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    • br Primary biliary cholangitis Primary biliary

    2019-06-20


    Primary biliary cholangitis Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is another rare but devastating immune-mediated cholangiopathy. Similar to PSC, PBC is characterized by portal inflammation leading to fibrosis and eventually cirrhosis. Distinct from PSC, advanced PBC is characterized by the destruction of small bile ducts leading to cholestatic injury and the subsequent hepatic damage associated with this event. Furthermore, PBC primarily affects middle-aged women, which is an opposite trend of that observed in PSC patients. While identified as an autoimmune disorder, PBC is not considered a classical autoimmune disorder and patients usually do not respond to immunosuppressants. Ursodeoxycholic order UCM05 (UDCA) was previously the only FDA approved treatment for PBC but tends to yield inconsistent results and a poor biochemical response. Obeticholic acid (OCA) is currently FDA approved for the treatment of PBC and tends to show favorable biochemical responses, but its direct effect on clinical outcome and quality of life have yet to be determined. Due to the varying efficacy of current treatment strategies, identifying other forms of therapy, such as miRNA-based therapeutics, could prove beneficial for patients suffering from PBC. PBC can be broken down into three subtypes based on clinical course: (i) gradually progressive, (ii) portal hypertension, and (iii) hepatic failure. The authors of this study separated samples from patients who had received two years of UDCA treatment into each category and analyzed the obtained serum samples. The authors identified 97 miRNAs that were differentially expressed among the different subtypes. Furthermore, heat mapping showed that miRNA profiles from hepatic failure and portal hypertension subtypes were clustered differently than those from the gradually progressive subtype or controls. The authors then honed in on miR-139-5p due to the large amount of total short reads obtained for this miRNA, and since it was previously reported as increased in the serum of PBC patients. The expression of miR-139-5p in lymphocytes that infiltrated the liver of PBC patients was significantly increased compared to controls, and in vitro work demonstrated that upregulation of miR-139-5p in hepatocytes correlated with increased tumor necrosis factor (TNF)-α secretion and repressed c-FOS gene transcription. Based on these findings, the authors concluded that miR-139-5p expression is enhanced during PBC and regulates inflammation via TNF-α and c-FOS regulation. A recent study aimed to evaluate the potential roles that miRNAs may play during PBC progression. The authors performed microarray analysis on healthy and PBC plasma samples and identified sixteen miRNAs that were differentially expressed in PBC plasma samples versus healthy controls. Their results also revealed that miR-92a was significantly downregulated in the plasma of PBC patients compared with healthy samples. In focusing specifically on peripheral blood mononuclear cells (PBMCs), the authors found that the expression pattern of miR-572 and miR-92a in PBMCs correlated with the decreased expression pattern seen in the plasma. Furthermore, miR-92a expression inversely correlated with the number of IL-17-producing T helper (Th17) cells, and the expression of miR-92a was highly co-localized with interleukin (IL)-17A in PBMCs isolated from PBC patients, suggesting a direct regulation of IL-17A by miR-92a. There was no correlation between the expression of other miRNAs and the Th17 population. Overall, these findings suggest a unique miRNA profile seen in the plasma of PBC patients that may be used as a diagnostic tool. However, this paper also identifies the possible role that miR-92a may play during the progression of PBC via regulation of Th17 cells. While this paper does not identify the exact role that miR-92a plays in Th17 cells, the authors hypothesized that miR-92a may regulate Th17 cell differentiation, based on other publications. Considering that Th17 cells are a pro-inflammatory cell type, modulation of miR-92a may be a therapeutic option for ameliorating the inflammatory phenotype associated with PBC.