Bcl-2–dependent oxidation of pyruvate dehydrogenase-E2, a primary biliary cirrhosis autoantigen, during apoptosis
Open accessAbstract
The close association between autoantibodies against pyruvate dehydrogenase-E2 (PDC-E2), a ubiquitous mitochondrial protein, and primary biliary cirrhosis (PBC) is unexplained.Many autoantigens are selectively modified during apoptosis, which has focused attention on apoptotic cells as a potential source of "neo-antigens" responsible for activating autoreactive lymphocytes.Since increased apoptosis of bile duct epithelial cells (cholangiocytes) is evident in patients with PBC, we evaluated the effect of apoptosis on PDC-E2.Autoantibody recognition of PDC-E2 by immunofluorescence persisted in apoptotic cholangiocytes and appeared unchanged by immunoblot analysis.PDC-E2 was neither cleaved by caspases nor concentrated into surface blebs in apoptotic cells.In other cell types, autoantibody recognition of PDC-E2, as assessed by immunofluorescence, was abrogated after apoptosis, although expression levels of PDC-E2 appeared unchanged when examined by immunoblot analysis.Both overexpression of Bcl-2 and depletion of glutathione before inducing apoptosis prevented this loss of autoantibody recognition, suggesting that glutathiolation, rather than degradation or loss, of PDC-E2 was responsible for the loss of immunofluorescence signal.We postulate that apoptotic cholangiocytes, unlike other apoptotic cell types, are a potential source of immunogenic PDC-E2 in patients with PBC.
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Oxidation of mitochondrial epitopes during apoptosis might form neoantigens recognized by anti-mitochondrial antibodies.
“The oxidation of mitochondrial epitopes during apoptosis might lead to formation of neoantigens that are recognized by anti-mitochondrial antibodies228.”
From The role of mitochondria in rheumatic diseases (2022) · cites this paper as [228]
The Discussion (page not provided) says that oxidation of PDC-E2 during apoptosis causes loss of the epitope recognized by primary biliary cirrhosis patient autoantibodies. It proposes that the reduced, unmodified form—not the oxidized form—activates PDC-E2-specific B cells. Although the Introduction raises the general possibility of apoptotic neoantigens, the paper's finding runs contrary to the claimed antibody recognition of oxidized mitochondrial epitopes. (LLM, conf=0.88)
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Self-citation
- Authors
- Odin, J. A., Huebert, R. C., Casciola-Rosen, L., LaRusso, N. F., & Rosen, A.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Mayo Clinic (US)
- Johns Hopkins University (US)
- Corresponding author
- Odin, Joseph A.
- Venue
- Journal of Clinical Investigation
- Published
- 2001-07-15
- Volume
- 108
- Issue
- 2
- Pages
- 223-232
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC203018
- OpenAlex
- W4249025813
- Cited by
- 220
- References
- 60
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 1 · 2023: 3 · 2022: 2 · 2021: 4 · 2020: 7 · 2019: 4 · 2018: 4 · 2017: 10 · 2016: 5 · 2015: 20 · 2014: 9 · 2013: 9 · 2012: 14
- FWCI
- 7.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (K08DK059653, R01DK024031, T32DK-07832)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR 44684, R01AR044684)
- National Institute of Dental and Craniofacial Research (R37DE012354, DE12354, R01DE012354)
- Topics
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
- Keywords
- primary biliary cirrhosis, pyruvate dehydrogenase E2, autoantigens, autoantibodies, apoptosis, Bcl-2, glutathione depletion, bile duct epithelial cells, cholangiocytes, mitochondrial proteins, neoantigens, caspase cleavage
- MeSH terms
- Autoantibodies, Autoantigens, Bile Ducts, Cell Line, Dithiothreitol, Epithelial Cells, Fluorescent Antibody Technique, Glutathione, Humans, Immune Sera, Liver Cirrhosis, Biliary, Lymphocyte Activation, Mitochondria, Pyruvate Dehydrogenase Complex, Transfection, Immunoblotting, Gene Expression Regulation, Enzymologic, Apoptosis, Genes, bcl-2, Dihydrolipoyllysine-Residue Acetyltransferase
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