Xenobiotics and loss of tolerance in primary biliary cholangitis

Abstract

Data from genome wide association studies and geoepidemiological studies established that a combination of genetic predisposition and environmental stimulation is required for the loss of tolerance in primary biliary cholangitis (PBC). The serologic hallmark of PBC are the presence of high titer anti-mitochondrial autoantibodies (AMA) that recognize the lipoyl domain of the mitochondrial pyruvate dehydrogenase E2 (PDC-E2) subunit. Extensive efforts have been directed to investigate the molecular basis of AMA. Recently, experimental data has pointed to the thesis that the breaking of tolerance to PDC-E2 is a pivotal event in the initial etiology of PBC, including environmental xenobiotics including those commonly found in cosmetics and food additives, suggesting that chemical modification of the PDC-E2 epitope may render its vulnerable to become a neo-antigen and trigger an immune response in genetically susceptible hosts. Here, we will discuss the natural history, genetics and immunobiology of PBC and structural constraints of PDC-E2 in AMA recognition which makes it vulnerable to chemical modification.

Keywords: Antimitochondrial autoantibodies; Primary biliary cholangitis; Pyruvate dehydrogenase E2; Breaking of tolerance; Xenobiotics

Core tip: Environment influences immune functions. In this paper, we examine how environmental chemicals can trigger autoimmunity in an organ specific autoimmune disease, primary biliary cholangitis (PBC). PBC is liver specific autoimmune disease characterized by high titer of anti-mitochondrial autoantibodies directed against the E2 subunit of pyruvate dehydrogenase (PDC-E2) lipoyl domain. Here, we present experimental evidence from quantitative structure-activity relationship and animal models that xenobiotic modification of the PDC-E2 lipoyl domain could lead to loss of self-tolerance and is a pivotal event in the initial etiology of PBC in genetically susceptible hosts.