Pathogenesis of primary biliary cirrhosis David E.J Jones  Journal of Hepatology  Volume 39, Issue 4, Pages 639-648 (October 2003) DOI: 10.1016/S0168-8278(03)00270-8

Fig. 1 A model for immune mediated BEC injury in PBC. In this model the final pathway leading to BEC loss is apoptosis triggered by cytotoxic T-cell (or other immune effector cell) pathways. Potential pro-apoptotic signals include Fas-ligand and granzyme B. Cytotoxic T-cell activity is supported in by CD4+ T-cell ‘help’ mediated in part by localised cytokine secretion. CD4+ T-cell activation is induced by professional APC. Much interest has recently been focused on the context of antigen presentation and, in particular, importance of activation of APCs via by pathogen-derived factors via the highly conserved family of TLR. This model does not imply the identity of the MHC class I and II restricted epitopes which could, based on the situ evidence of effector cell function alone, be derived from infectious agent and self antigens alike. Journal of Hepatology 2003 39, 639-648DOI: (10.1016/S0168-8278(03)00270-8)

Fig. 2 Models for the breakdown of CD4+ T-cell tolerance to self-PDC. (a) Molecular mimicry model: In this model exposure to a pathogen (viral, bacterial or other) derived epitope showing sequence homology with a self-PDC sequence results in a T-cell response showing cross-reactivity with the self-antigen. A key factor in such pathways could be the parallel action of pathogen-derived factors on APC TLRs altering the context of antigen presentation and promoting active immunity as opposed to tolerance. (b) Determinant density model: In this model potentially self-PDC reactive T-cells survive negative selection in the thymus because their TCR shows only low affinity for self-peptide/MHC. In the periphery the low TCR affinity means that expose to sporadic self-PDC derived peptides generated as ‘noise’ in the antigen processing pathways is insufficient to result in T-cell activation. Enrichment of APC presentation of self-PDC derived epitopes could, however, give sufficient low affinity presentation events to surpass a triggering threshold and induce CD4+ T-cell activation. Self-PDC enrichment could result from uptake by dendritic cells of self-PDC/anti-PDC complexes via the Fc receptor or of self-PDC by surface Ig of PDC-specific activated B-cells. In this model the B-cell response to PDC, although not pathogenetic in its own right plays a key role in promoting T-cell self-tolerance breakdown. Journal of Hepatology 2003 39, 639-648DOI: (10.1016/S0168-8278(03)00270-8)