Covalent modification as a mechanism for the breakdown of immune tolerance to pyruvate dehydrogenase complex in the mouse

Palmer, Jeremy M.; Robe, Amanda J.; Burt, Alastair D.; Kirby, John A.; Jones, David

doi:10.1002/hep.20248

Cited by 25 publications

(17 citation statements)

References 46 publications

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“…Furthermore, we have previously demonstrated that rabbits immunized with a xenobiotic-hapten, 6BH-BSA, produced self-AMA that had all the characteristics of human AMA in that they recognized PDC-E2, BCOADC-E2, and OGDC-E2 and inhibited PDC enzyme activity (9). Similarly, s.c. immunization of SJL/J mice with biotinylated murine PDC produced Ab and T cell reactivities to unmodified and modified murine PDC (25). Although mild inflammation in the portal tract was seen in immunized SJL/J mice, both the rabbit and the SJL mice model fall short of any evidence of the bile duct injury, cholestasis, or fibrosis that are characteristic of PBC livers (9).…”

Section: Discussionmentioning

confidence: 99%

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

Leung

Park

Tsuneyama

et al. 2007

The Journal of Immunology

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Although significant advances have been made in dissecting the effector mechanisms in autoimmunity, the major stumbling block remains defining the etiological events that precede disease. Primary biliary cirrhosis (PBC) illustrates this paradigm because of its high degree of heritability, its female predominance, and its extraordinarily specific and defined immune response and target destruction. In PBC, the major autoantigens belong to E2 components of the 2-oxo-acid dehydrogenase family of mitochondrially located enzymes that share a lipoylated peptide sequence that is the immunodominant target. Our previous work has demonstrated that synthetic mimics of the lipoate molecule such as 6-bromohexoanate demonstrate a high degree of reactivity with PBC sera prompted us to immunize groups of guinea pigs with 6-bromohexoanate conjugated to BSA. In this study, we provide serologic and immunohistochemical evidence that such immunized guinea pigs not only develop antimitochondrial autoantibody responses similar to human PBC, but also develop autoimmune cholangitis after 18 mo. Xenobiotic-immunized guinea pigs are the first induced model of PBC and suggest an etiology that has implications for the causation of other human autoimmune diseases. The data also reflect the likelihood that, in PBC, the multilineage antimitochondrial response is a pathogenic mechanism and that loss of tolerance and subsequent development of biliary lesions depends on either modification of the host mitochondrial Ag or a similar breakdown due to molecular mimicry.

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Section: Discussionmentioning

confidence: 99%

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

Leung

Park

Tsuneyama

et al. 2007

The Journal of Immunology

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“…153 Importantly, the immunization of SJL/J mice with covalently modified self PDC-E2 could elicit the breakdown of both T-and B-cell tolerance. 154 Lastly, and most recently, one common everyday additive, 2-octynoic acid, was identified by Amano et al 155 as a common antigen in PBC sera.…”

Section: Molecular Mimicrymentioning

confidence: 99%

Genes and (auto)immunity in primary biliary cirrhosis

et al. 2005

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Primary biliary cirrhosis (PBC) is a chronic autoimmune cholestatic liver disease most commonly encountered in postmenopausal women; it is characterized by high-titer serum autoantibodies to mitochondrial antigens, elevated serum IgM, progressive destruction of intrahepatic bile ducts, and ultimately liver cirrhosis and failure. The cytopathic mechanisms leading to the selective destruction of intrahepatic cholangiocytes are still largely unknown. The current theory on the pathogenesis of PBC indicated that environmental factors might trigger autoimmunity in genetically susceptible individuals. In fact, genetic predisposition is critical to disease onset and progression, yet peculiar among autoimmune diseases, as indicated by the lack of a strong association with major histocompatibility complex haplotypes. Further, the recently reported concordance rate among monozygotic twins strenghtens the importance of genetic factors, while also indicating that additional factors, possibly infectious agents or xenobiotics, intervene to trigger the disease. In this review, the available data regarding the genetic factors associated with PBC susceptibility and progression, as well as the available evidence regarding the immunomediated pathogenesis of PBC, will be critically illustrated and discussed.

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“…Among the events demonstrated to induce an antibody response cross-reactive with self-PDC are exposure to bacterial PDC 9,10 or other microbial structural mimics 34 and exposure to chemically modified PDC or mimicking xenobiotics. 35,36 Other potential events currently lacking demonstration of direct in vivo priming are exposure to PDC components modified during caspase cleavage in cells undergoing apoptosis 37 and exposure to cross-reactive retroviral proteins. 38 The diversity of the potential events giving rise to antibody responses cross-reactive with PDC, which could promote subsequent T-cell tolerance breakdown, suggests the intriguing possibility that PBC could represent a condition with a common final pathway (T-cell tolerance breakdown and target cell damage) but with multiple triggers .…”

Section: Discussionmentioning

confidence: 99%

A key role for autoreactive B cells in the breakdown of T‐cell tolerance to pyruvate dehydrogenase complex in the mouse†

et al. 2005

Self Cite

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The key immunological event in the pathogenesis of the autoimmune liver disease primary biliary cirrhosis is breakdown of T-cell self-tolerance to pyruvate dehydrogenase complex (PDC). The mechanism resulting in this breakdown of tolerance remains unclear. Mice exposed to self-PDC mount no immune response; however, animals coexposed to self-PDC and PDC of foreign origin (which in isolation induces a cross-reactive antibody but not an autoreactive T-cell response) show breakdown of T-cell as well as B-cell tolerance. This observation raises the possibility that a cross-reactive antibody response to self-PDC can promote breakdown of T-cell tolerance. The aim of this study was to address the hypothesis that breakdown of T-cell tolerance to PDC can be driven by the presence of B cells and/or antibodies cross-reactive with this self-antigen. Naive female SJL/J mice were exposed to self-PDC alone and in the presence of purified splenic B cells from animals primed with foreign PDC (or controls) or purified immunoglobulin (Ig) G from the same animals. Breakdown of T-cell tolerance was assessed by splenic T-cell

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Covalent modification as a mechanism for the breakdown of immune tolerance to pyruvate dehydrogenase complex in the mouse

Cited by 25 publications

References 46 publications

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

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

Genes and (auto)immunity in primary biliary cirrhosis

A key role for autoreactive B cells in the breakdown of T‐cell tolerance to pyruvate dehydrogenase complex in the mouse†

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