CHEMOKINE GENES

    Chemokines are a group of low molecular weight (¡«8 ª²14kDa), mostly basic structurally related proteins that function as potent mediators of inflammation by their ability to recruit and activate leukocytes[19,20]. There are two major subfamilies of chemokines: CXC chemokines like CXCL8/ILª²8 usually recruit neutrophils, whereas CC chemokines like CCL2 and CCL5 tend to attract monocytes[21].

    ILª²8 and its Receptor Genes  ILª²8 can cause a transient increase in cytosolic calcium concentrations and release of enzymes from granules, thus enhance the production of reactive oxygen species and increase chemotaxis to neutrophils. Cellular activities of ILª²8 are mediated by its two receptors, CXCR1 and CXCR2. Serum and cerebrospinal fluid levels of ILª²8 have been found to be elevated in BD patients and correlated with disease activity[22,23]. Concenª²tration of ILª²8 increase significantly in the aqueous humor of patients with acute anterior uveitis (AAU)[24].

    Duymazª²Tozkir et al[25] reported no skewed deviation of ILª²8 or CXCR2 gene polymorphisms in Turkish patients with BD. Yeo et al[26] reported no association between ILª²8 or CXCR1 gene polymorphisms and IAU either. On the contrary, Lee et al[27] found that though there were no SNPs associated with BD, the increased frequency of haplotype TAT inferred from SNPs ILª²8ª²353ª²A/T, ª²251A/T and +678T/C has strong association with BD. These results suggested that a combined effect of ILª²8 SNPs is necessary to disease susceptibility, while the individual effect is not strong enough to show it.

    CCL2 and its Receptor Genes  CCL2, known as monocyte chemoattractant proteinª²1 (MCPª²1), is a chemoattractive cytokine. In animal models CCL2 was shown to play a role in autoimmune response and was thought to participate in the leukocyte infiltration and protein leakage in AAU and in the induction of uveitis itself[28,29]. MCPª²1 can be detected easily in the aqueous humor of patients with active AAU[24]. CCL2 ª²2518A>G polymorphism, which correlates with individual difference in production of MCPª²1, was identified in the MCPª²1 gene distal regulatory region[30]; monocytes from individuals carrying ª²2518G allele produce more MCPª²1 after proper stimulus.

    Chen et al[31] found that CCL2 haplotype with GA/AA were more prevalent in females and AA/AA or AA/AT were more prevalent in males. Wegscheider et al[32] showed that carriers of CCL2ª²2518G allele were significantly more often in patients with HLAª²B27 associated AAU than HLAª²B27 positive controls. Another study[26] demonstrated that the frequency of MCPª²1 63555T allele was significantly higher in controls compared to patients with IAU, which indicated that T allele may be a protective marker against uveitis.

    The associations of SNPs in CCL2 gene and clinical phenotypes of uveitis were identified by the study of idiopathic immuneª²mediated posterior uveitis[33]. The results showed that CCL2ª²2518G allele was associated with a younger age onset of disease, the mean age of disease onset in patients with AA genotype was 41 years compared to 33 years in patients with G allele. The study also found that patients with CCR2 64I allele had a higher risk of developing an elevated intraocular pressure compared to patients with wildª²type genotype.

    CCL5 and its Receptor Genes  CCL5, earlier called regulated upon activation, normal Tª²cell expressed, and secreted (RANTES), is chemotactic for T cells and plays an active role in recruiting leukocytes into inflammatory sites. Two polymorphic sites (ª² 28 and ª² 403) in the upstream region of the CCL5 gene that contains cisª²acting element involved with CCL5 promoter activity[34,35]. They were in linkage disequilibrium. The CCL5ª² 403AA genotype was only found in male patients with BD but not in controls[31].

    Ahad et al[33] found that CCL5ª² 403GG genotype was associated with disease severity and G allele was associated with worse visual acuity (VA) in the affected eye. CCL5 del32 was found to be associated with visual outcome even after correction for disease phenotype and treatment. CCL5ª²59029 polymorphism was associated with the need for persistent corticosteroid therapy of more than 10mg per day to control inflammation. Yang et al[36] and Mojtahedi et al[37] reported no association of CCR5del32 polymorphism with BD but revealed a significant difference in distribution of the CCR5 del32 in female patients compared with female controls.

    CONCLUSION

    In addition to above gene polymorphisms, other cytokines and their receptor genes, such as ILª²6, ILª²10 and IFNª²¦Ã, have also been studied[9]. Studies of the genetics of uveitis have revealed that cytokine and chemokine gene polymorphisms have strong associations with uveitis. But current studies of these genes concentrated on caseª²control study, small sample size is a frequent problem and can result in insufficient statistical power and provide imprecise estimates of the disease association. In the future, largeª²scale studies and different populations will be necessary to validate the associations of these genes and uveitis development and clinical phenotypes.

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Clin North Am 2003;16(4):555ª²565

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10 Nakanishi K, Yoshimoto T, Tsutsui H, Okamura H. Interleukinª²18 is a unique cytokine that stimulates both Th1 and Th2 responses depending on its cytokine milieu. Cytokine Growth Factor Rev 2001;12(1):53ª²72

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13 Jang WC, Park SB, Nam YH, Lee SS, Kim JW, Chang IS, Kim KT, Chang HK.Interleukinª²18 gene polymorphisms in Korean patients with Behcet¬ðs disease. Clin Exp Rheumatol 2005;23:S59ª²63

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