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

Takanori Sasaki, Taiki Yajima, Tatsuro Shimaoka, Shuhei Ogawa, Takashi Saito, Kunihiro Yamaoka, Tsutomu Takeuchi, Masato Kubo

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)163-174
Number of pages12
JournalInternational immunology
Volume32
Issue number3
DOIs
Publication statusPublished - 2019 Dec 3

Keywords

  • IgG4-RD
  • T follicular helper cells
  • autoimmune disease
  • cytotoxic T lymphocytes
  • tofacitinib

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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