Scientific Publications by FDA Staff

Gut 2014 Nov;63(11):1728-36

IL-13Ralpha2-bearing, type II NKT cells reactive to sulfatide self-antigen populate the mucosa of ulcerative colitis.

Fuss IJ, Joshi B, Yang Z, Degheidy H, Fichtner-Feigl S, de Souza H, Rieder F, Scaldaferri F, Schirbel A, Scarpa M, West G, Yi C, Xu L, Leland P, Yao M, Mannon P, Puri RK, Fiocchi C, Strober W

OBJECTIVE: Previous studies have shown that ulcerative colitis (UC) is associated with the presence of lamina propria non-invariant (Type II) NKT cells producing IL-13 and mediating epithelial cell cytotoxicity. Here we sought to define the antigen(s) stimulating the NKT cells and to quantitate these cells in the UC lamina propria. DESIGN: Detection of Type II NKT cells in UC lamina propria mononuclear cells (LPMC) with lyso-sulfatide loaded tetramer and quantum dot-based flow cytometry and staining. Culture of UC LPMCs with lyso-sulfatide glycolipid to determine sulfatide induction of epithelial cell cytotoxicity, IL-13 production and IL-13Ralpha2 expression. Blinded quantum dot-based phenotypic analysis to assess UC LPMC expression of IL-13Ralpha2, CD161 and IL-13. RESULTS: Approximately 36% of UC LPMC were lyso-sulfatide tetramer positive, whereas few, if any, control LPMCs were positive. When tested, the positive cells were also CD3 and IL-13Ralpha2 positive. Culture of UC LPMC with lyso-sulfatide glycolipid showed that sulfatide stimulates UC LPMC production of IL-13 and induces UC CD161 LPMC-mediated cytotoxicity of activated epithelial cells; additionally, lyso-sulfatide induces enhanced expression of IL-13Ralpha2. Finally, blinded phenotypic analysis of UC LP MC using multicolour quantum dot-staining technology showed that approximately 60% of the LPMC bear both IL-13Ralpha2 and CD161 and most of these cells also produce IL-13. CONCLUSIONS: These studies show that UC lamina propria is replete with Type II NKT cells responsive to lyso-sulfatide glycolipid and bearing IL-13Ralpha2. Since lyso-sulfatide is a self-antigen, these data suggest that an autoimmune response is involved in UC pathogenesis.