36 and 37 Hypomorphic mutations in TTC7A have been found to cause VEOIBD without intestinal stricturing or severe immunodeficiency, most likely due to a defect in epithelial signaling. 38 Variants in genes that affect neutrophil granulocytes (and other phagocytes) predispose people to IBD-like intestinal inflammation. Chronic granulomatous disease is characterized by genetic defects in components of the phagocyte reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (phox) complex. Genetic mutations in all 5 components of the phagocyte NADPH Ponatinib clinical trial oxidase (phox)—gp91-phox (CYBB), p22-phox (CYBA), p47-phox (NCF1), p67-phox (NCF2),

and p40-phox (NCF4)—are associated with immunodeficiency and can cause IBD-like intestinal inflammation. As high as 40% of patients with CGD develop CD-like intestinal inflammation.39, 40 and 41

Multiple granulomas and the presence of pigmented macrophages can indicate the group of defects histologically. Missense variants in NCF2 that affect RAC2 binding sites have recently been reported in patients with VEOIBD. 42 Recently, several heterozygous functional hypomorphic variants in multiple components of the NOX2 NADPH oxidase complex were detected in patients with VEOIBD that do not cause CGD-like immunodeficiency but have a moderate effect on reactive oxygen species production and confer susceptibility to VEOIBD. 43 Tumor necrosis factor α inhibitors can resolve intestinal inflammation in patients with CGD but could increase the risk of severe infections in patients with http://www.selleckchem.com/products/bmn-673.html CGD. 44 Allogeneic hematopoietic stem cell transplantation (HSCT) can cure CGD and ifoxetine resolve intestinal inflammation. 44, 45 and 46 Monocytes produce high levels of IL-1 in patients with CGD, and an IL-1 receptor antagonist (anakinra) has been used to treat noninfectious colitis in those patients. 47

In addition to CGD, a number of other neutrophil defects are associated with intestinal inflammation. Defects in glucose-6-phosphate translocase (SLC37A4) 48 and 49 and glucose-6-phosphatase catalytic subunit 3 (G6PC3) 50 are associated with congenital neutropenia (and other distinctive features) but also predispose people to IBD. Leukocyte adhesion deficiency type 1 is caused by mutations in the gene encoding CD18 (ITGB2) and is associated with defective transendothelial migration of neutrophil granulocytes. Patients typically present with high peripheral granulocyte counts and bacterial infections, and some present with IBD-like features. 51 and 52 CD-like disease is a typical manifestation of glycogen storage disease type Ib, characterized by neutropenia and neutrophil granulocyte dysfunction.48, 49 and 53 Granulocyte colony-stimulating factor has been used to treat neutropenia and colitis in some patients with glycogen storage disease type Ib.53 In addition to neutrophil defects, defects in several other genes, including WAS, LRBA, BTK, CD40LG, and FOXP3, can lead to autoantibody-induced or hemophagocytosis-induced neutropenia.