Conventional type 1 dendritic cells are essential for the development of primary biliary cholangitis.

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.

Filaggrin 2 Deficiency Results in Abnormal Cell-Cell Adhesion in the Cornified Cell Layers and Causes Peeling Skin Syndrome Type A.

Peeling skin syndromes form a large and heterogeneous group of inherited disorders characterized by superficial detachment of the epidermal cornified cell layers, often associated with inflammatory features. Here we report on a consanguineous family featuring noninflammatory peeling of the skin exacerbated by exposure to heat and mechanical stress. Whole exome sequencing revealed a homozygous nonsense mutation in FLG2, encoding filaggrin 2, which cosegregated with the disease phenotype in the family. The mutation was found to result in decreased FLG2 RNA levels as well as almost total absence of filaggrin 2 in the patient epidermis. Filaggrin 2 was found to be expressed throughout the cornified cell layers and to colocalize with corneodesmosin that plays a crucial role in maintaining cell-cell adhesion in this region of the epidermis. The absence of filaggrin 2 in the patient skin was associated with markedly decreased corneodesmosin expression, which may contribute to the peeling phenotype displayed by the patients. Accordingly, using the dispase dissociation assay, we showed that FLG2 downregulation interferes with keratinocyte cell-cell adhesion. Of particular interest, this effect was aggravated by temperature elevation, consistent with the clinical phenotype. Restoration of corneodesmosin levels by ectopic expression rescued cell-cell adhesion. Taken together, the present data suggest that filaggrin 2 is essential for normal cell-cell adhesion in the cornified cell layers.