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Aberrant Expansion and Function of Follicular Helper T Cell Subsets in IgG4‐Related Disease
Author(s) -
Chen Yu,
Lin Wei,
Yang Hongxian,
Wang Mu,
Zhang Panpan,
Feng Ruie,
Chen Hua,
Peng Linyi,
Zhang Xuan,
Zhao Yan,
Zeng Xiaofeng,
Zhang Fengchun,
Zhang Wen,
Lipsky Peter E.
Publication year - 2018
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.40556
Subject(s) - b cell , peripheral blood mononuclear cell , immunofluorescence , antibody , biology , plasma cell , follicular phase , t cell , immunology , cell , immune system , in vitro , endocrinology , biochemistry , genetics
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 CD 4+ CXCR 5+ Tfh cells. Furthermore, the ability of circulating Tfh ( cT fh) cell subsets to induce B cell proliferation, apoptosis, and differentiation and to produce IgG4 was explored in cell cocultures in vitro. Results Frequencies of cT fh 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 CD 4+ CXCR 5+ ICOS + cT fh cells were positively correlated with the serum levels of IgG and IgG4, IgG4:IgG ratio, number of involved organs, and frequency of CD 19+ CD 24− CD 38 high plasmablasts/plasma cells. Levels of BLIMP ‐1 and IL ‐21 mRNA in peripheral CD 4+ 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 cT fh cells from healthy controls, cT fh 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.