Autoepitope Mapping and Reactivity of Autoantibodies to the Dihydrolipoamide Dehydrogenase–Binding Protein (E3bp) and the Glycine Cleavage Proteins in Primary Biliary Cirrhosis

Dubel, Laurence; Tanaka, Atsushi; Leung, Patrick S.C.; Water, Judy Van de; Coppel, Ross L.; Roche, Thomas E.; Johanet, Catherine; Motokawa, Yutaro; Ansari, Aftab A.; Gershwin, M. Eric

doi:10.1002/hep.510290403

Cited by 80 publications

(50 citation statements)

References 36 publications

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“…The major PDC-E2 epitope recognized by PBC patient autoantibodies maps to the inner lipoyl domain of PDC-E2, which contains sulfhydryl groups involved in enzyme function (56,57). Critical sulfhydryl groups are also present within the antigenic sites of several other PBC autoantigens (58,59). Additionally, PBC patient autoantibodies inhibit PDC activity in vitro (60).…”

Section: Figurementioning

confidence: 99%

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

Odin¹,

Huebert²,

et al. 2001

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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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Section: Figurementioning

confidence: 99%

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

Odin¹,

Huebert²,

et al. 2001

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“…Although antimitochondrial Abs (AMA) recognize several members of the 2-oxo-acid dehydrogenase complexes (2-OADC), the predominant reactivity is directed against E2 subunit of pyruvate dehydrogenase complex (PDC-E2) (3,4). A common feature of these proteins is the presence of lipoic acid-binding domains toward which patient autoantibodies are directed (5)(6)(7)(8). Moreover, the major autoepitope recognized by both CD4 ϩ and CD8 ϩ T cells is localized to peptides that are part of the same inner lipoyl domain (9).…”

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confidence: 99%

Immunization with a Xenobiotic 6-Bromohexanoate Bovine Serum Albumin Conjugate Induces Antimitochondrial Antibodies

Leung

Quan

Park

et al. 2003

The Journal of Immunology

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128

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The E2 subunit of pyruvate dehydrogenase complex (PDC-E2) is the major autoantigen recognized by antimitochondrial Abs (AMA) in primary biliary cirrhosis (PBC). Recently, we replaced the lipoic acid moiety of PDC-E2 with a battery of synthetic structures designed to mimic a xenobiotically modified lipoyl hapten on a 12-aa peptide that was found within the immunodominant autoepitope of PDC-E2 and demonstrated that AMA in PBC reacted against several organic modified mimotopes as well as, or sometimes significantly better than, the native lipoyl domain. Based on this data, we immunized rabbits with one such xenobiotic organic compound, 6-bromohexanoate, coupled to BSA. One hundred percent of immunized rabbits developed AMA that have each and every characteristic of human AMAs with reactivity against PDC-E2, E2 subunit of branched chain 2-oxo-acid dehydrogenase, and E2 subunit of 2-oxoglutarate dehydrogenase complex. The rabbit AMA also inhibited enzymatic function of PDC-E2 and, importantly, binds to peptide sequences not present in the xenobiotic carrier immunogen. In contrast, BSA-immunized controls did not produce such activity. Our observation that animals immunized with a xenobiotic BSA complex produce autoantibodies that react not only with the xenobiotic, but also with mitochondrial autoantigens recognized by autoimmune PBC sera, suggests that environmental xenobiotic agents can be a risk factor for the induction of PBC.

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“…In excess of 95% of patients with PBC have serum antibodies reactive with the inner lipoyl domain of the dihydrolipoamide acetyltransferase (E2) and the E3 binding protein (E3BP) components of self-PDC (Dubel et al, 1999;Palmer et al, 1993Palmer et al, , 1999Surh et al, 1990). Moreover, peripheral blood T cells reactive with self-PDC-E2 are present in the majority of patients with PBC but absent from normal controls (Jones et al, 1997;Shimoda et al, 1995).…”

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confidence: 99%

Investigation of a Mechanism for Accelerated Breakdown of Immune Tolerance to the Primary Biliary Cirrhosis–Associated Autoantigen, Pyruvate Dehydrogenase Complex

Jones

Palmer

Bennett

et al. 2002

Laboratory Investigation

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SUMMARY: Primary biliary cirrhosis (PBC) is an autoimmune liver disease characterized by autoreactive T-and B-cell responsesto the highly conserved enzyme pyruvate dehydrogenase complex (PDC). In this study we have examined the breakdown of T-cell tolerance to self-PDC using a mouse model. Female SJL/J mice were sensitized intraperitoneally with foreign-PDC (bovine) and/or self-PDC (murine) in complete Freund's adjuvant, and serum, spleen, and liver tissue was taken 8 weeks later. Animals sensitized with foreign-PDC produced IgG antibodies that were reactive with both foreign and self-PDC, but splenic T cells from these animals only responded to stimulation with foreign PDC. Sensitization with self-PDC elicited neither antibodies nor reactive T cells. Significantly, cosensitization with mixed self-PDC and foreign-PDC resulted in a full breakdown of self-tolerance, with generation of both antibody and T-cell responses to self-PDC of the type seen exclusively in human PBC patients. Mild bile duct lesions deficient in CD8 ϩ T cells were seen 8 weeks after sensitization with either foreign or self-PDC. However, after sensitization with mixed self-PDC and foreign-PDC, these lesions were significantly larger and heavily infiltrated by CD8 ϩ T cells. Liver-infiltrating T cells derived from the self-PDC and foreign-PDC cosensitized but not from control animals showed reactivity with self-PDC, suggesting a possible role for autoreactive PDC-specific T-cell responses in the pathogenesis of the observed histologic changes. It is likely that B-cell cross-reactivity between foreign and self-PDC enhances the potential for breakdown of T-cell self-tolerance by allowing efficient presentation of self-antigens in the inoculum. This model may provide a useful system for investigating the etiology and treatment of PBC. (Lab Invest 2002, 82:211-219).

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Autoepitope Mapping and Reactivity of Autoantibodies to the Dihydrolipoamide Dehydrogenase–Binding Protein (E3bp) and the Glycine Cleavage Proteins in Primary Biliary Cirrhosis

Cited by 80 publications

References 36 publications

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

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

Immunization with a Xenobiotic 6-Bromohexanoate Bovine Serum Albumin Conjugate Induces Antimitochondrial Antibodies

Investigation of a Mechanism for Accelerated Breakdown of Immune Tolerance to the Primary Biliary Cirrhosis–Associated Autoantigen, Pyruvate Dehydrogenase Complex

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