Possible involvement of chemokine C‐C receptor 7⁻programmed cell death‐1⁺ follicular helper T‐cell subset in the pathogenesis of autoimmune hepatitis

Abstract

Background and Aim: Recent studies have demonstrated that B cells and follicular helper T (Tfh) cells, which are central regulators of humoral immune response, contribute to the development and progression of autoimmune diseases. Because Tfh cells can be divided into several subsets with distinct functional properties, this study aimed to examine the roles of different subsets of circulating Tfh cells in the immune pathogenesis of autoimmune hepatitis (AIH). Methods: Thirty-five patients with AIH, 28 patients with primary biliary cholangitis, 22 patients with chronic hepatitis B (CHB), and 44 health controls (HC) were enrolled. The frequencies of different Tfh subsets in the blood and liver were examined by flow cytometry and immunohistochemical staining. The function of circulating Tfh subsets was examined after in vitro stimulation. Results: In newly diagnosed AIH patients, the frequency of circulating chemokine C-C receptor 7À programmed cell death-1 + Tfh subset was significantly increased compared with that in CHB patients and HC, significantly correlated with clinical parameters, including serum IgG, prothrombin time and albumin levels, and significantly decreased after corticosteroid treatment. In the liver of AIH patients, the frequencies of activated Tfh subsets were significantly increased and positively correlated with those in the blood. Moreover, the ability to produce interleukin-21 and interleukin-17 from circulating Tfh cells was significantly increased in AIH patients compared with HC. Conclusions: These results significantly extend our understanding of Tfh subsets in AIH and suggest a potential role of dysregulated chemokine C-C receptor 7À programmed cell

Usefulness of chemokine C‐C receptor 7−/programmed cell death‐1+ follicular helper T cell subset frequencies in the diagnosis of autoimmune hepatitis

“…Uncontrolled generation of circulating Tfh cells might reflect germinal center dysregulation and play an important role in amplifying autoreactive B cells, promoting pathogenic autoantibody production, the onset of clinical symptoms, and continued immune responsiveness, and eventually leading to irreversible tissue damage . The CCR7 − PD‐1 + Tfh subset could promote naïve and memory B cells to differentiate into plasma cells, and these mature cells produce IgG and are involved in the pathogenesis of AIH . We hypothesized that the frequency of CCR7 − PD‐1 + Tfh cells would increase earlier than serum IgG levels.…”

“…A total of 12 patients at the onset of AIH, 24 hepatitis B virus (HBV)‐infected patients, and 3 drug‐induced liver injury (DILI) patients were sequentially enrolled in this study at the Niigata University Medical and Dental Hospital (Niigata, Japan). Some of these samples were used in a former study . All the patients with AIH were diagnosed as definite type I AIH by the Japan diagnostic criteria, which include prednisolone efficacy .…”

“…Dysregulated Tfh cells have been shown to play an important role in the induction and progression of the murine model of AIH, and a recent report showed that the frequency of Tfh cells increased significantly in human AIH . Although Tfh cells can be divided into several subsets with distinct functional properties, we recently revealed that chemokine C‐C receptor 7 (CCR7) − /PD‐1 + Tfh cells play important roles in the pathogenesis of human AIH . We hypothesized that because Tfh cells promote B cell maturity and these B cells secrete IgG and ANA, Tfh cells might appear in the peripheral blood before the increases in serum IgG or ANA in patients with AIH.…”

Immune Alterations in Patients With Type 1 Autoimmune Hepatitis Persist Upon Standard Immunosuppressive Treatment

“…The major immune characteristic of AIH is the presence of a marked clusters of differentiation (CD4) and CD8 T‐cell infiltrate involved in hepatocellular damage; however, the precise molecular and cellular mechanisms are still not known. Although dysfunction of regulatory T cells (Tregs) is still debated, recent studies have implicated other lymphocyte subsets, such as γδ T cells, follicular helper T cells (Tfh), and T helper 17 cells (Th17) . An exhaustive analysis of a large panel of major lymphocyte subsets might be useful in drawing a general picture of the immune alterations in AIH.…”

“…Although dysfunction of regulatory T cells (Tregs) is still debated, (9)(10)(11)(12)(13)(14) recent studies have implicated other lymphocyte subsets, such as γδ T cells, (15) follicular helper T cells (Tfh), and T helper 17 cells (Th17). (16)(17)(18)(19) An exhaustive analysis of a large panel of major lymphocyte subsets might be useful in drawing a general picture of the immune alterations in AIH.…”