SHIP deficiency causes Crohn's disease-like ileitis

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

IEC barrier defects that may contribute to CD development include the inability of a Paneth cell-derived NOD2 variant to expel luminal bacteria, 18 diminished IEC autophagy and antimicrobial granule exocytosis, 19 altered IEC toll-like receptor expression with potentially dysregulated responses to common bacterial motifs, 20 altered IEC cytokine expression 21 and increased IEC paracellular permeability to enteric luminal contents, perhaps due to inadequate formation of IEC tight junctions. 22 Although animal models of IBD have been described, most model systems affect the large intestine, do not manifest CD-specific histopathological features, and are often induced rather than spontaneously developing models. 5 7 23 Only two animal models spontaneously develop chronic inflammation of the ileum, the SAMP1/Yit mouse 24 and the TNF ΔARE mouse. 25 SAMP1/Yit mice spontaneously develop terminal ileitis by 10 weeks of age driven by Th1-and Th2-type immune responses, the severity of which can be decreased by antitumour necrosis factor (TNF) antibodies. 23 26 27 Although SAMP1/Yit mesenteric lymph node CD4 + T cells are capable of adoptively transferring ileitis to severe combined immunodeficient (SCID) mice, increased IEC paracellular permeability appears to be the primary susceptibility factor in this model. 22 The TNF ΔARE mouse model was generated by deletion of 69bp within the AU-rich region (ARE) of the gene that encodes TNF, resulting in increased systemic TNF levels associated with expansion of CD8 + effector cell subpopulations that mediate chronic ileitis and arthritis in both heterozygous and homozygous mice. 25 28 Haematopoietic cells of neither the SAMP1/Yit nor the TNF ΔARE mouse are capable of adoptively transferring CD-like disease to an immunocompetent host.