Therefore, pathogens could be introduced by the procedure itself. Although bile was not obtained by ERCP in the study by Olsson et al., they reported previous ERCP as a risk factor for positive bile cultures.[6] After having shown the presence of pathogens in bile and portal tracts of patients with PSC, we investigated whether

PSC patients may manifest an increased Th17 response after pathogen stimulation. Here, we report that in patients with PSC, but not in patients with PBC, stimulation of PBMCs with heat-inactivated bacteria led to a marked induction of Th17 responses. There was no difference AZD6244 cost between patients’ own pathogens and standard pathogens, but it should be noted that nonpathogenic E. coli strains were not able to elicit an increase in IL-17A expression. Of note, and in line with the deleterious effects of Candida cholangitis on the progression of disease, stimulation of PBMCs with inactivated C. albicans led to the highest expression of IL-17A in up to 30% of CD4+ T cells (Fig. 3C). In addition, more Th17 cells were found to coexpress IFN-γ (Th1/Th17 cells) after Rapamycin ic50 stimulation with E. faecalis or C. albicans (Fig. 5). These cells may be especially relevant for the development of autoimmune diseases[30, 31] and for memory functions involved in the defense

against S. aureus and C. albicans.[28] IL-17A-expressing lymphocytes could be detected around bile ducts of patients with PSC. Whereas these cells can be found in other inflammatory liver diseases as well,[32] Lepirudin it is interesting to note that IL-17A receptors are expressed on biliary epithelial cells (BECs), and that upon stimulation with IL-17, BECs produce proinflammatory cytokines, such as IL-1β, IL-6, and IL-23.[33] These cytokines could, in turn, promote the

survival of Th17 cells. It is tempting to speculate that these cytokines could not only increase the survival of Th17 cells themselves,[34] but also stimulate fibroblasts to induce periductular fibrosis.[35, 36] Selective stimulation of the TLR-5 and −7 ligands, but not stimulation with other TLR ligands, also led to the induction of IL-17A in PSC, but not in the control groups. Further elucidation of signaling pathways involved may help to understand this aberrant response to pathogens. These results are reminiscent of data obtained in IBD patients, where the IL-23/Th17 axis has been reported to shape inflammatory response in the gut.[11] In children with IBD, an aberrant Th17 response to TLR stimulation and stimulation with Candida has been demonstrated previously.[37] Additionally, polymorphisms in genes relevant for the generation and maintenance of Th17 cells, such as the IL-23 receptor, were highly associated with IBD in GWAS.[38] Of note, in the patients reported on here, aberrant Th17 response was independent from the presence or absence of IBD, strongly suggesting that this is a feature of PSC itself and not the associated IBD.