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Regulatory T cells with a defect in inhibition on co-stimulation deteriorated primary biliary cholangitis.

ABSTRACT: Regulatory T cells (Tregs) play an indispensable role in the progression of primary biliary cholangitis (PBC). Although Tregs could normalize costimulation in in vivo and in vitro models, it is obscure whether and how Tregs mediate these effects in PBC. Herein we focused on the quantitative and functional characteristics of Tregs in PBC. The number and proportion of Tregs, and the production of interleukin (IL)-10 were all significantly less in the PBC patients than in the healthy controls (HCs). In addition, compared to the HCs, the costimulatory CD86 of the circulation and liver were significantly higher in the patients with PBC. CD86 expression on CD1c⁺ cells negatively correlated with the proportion of Tregs. There was also a positive correlation between mayo risk score and the ratio of CD86/Treg. In vitro experiments showed that inhibition of CD86 expression on CD1c⁺ cells by Tregs was significantly weakened in the PBC patients. Furthermore, the autoantibodies from the PBC patients could promote CD86 expression on CD1c⁺ cells and transforming growth factor-? production by human hepatic stellate cells. Overall, Tregs declined in inhibition on co-stimulation expression in the presence of autoantibodies, which could be associated to PBC-related bile duct injury and fibrosis. This indicated that maintenance of balance of co-stimulation and Tregs could be beneficial for PBC.

SUBMITTER: Chen J

PROVIDER: S-EPMC5752452 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Regulatory T cells with a defect in inhibition on co-stimulation deteriorated primary biliary cholangitis.

Chen Jianing J Hou Xianliang X Jia Hongyu H Cui Guangying G Wu Zhongwen Z Wang Lin L Lu Chong C Wu Wei W Wei Yingfeng Y Uede Toshimitsu T Li Lanjuan L Lian Zhexiong Z Diao Hongyan H

Oncotarget 20171126 65

Regulatory T cells (Tregs) play an indispensable role in the progression of primary biliary cholangitis (PBC). Although Tregs could normalize costimulation in <i>in vivo</i> and <i>in vitro</i> models, it is obscure whether and how Tregs mediate these effects in PBC. Herein we focused on the quantitative and functional characteristics of Tregs in PBC. The number and proportion of Tregs, and the production of interleukin (IL)-10 were all significantly less in the PBC patients than in the healthy ...[more]

PMID: 29312539

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Project description:Background & aimsAutoimmune liver disease (AILD) is thought to result from a complex interplay between genetics and the environment. Studies to date have focussed on primary biliary cholangitis (PBC) and demonstrated higher disease prevalence in more urban, polluted, and socially deprived areas. This study utilises a large cohort of patients with PBC and primary sclerosing cholangitis (PSC) to investigate potential environmental contributors to disease and to explore whether the geo-epidemiology of PBC and PSC are disease-specific or pertain to cholestatic AILD in general.MethodsAll adult patients with PBC and PSC in a tightly defined geographical area within the UK were identified. Point- and area-based analyses and structural equation modelling (SEM) were used to investigate for disease clustering and examine for relationships between prevalence, distribution of environmental contaminants, and socio-economic status.ResultsWe identified 2,150 patients with PBC and 472 with PSC. Significant spatial clustering was seen for each disease. A high prevalence of PBC was found in urban, post-industrial areas with a strong coal-mining heritage and increased environmental cadmium levels, whereas a high PSC prevalence was found in rural areas and inversely associated with social deprivation.ConclusionsThis study demonstrates spatial clustering of PBC and PSC and adds to our understanding of potential environmental co-variates for both diseases. Disease clustering, within the same geographical area but over different scales, is confirmed for each disease with distinct risk profiles identified and associations with separate putative environmental factors and socio-economic status. This suggests that different triggers and alternative pathways determine phenotypic expression of autoimmunity in the affected population. Co-variate analysis points towards the existence of specific disease triggers.Lay summaryThis study looked for potential environmental triggers in patients with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) living in the north-east of England and north Cumbria. We found that PBC was more common in urban areas with a history of coal mining and high levels of cadmium whereas PSC was more common in rural areas with lower levels of social deprivation.

Project description:Purpose of reviewPrimary biliary cholangitis (PBC) is characterized by autoimmune damage of intrahepatic bile ducts associated with a loss of tolerance to mitochondrial antigens. PBC etiopathogenesis is intriguing because of different perplexing features, namely: a) although mitochondria are present in all cell types and tissues, the damage is mainly restricted to biliary epithelial cells (BECs); b) despite being an autoimmune disorder, it does not respond to immunosuppressive drugs but rather to ursodeoxycholic acid, a bile salt that induces HCO3- rich choleresis; c) the overwhelming female preponderance of the disease remains unexplained. Here we present an etiopathogenic view of PBC which sheds light on these puzzling facts of the disease.Recent findingsPBC develops in patients with genetic predisposition to autoimmunity in whom epigenetic mechanisms silence the Cl-/HCO3- exchanger AE2 in both cholangiocytes and lymphoid cells. Defective AE2 function can produce BECs damage as a result of decreased biliary HCO3- secretion with disruption of the protective alkaline umbrella that normally prevents the penetration of toxic apolar bile salts into cholangiocytes. AE2 dysfunction also causes increased intracellular pH (pHi) in cholangiocytes, leading to the activation of soluble adenylyl cyclase, which sensitizes BECs to bile salt-induced apoptosis. Recently, mitophagy was found to be inhibited by cytosolic alkalization and stimulated by acidification. Accordingly, we propose that AE2 deficiency may disturb mitophagy in BECs, thus, promoting the accumulation of defective mitochondria, oxidative stress and presentation of mitochondrial antigens to the immune cells. As women possess a more acidic endolysosomal milieu than men, mitophagy might be more affected in women in an AE2-defective background. Apart from affecting BECs function, AE2 downregulation in lymphocytes may also contribute to alter immunoregulation facilitating autoreactive T-cell responses.SummaryPBC can be considered as a disorder of Cl-/HCO3- exchange in individuals with genetic predisposition to autoimmunity.

Dataset Information

Regulatory T cells with a defect in inhibition on co-stimulation deteriorated primary biliary cholangitis.

Publications

Regulatory T cells with a defect in inhibition on co-stimulation deteriorated primary biliary cholangitis.

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