Dysregulated TFR and TFH cells correlate with B‐cell differentiation and antibody production in autoimmune hepatitis

Abstract

Follicular helper T (TFH) cell provides germinal centre (GC) B cell with critical signals for autoantibody production in the immunopathogenesis and progression of autoimmune hepatitis (AIH). However, the immunoregulatory functions of follicular regulatory T (TFR) cell in AIH are still unclear. The numbers of circulating TFR/ TFH cells were measured in AIH patients. Moreover, we established experimental autoimmune hepatitis (EAH) model to examine the function of TFR cells on B-cell differentiation and autoantibody production in vivo and vitro. AIH patients had significantly increased numbers of TFH cells and decreased numbers of TFR cells as well as imbalanced TFR/TFH-type cytokines (IL-10, TGF-β1 and IL-21) compared with healthy controls (HCs). In addition, TFR cell numbers negatively correlated with TFH cell numbers. Also, serum hypergammaglobulinaemia (IgG and IgM) concentrationnegatively correlated the levels of serum IL-21, but positively correlated with the levels of serum IL-10 in AIH patients. Furthermore, in comparison with control group, significantly higher frequencies of spleen TFR cells but lower frequencies of spleen TFH cells were detected in the EAH group. Further analysis found that TFR cells simultaneously express the phenotypic characteristics of Treg and TFH cells, but exercise as negative regulators of autoantibody production in vitro culture. Our findings demonstrated that dysregulated between TFR and TFH cells might cause excessive production of autoantibodies and destruction of the immune homeostasis, leading to the immunopathological process in AIH.

Regulatory T Cells in Autoimmune Hepatitis: Unveiling Their Roles in Mouse Models and Patients

“…Tregs, the main regulators of the immune system, can work with other cells in the liver, contributing to the disease process of immune-mediated liver injury ( Figure 3 ). It is well-documented that an imbalance between Tregs and effector T cells is related to AIH pathogenesis ( 114 , 115 ). The Treg/Th17 ratio has been regarded as a predictor of the degree of liver inflammation, as well as a therapeutic target in AIH ( 30 , 83 , 85 , 89 , 116 ).…”

Immunoregulatory Cells in Myasthenia Gravis

“…Tfr and Tfh cells regulate humoral immunity in opposite directions (104). Imbalance between these two populations dysregulates production of autoantibodies, promoting pathogenic autoimmunity (105,106). Tfr and Tfh cells primarily reside in GCs (98).…”

Autoimmmune hepatitis

“…TFH, a subset of antigen-experienced CD4 T cells, are located in secondary lymphoid organs and promote the differentiation of B cells into memory B cells and plasma cells; they secrete high amounts of IL-21 and have counterparts in the circulation. Chemokine C-C receptor 7 negative/programmed cell death-1 positive (CCR7-/PD-1 + ) TFH have been reported to be more frequent in the peripheral blood of AIH patients than in controls, including healthy subjects and patients with CHB, and have been suggested to be a diagnostic marker of AIH [ 81 – 83 ]. However, when appropriate controls were investigated, no difference was observed between AIH and PBC, undermining the concept that an elevation of these cells is a marker specific for AIH [ 83 ].…”