ArticleJournal of immunology (Baltimore, Md. : 1950)2013
Antimitochondrial antibody recognition and structural integrity of the inner lipoyl domain of the E2 subunit of pyruvate dehydrogenase complex.
Article in Journal of immunology (Baltimore, Md. : 1950), 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed.
- Detection of Diagnostic Antibodies in Immune-Mediated Diseases: A Focus on Antigens and Technologies.Chembiochem : a European journal of chemical biology · 2026Review
- Probing the Effects of Multisite Mutations in the Lipoic Acid Region of the BCOADC-E2 Protein.International journal of molecular sciences · 2024Article
- New insights into the pathogenesis of primary biliary cholangitis asymptomatic stage.World journal of gastroenterology · 2023Review
- Cardiac involvement in anti-MDA5 dermatomyositis: a case-based review.Clinical rheumatology · 2023Review
- Autoimmunity affecting the biliary tract fuels the immunosurveillance of cholangiocarcinoma.The Journal of experimental medicine · 2021Article
- Animal Models of Autoimmune Liver Diseases: a Comprehensive Review.Clinical reviews in allergy & immunology · 2020Review
- Current Understanding of Natural Antibodies and Exploring the Possibilities of Modulation Using Veterinary Models. A Review.Frontiers in immunology · 2020Review
- Pathogen infections and primary biliary cholangitis.Clinical and experimental immunology · 2019Review
- Biomarkers for primary biliary cholangitis: current perspectives.Hepatic medicine : evidence and research · 2018Review
- Environmental basis of primary biliary cholangitis.Experimental biology and medicine (Maywood, N.J.) · 2018Review
- Toward solving the etiological mystery of primary biliary cholangitis.Hepatology communications · 2017Article
- The fingerprint of antimitochondrial antibodies and the etiology of primary biliary cholangitis.Hepatology (Baltimore, Md.) · 2017Article
- Diagnostic autoantibodies for autoimmune liver diseases.Clinical & translational immunology · 2017Review
- The modulation of co-stimulatory molecules by circulating exosomes in primary biliary cirrhosis.Cellular & molecular immunology · 2017Article
- Epigenetics and Primary Biliary Cirrhosis: a Comprehensive Review and Implications for Autoimmunity.Clinical reviews in allergy & immunology · 2016Review
- A contemporary perspective on the molecular characteristics of mitochondrial autoantigens and diagnosis in primary biliary cholangitis.Expert review of molecular diagnostics · 2016Review
- Xenobiotics and loss of tolerance in primary biliary cholangitis.World journal of gastroenterology · 2016Review
- Obeticholic acid for the treatment of primary biliary cholangitis in adult patients: clinical utility and patient selection.Hepatic medicine : evidence and research · 2016Review
- Evaluation of indeterminate biliary strictures.Nature reviews. Gastroenterology & hepatology · 2016Review
- The coexistence of Sjögren's syndrome and primary biliary cirrhosis: a comprehensive review.Clinical reviews in allergy & immunology · 2015Review
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Authors and funding
13 authors.
Funding
Abstract
Antimitochondrial autoantibodies (AMAs), the serological hallmark of primary biliary cirrhosis, are directed against the lipoyl domain of the E2 subunit of pyruvate dehydrogenase (PDC-E2). However, comprehensive analysis of the amino acid residues of PDC-E2 lipoyl β-sheet with AMA specificity is lacking. In this study, we postulated that specific residues within the lipoyl domain are critical to AMA recognition by maintaining conformational integrity. We systematically replaced each of 19 residue peptides of the inner lipoyl domain with alanine and analyzed these mutants for reactivities against 60 primary biliary cirrhosis and 103 control sera. Based on these data, we then constructed mutants with two, three, or four replacements and, in addition, probed the structure of the substituted domains using thiol-specific spin labeling and electron paramagnetic resonance (EPR) of a (5)Ile→Ala and (12)Ile→Ala double mutant. Single alanine replacement at (5)Ile, (12)Ile, and (15)Glu significantly reduced AMA recognition. In addition, mutants with two, three, or four replacements at (5)Ile, (12)Ile, and (15)Glu reduced AMA reactivity even further. Indeed, EPR reveals a highly flexible structure within the (5)Ile and (12)Ile double-alanine mutant. Autoreactivity is largely focused on specific residues in the PDC-E2 lipoyl domain critical in maintaining the lipoyl loop conformation necessary for AMA recognition. Collectively, the AMA binding studies and EPR analysis demonstrate the necessity of the lipoyl β-sheet structural conformation in anti-PDC-E2 recognition.
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