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).

The autoimmune liver disease primary biliary cirrhosis (PBC) is characterized by the breakdown of normal immune self tolerance to pyruvate dehydrogenase complex (PDC). How tolerance is broken to such a central and highly conserved self antigen in the initiation of autoimmunity remains unclear. One postulated mechanism is that reactivity arises to an altered form of self antigen with subsequent cross-reactivity to native self. In this murine study, we set out to examine whether sensitization with a covalently modified form of self PDC can give rise to the pattern of breakdown of B-cell and T-cell tolerance to self PDC seen in PBC patients. The notion that altered self can lead to tolerance breakdown was studied by sensitizing SJL/J mice with a covalently modified (

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

Background: Autoantibody responses reactive with the E2 and E3BP components of pyruvate dehydrogenase complex (PDC), which characterise primary biliary cirrhosis (PBC) crossreact, precluding the identification, from serological studies, of the antigen to which the principal breakdown of tolerance occurs. Although autoreactive T‐cell responses to PDC‐E2 have been well characterised it is, at present, unclear whether T‐cell tolerance breakdown also occurs to PDC‐E3BP. The aims of this study were to characterise autoreactive T‐cell responses to PDC‐E3BP in PBC and potential factors regulating their expression. Methods: Peripheral blood T‐cell proliferative responses to purified recombinant human PDC‐E2 and PDC‐E3BP at a range of concentrations were characterised in PBC patients and control subjects. Results: T‐cell proliferative responses to both E2 and E3BP were absent from control subjects (median peak stimulation index (SI) to PDC‐E2 1.2 [range 0.3–1.9], 0/10 positive (SI>2.32), median peak SI to PDC‐E3BP 1.1 [0.7–2.1]], 0/10 positive). Significant responses to PDC‐E2 were seen in the majority of patients (median peak SI 11.4 [0.4–24.4], 17/20 (85%) positive) but to PDC‐E3BP in only a minority (median peak SI 1–9 [0.6–9.95], 8/20 (40%) positive). Where responses to PDC‐E3BP were seen they were universally secondary to responses to PDC‐E2. Conclusions: Despite the presence of antibodies reactive with PDC‐E3BP in the majority of PBC patients this self‐protein is not a dominant T‐cell autoantigen in PBC.

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