao  Is a corresponding author
  12. Fubin Li  Is a corresponding author
  1. Shanghai Jiao Tong University, China
  2. First Affiliated Hospital of Soochow University, China

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.

Data availability

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.

Article and author information

Author details

  1. 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..
  2. Jian Su

    Jiangsu Institute of Hematology, First Affiliated Hospital of Soochow University, Suzhou, China
    Competing interests
    No competing interests declared.
  3. Shengru Zhou

    Department of Dermatology, Shanghai Jiao Tong University, Shanghai, China
    Competing interests
    No competing interests declared.
  4. Yingjie Zhao

    Shanghai Institute of Immunology, Shanghai Jiao Tong University, Shanghai, China
    Competing interests
    No competing interests declared.
  5. 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..
  6. 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..
  7. Mingdong Liu

    Shanghai Institute of Immunology, Shanghai Jiao Tong University, Shanghai, China
    Competing interests
    No competing interests declared.
  8. 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.
  9. 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.
  10. Meng Pan

    Department of Dermatology, Shanghai Jiao Tong University, Shanghai, China
    For correspondence
    pm10633@rjh.com.cn
    Competing interests
    No competing interests declared.
  11. 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.
  12. 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..
    ORCID icon "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.

Reviewing Editor

  1. Tomohiro Kurosaki, Osaka University, Japan

Publication history

  1. Preprint posted: December 8, 2020 (view preprint)
  2. Received: December 8, 2021
  3. Accepted: August 2, 2022
  4. Accepted Manuscript published: August 3, 2022 (version 1)
  5. Version of Record published: August 17, 2022 (version 2)

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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  1. Yanxia Bi
  2. Jian Su
  3. Shengru Zhou
  4. Yingjie Zhao
  5. Yan Zhang
  6. Huihui Zhang
  7. Mingdong Liu
  8. Aiwu Zhou
  9. Jianrong Xu
  10. Meng Pan
  11. Yiming Zhao
  12. Fubin Li
(2022)
Distinct impact of IgG subclass on autoantibody pathogenicity in different IgG4-mediated diseases
eLife 11:e76223.
https://doi.org/10.7554/eLife.76223

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