Background:
Mucosal-associated invariant T (MAIT) cells constitute up to 30% of liver-resident T cells,1,2
suggesting an important role in the pathogenesis of liver diseases. Recent studies have documented
antimicrobial, immune-regulatory, and pro-fibrogenic functions of murine and human MAIT cells.3-5 MAIT
cells respond to bacterial metabolites produced in the vitamin B2 synthesis pathway,6 what places them at a
central position in the immunological gut-liver axis. There is a strong clinical association of primary sclerosing
cholangitis (PSC) with inflammatory bowel disease (IBD),7 the latter being associated with a decreased
intestinal barrier integrity, changes in gut microbiome, and strong mucosal inflammatory responses also
involving MAIT cells.8,9 Little is known on the involvement of MAIT cells and their bacteria-derived ligands in
the pathogenesis of PSC.
Hypothesis:
Recently, we have found increased levels of MAIT cell stimulatory ligands in the blood of patients
with active IBD and also portal hypertension,10 providing evidence that in these conditions, associated with a
leaky gut, higher levels of MAIT cell stimulatory antigens (Ags) are reaching the liver. We hypothesize that
increased MAIT cell activation and pro-fibrogenic function might be involved in the pathogenesis of PSC.
Study plan: In the current translational study, we propose the analysis of microbial metabolite Ag levels in sera
of patients with PSC, IBD, and IBD-related PSC, as well as the correlation of serum Ag abundance with the
MAIT cell phenotype and function in the blood and liver of these patients.
Clinical significance:
Our study addressing the role of MAIT cells in PSC and IBD-related PSC will be entirely
performed using clinical samples and state-of-the-art methodology in the field, thus being of utmost
significance for the progress in elucidating the pathogenic mechanisms of IBD-related liver disease. In
perspective, it represents translational research with a clinical focus aimed at discovering new treatment
options for PSC. Additionally, measurement of circulating MAIT cell Ag levels could be considered as part of
a diagnostic test panel for assessing gut integrity in the context of IBD and autoimmune liver diseases.