Electrophile-modified lipoic derivatives of PDC-E2 elicits anti-mitochondrial antibody reactivity

Division of Rheumatology, Allergy, and Clinical Immunology, Department of Internal Medicine, University of California, Davis, CA 95616, USA.
Journal of Autoimmunity (Impact Factor: 8.41). 07/2011; 37(3):209-16. DOI: 10.1016/j.jaut.2011.06.001
Source: PubMed


Our laboratory has hypothesized that xenobiotic modification of the native lipoyl moiety of the major mitochondrial autoantigen, the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), may lead to loss of self-tolerance in primary biliary cirrhosis (PBC). This thesis is based on the finding of readily detectable levels of immunoreactivity of PBC sera against extensive panels of protein microarrays containing mimics of the inner lipoyl domain of PDC-E2 and subsequent quantitative structure-activity relationships (QSARs). Importantly, we have demonstrated that murine immunization with one such mimic, 2-octynoic acid coupled to bovine serum albumin (BSA), induces anti-mitochondrial antibodies (AMAs) and cholangitis. Based upon these data, we have focused on covalent modifications of the lipoic acid disulfide ring and subsequent analysis of such xenobiotics coupled to a 15mer of PDC-E2 for immunoreactivity against a broad panel of sera from patients with PBC and controls. Our results demonstrate that AMA-positive PBC sera demonstrate marked reactivity against 6,8-bis(acetylthio)octanoic acid, implying that chemical modification of the lipoyl ring, i.e. disruption of the S-S disulfide, renders lipoic acid to its reduced form that will promote xenobiotic modification. This observation is particularly significant in light of the function of the lipoyl moiety in electron transport of which the catalytic disulfide constantly opens and closes and, thus, raises the intriguing thesis that common electrophilic agents, i.e. acetaminophen or non-steroidal anti-inflammatory drugs (NSAIDs), may lead to xenobiotic modification in genetically susceptible individuals that results in the generation of AMAs and ultimately clinical PBC.

27 Reads
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Primary biliary cirrhosis (PBC) is a chronic, cholestatic, autoimmune liver disease characterised by the destruction of small- and medium-sized bile ducts. The serological hallmark of PBC includes antimitochondrial antibodies (AMA). The disease has a striking female predominance, and primarily affects women of middle-age. First-degree relatives, and in particular female relatives, are known to have an increased risk of developing the disease. Several studies have attempted to explain the female predominance of PBC, and autoimmune diseases in general. Two components that are of interest in PBC include monosomy X and xenobiotics. Monosomy X has been noted to be prevalent in the peripheral blood mononuclear cells of PBC patients. Xenobiotics, which are exogenous chemicals not normally found within the body, have been implicated in the modification of, and loss of, tolerance to AMA. Several cosmetics are known to contain these xenobiotics, which is of interest given the information provided in regards to known risk factors for PBC development. This review will focus on X monosomy and xenobiotics, which appear to constitute the X-factor of PBC.
    Autoimmunity Highlights 12/2012; 3(3). DOI:10.1007/s13317-012-0043-2
  • [Show abstract] [Hide abstract]
    ABSTRACT: Sjögren's syndrome (SS) or autoimmune epithelitis is a prototype autoimmune disorder with unique features: a broad clinical spectrum that extends from local exocrinopathy to systemic disease and lymphoma development, and an easy access to the inflamed tissues (minor salivary glands; MSG), which enables the investigators to study the autoimmune processes. The autoimmune lesion consists of lymphocytic infiltrates that develop around the ducts and vary in severity and composition. T cells (mainly CD4(+)) are the dominant lymphocytes in mild MSG lesions, whereas B cells in severe ones. Th1 cytokines predominate in SS infiltrates, albeit Th2 and Th17 responses have been also reported. Notably, increased infiltration by IL-18(+) cells has been associated with parotid gland enlargement and C4-hypocomplementemia, which are adverse prognostic factors for lymphoma development. Even though SS pathogenesis has not been fully revealed, several aspects have been delineated. Among them, the key role of MSG epithelia in the initiation and perpetuation of local autoimmune responses is well-established and involves the capacity of epithelial cells to mediate the recruitment, homing, activation, proliferation and differentiation of immunocytes. In addition, genetic features, including certain HLA phenotypes and polymorphisms in genes encoding cytokines or factors implicated in cytokine signaling, environmental (such as viruses) and hormonal factors are thought to participate in disease pathogenesis. Herein, the known aspects of SS pathogenesis, as well as unmet issues are discussed.
    Journal of Autoimmunity 02/2012; 39(1-2):4-8. DOI:10.1016/j.jaut.2012.01.002 · 8.41 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: INTRODUCTION: Many different drugs and xenobiotics (chemical compounds foreign to an organism) can injure the bile duct epithelium and cause inflammatory bile duct diseases (cholangiopathies) ranging from transient cholestasis to vanishing bile duct syndrome, sclerosing cholangitis with development of biliary fibrosis and cirrhosis. Animal models of xenobiotic-induced liver injury have provided major mechanistic insights into the molecular mechanisms of xenobiotic-induced cholangiopathies and biliary fibrosis including primary biliary cirrhosis and primary sclerosing cholangitis. AREAS COVERED: In this review, the authors discuss the basic principles of xenobiotic-induced liver and bile duct injury and biliary fibrosis with emphasis on animal models. A PubMed search was performed using the search terms "xenobiotic," "liver injury," "cholestasis," and "biliary fibrosis." Reference lists of retrieved articles were also searched for relevant literature. EXPERT OPINION: Xenobiotic-induced cholangiopathies are underestimated and frequently overlooked medical conditions due to their often transient nature. However, biliary disease may progress to vanishing bile duct syndrome, biliary fibrosis, and cirrhosis. Moreover, xenobiotics may prime the liver for subsequent liver disease by other agents and may also contribute to the development of hepatobiliary cancer though interaction with resident stem cells.
    Expert Opinion on Drug Metabolism &amp Toxicology 03/2012; 8(5):571-80. DOI:10.1517/17425255.2012.674511 · 2.83 Impact Factor
Show more