SHIP deficiency causes Crohn's disease-like ileitis

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

Crohn's disease (CD) is a chronic, relapsing idiopathic inflammatory bowel disease (IBD) that can affect various sites within the gastrointestinal tract, but classically the ileum, which leads to abdominal cramping, diarrhoea and gastrointestinal bleeding. 1e4 CD histopathological lesions begin with the formation of multiple aphthoid ulcers infiltrated by neutrophils, which progress and coalesce into sharply delimited, regional, transmural inflammations with granuloma formation, thickening of the muscularis propria, strictures, fissures and fistulas. 1e4 Although genome-wide association studies have identified more than 30 susceptibility loci for IBD that disturb either intestinal epithelial cell (IEC) barrier homeostasis or immune effector cell functions and interactions with luminal flora and antigens, 5e7 many susceptibility genes possess differing functions in IEC and haematopoietic cells, and primary IEC or immunological defects in genetically susceptible individuals often remain enigmatic. 8 9 Primary immunological alterations proposed to contribute to the development of CD pathology include increased expression of Th1-polarising cytokines interleukin (IL)-12 and interferon g by cells in the lamina propria, 10 11 aberrant IL-23initiated Th17-associated immune responses, 12 13 defects in regulatory T cell (Treg) modulation of effector functions via transforming growth factor b or IL-10 dependent mechanisms, 14 aberrant B-cell specificity and serum autoreactivity 15 and myeloid cell dysfunction. 16 That primary defects in immune cell function contribute to CD in some patients is supported by reports of disease remission following allogeneic bone marrow transplantation. 17 This paper is freely available online under the BMJ Journals unlocked scheme, see http:// gut.bmj.com/site/about/ unlocked.xhtml