Summary for the Clinician

• The recent finding of NOD2 associated with a rare familial granulomatous disease has been promising, although so far has not been found to be associated with other granulomatous uveitides

• Finding TNF associated polymorphisms provides hope that further research will provide a means to predict who will respond best to specific therapeutic agents

Other Ocular Diseases

Inflammation is involved in the pathogenesis of many ocular diseases, not only those thought to be due to primarily to autoimmunity or infection. Such diverse entities as dry eye,macular degeneration [5,7,89,95], diabetic retinopathy [24] and glaucoma [113,119] have been shown to have an inflammatory component. The prognosis of patients with choroidal melanoma may also be in part determined by HLA and other genetic risk factors, as may be expected by the role of the immune system in controlling malignancies.

No immunogenic studies of macular degeneration have been published, although manipulation of genes involved in the immune response has resulted in the development of a murine model of disease [5].

Despite the putative involvement of T cells [106], cytokines [19,120], IL-6 [48], and chemo-kines [13,20] in diabetic eye disease,a consistent HLA association has not been found. HLA-DQB1*0201 and HLA-DQB1*0302 were thought to be associated with severe retinopathy, with HLA-DR3 and HLA-DR4 being involved by linkage disequilibrium in one study [1]. HLA-DR3 and HLA-DR4 were not associated with the diabetic retinopathy in a more recent study [117], while an association with HLA-B*62, HLA-Cw4 and HLA-DQ4, and in particular with the HLA-Cw4/DR4/DQ4 haplotype in patients with type 2 diabetes, was described [71]. These discrepancies are not surprising; multiple environmental and genetic factors contribute to the development of diabetic retinopathy, and different patient populations have been studied. It may be that genes related to these other mediators of inflammation will be found that are more critical in the inflammatory response in diabetic retinopathy.

Primary open angle glaucoma was associated with the HLA-DRB1*0407-DQB1*0302 in Mexican Mestizos [28]. A TNF gene polymor phism was found in Chinese patients with primary open angle glaucoma [57].

Summary for the Clinician

• Macular degeneration, diabetic retinopathy, glaucoma and dry eye have an inflammatory component; future research in the immunogenetics of these diseases may provide insights into pathogenesis

Conclusion

Genetic associations are useful for providing supportive evidence for the diagnosis of specific entities in the work-up of patients with uveitis. No specific HLA type makes the diagnosis, however. Immunogenetic research has presented us with the profound challenge of trying to understand the reasons for the impressive HLA associations with ocular inflammatory disease. This would have implications for non-ocular diseases as well. As our understanding of the human genome becomes more sophisticated and our research techniques more robust, we will be able to evaluate additional genetic contributions to the pathogenesis not only of uveitis, but other ocular diseases including macular degeneration, diabetic retinopathy, glaucoma and intraocular tumours. This will allow a better understanding of disease mechanisms and the design of novel therapies.

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