Imbalance toward TFH 1 cells playing a role in aberrant B cell differentiation in systemic sclerosis

Abstract

Objective SSc is a connective tissue disease with multisystem disorder induced by the inflammation and fibrosis following T and B cell abnormalities. Follicular helper CD4+ T (TFH) cells play a crucial role in the formation of germinal centres and specialize in interacting to aid B cell differentiation. We aimed to investigate TFH cells and their subsets to evaluate their involvement with B cell alteration in SSc. Method Circulating TFH cells (cTFH), B cells and their subsets were assessed by flow cytometry. The concentration of serum cytokines was measured by cytokine array assay. Immunohistochemistry and IF were performed to evaluate the migration of TFH cells in SSc skin lesions. Results The proportion of cTFH cells did not differ from controls, but their subsets were imbalanced in SSc patients. The frequency of TFH 1 was increased and correlated with ACA titre, serum IgM or CRP levels of patients, and cytokine concentrations of IL-21 and IL-6 that induce B cell differentiation in SSc. cTFH cells from SSc showed activated phenotype with expressing higher cytokine levels compared with controls. The frequency of TFH 17 was also increased, but was not correlated with a high level of Th17 cytokines in patients’ sera. Furthermore, infiltration of TFH cells was found in skin lesion of SSc patients. Conclusion We here describe an imbalance of cTFH toward TFH 1 that may induce B cell alteration through IL-21 and IL-6 pathways and promote inflammation, contributing to the pathogenesis of SSc disease.

TFH cells in systemic sclerosis

“…In SSc patients, abnormalities in the number or frequency of cTfh are inconstant. While cTfh cells are increased in SSc patients compared with healthy subjects and expresses a high level of PD-1 and other activation markers including HLA-DR or ICOS in a first study [ 24 ], in the other studies, the frequency of cTfh among CD4 + T cells is similar between SSc patients and healthy subjects [ 25 , 26 ]. Heterogeneity of both severity and duration of the disease and pathophysiological features could explain these observations.…”

“…Recently, a study based on homogeneous population of early dcSSc highlighted that cTfh cells are significantly increased in SSc patients than healthy subjects [ 29 ]. Moreover, loss of cTfh homeostasis has been observed [ 25 ]. According to Morita et al .…”

“…Tfh cells induce B cells differentiation and promote immunoglobulin secretion by IL-21 secretion. During SSc, cTfh cells impairment is associated with an imbalance of B cell subsets [ 25 , 35 ]. Frequencies of both naïve B cells and plasmablasts are increased while the frequency of memory B cells is reduced.…”

“…In tissue, several studies conducted in animals and humans have described that T cells are involved in skin fibrosis generation [ 36 , 37 ] and Tfh-like cells infiltrates were found in skin lesions from SSc patients [ 25 , 38 , 39 ]. This infiltrate have an increased frequency than healthy subjects and is positively correlated with mRSS and with a breakdown product of collagen I involved in ECM synthesis [ 38 ].…”

“…Several other positive or negative costimulatory signals participate in Tfh cell differentiation and activation. Among them, CD40L and ICOS, and its binding partners CD40 and ICOS-L expressed by B cells or dendritic cells (DCs) are involved in the pathogenesis of SSc [ 60 , 61 ] and strongly expressed by cTfh in SSc patients [ 24 , 25 ]. In animal models, blocking ICOS or CD40L reduces the frequency of Tfh [ 19 ].…”