• TLRs and the related IL1 receptors share a conserved homophilic domain, termed the Toll/IL1 receptor (TIR) recognition domain, which recruits a common adaptor molecule, MyD88, following ligand binding. This leads to the formation of a complex with tumor necrosis factor receptor associated factor-6 (TRAF6) and the IL1 receptor associated protein kinase-1 (IRAK-1) and IRAK-4. IRAK-1 and TRAF-6 then dissociate from this complex and associate with transforming growth factor b (TGFb)-activated kinase (TAK-1) and the TAK-1 binding proteins, TBP-1 and -2. This in turn activates TAK-1, leading to the phosphorylation and activation of IkB kinase complex and culminating in the degradation of IkB and activation of NFkB (Figure 1). Both MyD88 and TIR8 (an intracellular decoy receptor that traps TRAF-6/IRAK-1) knockout mice show increased susceptibility to DSS-induced colitis.14'15

A further example of how the TLR system plays a role in augmenting the breakdown in tolerance has come from preclinical models of autoimmune diabetes, in which transgenic mice expressing the lymphocytic choriomeningitis virus glycoprotein (LCMV-GP), under the control of the rat insulin promoter, were infected with LCMV-GP peptide.16 Infection caused the generation of large numbers of autoreactive cytotoxic CD8+ T cells, but did not induce autoimmune diabetes in the absence of treatment with certain TLR ligands. The relevance to IBD is compelling and underscores the significance of the preclinical phenotype observed in the NOD2 mutant and MyD88~/ _ mice.

Are there other factors that create an abnormal immune response and precipitate chronic intestinal inflammation? The loss of local tolerance may also be due to the loss of regulatory cells (e.g., Th3 or Tr1), as is typified by the phenotypes of the IL10 and TGFpi knockout mice. Alternatively, a breakdown in barrier function, which would permit the access of inflammatory bacterial products to the local immune system, might overwhelm normal regulation. One example of how an apparent abnormality in mucosal permeability might contribute to the development of IBD has emerged from studies on the MDRla locus (OMIM 171050). The Mdrla~/ ~ transgenic mouse was created, in part, to understand the contribution of the P-glycoprotein efflux transporter, expressed on intestinal epithelium, on drug absorption. However, these mice also display mucosal barrier dysfunction, characterized by increased basal colonic ion transport, altered tight junction function, and increased bacterial translocation, and consequently develop a severe spontaneous inflammatory colitis.17 The MDRla gene is expressed on chromosome 7q in human, a known IBD susceptibility locus. It is a highly polymorphic gene and genetic polymorphisms, which lower protein expression, have also been identified in CD and UC patients.18'19 Whether the Mdr1a efflux pump performs a housekeeping function, by actively reducing mucosal exposure to commensal pathogenic antigens or xenobiotics, or is responsible from some other mechanism in maintaining mucosal barrier function, remains to be determined. Likewise, the identification of other pathways responsible for the potential breakdown in mucosal tolerance in IBD remains to be identified.

In contrast to the NOD2/CARD15 gene susceptibility locus for CD, no specific gene defect has been linked to UC. A region of the major histocompatibility complex (MHC) locus on chromosome 6p that contains the human leukocyte antigen (HLA) class I and II histocompatability locus, however, has been implicated in increased UC susceptibility. In particular, the association between HLA-B27 and the development of extraintestinal conditions (Table 2) such as ankylosing spondylitis in patients with UC is reproduced in a transgenic rat model.20 CD patients with HLA-A2, DR1, and DQw5 are more likely to develop extraintestinal disease. Furthermore, in some populations, the DRB1*1502 allele is positively associated with UC and the DRB1*0103 allele is associated with both severe inflammation and an increased probability of colectomy.

Although the detection of disease-associated variants has greatly advanced our understanding of the primary events that lead to the development of IBD, in a subgroup of patients with CD especially, the implications of these findings for diagnostic algorithms and therapeutic modalities are less clear.

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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