594 Current Genomics, 2010, Vol. 11, No. 8 ing its role as a negative regulator of the pro-inflammatory IL33/ IL1RL1 isoform A axis. Human data on the other hand clearly demonstrate a consistent increase of IL1RL1 isoform B in an array of pathological conditions as well as the corre- lation of this increase with severity. Additionally, there was a report of an animal study showing that mice deficient in IL1RL1 showed attenuated airway inflammation after chal- lenge with an allergen [51], suggesting that IL1RL1 isoform B might be participating in the excessive inflammation ob- served in asthma. However, the model used for this study was the transgenic TCR-mouse model; these animals are pre- disposed to autoimmune disorders because they carry rear- ranged TCR and genes from a diabetogenic T cell clone. The above studies do not seem to be consistent with the antagonist role of IL1RL1 isoform B but rather indicate a possible involvement in the pathology. An alternative expla- nation would be that the increase of IL1RL1 isoform B is a means of preventing an exaggerated immune response but either occurs too late or is insufficient to remedy to the pathological state. Evidently, soluble IL1RL1 plays a role in the regulation of the immune response, notably in severe disease. Exactly what that role is and the mechanisms underlying it need to be clarified in order to develop efficient strategies for develop- ing therapeutics using the IL1RL1 proteins. Recent human data in Chronic Obstructive Pulmonary Disease (COPD) seem to indicate an involvement of soluble IL1RL1 in the early stages of COPD [52]. This study how- ever involved a small number of patients and needs replica- tion. Allergy and Immune Disorders A SNP in the distal promoter region of IL1RL1, rs6543116 (-26999G/A), was associated with increased risk for atopic dermatitis and up-regulation of gene expression [53]. This study suggested a functional effect of rs6543116 as the A allele correlated with an up-regulation of the gene transcription as well as serum levels. The same group re- ported the association of serum levels of IL33 and SNPs in the IL33 gene with Japanese cedar pollinosis, the most com- mon form of allergic rhinitis in Japan [54]. In addition, Cas- tano et al. found a protective association of IL1RL1 SNPs with chronic rhinosinusitis using a cohort of surgery- unresponsive chronic rhinitis patients, this association was stronger in more severe disease [55]. IL33 signaling through IL1RL1 was shown to be in- volved in anaphylactic shock in an animal model study ex- amining the response of IgE-sensitized mice to IL33 treat- ment [23]. The same authors had shown elevated IL33 levels in the serum of atopic patients undergoing surgery; this ef- fect was demonstrated to derive purely from innate immunity as T or B cells were not required. The pathological effect could be prevented by treatment with anti-IL33 antibody or soluble IL1RL1 and was not observed in ST2-/- animals [23]. IL1RL1 and closely linked genes have been implicated in an array of autoimmune diseases. Levels of IL1RL1 isoform B have been shown to be increased in various conditions such as Systemic Lupus Erythematosus (SLE), sclerosis, and Akhabir and Sandford rheumatoid arthritis (RA) [56]. Mok et al. found that ele- vated serum IL1RL1 isoform B levels in SLE patients corre- lated with disease activity [57]. To date, GWAS performed in Chinese and European populations have not found asso- ciation of IL1RL1 SNPs with RA [58, 59]. Studies in animal models demonstrated that recombinant IL1RL1 isoform B protein, or anti-IL1RL1 antibody could significantly attenuate the severity of experimental arthritis [60, 61] and IL1RL1 knock-out mice were shown to develop less severe form of disease and had reduced pro- inflammatory cytokine production. Additionally, human studies have shown increased levels of IL33 and IL1RL1 in RA synovium paralleling increased inflammation [62]. Stud- ies in animal models strongly suggest that the involvement of IL33/IL1RL1 in RA is through triggering mast cell de- granulation in the RA synovium [63]. Although there is good evidence for a role of IL33/IL1RL1 in human and experi- mental arthritis, no SNPs in these genes were found associ- ated with susceptibility to RA in GWAS data [64]. The IL1RL1/IL33 signaling axis was implicated in in- flammatory bowel disease (IBD) for the first time in two recent studies characterizing IL1RL1 and IL33 protein and mRNA expression in IBD patients [65]. There was an in- crease in soluble IL1RL1 levels in the gut, which was mainly associated with the active state of ulcerative colitis, indicat- ing a possible negative regulation of the IL1RL1/IL33 path- way in order to dampen the inflammation. Pastorelli et al. confirmed the observation of elevated levels of IL1RL1 and IL33 in the serum and mucosa of IBD patients; they also showed that anti-TNF decreased IL1RL1 isoform A levels and increased the soluble isoform making more decoy recep- tor available in order to sequester IL33 and reduce the in- flammation [66]. A SNP 1.5 kb downstream of IL18RAP (rs917997) was associated with susceptibility to IBD in a Dutch population; the same SNP was associated with celiac disease in three European populations [67]. rs917997 along with another SNP in the intergenic region between IL1RL1 and IL18R1 (rs13015714) were associated with celiac disease in a GWAS of a UK population [68]. The same SNP downstream of IL18RAP (rs917997) was associated with Crohn's disease in a GWAS [69]. These genetic and mechanistic data suggest that IL1RL1/IL33 plays a role in the gut mucosa similar to the airway epithelium i.e. IL1RL1 isoform A/IL33 eliciting a Th2 immune response and IL1RL1 isoform B serving as a negative regulator. There is evidence that IL1RL1 directly acts on macro- phages to suppress their ability to produce pro-inflammatory cytokines [42]. Macrophages are instrumental in diabetes pathogenesis. In an animal model of diabetes (multiple low- dose streptozotocin-induced diabetes), Mensah-Brown et al. [70] showed that specific disruption of the IL1RL1 gene sig- nificantly enhanced inflammation in their mouse model as estimated by an increase in cellular infiltration in pancreatic islets and a reduction in cells immuno-positive for insulin. Recently, a genetic linkage study demonstrated linkage of chromosome 2 with type 2 diabetes with a LOD score of 4.5 [71]. Follow-up genetic studies are warranted to narrow