A contemporary perspective on the molecular characteristics of mitochondrial autoantigens and diagnosis in primary biliary cholangitis

Abstract

Primary biliary cholangitis (PBC) is an autoimmune hepatobiliary disease characterized by immune mediated destruction of the intrahepatic small bile ducts and the presence of antimitochondrial antibodies (AMAs). The mitochondrial autoantigens have been identified as the E2 subunits of the 2-oxo-acid dehydrogenase complex, including the E2 subunits of pyruvate dehydrogenase, branched-chain 2-oxo acid dehydrogenase complex, oxoglutarate dehydrogenase complex, E3 binding protein and PDC E1 alpha subunit. The AMA epitope is mapped within the E2 lipoic acid binding domain, which is particularly important for oxidative phosphorylation. In addition, lipoic acid, which serves as a swinging arm to capture electrons, is particularly susceptible to an electrophilic attack and may provide clues to the etiology of PBC. This review emphasizes the molecular characteristics of AMAs, including detection, immunochemistry and the putative role in disease. These data have significance not only specifically for PBC, but generically for autoimmunity.

The fingerprint of antimitochondrial antibodies and the etiology of primary biliary cholangitis

“…This is an issue throughout autoimmunity, often called "searching for the holy grail." (2,(31)(32)(33)(34)(35)(36) Using high-resolution structural analysis and modeling studies on the lipoyl domains of PDC-E2, LA is prominently displayed on the outer surface of PDC-E2 and rotates by means of a "swinging arm" with respect to the bulk of the molecule. (19) In PDC-E2, LA is covalently attached with the group of lysine (Lys259) by an amide bond.…”

“…The presence of antimitochondrial autoantibodies (AMA) is widely utilized for the diagnosis of primary biliary cholangitis (PBC) . AMA can be detected before the appearance of disease symptoms.…”

“…Although AMA is not associated with disease severity/prognosis, its presence before the development of liver pathology raises the possibility that it may contain information about early events in PBC. AMA recognize a unique conformational epitope within the inner lipoyl domain (ILD) of PDC‐E2 (amino acid [aa] residue 177‐314), and we have hypothesized that the loss of tolerance to PDC‐E2 is a result of chemical modification of this epitope following xenobiotic exposure . In fact, quantitative structure‐activity relationship analysis demonstrated that when the lipoyl domain of PDC‐E2 is modified with specific synthetic lipoyl mimics, some of the ensuing structures are recognized by AMA—often at levels higher than native PDC‐E2 .…”

“…E2 (amino acid [aa] residue 177-314), (2) and we have hypothesized that the loss of tolerance to PDC-E2 is a result of chemical modification of this epitope following xenobiotic exposure. (4) In fact, quantitative structure-activity relationship analysis demonstrated that when the lipoyl domain of PDC-E2 is modified with specific synthetic lipoyl mimics, some of the ensuing structures are recognized by AMA-often at levels higher than native PDC-E2.…”

Finding the cure for primary biliary cholangitis – Still waiting

“…Until relatively recently, there has not been a single new therapy introduced in primary biliary cholangitis (PBC) for nearly 20 years despite intensive efforts and remarkable discoveries in human and murine models of PBC and in liver immunology. [1][2][3][4][5][6][7][8][9] In this current issue, we were delighted to read the paper entitled "Old and New Treatments for Primary biliary Cholangitis". 10 In this article, the authors have carefully described the therapies used in PBC.…”