SHIP deficiency causes Crohn's disease-like ileitis

Kerr, William G; Park, Mi-Young; Maubert, Monique; Engelman, Robert W

Seventy-nine 6e8 week old mice, including 26 SHIP À/À mice, 26 SHIP DIP/DIP mice, one PI3K +/À SHIP À/À and 26 wild type littermates, each of both sexes were submitted to systematic, comprehensive necropsies, with histopathological examination of the entire insufflated alimentary tract. Primary gastrointestinal lesions were present only within the ileum of SHIP-deficient mice, and consisted of a segmental ileitis. Lesions were graded according to the extent of inflammation as grade 0e6 (figures 1e6). Of the 53 SHIP-deficient mice evaluated, only 3 of the 53 (6%) of SHIP-deficient mice lacked ileitis, while 50 of the 53 (94%) of SHIP-deficient mice had some degree of ileitis, significantly more than the absence of ileitis in WT littermates (p<0.001). Both SHIP À/À and SHIP DIP/DIP that harbour deletions in exons encoding different regions in the SHIP1 locus developed ileitis with comparable frequency with 25 of 26 (96%) of SHIP À/À mice, and 24 of 26 (92%) of SHIP DIP/DIP mice affected with comparable mean ileitis inflammatory grades of 4.262.1 and 4.062.2, respectively. Ileitis was also observed in a PI3K +/À SHIP À/À mouse (grade 4), indicating that a third independent SHIP mutant strain develops this pathology and that PI3K haploinsufficiency does not protect from development of ileitis. PI3K +/À SHIP +/+ and PI3K +/À SHIP +/À controls showed no evidence of ileitis (grade 0). Inflammatory lesions of the ileum in all SHIP-deficient mice analysed were present on a background of otherwise unaffected, uninflamed gastrointestinal tract.