Bcl-2–dependent oxidation of pyruvate dehydrogenase-E2, a primary biliary cirrhosis autoantigen, during apoptosis

Abstract

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.

Induction of Primary Biliary Cirrhosis in Guinea Pigs following Chemical Xenobiotic Immunization

“…Although the precise physiological effect and mechanisms of AMA in the in vivo function of pyruvate dehydrogenase is unclear, it has been postulated that AMA can induce apoptosis of bile duct epithelial cells (BEC) through caspase activation (18). Interestingly, unlike other cell types in which autoantibody recognition of PDC-E2 was abrogated after apoptosis, the antigenicity of PDC-E2 persisted in apoptotic BEC (19). IL-1 increases the efficacy of Ag processing and presentation (20).…”

Caspase induction by IgA antimitochondrial antibody: IgA-mediated biliary injury in primary biliary cirrhosis

“…2 The destruction of biliary cells probably involves the recognition of an intact autoepitope recognized by CD4 and CD8 cells, as well as by autoantibody; this appears to be unique to biliary cells. 2,26,27 Two main pathways exist for caspase activation: activation via cell surface death receptors or via intracellular stress. It is intriguing to speculate that during transcytosis anti-PDC-E2 IgA might induce cellular stress by interacting with newly synthesized PDC-E2 migrating from the endoplasmic reticulum (ER) to the mitochondria.…”

Antimitochondrial antibodies in acute liver failure: Implications for primary biliary cirrhosis

“…10,11 Importantly, AMA induction and perpetuation appears sensitive to the oxidative state of the tissues involved. [12][13][14] We hypothesized that in patients with ALF, AMA may be induced by the combination of oxidative stress and liver cell death, resulting in exposure of the immune system to both native and modified intracellular proteins. This transient induction of AMA could proceed to PBC if the immune response occurs in genetically susceptible subjects.…”