title: Electrophile-modified lipoic derivatives of PDC-E2 elicits anti-mitochondrial antibody reactivity.
abstract: 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.
authors.affiliation: Division of Rheumatology, Allergy, and Clinical Immunology, Department of Internal Medicine, University of California, Davis, CA 95616, USA.
authors.forename: Phornnop
authors.initials: P
authors.lastname: Naiyanetr
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Butler
authors.forename: Liping
authors.initials: L
authors.lastname: Meng
authors.forename: Janice
authors.initials: J
authors.lastname: Pfeiff
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Kenny
authors.forename: Kathryn G
authors.initials: KG
authors.lastname: Guggenheim
authors.forename: Roman
authors.initials: R
authors.lastname: Reiger
authors.forename: Kit
authors.initials: K
authors.lastname: Lam
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Kurth
authors.forename: Aftab A
authors.initials: AA
authors.lastname: Ansari
authors.forename: Ross L
authors.initials: RL
authors.lastname: Coppel
authors.forename: Marcos
authors.initials: M
authors.lastname: López-Hoyos
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
authors.forename: Patrick S C
authors.initials: PS
authors.lastname: Leung
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000276:immunology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000276:immunology; D001323:Autoantibodies / Q000097:blood* / Q000276:immunology; D001324:Autoantigens / Q000097:blood / Q000276:immunology*; D015551:Autoimmunity; D002417:Cattle; D002761:Cholangitis / Q000097:blood / Q000209:etiology / Q000276:immunology*; D051047:Dihydrolipoyllysine-Residue Acetyltransferase / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry / Q000276:immunology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008105:Liver Cirrhosis, Biliary / Q000097:blood / Q000209:etiology / Q000276:immunology*; D051379:Mice; D008928:Mitochondria / Q000737:chemistry / Q000276:immunology*; D024101:Mitochondrial Proteins / Q000276:immunology*; D017434:Protein Structure, Tertiary; D021281:Quantitative Structure-Activity Relationship; D012709:Serum Albumin / Q000737:chemistry / Q000276:immunology; D008063:Thioctic Acid / Q000276:immunology / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001323:Autoantibodies; D001324:Autoantigens; D005229:Fatty Acids, Monounsaturated; D024101:Mitochondrial Proteins; D012709:Serum Albumin; D000082:Acetaminophen; C060855:2-octynoic acid; D008063:Thioctic Acid; C052359:DLAT protein, human; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; C494878:Dlat protein, mouse