SHIP deficiency causes Crohn's disease-like ileitis

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

Although the SAMP1/Yit mouse 24 and the TNF ΔARE mouse 25 spontaneously develop ileitis, the present SHIP-deficient mouse is unique in that it recapitulates the CD phenotype apparently through perturbation of immune cell populations that can be transferred to a WT host. There are a number of possible candidates for the enteritis-inducing cell. Because we observed neutrophilic infiltrates in the distal ileum lamina propria of most SHIP-deficient mice, we speculate that inappropriate responses by neutrophils to commensal microflora in the lumen of the ileum may underlie or trigger the immune attack. SHIP plays a pivotal role in preventing neutrophilia, as granulocyte numbers in peripheral blood are profoundly increased in SHIP À/À mice 41 as well as mice treated with a SHIP1 selective inhibitor, 3AC. 49 Inappropriate effector function by SHIP À/À neutrophils at organ sites has not been examined to date, and thus our findings represent the first indication of neutrophil-mediated tissue damage in SHIP-deficient hosts. Conversely, it seems unlikely that the enteritis results from inappropriate T cell attack in the small intestine, as SHIP-deficiency causes a profound local deficit in both CD4 and CD8 T cell numbers in the small intestine, while normal numbers of Treg cells are still present at this site.