[Research Articles] A heterozygous germline CD100 mutation in a family with primary sclerosing cholangitis
Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disease without clear etiology or effective treatment. Genetic factors contribute to PSC pathogenesis, but so far, no causative mutation has been found. We performed whole-exome sequencing in a family with autosomal dominant inheritance of PSC and identified a heterozygous germline missense mutation in SEMA4D, encoding a K849T variant of CD100. The mutation was located in an evolutionarily conserved, unstructured cytosolic region of CD100 affecting downstream signaling. It was found to alter the function of CD100-expressing cells with a bias toward the T cell compartment that caused increased proliferation and impaired interferon- (IFN-) production after stimulation. Homologous mutation knock-in mice developed similar IFN- impairment in T cells and were more prone to develop severe cholangitis when exposed to 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet. Transfer of wild-type T cells to knock-in mice before and during DDC exposure attenuated cholangitis. Taken together, we identified an inherited mutation in the disordered cytosolic region of CD100 resulting in T cell functional defects. Our findings suggest a protective role for T cells in PSC that might be used therapeutically.
Source: Science Translational Medicine - Category: Biomedical Science Authors: Jiang, X., Bergquist, A., Löscher, B.-S., Venkatesh, G., Mold, J. E., Holm, K., Laerdahl, J. K., Skanland, S. S., Maleki, K. T., Cornillet, M., Tasken, K., Franke, A., Karlsen, T. H., Björkström, N. K., Melum, E. Tags: Research Articles Source Type: research
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