Distinct impact of IgG subclass on autoantibody pathogenicity in different IgG4-mediated diseases
- Shanghai Jiao Tong University, China
- 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
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.
Metrics
-
- 1,431
- views
-
- 300
- downloads
-
- 3
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Further reading
-
- Biochemistry and Chemical Biology
- Immunology and Inflammation
During parasitoid wasp infection, activated immune cells of Drosophila melanogaster larvae release adenosine to conserve nutrients for immune response. S-adenosylmethionine (SAM) is a methyl group donor for most methylations in the cell and is synthesized from methionine and ATP. After methylation, SAM is converted to S-adenosylhomocysteine, which is further metabolized to adenosine and homocysteine. Here, we show that the SAM transmethylation pathway is up-regulated during immune cell activation and that the adenosine produced by this pathway in immune cells acts as a systemic signal to delay Drosophila larval development and ensure sufficient nutrient supply to the immune system. We further show that the up-regulation of the SAM transmethylation pathway and the efficiency of the immune response also depend on the recycling of adenosine back to ATP by adenosine kinase and adenylate kinase. We therefore hypothesize that adenosine may act as a sensitive sensor of the balance between cell activity, represented by the sum of methylation events in the cell, and nutrient supply. If the supply of nutrients is insufficient for a given activity, adenosine may not be effectively recycled back into ATP and may be pushed out of the cell to serve as a signal to demand more nutrients.
-
- Immunology and Inflammation
- Structural Biology and Molecular Biophysics
Increasing evidence suggests that mechanical load on the αβ T-cell receptor (TCR) is crucial for recognizing the antigenic peptide-bound major histocompatibility complex (pMHC) molecule. Our recent all-atom molecular dynamics (MD) simulations revealed that the inter-domain motion of the TCR is responsible for the load-induced catch bond behavior of the TCR-pMHC complex and peptide discrimination (Chang-Gonzalez et al., 2024). To further examine the generality of the mechanism, we perform all-atom MD simulations of the B7 TCR under different conditions for comparison with our previous simulations of the A6 TCR. The two TCRs recognize the same pMHC and have similar interfaces with pMHC in crystal structures. We find that the B7 TCR-pMHC interface stabilizes under ∼15 pN load using a conserved dynamic allostery mechanism that involves the asymmetric motion of the TCR chassis. However, despite forming comparable contacts with pMHC as A6 in the crystal structure, B7 has fewer high-occupancy contacts with pMHC and exhibits higher mechanical compliance during the simulation. These results indicate that the dynamic allostery common to the TCRαβ chassis can amplify slight differences in interfacial contacts into distinctive mechanical responses and nuanced biological outcomes.
