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Title: Cytokines profiles in patients with rheumatoid arthritis: Genetic polymorphisms, protein and gene expressions of tumour necrosis factor-x interleukin-18 and interleukin-18 binding proteins
Keywords: Rheumatoid arthritis,cytokines,polymorphisms, IL-18-binding protein
Issue Date: 29-Mar-2007
Citation: SUPPIAH PARAMALINGAM SIVALINGAM (2007-03-29). Cytokines profiles in patients with rheumatoid arthritis: Genetic polymorphisms, protein and gene expressions of tumour necrosis factor-x interleukin-18 and interleukin-18 binding proteins. ScholarBank@NUS Repository.
Abstract: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by severe joint deformities, its pathogenesis involved interactions of complex cytokines networks and gene polymorphisms. The clinical manifestations of the disease in different ethnic groups can vary, depending on the differential expression of specific cytokines. We hypothesize that genetic association of HLA-DRB1*04 and its association with differential cytokine expressions modify the disease pattern in RA. We also postulate that increased IL-18 level may be associated with disease severity. In our study of HLA-DRB1*04 and cytokines genes polymorphisms in Singaporean Chinese with RA, the HLA-DRB1*0405 was identified as a marker of disease susceptibility. However it was not associated with severity. Sera from RA patients were assayed for both Th-1 and Th-2 cytokines to understand the profiles of pro-inflammatory and anti-inflammatory cytokines. Pro-inflammatory cytokines (IL-1, IL-6, IL-8, IL-18 and TNF- alpha) were significantly elevated in RA patients, while TGF-I? was elevated in controls. When RA patients were categorized according to disease activity, the soluble receptors sTNFR1 and sTNFR2 were noted to be significantly elevated in inactive RA patients. We postulate that two single nucleotide polymorphisms (SNPs) located at positions -607 and -137 in the IL-18 gene promoter may be associated with susceptibility to the development of RA. A significantly higher frequency of a??AAa?? genotype at position -607 was noted in healthy controls when compared to RA patients. This implies that the a??AAa?? genotype at position -607 may confer a protective effect against development of RA. Constitutive levels of IL-18 mRNA and protein were increased in RA patients, whereas the IL-18BP mRNA expressions were decreased. When analysed according to disease activity, we observed that IL-18 mRNA expression was increased in active patients, in contrast to IL-18BP which was increased in patients with inactive diseases. Lower mRNA expressions and IL-18 protein production were associated with the a??AAa?? genotype, which is considered to confer protection against RA development. Our findings were correlated in-vivo by treatment of active RA patients with TNF-alpha monoclonal antibody (infliximab). Rapid and stable reductions in serum concentrations of TNF- alpha in RA patients were observed. However, it failed to reduce the serum concentration of IL-18 in two out of seven patients. Interestingly, these two patients had persistently active disease, which can perpetuate the chronic inflammatory process. In conclusion, our findings indicate that there is a differential expression of IL-18 and IL-18BP that are associated with disease activity in RA patients. The protein expression of IL-18 or IL-18 complexed with IL-18BP locally is vital in determining the net IL-18 biological activity and disease causation. In our study, anti-TNF therapy was not effective in some patients, suggesting that other cytokines may play important roles in disease causation. In subsets of RA patients, targeting molecules (novel anti IL-18 therapy) that are directly involved in the chronic inflammatory process may be more efficacious and specific in slowing disease progression.
Appears in Collections:Ph.D Theses (Open)

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