A major unanswered question in PBC is that although all nucleated cells have mitochondria, the damage is limited to small biliary epithelial cells (BECs).27, 28 In this regard, there have been a number of studies that have focused on identifying the unique properties of BECs,

as compared with epithelial cells from other tissues. One such finding has been the unique process of buy Selinexor apoptosis in BECs after exposure of PDC-E2 to the effector processes of the immune system. The data presented herein adds significance to the concept of a role for unique pathways involved in the apoptosis of BECs in PBC. Thus, BECs express CD40 and are exquisitely sensitive to CD40L-mediated apoptosis29; indeed, after stimulation with CD40L, there is a sustained up-regulation of Fas ligand, and induction of apoptosis is accompanied by the activation of the activator protein 1 (c-Fos/c-Jun) and phosphorylated

signal transducer and activator of transcription 3 signaling pathways.30, 31 It is important to note that inadequate glutathiolation has been reasoned to lead to the exposure of PDC-E2 by biliary cells, making the BECs a potential source of neoantigens responsible for the activation of autoreactive T lymphocytes.32, 33 We extended this work and demonstrated that in contrast to high throughput screening compounds other epithelial cells, PDC-E2 remains immunologically intact within the apoptotic bleb when BECs undergo apoptosis.34 We also demonstrated that there was a marked increase in inflammatory cytokine production in the presence

of the unique triad of normal BEC blebs, PBC monocyte-derived macrophages, and AMA.35 We interpret these data to suggest that the presence of intact immunologically active PDC-E2 within the blebs of BECs gives rise to a local proinflammatory milieu. Importantly, it has also been suggested that macrophages can directly kill BECs via CD40-CD40L interaction.36 This insight into innate immunity provides one explanation for our understanding of BEC destruction and the key role of CD40-CD40L axis in this process. In a larger context, it has an implication in our understanding of the tissue specificity of many autoimmune diseases. Finally, Fossariinae high levels of CD40L expression in PBC patients appear to be related to elevated levels of serum IgM, a common, distinct feature of PBC. Little is known about the mechanism of hyper-IgM in PBC. CD40L has a crucial role in Ig class switching in B cells and mutations in the gene encoding CD40L are known to induce X-linked hyper-IgM syndrome.5 An early study by Higuchi et al. investigated the presence of mutations in the CD40L gene in PBC patients by single-strand conformational polymorphism. However, the results of these studies led to a failure to identify any differences between patients and controls.