The role of a mutation in a familial syndrome of sclerosing cholangitis

In our research proposal, we aimed to prove that a familial PSC disease is caused by a mutation leading to functional changes in CD100 positive T cells. During the project period, we have generated solid data to support our hypothesis and successfully achieved our aim. First, we identified a heterozygous germline missense mutation in SEMA4D, encoding a K849T variant of CD100 as a cause of PSC. We also revealed that the mutation was located in an evolutionarily conserved, unstructured cytosolic region of CD100 affecting downstream signaling. Second, we demonstrated the role of CD100 and CD100 K849T mutation in cholangitis by genetically modified mouse models. We employed CD100 knock-out mice and also generated CD100 mutated mice which carry the homology CD100 mutation by CRISPR germline replacement. Both CD100 knock-out and CD100 mutated mice developed more severe cholangitis when subjected to a toxic diet-feeding model which mimics PSC. Third, we found that the mutation alters the function of CD100-expressing cells with a bias toward the T cell compartment that caused increased proliferation and impaired interferon-gamma production after stimulation. Finally, we transferred wild-type T cells to CD100 mutated mice and found the cholangitis was mitigated in them. Taken together, we identified an inherited mutation in the disordered cytosolic region of CD100 resulting in T cell functional defects that link to PSC pathogenesis. Our findings suggest a protective role for T cells in PSC that might be used therapeutically. Key results of this successful project have been published in the prestigious journal Science Translational Medicine with the title 'A heterozygous germline CD100 mutation in a family with primary sclerosing cholangitis', and remaining results are expected to be published over the course of 2022. Based on the knowledge generated so far, CD100 mutation screening for disease prediction in familial cases of PSC should be considered relevant. The findings that mutated T cells are functionally impaired and adoptive transfer of wild-type T cells mitigates disease in mice inform the development of personalized treatment for PSC patients who share similar disease mechanisms. Therefore, our study may help establish a framework for personalized medicine for PSC and follow-up projects are being planned to bring forward this opportunity.