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

Abstract

ObjectiveTo determine the number and function of follicular helper T (Tfh) cell subsets in IgG4‐related disease (IgG4‐RD).MethodsMononuclear 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.ResultsFrequencies 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.ConclusionTfh cell subsets are expanded in IgG4‐RD and may play pivotal roles in the pathogenesis of the disease.

Efficacy and safety of iguratimod plus corticosteroid as bridge therapy in treating mild IgG4‐related diseases: A prospective clinical trial

“…In addition, there are some studies published in Chinese which showed iguratimod treatment was effective for primary Sjögren's syndrome and patient's serum Ig was decreased as well. As we know, one of the most prominent characteristics of IgG4‐RD is activation of B cells and plasmablast cells, which excrete large amount of serum IgG and IgG4 . Therefore, we think that iguratimod treatment may be effective in the treatment of IgG4‐RD.…”

“…Immunoglobulin G4‐related disease (IgG4‐RD) is a newly defined chronic fibro‐inflammatory disorder characterized by elevated serum IgG4 levels, tumefactive lesions with a dense lymphoplasmacytic infiltration rich in IgG4 positive plasma cells and storiform fibrosis of related organs . Glucocorticoids are the first‐line agents for the treatment of IgG4‐RD; however, in order to maintain long‐term disease stability and avoid disease relapse, usually glucocorticoids maintenance therapy should last for a long period, which may induce various glucocorticoid‐associated adverse reactions.…”

Identifying clinical subgroups in IgG4-related disease patients using cluster analysis and IgG4-RD composite score

“…And the independents introduced in IgG4-RD CS prediction model are supported by previous evidences. Such abnormalities of specific lymphocyte subsets are present in the blood of patients with IgG4-RD, including CD4+ cytotoxic T lymphocytes (CTL), follicular helper T (Tfh) cell, CD19+CD24−CD38hi plasmablasts/ plasma cells, and so on [32,[40][41][42][43][44], and the role of Eosinophil in IgG4-RD has been reported in previous studies [15,16,45,46]. Finally, after we performed cluster analysis in different genders, IgG4-RD CS presented superior ability to guide treatment in female patients.…”

Advances in the diagnosis and management of IgG4 related disease

“…Circulating Tfh1 and Tfh2 cells expressing programmed cell death protein 1 (PD1) are expanded in patients with IgG4-RD and correlate with disease activity, plasmablast numbers, and serum concentrations of IgG4 and interleukin 4 444546. PD1 positive Tfh2 cells drive IgG4 class switch in vitro, enhance proliferation of IgG4 committed B cells, and facilitate differentiation of naive B cells into plasmablasts/plasma cells, resulting in increased IgG4 secretion 464748. Activated Tfh cells expressing interleukin 4 and interleukin 21 are also found in tertiary lymphoid structures of IgG4-RD affected tissues and likely contribute to germinal center formation 1495051.…”