BaCKgRoUND aND aIMS: T cells from patients with primary sclerosing cholangitis (PSC) show a prominent interleukin (IL)-17 response upon stimulation with bacteria or fungi, yet the reasons for this dominant T-helper 17 (Th17) response in PSC are not clear. Here, we analyzed the potential role of monocytes in microbial recognition and in skewing the T-cell response toward Th17. appRoaCH aND ReSUltS: Monocytes and T cells from blood and livers of PSC patients and controls were analyzed ex vivo and in vitro using transwell experiments with cholangiocytes. Cytokine production was measured using flow cytometry, enzyme-linked immunosorbent assay, RNA in situ hybridization, and quantitative real-time PCR. Genetic polymorphisms were obtained from ImmunoChip analysis. Following ex vivo stimulation with phorbol myristate acetate/ ionomycin, PSC patients showed significantly increased numbers of IL-17A-producing peripheral blood CD4 + T cells compared to PBC patients and healthy controls, indicating increased Th17 differentiation in vivo. Upon stimulation with microbes, monocytes from PSC patients produced significantly more IL-1β and IL-6, cytokines known to drive Th17 cell differentiation. Moreover, microbe-activated monocytes induced the secretion of Th17 and monocyte-recruiting chemokines chemokine (C-C motif) ligand (CCL)-20 and CCL-2 in human primary cholangiocytes. In livers of patients with PSC cirrhosis, CD14 hi CD16 int and CD14 lo CD16 hi monocytes/ macrophages were increased compared to alcoholic cirrhosis, and monocytes were found to be located around bile ducts. CoNClUSIoNS: PSC patients show increased Th17 differentiation already in vivo. Microbe-stimulated monocytes drive Th17 differentiation in vitro and induce cholangiocytes to produce chemokines mediating recruitment of Th17 cells and more monocytes into portal tracts. Taken together, these results point to a pathogenic role of monocytes in patients with PSC. (Hepatology 2020;72:1310-1326). P rimary sclerosing cholangitis (PSC) is a chronic liver disease characterized by inflammation and fibrosis of the intra-and extrahepatic bile ducts,
The immune system responds differently in women and in men. Generally speaking, adult females show stronger innate and adaptive immune responses than males. This results in lower risk of developing most of the infectious diseases and a better ability to clear viral infection in women (1-5). On the other hand, women are at increased risk of developing autoimmune diseases (AID) such as rheumatoid arthritis, multiple sclerosis (MS), systemic lupus erythematosus (SLE), Sjögren's syndrome, and the autoimmune liver diseases autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) (6). Factors contributing to the female sex bias in autoimmune diseases include environmental exposure, e.g., microbiome, behavior, and genetics including X chromosomal inactivation of genes. Several lines of evidence and clinical observations clearly indicate that sex hormones contribute significantly to disease pathogenesis, and the role of estrogen in autoimmune diseases has been extensively studied. In many of these diseases, including the autoimmune liver diseases, T cells are thought to play an important pathogenetic role. We will use this mini-review to focus on the effects of androgens on T cells and how the two major androgens, testosterone and dihydrotestosterone, potentially contribute to the pathogenesis of autoimmune liver diseases (AILD).
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease that is believed to be driven by a CD4 + T cell response to liver Ags. However, the pathogenic function of CD4 + effector T cells in AIH is not fully understood. To characterize liver-infiltrating lymphocytes in AIH, we determined the cytokine production of infiltrating cells obtained from biopsy material by quantitative RT-PCR and flow cytometry. A cytokine quantitiative RT-PCR array of AIH specimens revealed that TNF was the most strongly upregulated cytokine, as compared with control livers. To confirm this finding, we determined the frequencies of TNF-producing CD4 + T cells in peripheral blood and in liver biopsy specimens in comparison with those of CD4 + T cells producing IFN-g or IL-17. In AIH, TNF-producing CD4 + T cells were significantly expanded, both in blood and liver, whereas IL-17-producing CD4 + T cells were not. However, the majority of the TNF-producing CD4 + T cells in AIH also produced IFN-g, suggesting that TNF producers might represent a pathogenic activation state of Th1 cells. Ag-specific stimulation of PBMC from AIH patients with the AIH-associated autoantigen SEPSECS resulted in significant TNF production only in patients manifesting SLA/LP autoantibodies targeting SEPSEC but not in healthy individuals who do not manifest this reactivity. Taken together, our findings indicated that TNF-producing CD4 + T cells are expanded in AIH, both in blood and in liver. TNF-producing CD4 + T cells in AIH seem to be aberrantly activated Th1 cells. Our findings provide a rationale for therapeutic efforts using TNF blockade in AIH.
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