Aberrant Expansion and Function of Follicular Helper T Cell Subsets in IgG4-Related Disease

Arthritis Rheumatol. 2018 Nov;70(11):1853-1865. doi: 10.1002/art.40556. Epub 2018 Aug 29.

Abstract

Objective: To determine the number and function of follicular helper T (Tfh) cell subsets in IgG4-related disease (IgG4-RD).

Methods: Mononuclear cells from the peripheral blood and involved tissue of patients with IgG4-RD were assessed for Tfh cells and their subsets, and levels of B cell lymphoma 6 (Bcl-6), B lymphocyte-induced maturation protein 1 (BLIMP-1), and interleukin-21 (IL-21) messenger RNA (mRNA). Immunohistochemical and immunofluorescence techniques were used to assess the involved tissue of patients to determine the location of IL-21, Bcl-6, and CD4+CXCR5+ Tfh cells. Furthermore, the ability of circulating Tfh (cTfh) cell subsets to induce B cell proliferation, apoptosis, and differentiation and to produce IgG4 was explored in cell cocultures in vitro.

Results: Frequencies of cTfh cells were significantly increased in the peripheral blood of patients with IgG4-RD, and even higher frequencies were observed in the involved tissue. Percentages of programmed cell death protein 1 in CD4+CXCR5+ICOS+ cTfh cells were positively correlated with the serum levels of IgG and IgG4, IgG4:IgG ratio, number of involved organs, and frequency of CD19+CD24-CD38high plasmablasts/plasma cells. Levels of BLIMP-1 and IL-21 mRNA in peripheral CD4+ T cells were increased in patients with IgG4-RD compared to healthy controls, and this was correlated with the levels of serum IgG4. Moreover, in the involved tissue, Bcl-6, IL-21, and Tfh cells were highly expressed. Compared to cTfh cells from healthy controls, cTfh cells from patients with IgG4-RD could facilitate B cell proliferation and inhibit B cell apoptosis more efficiently, and enhanced the differentiation of naive B cells into switched memory B cells and plasmablasts/plasma cells, with a resultant increase in the secretion of IgG4. Notably, the cTfh1 and cTfh2 cell subsets were the most effective at providing B cell help.

Conclusion: Tfh cell subsets are expanded in IgG4-RD and may play pivotal roles in the pathogenesis of the disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Apoptosis
  • B-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes
  • Case-Control Studies
  • Cell Proliferation
  • Coculture Techniques
  • Female
  • Humans
  • Immunoglobulin G4-Related Disease / genetics
  • Immunoglobulin G4-Related Disease / immunology*
  • In Vitro Techniques
  • Interleukins / genetics
  • Lymphopoiesis
  • Male
  • Middle Aged
  • Positive Regulatory Domain I-Binding Factor 1
  • Proto-Oncogene Proteins c-bcl-6
  • RNA, Messenger / metabolism
  • Receptors, CXCR5
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocytes, Helper-Inducer / immunology*

Substances

  • BCL6 protein, human
  • CXCR5 protein, human
  • Interleukins
  • Proto-Oncogene Proteins c-bcl-6
  • RNA, Messenger
  • Receptors, CXCR5
  • PRDM1 protein, human
  • Positive Regulatory Domain I-Binding Factor 1
  • interleukin-21