Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 108, Issue 2, Pages 223-232Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI200110716
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Funding
- NIAMS NIH HHS [AR-44684, R01 AR044684] Funding Source: Medline
- NIDCR NIH HHS [R01 DE012354, R37 DE012354, DE-12354] Funding Source: Medline
- NIDDK NIH HHS [K08 DK059653, T32DK-07832, R01 DK024031] Funding Source: Medline
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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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