In 2010, an international collaborative project first identified chromosome 11q13 as a risk factor for Crohn's disease from the meta-analysis of six different genome-wide association studies (GWAS) [Franke et al. Nature Genet. doi: 10.1038/ng.717]. In addition, 11q13 has been shown to be a susceptibility locus for other auto-immune and chronic inflammatory conditions such as alopecia areata [Petukhova et al. Nature. doi: 10.1038/nature09114], leprosy [Lui et al. Nature Genet. doi: 10.1038/ng.3212] and psoriasis [Ellinghaus et al. doi: 10.1016/j.ajhg.2012.02.020].
In 2012, the analysis of GWAS data from patients in three different Europe centres confirmed that chromosome 11q13.1 was a susceptibility locus for sarcoidosis, with the CDCC88B gene identified as the most likely risk factor for disease.
More recently, Philippe Gros and colleagues, from McGill University in Canada, have employed N-ethyl N-nitrosourea-mutagenised mice to demonstrate that Cdcc88b is an important regulator of T cell function, and is also expressed in myeloid cells [Kennedy et al. J. Exp. Med. doi: 10.1084/jem.20140455]. With regard to disease pathogenesis, Cdcc88bmut mice were shown to be protected from fatal brain inflammation in a mouse model of malaria.
The McGill scientists have now published a follow-up paper which has sought to explore the importance of CCDC88B in IBD. In this new publication [Fodil et al. Nat. Commun. doi: 10.1038/s41467-017-01381-y], the effect of ccdc88b mutation on two different mouse models of IBD is examined and analysis of CCDC88B expression in human inflammatory bowel disease is also presented. Their main findings are summarized below:
DSS-induced acute colitis in C57BL/6 mice was associated with accumulation of Ccdc88b‑positive lymphoid (defined on the basis of CD3, CD4 or CD8 expression) and myeloid cells (defined on the basis of CD11b expression).
Ccdc88b mutant mice demonstrated a significant reduction in the severity of DSS‑induced acute colitis, relative to wild-type mice, including:
- Large reductions in body weight
- Gross and microscopic histopathological changes in the large bowel
- Reduced expression of neutrophil chemoattractants MCP1 and KC and of pro‑inflammatory cytokines IL1β,TNF and IL6 mRNAs.
Adoptive transfer of naïve (CD4+CD45RBhi) T cells isolated from Ccdc88b mutant mice resulted in significantly less pathological change in the large bowel of Rag1-/-‑recipient mice, as compared to naïve T cells from wild-type donor mice. The reduction in the severity of the observed colitis was associated with a decrease in the infiltration of Ccdcc88b-positive T cells into the colonic mucosa and submucosa.
Comparison of the expression of quantitative trait loci (eQTL: regions of DNA that contain sequence variants associated with the differential expression of either cis or trans genes) associated with CCDC88B expression in different leukocyte populations obtained from IBD patients, and GWAS analysis of single nucleotide polymorphisms associated with Crohn's disease, was performed. This revealed a significant positive correlation between disease risk and the expression of CCDC88B in CD14+ myeloid cells, with the SNP which conferred the highest risk of CD mapping locally (6kb distant) to the eQTL with greatest influence on CCDC88B expression.
Colonic inflammation in patients with IBD (both Crohn's and Ulcerative Colitis) was associated with the presence of CCDC88B+CD4+ T cells and CCDC88B+CD68+ monocytes/macrophages in the mucosa.
The data from the mouse adoptive T cell transfer model demonstrates the importance of Ccdc88b function in CD4+ T cells for colitis development. The data obtained from studies of colon samples from IBD patients supports the role of CCDC88B expression in myeloid lineage cells as a risk factor in disease.
The authors propose that CCDC88B functions through its known interaction with the protein DOCK8 (Detector of Cytokines 8) [Ham et al. J. Immunol. doi: 10.4049/jimmunol.1402897], to promote cell homing to specific sites, in response to inflammatory signals. DOCK8 facilitates Rho-GTPase function and thereby influences cell structure, adhesion and migration [Meller et al. J. Cell Sci. doi: 10.1242/jcs.02671]. DOCK8 itself may be activated by its interaction with Myd88; for example, through TLR9‑engagement by CpG DNA [Jabara et al. Nat Immunol. doi: 10.1038/ni.2305]. Precisely how CCDC88B modulates inflammatory cell migration to the gut and its dependence on DOCK8 remains to be determined, but the results do shed some light on how the 11q13 risk locus may function to promote colonic inflammation.