VEOIBD has been described in a number of hyperinflammatory and autoinflammatory disorders such as mevalonate

kinase deficiency,54 and 55 phospholipase C-γ2 defects,56 familial Mediterranean fever,57, 58 and 59 Hermansky–Pudlak syndrome (type 1, 4, and 6),60, 61, 62, 63 and 64 X-linked lymphoproliferative syndrome type 165 and type 2,66, 67 and 68 or familial BIBW2992 in vivo hemophagocytic lymphohistiocytosis type 5.69 Among these, mevalonate kinase deficiency is a prototypic autoinflammatory disorder, characterized by increased activation of caspase-1 and subsequent activation of IL-1β.70 Inhibiting IL-1β signaling with antibodies that block IL-1β or IL-1 receptor antagonists can induce complete or partial remission in patients, including those with VEOIBD.54, 55 and 71 X-linked lymphoproliferative syndrome 2 is caused by defects in the XIAP gene. At least 20% of patients with XIAP defects develop a CD-like immunopathology selleck kinase inhibitor with severe fistulizing perianal phenotype. 66, 67, 68, 72 and 73 In

these patients, Epstein–Barr virus infections can lead to life-threatening hemophagocytic lymphohistiocytosis. Originally associated with a poor outcome after HSCT, 74 less toxic induction regimens could improve the prognosis and cure this form of IBD. 67 and 73 IBD-like immunopathology is a common finding in patients with defects in the adaptive immune system. Multiple genetic defects that disturb T- and/or B-cell selection and activation can cause complex immune dysfunction, including immunodeficiency and autoimmunity as well as intestinal inflammation. Disorders Oxaprozin associated with IBD-like immunopathology include B-cell defects such as common variable immunodeficiency (CVID), hyper-immunoglobulin (Ig) M syndrome, and agammaglobulinemia.75, 76, 77, 78 and 79 Several other primary immune deficiencies,

such as Wiskott–Aldrich syndrome80 (WAS) and atypical SCID or Omenn syndrome81 and 82 can also cause IBD-like intestinal inflammation. Patients with CVID have clinical features of different types of IBD, spanning CD, UC, and ulcerative proctitis–like findings.83 and 84 Although CVID is largely polygenic, a small proportion of cases of CVID have been associated with specific genetic defects. CVID type 1 is caused by variants in the gene encoding the inducible T-cell costimulator (ICOS), 85 and 86 whereas CVID type 8 is caused by variants in LRBA. 87, 88 and 89 Patients with these mutations can present with IBD-like pathology. Recently, IBD and CVID-like disease was described in a family with IL-21 deficiency. 90 Patients with agammaglobulinemia, caused by defects in BTK or PIK3R1, as well as patients with subtypes of hyper IgM syndrome caused by defects in CD40LG, AICDA, or IKBKG can develop IBD-like immunopathology.