SHIP deficiency causes Crohn's disease-like ileitis.

Abstract

Inflammatory bowel disease (IBD) can arise from genetic mutations that compromise intestinal epithelial cell integrity or immune regulation. SHIP has previously been shown to play a pivotal role in limiting the number of immunoregulatory cells and their function. To determine whether SHIP plays a pivotal role in control of immune tolerance in the gut mucosa. Gastrointestinal pathology was assessed in three separate strains of SHIP-deficient mice and their respective wild-type (WT) littermates. Gastrointestinal pathology was analysed in SHIP-deficient hosts reconstituted with WT haematopoietic cell grafts, and WT hosts reconstituted with SHIP-deficient haematopoietic cell grafts including whole splenocytes, purified T cells or natural killer (NK) cells. Major immune cell populations were also analysed in the small intestine of SHIP-deficient mice and WT controls. SHIP-deficient mice developed segmental, transmural pyo-granulomatous ilietis that recapitulated classical features of Crohn's disease enteric pathology. Analysis of haematopoietic chimeras showed that WT bone marrow reconstitution of SHIP⁻/⁻ hosts corrects ileitis. Reconstitution with SHIP⁻/⁻ splenocytes transferred ileitis to WT hosts. Adoptive transfer of purified SHIP⁻/⁻ T cells or NK cells to WT hosts did not transfer ileitis. There was a paucity of both CD4 and CD8 T cells in the small intestines of SHIP-deficient mice; however, neutrophil numbers were significantly increased. SHIP plays a pivotal role in immune function in the intestine; further scrutiny of this pathway in IBD patients is warranted. It is proposed that SHIP-deficient ileitis results from a local deficit in mucosal T cell immunity that promotes a damaging granulocyte-monocyte inflammation of the distal ileum.