Abstract
This study is aimed at examining the potential role of regulatory T- (Treg-) Th1-Th17-Th22 cells in the pathogenic process of autoimmune hepatitis (AIH). The numbers of Foxp3+Tregs and Th1, Th17, and Th22 cells were measured in 32 AIH patients using flow cytometry. Moreover, a murine model of experimental autoimmune hepatitis (EAH) was also established and used to investigate the function of Treg-Th1-Th17-Th22 cells in disease progression. AIH patients undergoing an active state had significantly decreased numbers of CD3+CD4+CD25+Foxp3+Tregs and increased numbers of CD3+CD4+CD25−Foxp3+T, CD3+CD4+IFN-γ+Th1, CD3+CD4+IL-17+Th17, and CD3+CD4+IL-2+Th22 cells as well as higher levels of Th1/Th17/Th22-type cytokines compared to AIH patients in remission and HC. Additionally, the numbers of CD3+CD4+CD25+Foxp3+Tregs were negatively correlated with the numbers of Th1-Th17-Th22 cells. Also, the serum levels of IL-17A and IL-22 were correlated positively with liver injury (ALT/AST), whereas the serum levels of IL-10 were correlated negatively with hypergammaglobulinaemia (IgG, IgM) in AIH patients. Interestingly, the percentages of spleen Tregs, expression of Foxp3 mRNA, and liver IL-10 levels decreased, whereas the percentages of spleen Th1-Th17-Th22 cells, expression of T-bet/AHR/RORγt mRNA, and liver IFN-γ, IL-17, and IL-22 levels increased in the murine model of EAH. Our findings demonstrated that an imbalance between Tregs and Th1-Th17-Th22 cells might contribute to the pathogenic process of AIH.
Highlights
Autoimmune hepatitis (AIH) is a type of autoimmune inflammatory liver disease characterized by hypergammaglobulinaemia, circulating autoantibodies, and the liver injury with elevated levels of serum liver enzymes [1]
We found that the serum levels of alanine transaminase (ALT), AST, γ-GGT, and ALP were significantly descending compared to per-treatment values
We found a strong Th1 and Th17 proinflammatory response with increased levels of serum/liver Th1-type (IFN-γ) and Th17-type (IL-17A) cytokines in AIH patients undergoing an active state and experimental autoimmune hepatitis (EAH) mice, indicating that Th1 and Th17 cells have critical functions in the pathogenic process of AIH, which were consistent with previous studies [6,7,8,9]
Summary
Autoimmune hepatitis (AIH) is a type of autoimmune inflammatory liver disease characterized by hypergammaglobulinaemia, circulating autoantibodies, and the liver injury with elevated levels of serum liver enzymes [1]. While genetic and environmental factors contribute to the pathogenic process of AIH [2], dysfunctional immune responses are crucial for the development and progression of AIH [3]. Numerous studies have revealed a transient and moderate increase in the production of Th1 cytokines, including interleukin-2 (IL-2), interferon-γ (IFN-γ), and tumor necrosis factor α (TNF-α) in AIH patients [6, 7]. Recent studies suggested that Th17 cells and further released cytokine IL-17 may induce accumulation of proinflammatory cells [8, 9], which contributed to the occurrence of AIH. In addition to well-characterized Th1 and Th17 lymphocytes, a new IL-22-producing T cell, termed Th22 cell, has been described as expressing its key cytokine IL-22, which can activate signal transduction and transcription 3 (STAT3) [10].
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