Synergistic effect of IgG4 antibody and CTLs causes tissue inflammation in IgG4-related disease

Abstract IgG4-related disease (IgG4-RD) is characterized by multi-organ irreversible damage resulting from tissue-specific infiltration of IgG4+ plasma cells and cytotoxic T lymphocytes (CTLs). However, whether IgG4 antibody contributes to the inflammation remains unclear. In this study, we establis...

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Published in:International immunology 2020-03, Vol.32 (3), p.163-174
Main Authors: Sasaki, Takanori, Yajima, Taiki, Shimaoka, Tatsuro, Ogawa, Shuhei, Saito, Takashi, Yamaoka, Kunihiro, Takeuchi, Tsutomu, Kubo, Masato
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container_title International immunology
container_volume 32
creator Sasaki, Takanori
Yajima, Taiki
Shimaoka, Tatsuro
Ogawa, Shuhei
Saito, Takashi
Yamaoka, Kunihiro
Takeuchi, Tsutomu
Kubo, Masato
description Abstract IgG4-related disease (IgG4-RD) is characterized by multi-organ irreversible damage resulting from tissue-specific infiltration of IgG4+ plasma cells and cytotoxic T lymphocytes (CTLs). However, whether IgG4 antibody contributes to the inflammation remains unclear. In this study, we established a mouse model that enabled us to evaluate the pathogenic function of IgG4 antibodies in response to a tissue-specific autoantigen using recombinant ovalbumin (OVA)-specific human IgG4 monoclonal antibody (rOVA-hIgG4 mAb) and the mice expressing OVA of the pancreatic islets (RIP-mOVA mice). We found no inflammatory effect of rOVA-hIgG4 mAb transfer alone; however, co-transfer with OVA-specific CD8 CTLs (OT-I T cells) induced tissue damage with dense lymphocytic inflammation in the pancreas of RIP-mOVA mice. rOVA-hIgG4 mAb caused accumulation of conventional DC1 cells (cDC1s) in the lymphoid tissues, and the dendritic cells (DCs) activated the OT-I T cells via cross-presentation. We also revealed that the synergistic effects of CTLs and antibodies were observed in the other subclasses including endogenous antibodies if they recognized the same antigen. The transfer of OVA-specific CD4 helper T cells (OT-II T cells) into RIP-mOVA mice induced the production of anti-OVA antibody, which had a synergistic effect, through acquisition of a T follicular helper (TFH) phenotype. Moreover, using OT-II T cells deficient in Bcl6 caused lower anti-OVA antibody production and inflammation with OT-I T cells. Our results indicated that autoreactive IgG4 antibodies play an important role of the tissue-specific CTL response in IgG4-RD. Autoantigen-specific IgG4 synergizes with CTLs in IgG4-RD
doi_str_mv 10.1093/intimm/dxz073
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title Synergistic effect of IgG4 antibody and CTLs causes tissue inflammation in IgG4-related disease
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