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

• Published in: International immunology Vol. 32; no. 3; pp. 163 - 174
• Main Authors: Sasaki, Takanori, Yajima, Taiki, Shimaoka, Tatsuro, Ogawa, Shuhei, Saito, Takashi, Yamaoka, Kunihiro, Takeuchi, Tsutomu, Kubo, Masato
• Format: Journal Article
• Language: English
• Published: UK Oxford University Press 07.03.2020
• Subjects: cytotoxic T lymphocytes; autoimmune disease; T follicular helper cells; IgG4-RD; tofacitinib
• ISSN: 1460-2377; 1460-2377
• DOI: 10.1093/intimm/dxz073

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