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D. Atan, S.J. Turner, D.J. Kilmartin, J.V. Forrester, A.D. Dick, A.J. Churchill; Cytokine Gene Polymorphism in Sympathetic Ophthalmia . Invest. Ophthalmol. Vis. Sci. 2003;44(13):675.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Sympathetic ophthalmia (SO) is an autoimmune disorder where the identification of genomic associations could enhance our understanding of this disease. Previous work showed that the human leucocyte antigen haplotype, HLA-DRB1*04-DQA1*03, is a marker of increased susceptibility and severity of SO in British and Irish patients. There is growing evidence that single nucleotide polymorphisms (SNPs) in cytokine gene promoter regions (eg. IL-10 -1082A/G, TNFα -308A/G, and TNFß NcoI site A/G) influence the development of autoimmune disease. They affect the binding of transcription factors and consequently regulate cytokine production levels. The purpose of this study was to test the hypothesis that individuals who are genetically predisposed to secrete high levels of TNF and low levels of IL-10 would be more susceptible to disease and have a worse outcome. Methods: 27 British and Irish patients with SO were recruited after 18 months of British Ophthalmological Surveillance and compared with 51 matched controls. Genotyping of the IL-10 and TNF genes was performed using the polymerase chain reaction and sequence specific primers (SSP-PCR). Results: Analysis showed a reduced frequency of the -592A allele of the IL-10 promoter in SO patients. There were no other significant differences in allele or haplotype frequencies at other sites in the IL-10 or TNF promoter regions between patients and controls. In SO patients, there was a significant association between the IL-10 -1082A allele and more severe disease. These patients were more likely to experience recurrences while on systemic therapy and to need vitreo-retinal surgery. Moreover, there was a non-significant trend for these patients to need higher maintenance doses of steroids. Conclusions: SO is mediated by CD4+ Th1 cells which secrete pro-inflammatory cytokines such as tumour necrosis factors α and ß (TNF). They are inhibited by the anti-inflammatory cytokine, interleukin-10 (IL-10). The -1082G/A SNP is associated with altered levels of in vitro IL-10 expression: -1082G with high and -1082A with low. In the context of an extended IL-10 haplotype, -1082G/-819C/-592C or GCC is associated with high transcriptional activity and ACC or ATA are associated with lower transcriptional activity. The functional influence of the SNP at -592 on IL-10 production is not as yet known. However our results show that SO patients who are low IL-10 producers are more likely to have severe disease.
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