1. Pathogenesis of primary biliary cirrhosis
David E.J Jones 
Journal of Hepatology 
Volume 39, Issue 4, Pages (October 2003)
DOI: /S (03)

2. 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  , DOI: ( /S (03) )

3. 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  , DOI: ( /S (03) )