RESUMEN
BACKGROUND & AIMS: Primary biliary cholangitis (PBC) is a progressive-cholestatic autoimmune liver disease. Dendritic cells (DC) are professional antigen-presenting cells and their prominent presence around damaged bile ducts of PBC patients are documented. cDC1 is a rare subset of DC known for its cross-presentation abilities and interleukin 12 production. Our aim was to assess the role of cDC1 in the pathogenesis of PBC. METHODS: We utilized an inducible murine model of PBC and took advantage of the DC reporter mice Zbtb46gfp and the Batf3-/- mice that specifically lack the cDC1 subset. cDC1 cells were sorted from blood of PBC patients and healthy individuals and subjected to Bulk-MARS-seq transcriptome analysis. RESULTS: Histopathology assessment demonstrated peri-portal inflammation in wild type (WT) mice, whereas only minor abnormalities were observed in Batf3-/- mice. Flow cytometry analysis revealed a two-fold reduction in hepatic CD8/CD4 T cells ratio in Batf3-/- mice, suggesting reduced intrahepatic CD8 T cells expansion. Histological evidence of portal fibrosis was detected only in the WT but not in Batf3-/- mice. This finding was supported by decreased expression levels of pro-fibrotic genes in the livers of Batf3-/- mice. Transcriptome analysis of human cDC1, revealed 78 differentially expressed genes between PBC patients and controls. Genes related to antigen presentation, TNF and IFN signalling and mitochondrial dysfunction were significantly increased in cDC1 isolated from PBC patients. CONCLUSION: Our data illustrated the contribution the cDC1 subset in the pathogenesis of PBC and provides a novel direction for immune based cell-specific targeted therapeutic approach in PBC.
Asunto(s)
Factores de Transcripción con Cremalleras de Leucina de Carácter Básico , Células Dendríticas , Modelos Animales de Enfermedad , Cirrosis Hepática Biliar , Proteínas Represoras , Animales , Células Dendríticas/inmunología , Ratones , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/deficiencia , Cirrosis Hepática Biliar/genética , Cirrosis Hepática Biliar/patología , Cirrosis Hepática Biliar/inmunología , Humanos , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Ratones Noqueados , Femenino , Hígado/patología , Hígado/inmunología , Ratones Endogámicos C57BL , Linfocitos T CD8-positivos/inmunología , Masculino , Factores de TranscripciónRESUMEN
Autoimmune diseases are common conditions characterized by loss of tolerance, female predominance and a remarkable heterogeneity among different populations. Most often they are polygenic and several genetic loci have been linked with the risk of developing autoimmune diseases. However, causal inference is difficult. When the genomic revolution began there were high hopes of translating fast genetic analyses to the bedside but this has proven to be challenging. Nonetheless, over the last decade, fine-mapping strategies have greatly improved; one of the most significant research lines focuses on the in vivo and ex vivo definition of the effect of genetic variants within the target tissues and within specific subpopulations of immune cells that are involved in the disease pathogenesis. This strategy also includes the longitudinal tracking of a large number of immunophenotypes in many individuals to build a large reference atlas for variant characterization. In this review, we discuss the results obtained by GWAS in autoimmune diseases and review recent advances in fine mapping strategies. More importantly, we discuss gaps and future directions.