Primary biliary cirrhosis is a generalized autoimmune epithelitis

Abstract

Primary biliary cirrhosis (PBC) is a chronic progressive autoimmune cholestatic liver disease characterized by highly specific antimitochondrial antibodies (AMAs) and the specific immune-mediated injury of small intrahepatic bile ducts. Unique apoptotic feature of biliary epithelial cells (BECs) may contribute to apotope presentation to the immune system, causing unique tissue damage in PBC. Perpetuation of inflammation may result in senescence of BECs, contributing to irreversible loss of bile duct. In addition to the classic liver manifestations, focal inflammation and tissue damage are also seen in salivary glands and urinary tract in a significant proportion of PBC patients. These findings provide potent support to the idea that molecular mimicry may be involved in the breakdown of autoimmune tolerance and mucosal immunity may lead to a systematic epithelitis in PBC patients. Thus, PBC is considered a generalized epithelitis in clinical practice.

Figure 1

Microbial mimic can trigger the self-destructing immunopathogenic process in primary biliary cirrhosis (PBC). PBC-specific mitochondrial autoantigens remains structurally intact and retains its immunogenicity during biliary epithelial cell (BEC) apoptosis leading to the formation of apotope which can be recognized by circulating anti-mitochondrial autoantibody (AMA). The immune complex would stimulate innate and adaptive immunity in s subject with a susceptible genetic background. Progressive BEC damage tilts the balance between cellular injury and proliferative repair, leading to BEC senescence. The senescent BECs can secret a large amount of senescence-associated secretory phenotype (SASP) which may exert cytolytic response on the senescent cells and neighbouring cells. All of these processes can result in the progressive loss of bile ducts and liver fibrosis.

Figure 2

A pathogenetic view of the relationship between autoimmune epithelitis and PBC. (1) PBC-specific mitochondrial autoantigens remains structurally intact and retains its immunogenicity during BECs apoptosis, leading to selective damage of small bile ducts; (2) Progressive BEC damage may lead to BEC senescence and production of SASPs, resulting in progressive loss of bile ducts and liver fibrosis; (3) Infectious agents, such as E. coli, may drive urethral epithelitis via molecular mimicry, which may be an initial event in PBC immunological breakdown; (4) IgA AMA may be presents in bile, urine and saliva, supporting the idea that IgA AMA is not restricted to biliary tissues but is a more general phenomenon in PBC; and (5) Mucosal immunity in other ductal epithelial tissues such as salivary glands, urinary tract, and gut may induce generalized epithelitis in PBC.