Ocular inflammatory diseases, including uveitis, cause significant visual loss. Using a pathway specific gene chip with genes which are known to be involved in focused signaling pathways, e.g. inflammatory and autoimmune pathways, we found that there exist 4 distinct molecular gene expression profiles when comparing those from uveitis patients to those from normal donors. We termed those profiles molecular signatures for uveitis. Among those genes evaluated 9 genes had not been reported to be involved in uveitis. Of particular interest is the identification of IL-22. The expression of IL-22 has been recently associated with Th17 cells. We showed for the first time that IL-22 resulted in apoptosis in cultured primary RPE cells, possibly by decreasing the phosphorylated-Bad level. In addition, we saw increased IL-17 activity in the immune cells of patients with age related macular degeneration. This past year we have particularly concentrated on epigenetic changes associated with disease. The current understanding of epigenetics is the study of mechanisms that control somatically heritable gene expression status without changes in the underlying DNA sequence, including 1) DNA methylation/demethylation 2) Histone modification (Acetylation/deacetylation) 3). Chromatin structural modification and 4) Control of transcription by non-coding RNAs (siRNA, miRNA). We have initiated a long term investigation on the involvement of DNA methylation in the immune system, focusing on cell subpopulations and gene specific DNA methylation patterns and its involvement in autoimmunity and intraocular inflammatory disease. DNA methylation has been shown to participate in the control of hematopoeitic cell development. Comprehensive studies on DNA methylation in controlling cytokine expression in other immune cells, e.g., monocytes, NK cells and B cells, and genes with anti-inflammatory effect, e.g., IL-10 gene, have been lacking We have evaluated patients with age related macular degeneration, starting with twins who have disparate disease, then siblings and then a wider population of AMD patients. Although recent studies have demonstrated strong genetic associations between AMD and SNPs in a number of genes, other modes of regulation are also likely to play a role in the etiology of this disease. We identified a significantly decreased level of methylation on the IL17RC promoter in AMD patients. Furthermore, we showed that hypomethylation of the IL17RC promoter in AMD patients led to an elevated expression of its protein and messenger RNA in peripheral blood as well as in the affected retina and choroid, suggesting that the DNA methylation pattern and expression of IL17RC may potentially serve as a biomarker for the diagnosis of AMD and likely plays a role in disease pathogenesis. In addition, patients with steroid refractory uveitis have a characteristic subpopulation of steroid refractory CD4+ T cells in their peripheral blood. Previously studies have demonstrated that this steroid refractory phenotype is restricted to the central memory pool of CD4+ cells which have the capacity to generate IL-17. We therefore compared transcriptomic responses of Th1 and Th17 cells to corticosteroids in order to identify novel biomarkers and targets for therapeutic intervention in steroid refractory disease. Steroid referactory patients have a greater propensity than sensitive patients to generate Th17 cells, but Th17 cells from either group of patients have a similarly restricted change in gene expression following exposure to Dex compared with Th1 cells. Using additional techniques we have identified that a subgroup of uveitis patients have markedly shortened telomere length.

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National Eye Institute (NEI)
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Schewitz-Bowers, Lauren P; Lait, Philippa J P; Copland, David A et al. (2015) Glucocorticoid-resistant Th17 cells are selectively attenuated by cyclosporine A. Proc Natl Acad Sci U S A 112:4080-5
Liu, Baoying; Dhanda, Ashwin; Hirani, Sima et al. (2015) CD14++CD16+ Monocytes Are Enriched by Glucocorticoid Treatment and Are Functionally Attenuated in Driving Effector T Cell Responses. J Immunol 194:5150-60
Chen, Ping; Denniston, Alastair; Hannes, Susan et al. (2015) Increased CD1c+ mDC1 with mature phenotype regulated by TNF?-p38 MAPK in autoimmune ocular inflammatory disease. Clin Immunol 158:35-46
Dagur, Pradeep K; Biancotto, Angélique; Stansky, Elena et al. (2014) Secretion of interleukin-17 by CD8+ T cells expressing CD146 (MCAM). Clin Immunol 152:36-47
Wu, Wenting; Jin, Ming; Wang, Yujuan et al. (2014) Overexpression of IL-17RC associated with ocular sarcoidosis. J Transl Med 12:152
Thompson, Ian A; Liu, Baoying; Sen, H Nida et al. (2013) Association of complement factor H tyrosine 402 histidine genotype with posterior involvement in sarcoid-related uveitis. Am J Ophthalmol 155:1068-1074.e1
Wei, Lai; Chen, Ping; Lee, Joo Hyun et al. (2013) Genetic and Epigenetic Regulation in Age-related Macular Degeneration. Asia Pac J Ophthalmol (Phila) 2:269-74
Lima, Breno R; Nussenblatt, Robert B; Sen, H Nida (2013) Pharmacogenetics of drugs used in the treatment of ocular inflammatory diseases. Expert Opin Drug Metab Toxicol 9:875-82
Yeh, Steven; Albini, Thomas A; Moshfeghi, Andrew A et al. (2012) Uveitis, the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT), and intravitreal biologics for ocular inflammation. Am J Ophthalmol 154:429-435.e2
Wei, Lai; Liu, Baoying; Tuo, Jingsheng et al. (2012) Hypomethylation of the IL17RC promoter associates with age-related macular degeneration. Cell Rep 2:1151-8

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