【文献阅读029】PSC的免疫学发病机制研究（8）

The intricated relationship between PSC and lBD is difficult to dissect. Current studies estimate that 2%-7% of patients with lBD could have a concomitant PSC, often diagnosed later in life. In addition, 60%-90% of patients with PSC have lBD with specific features and represent a relatively milder progressive phenotype.^[110,111] in this context, the relationship between the gut and the liver including its immunobiology, has been studied, mainly focusing on the intestinal microbiota, the mucosal inflammation, the associated leaky gut, and bile acid homeostasis. In this context, the shared clonal overlap of both T cells and B cells (both discussed above) between gut and liver is intriguing.^[93,94]

Intestinal inflammation and associated gut dysbiosis are thought to disrupt bile acid homeostasis,^[112,113] a feature described in patients with PSC.^[114,115] Moreover, these bile acids have been shown to modulate the balance of Th17 cells and Tregs in experimental models.^[112,116] Recently, right-sided colonic biopsies from patients with PSC-lBD and lBD analyzed by bulk RNAseq, scRNAseq, and flow cytometry identified distinct features of intestinal inflammation in PSC-IBD compared with lBD where PSC-lBD inflammation was characterized by the presence of IL-17+FoxP3+ CD4 T cells as well as lgG-secreting plasma cells.^[95] In addition, even in the absence of lBD, an increased expression of IL17A and IFNG in intestinal biopsies and a dysbiotic microbiota was reported in the vast majority of patients with PSC.^[117]

However, a study analyzing biliary brush samples from patients with PSC revealed no difference in biliary neutrophil or T-cell abundance in relation to IBD status.^[9] Gut inflammation increased mucosal permeability and translocation of bacterial product could potentially cause biliary inflammation. In such a context, an enhanced response of cholangiocytes to endotoxins has been reported in patients with PSC.^[118] In addition, human cholangiocytes exposed to bile from patients with PSC, which often contained microbial DNA, were able to in some cases activate MAlT cells in an MR1-dependent manner.^[71]

PSC microbiota studies have revealed a global decrease in diversity associated with an overrepresentation of specific strains^[119-122] and some functional specificities.^[123] Results from germ-free mouse models suggested both protective and aggravated effects on cholestasis progression due to the microbiota.^[124,125]However, fecal microbiota from patients with PSC-IBD transferred to gnotobiotic mice led to, in some cases, activation of Th17 cells in the liver.^[126] These mice had increased susceptibility to DDC diet-induced hepatobiliary injury with higher serum bilirubin, ALP, and Th17 response in the liver as compared with germ-free mice.^[126] 16s rRNA sequencing of mesenteric lymphnodes identified Klebsiella pneumoniae, Proteus mirabilis, and Enterococcus gallinarum in those mice as well as in metagenomic analysis of PSC patient microbiota as compared with controls.^[126]In DDC-fed gnotobiotic mice colonized with these bacteria, inhibition of Th17 differentiation ameliorated hepatobiliary injury and fibrosis.^[126]Interestingly, K.pneumoniae derived from mesenteric lymph nodes was found to induce pores in colonic epithelial cells in vitro, and the use of a k.pneumoniaenon-pore-forming strain in the 3-bacterial mix inoculated into germ-free mice led to decreased Th17 response in the liver.^[126]

Although most patients with PSC also have lBD, the shared and specific immunobiological features of these entities remain poorly characterized. In recent years, studies have provided data on the microbiota composition of patients with PSC as well as their inflammatory landscape of the gut. Still, the mechanistic involvement of the liver and gut immune systems in this context remains poorly understood.