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Electrophile-modified lipoic derivatives of PDC-E2 elicits anti-mitochondrial antibody reactivity
- Source :
- Journal of Autoimmunity. 37:209-216
- Publication Year :
- 2011
- Publisher :
- Elsevier BV, 2011.
-
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.
- Subjects :
- Cholangitis
Immunology
Serum albumin
Quantitative Structure-Activity Relationship
Autoimmunity
Enzyme-Linked Immunosorbent Assay
Mitochondrion
Dihydrolipoyllysine-Residue Acetyltransferase
Autoantigens
Article
Fatty Acids, Monounsaturated
Mitochondrial Proteins
Mice
chemistry.chemical_compound
Protein structure
Animals
Humans
Immunology and Allergy
Bovine serum albumin
Serum Albumin
Acetaminophen
Autoantibodies
Thioctic Acid
biology
Liver Cirrhosis, Biliary
Chemistry
Anti-Inflammatory Agents, Non-Steroidal
Pyruvate dehydrogenase complex
Mitochondria
Protein Structure, Tertiary
Lipoic acid
Biochemistry
biology.protein
Cattle
Xenobiotic
Hydrophobic and Hydrophilic Interactions
Subjects
Details
- ISSN :
- 08968411
- Volume :
- 37
- Database :
- OpenAIRE
- Journal :
- Journal of Autoimmunity
- Accession number :
- edsair.doi.dedup.....a9f86fe3533e2b5ca05c83fe8528ceef