The immunology of primary biliary cirrhosis: the end of the beginning?

Abstract

The chronic liver disease primary biliary cirrhosis (PBC) is characterised by autoreactive B-cell and T-cell responses directed against mitochondrial antigens. In recent years these responses have been extensively characterised and the principal PBC associated autoantigen identified as pyruvate dehydrogenase complex (PDC). The identification of anti-PDC responses (present in over 95% of PDC patients) has given rise to important questions pertinent to our understanding of the pathogenesis of PBC. What specific role to anti-PDC responses play in target cell damage? How and why does immune tolerance break down to as highly conserved and ubiquitously expressed self-antigen as PDC? Why does breakdown in tolerance to an antigen present in all nucleated cells result in damage restricted to the intra-hepatic bile ducts? In attempting to answer these key questions we have, in this review, proposed a unifying hypothesis for the pathogenesis of PBC.

Fig. 1

Suggested model for the breakdown of self-tolerance in (a) a murine model and (b) humans with PBC. In both cases the model hinges on the initial development of an immune response to a nonself form of PDC (bovine in the mouse model, bacterial or xenobiotically modified or caspase cleaved self in the suggested human model). Sufficient sequence diversity exists in each case between nonself and the equivalent self-PDC to allow the development, in the correct inflammatory environment (adjuvant driven in the murine model, secondary to local infection in the human model) of non-cross-reactive T-cell responses. There is, in each case, however, sufficient similarity between the priming nonself-PDC and self-PDC to allow full B-cell cross-reactivity. Cross-reactive B-cell responses then promote epitope spreading within the priming nonself-PDC variant from nonconserved to conserved epitopes resulting in the breakdown of T-cell tolerance to self-PDC characteristic of both the murine model and human PBC. Alternative suggested mechanisms for this B-cell effect are direct presentation of self-PDC by cross-reactive activated B-cells and uptake of complexes of self-PDC and cross-reactive antinon-self-PDC by professional antigen presenting cells. Self-PDC is present in the murine model as a result of deliberate cosensitization. It would be suggested to be present in the local microenvironment in the human model as a result of release by necrotic PDC rich cells.

Fig. 1

Suggested model for the breakdown of self-tolerance in (a) a murine model and (b) humans with PBC. In both cases the model hinges on the initial development of an immune response to a nonself form of PDC (bovine in the mouse model, bacterial or xenobiotically modified or caspase cleaved self in the suggested human model). Sufficient sequence diversity exists in each case between nonself and the equivalent self-PDC to allow the development, in the correct inflammatory environment (adjuvant driven in the murine model, secondary to local infection in the human model) of non-cross-reactive T-cell responses. There is, in each case, however, sufficient similarity between the priming nonself-PDC and self-PDC to allow full B-cell cross-reactivity. Cross-reactive B-cell responses then promote epitope spreading within the priming nonself-PDC variant from nonconserved to conserved epitopes resulting in the breakdown of T-cell tolerance to self-PDC characteristic of both the murine model and human PBC. Alternative suggested mechanisms for this B-cell effect are direct presentation of self-PDC by cross-reactive activated B-cells and uptake of complexes of self-PDC and cross-reactive antinon-self-PDC by professional antigen presenting cells. Self-PDC is present in the murine model as a result of deliberate cosensitization. It would be suggested to be present in the local microenvironment in the human model as a result of release by necrotic PDC rich cells.