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vol. 14

Therapeutic and immunological interventions in primary biliary cholangitis: from mouse models to humans

Atsushi Tanaka, Patrick S.C. Leung, Howard A. Young, M. Eric Gershwin

Arch Med Sci 2018; 14, 4: 930–940
Online publish date: 2017/10/24
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Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease that predominantly affects women in their fifth and sixth decades. The diagnostic hallmarks of PBC are detection of anti-mitochondrial antibodies (AMAs) and chronic non-suppurative destructive cholangitis (CNSDC) of small- and medium-sized intrahepatic bile ducts in liver histological examination [1, 2]. A significant amount of data suggests that immunological activity against small biliary epithelial cells (BECs), found histologically as portal inflammation, leads to clinical disease. In PBC, as with other autoimmune diseases, both genetic and environmental factors contribute to the development of pathology [3–8]. The first-line therapy of PBC is ursodeoxycholic acid (UDCA), although obeticholic acid (OCA) has been approved recently for patients with an incomplete response to UDCA [9–11]. Unfortunately, unlike other autoimmune diseases, no successful clinical trials of biologics have been conducted, and the mechanisms of action of UDCA and OCA are not fully understood [12–16].
The clinical phenotype and the natural history of PBC vary between patients and can have other overlapping autoimmune diseases [12, 17–19]. For example, some patients may have mild elevation of liver enzyme levels and remain asymptomatic for life. By contrast, other patients can develop signs of liver failure and rapidly decompensate despite therapy, requiring liver transplantation. A presumption is that these differences are due to genetic and environmental factors, both contributing to the development of PBC to various degrees in each patient [4, 7, 20]. Although multiple genome-wide association studies (GWASs) have been reported differences in several genes [21–24], their clinical implications and relevance remain elusive [25]. In fact, in PBC, in autoimmune diseases, including PBC, the results of GWASs have been disappointing, and efforts have been made recently for both deep sequencing and study of epigenetic events [26–30]. To understand the importance of developing a useful mouse model, other aspects of PBC such as spectra of disease and gender dominance should be considered [18, 31].

Toward solving the etiological mystery

Most autoimmune diseases, including PBC, have a strong sex bias towards women [32, 33]. Male and female immune responses differ and are affected by sex hormones, X-linked genes, and sex-specific microbiota [34–38]. Despite extensive studies with...

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