CCDC88B is required for pathogenesis of inflammatory bowel disease

Abstract

Inflammatory bowel disease (IBD) involves interaction between host genetic factors and environmental triggers. CCDC88B maps within one IBD risk locus on human chromosome 11q13. Here we show that CCDC88B protein increases in the colon during intestinal injury, concomitant with an influx of CCDC88B+lymphoid and myeloid cells. Loss of Ccdc88b protects against DSS-induced colitis, with fewer pathological lesions and reduced intestinal inflammation in Ccdc88b-deficient mice. In a T cell transfer model of colitis, Ccdc88b mutant CD4+ T cells do not induce colitis in immunocompromised hosts. Expression of human CCDC88B RNA and protein is higher in IBD patient colons than in control colon tissue. In human CD14+ myeloid cells, CCDC88B is regulated by cis-acting variants. In a cohort of patients with Crohn’s disease, CCDC88B expression correlates positively with disease risk. These findings suggest that CCDC88B has a critical function in colon inflammation and the pathogenesis of IBD.

CCDC88B is required for mobility and inflammatory functions of dendritic cells

“…7 In humans, the CCDC88B gene maps within a locus on Chromosome 11 (11q13) that contains >20 genes in linkage disequilibrium that is associated with susceptibility to several inflammatory conditions including psoriasis, primary biliary cirrhosis, MS, and inflammatory bowel disease (IBD). [11][12][13] Using a mouse model of dextran sulfate sodium (DSS)-induced colitis, we showed that Ccdc88b-deficent mice are protected against intestinal colitis; likewise, in a T cell transfer model of colitis, Ccdc88b-deficent T cells did not induce colitis in immunocompromised Rag1 −/− mutant mice. 13 Parallel studies in humans showed that the CCDC88B protein and mRNA are elevated in the colon of IBD patients.…”

“…[11][12][13] Using a mouse model of dextran sulfate sodium (DSS)-induced colitis, we showed that Ccdc88b-deficent mice are protected against intestinal colitis; likewise, in a T cell transfer model of colitis, Ccdc88b-deficent T cells did not induce colitis in immunocompromised Rag1 −/− mutant mice. 13 Parallel studies in humans showed that the CCDC88B protein and mRNA are elevated in the colon of IBD patients. Furthermore, expression of CCDC88B mRNA was found to be regulated by cis-acting variants in CD14 + myeloid cells, with CCDC88B mRNA expression correlated positively with disease risk in a cohort of Crohn's disease (CD) patients.…”

“…The pleiotropic T cell defect of Ccdc88b mouse mutants has been clearly established. 7,13 However, it remains to be determined if this deficiency is a primary defect of T cells, or is secondary to a possible tection against CD. 7,13 In addition, a recent study has documented a physical interaction between the CCDC88B protein and Dedicator of cytokinesis 8 (DOCK8).…”

“…7,13 However, it remains to be determined if this deficiency is a primary defect of T cells, or is secondary to a possible tection against CD. 7,13 In addition, a recent study has documented a physical interaction between the CCDC88B protein and Dedicator of cytokinesis 8 (DOCK8). 14 Dock8-deficient mice display a defect in both the myeloid and lymphoid compartments, 15,16 including a migratory defect of leukocytes in vivo and in vitro in a 3D collagen gel matrix.…”

Current Insights in Genetics of Sarcoidosis: Functional and Clinical Impacts

“…Another interesting gene identified by GWAS was CCDC88B (coiled-coil domain-containing protein 88B) located on chromosome 11q13, which encodes a positive regulator of T-cell maturation and inflammatory function involved in inflammatory bowel diseases [65,66]. Together with other 11q13.1 loci, the rs479777 SNP of CCDC88B was significantly associated with sarcoidosis in a German study.…”