Ocular inflammatory diseases, including uveitis and AMD, cause significant visual loss. Using a variety of immune techniques we have evaluated various characteristics of immune cells in these diseases, including signaling pathways, e.g. inflammatory and autoimmune pathway. We have seen varying molecular signatures for uveitis. Of particular interest is the identification of IL-22. The expression of IL-22 has been recently associated with Th17 cells which is elevated in the serum of AMD and uveitis patients. We have shown 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. We have reported epigenetic alterations the immune cells of AMD patients but this remains to be verified. In an animal model for uveitis, we have seen that epigenetic altering medication affects positively the expression of active disease, and changes were noted in vitro on human cells. In addition an increase in the presence of immune markers such as IL-17 and its receptor in the eyes of AMD were noted, whatever their mechanism may be. 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 refractory patients have a greater propensity than sensitive patients to generate Th17 cells, and Th17 cells from either group of patients respond differently following exposure to Dex as compared with Th1 cells. Using gene expression profiling a restricted response to glucocorticoids was noticed. Of interest that there was a large genome shift in response to cyclosporine A. Since steroid resistance is an important clinical problem, this information would suggest strongly that new therapeutic which target either Th17 cells or the effector memory T helper cell population from which they are derived would be candidates for drug development. Of interest is the finding that in humans, glucocorticoid therapy affects the subtype of monocytes, inducing the subtype that is associated with the induction of T regulatory cells. Using additional techniques we have identified that a subgroup of uveitis patients have markedly shortened telomere length. In addition we have noted circulating IL-17 in sarcoidosis patients which is associated with active disease. Patients with sarcoidosis were noted to have an elevated IL-17RC expression on CD8+ cells. In addition we have noted that CD8+ T cells, which are now designated as Tc17 cells, produce IL-17 and are characterized by CD146 expression. We have also studies dendritic cells in patients with ocular inflammatory disease. What was noted was the association of CD1c+mDCs with activity, and this appears to be regulated by TNF-alpha-p38 MAPK. We are pursuing the hypothesis that this could be a biomarker for activity before the disease becomes clinically apparent.

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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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