Does innate immune response defect underlie inflammatory bowel disease in the Asian population?

T he normal intestine encounters a high concentration of foreign antigen, bacteria, and food, across a large surface area that approximates to that of a tennis court. Despite the fact that this antigenic load is separated from the largest complement of lymphocytes in the body (gut associated lymphoid tissue, GALT) by only a single layer of polarised intestinal epithelium, most people do not mount an immune response to foreign antigens. The mucosal immune system has evolved to balance the need to respond to pathogens while maintaining active tolerance to commensal bacteria and food antigens. In inflammatory bowel disease (IBD), this tolerance breaks down and inflammation supervenes driven by the intestinal microbial flora. Tolerance is based both on the protection offered by the evolutionary conserved innate immune response that is non-antigen specific and the antigen specific adaptive immune response that develops upon antigen exposure. Current key targeted therapeutic strategies are directed against important cytokines that drive the adaptive immune response (anti-TNF antibodies), prevention of trafficking of lymphocytes to the intestine (a4 integrin antibodies), or induction of apoptosis of lymphocytes. ‘‘Permanent’’ tolerance, however, is not restored and relapses are virtually inevitable when treatment is withdrawn. Understanding the molecular mechanisms of the breakdown of tolerance resulting from a defect in the innate immune response would potentially permit identification of novel therapeutic strategies. Identification of specific genetic mutations affecting the innate immune response associated with IBD disease lends credibility and rationale for pursuing this line of research. While it is now undisputed that enteric bacterial flora play a key part in the pathogenesis of IBD, both ulcerative colitis (UC) and Crohn’s disease (CD), the exact mechanism resulting in the loss of tolerance of the intestinal mucosa to its bacterial neighbours remains elusive. The role of host genetic regulation of the innate immune response in the pathogenesis of CD has been brought to sharp focus by the identification of the NOD2 (CARD15) mutations on chromosome 16q12 strongly associated with CD, especially with ileal involvement. 2 The specific ligand of cytosolic NOD2 is identified to be muramyl dipeptide, a component of peptidoglycan, which is a constituent of bacterial cell walls, and is recognised by the leucine rich repeat (LRR) region of NOD2. NOD2, expressed on monocytes, macrophages, and dendritic cells as well as Paneth cells and intestinal epithelial cells, is a member of the pattern recognition receptor (PRR) family that recognises pathogen associated molecular patterns (PAMPs) that characterise micro-organisms and activates intracellular signalling pathways. The NOD2 protein is structurally related to the well described R proteins in plants, which mediate host resistance to microbial pathogens and induce NF-kB proinflammatory pathways. Pathogens and commensal bacteria of human intestinal flora share many of these PAMPs. Some years before the discovery of NOD2 gene, researchers had identified the toll-like receptors (TLR), which are a large family of cell surface PRRs that recognise a range of microbial associated molecules (table 1). These play an important part in combating the invasion of pathogens as a frontline defence. TLRs are composed of an intracytoplasmic toll/interleukin1 receptor domain and extracellular leucine rich repeat region (LRR). TLR4 specifically binds the lipid A portion of lipopolysaccharide (LPS), which is a component of Gram negative bacteria, leading to NF-kB activation. A novel association between TLR4 polymorphism with both UC and CD has been recently described in Belgian cohorts, and with CD (less strongly with UC) in Greek and with UC alone in German IBD populations. In the Belgian and Greek IBD populations, allele frequency of TLR4 Asp299Gly was increased, whereas in the German population, TLR4 Thr399Ile mutation was increased in frequency. In addition to TLR4, CD14 (a GPI anchored molecule on the cell surface of monocytes) is also involved in recognising LPS complexed with LPS binding protein (LBP). In the Greek population the T allele and TT genotype frequencies of CD14 promoter were significantly higher in CD patients compared with healthy people. In a recent report, it was shown that in Hungarian CD patients, the frequency of TLR4 polymorphism was not increased compared with controls. In a German IBD population, the T allele and TT genotype frequencies of CD14 promoter were found increased in CD population but not in UC population, whereas in a Japanese population promoter polymorphism of CD14 gene seemed to confer a genetic predisposition to UC. It is intuitive to hypothesise that innate immune response defects leading