Potential Role of NK Cells in the Pathogenesis of Inflammatory Bowel Disease

NK cells are a major component of the innate immune system and play an important role in the tissue inflammation associated with autoimmune diseases such as inflammatory bowel disease (IBD). NK cells are unique in bearing both stimulatory and inhibitory receptors specific for MHC class I molecules, and their function is regulated by a series of inhibiting or activating signals. The delicate balance between activation and inhibition that decides NK cell final action provides an opportunity for their possible modulatory effect on specific therapeutic settings. Intestinal NK cells are phenotypically distinct from their counterparts in the blood and resemble “helper” NK cells, which have potentially important functions both in promoting antipathogen responses and in the maintenance of intestinal epithelial homeostasis. NK cell activities have been found to be significantly below normal levels in both remissive and active stages of IBD patients. However, some proinflammatory cytokines (e.g., IL-15, IL-21, and IL-23) could potently induce NK cell activation to secret high levels of proinflammatory cytokines (e.g., IFN-γ and TNF) and promote the cytolytic activities against the target cells. This paper provides the characteristics of intestinal NK cells and their potential role in the pathogenesis of IBD

Zhang, et al, Expression of iKIR-HLA-Cw in patients with inflammatory bowel disease Expression of iKIR-HLA-Cw in patients with inflammatory bowel disease

Abstract Objective. To investigate the distribution of inhibitory killer cell immunoglobulin-like receptor (iKIR) and its ligand human leukocyte antigen C locus (HLA-Cw) in patients with inflammatory bowel disease (IBD), and explore whether iKIR/HLA-Cw combinations are associated with IBD susceptibility. Methods. The iKIR in 100 patients with ulcerative colitis (UC), 52 patients with Crohn's disease (CD) and 106 randomly ethnically matched healthy controls was phenotyped by sequence-specific primer PCR (PCR-SSP). HLA-Cw was phenotyped by CLOCUS SSP UNITRAY ® . The combination of HLA-Cw and its corresponding iKIR in individual was analyzed subsequently. Results. The KIR2DL1 and KIR2DL3 gene phenotype frequencies in UC patients were 0.710 and 0.620 respectively, both significantly lower than those in healthy controls, and the KIR2DL1 gene phenotype frequency in CD patients was 0.731, significantly lower than that in healthy controls. KIR2DL1-HLA-C2 combination in patients with UC and CD were 0.380 and 0.404 respectively, both significantly lower than that in healthy controls. Conclusion. The susceptibility to IBD is associated with decreased KIR2DL1-HLA-C2 combination

Altered DNA methylation within DNMT3A, AHRR, LTA/TNF loci mediates the effect of smoking on inflammatory bowel disease

This work aims to investigate how smoking exerts effect on the development of inflammatory bowel disease (IBD). A prospective cohort study and a Mendelian randomization study are first conducted to evaluate the association between smoking behaviors, smoking-related DNA methylation and the risks of Crohn’s disease (CD) and ulcerative colitis (UC). We then perform both genome-wide methylation analysis and co-localization analysis to validate the observed associations. Compared to never smoking, current and previous smoking habits are associated with increased CD (P = 7.09 × 10−10) and UC (P < 2 × 10−16) risk, respectively. DNA methylation alteration at cg17742416 [DNMT3A] is linked to both CD (P = 7.30 × 10−8) and UC (P = 1.04 × 10−4) risk, while cg03599224 [LTA/TNF] is associated with CD risk (P = 1.91 × 10−6), and cg14647125 [AHRR] and cg23916896 [AHRR] are linked to UC risk (P = 0.001 and 0.002, respectively). Our study identifies biological mechanisms and pathways involved in the effects of smoking on the pathogenesis of IBD

Bi-directional Mendelian randomization analysis provides evidence for the causal involvement of dysregulation of CXCL9, CCL11 and CASP8 in the pathogenesis of ulcerative colitis

Background and Aims Systemic inflammation is well recognised to be associated with ulcerative colitis [UC], but whether these effects are causal or consequential remains unclear. We aimed to define potential causal relationship of cytokine dysregulation with different tiers of evidence. Methods We first synthesised serum proteomic profiling data from two multicentred observational studies, in which a panel of systemic inflammatory proteins was analysed to examine their associations with UC risk. To further dissect observed associations, we then performed a bidirectional two-sample Mendelian randomisation [TSMR] analysis from both forward and reverse directions using five genome-wide association study [GWAS] summary level data for serum proteomic profiles and the largest GWAS of 28 738 European-ancestry individuals for UC risk. Results Pooled analysis of serum proteomic data identified 14 proteins to be associated with the risk of UC. Forward MR analysis using only cis-acting protein quantitative trait loci [cis-pQTLs] or trans-pQTLs further validated causal associations of two chemokines and the increased risk of UC: C-X-C motif chemokine ligand 9 [CXCL9] [OR 1.45, 95% CI 1.08, 1.95, p = 0.012] and C-C motif chemokine ligand 11 [CCL11] [OR 1.14, 95% CI 1.09, 1.18, p = 3.89 x 10(-10)]. Using both cis- and trans-acting pQTLs, an association of caspase-8 [CASP8] [OR 1.04, 95% CI 1.03, 1.05, p = 7.63 x 10(-19)] was additionally identified. Reverse MR did not find any influence of genetic predisposition to UC on any of these three inflammation proteins. Conclusion Pre-existing elevated levels of CXCL9, CCL11 and CASP8 may play a role in the pathogenesis of UC