Primary biliary cirrhosis (PBC) is an autoimmune liver disease characterized by the destruction of small intrahepatic bile ducts. Incomprehensible and complicated autoreactive responses participate in the development and progression of PBC, which involve various immune cells and inflammatory mediators. Based on the aspects of innate immunity and adaptive immunity, this article summarizes recent advances in the research on PBC pathogenesis at cellular and molecular levels and evaluates the clinical application of these studies. This article not only gives a feasible direction for researchers and clinicians in this study field, but also provides a theoretical basis for clinical diagnosis and novel therapeutic strategies.

Primary biliary cholangitis (PBC) is a chronic cholestatic autoimmune disease caused by the attack of the liver by the immune system and is commonly seen in middle-aged women.The pathological features of this disease include the infiltration of a large number of innate immune cells (NK cells,NK T cells,and monocytes,etc.) and adaptive immune cells (T lymphocytes and B lymphocytes) at the portal area and injury of small intrahepatic bile ducts.In addition,PBC patients have high serum levels of anti-mitochondrial antibodies and inflammatory cytokines such as interferon-γ,tumor necrosis factor-α,interleukin-6,and interleukin-12.Although current studies have shown that autoreactive T cells are the major effector cells for PBC,NK cells,NK T cells,monocytes,and B cells around the portal vein also directly or indirectly participate in the development and progression of PBC.This article systematically summarizes the role of innate immune cells,adaptive immune cells,and related chemokines in the pathogenesis of PBC,in order to provide a theoretical basis for a deep understanding of the immunological pathogenesis of PBC.

Objective:To investigate the clinical features of primary biliary cholangitis (PBC) with thyroid disease (TD) and the association between TD and PBC.Methods:From 2005 to 2017, clinical data of PBC patients from the affiliated hospital of Qingdao university were retrospectively analyzed. All PBC patients were divided into 2 groups according to whether they have TD. The general conditionsand clinical manife-stations in the two groups were analyzed. T-test, nonparametric test, Chi-square test and Fisher's exact test-swere applied to compare datain subgroups. Results:A total of 148 PBC patients were involved in to our study, of which 45 cases (30.4%) had TD. PBC patients with TD showed a higher incidence of Sj?gren's synd- rome (SS) (33.3% vs 17.5%, χ2=4.545, P=0.033). Moreover, there was a higher positive rate of anti-SP100 and anti-SSB antibody in PBC patients with TD (20.0% vs 5.8%, χ2=5.440, P=0.020; 20.0% vs 2.9%, χ2=10.087, P=0.001) compared with patients without. PBC patients without TD presented a higher incidence of abdominal distension and jaundice (29.1% vs 11.1%, χ2=5.629, P=0.018; 23.3% vs 8.9%, χ2=4.241, P=0.039) compared to patients with TD. The ratio of patients with elevated total bilirubin (TBiL), direct bilirubin (DBiL), or increased alkaline phosphatase (ALP) was higher in PBC without TD group(40.8% vs 17.8%, χ2=7.405, P=0.007; 43.7% vs 17.8%, χ2=9.147, P=0.002; 69.9% vs 51.1%, χ2=4.811, P=0.028). Correspondingly, PBC patients without TD was associated with a higher probability of cirrhosis and portal hypertension (40.8% vs 22.2%, χ2=4.731, P=0.030; 25.2% vs 8.9%, χ2=5.183, P=0.023). Conclusion:TD has no effect on the natural history of PBC. PBC patients with TD are associated with a lower probability of liver fibrosis, portal hypertension and cholestasis symptoms but a higher incidence of SS when compared with PBC patients without TD. Multi-disciplinary approach should be implemented to the mag-nagement of PBC.

Primary biliary cholangitis (PBC) is an inflammatory and cholestatic liver disease caused by autoimmune response targeting the small- and medium-sized intrahepatic bile ducts. The most specific manifestations of this diseases in clinical practice were positive anti-mitochondrial antibody and selective destruction of small- and medium-sized bile ducts based on liver histology. Since it is difficult to obtain the clinical samples of early-stage PBC, the construction and optimization of mouse models is an important method to investigate the pathogenesis of PBC. An understanding of the modeling principles of PBC animal models and disease features in serology, histology, and cytology not only helps to improve the awareness of PBC, but also helps to design scientific and rational research protocols.

ObjectiveTo investigate the impact of cancer-associated fibroblasts （CAFs） on immunotherapy and liver metastasis in colorectal cancer （CRC）. MethodsThe single-cell sequencing data （GSE205506） of CRC patients with mismatch repair deficiency （MMRd） were downloaded from the gene expression omnibus database， and R software was used to preprocess the original sequencing data and establish the umap of fibroblast subpopulations， with each subpopulation named based on signature genes. GraphPad was used for the statistical analysis of the proportion of each fibroblast subpopulation， and the key subpopulations with significant differences were analyzed among CRC patients before and after PD-1 immunotherapy， as well as between the patients with pathological complete response （pCR） and those without pCR （non-pCR） after treatment. The analysis of differentially expressed genes and the gene pathway enrichment analysis were performed for the key subpopulations. The TCGA database was used to perform a prognostic and survival analysis of the signature genes of key CAF subpopulations， and RNA sequencing data were used to score and calculate the proportion of key CAF subpopulations in the primary lesions of CRC patients with liver metastasis. The independent-samples t test was used for comparison of normally distributed continuous data between two groups； the Kaplan-Meier method was used to plot survival curves， and the log-rank test was used to calculate survival rates. CellPhoneDB software was used to analyze the receptor-ligand interaction between fibroblast subpopulations and tumor cells， and in vitro cell experiments were used to validate the effect of NRG1， a key ligand molecule， on the migration and invasion abilities of CRC cells. ResultsAfter PD-1 immunotherapy for CRC patients， there was a significant reduction in the proportion of F6_MMP1⁺CAFs （P<0.001）， which was only observed in patients achieving complete remission after immunotherapy. F6_MMP1⁺CAFs were upregulated， as well as the genes and signaling pathways associated with tumor migration and invasion， and in addition， there was a significant increase in F6_MMP1⁺CAFs in the tumor tissue of CRC patients with liver metastasis （P<0.000 1）. As a ligand， NRG1 expressed by F6_MMP1⁺CAFs interacted with ERBB3 receptor expressed by tumor cells， and the in vitro experiments confirmed that NRG1 promoted the migration and invasion abilities of tumor cells by activating the ERBB signaling pathway （P<0.05）. ConclusionF6_MMP1⁺CAFs may affect the efficacy of PD-1 immunotherapy in CRC patients and play an important role in promoting liver metastasis in CRC. F6_MMP1⁺CAFs， along with NRG1 that is produced by them and can promote tumor metastasis， can be used as potential therapeutic targets and prognostic markers for CRC.