In collaboration with Dr. Siamon Gordon of Oxford University and Dr. Miller of the NEI, we have initiated studies on human macrophages focusing on 1) the interaction of human macrophages with human retinal pigmented epithelial cells and 2) phenotypic and functional heterogeneity of human macrophages and its implication in autoimmune intraocular inflammatory diseases. We have found that human RPE cells can interfere with the normal processes of differentiation and maturation of macrophages. We have combined flow cytometry, vibrotome immunohistochemistry and flat-mount techniques plus confocal immunomicroscopy to evaluate inflammatory responses in animal models of ocular disease. We have discovered that there is a dynamic and complex movement of immune cells during the development of CNV in the mouse. We also induced experimental autoimmune uveitis in wild type and SR-A1 knockout mice. SR-A1 deletion inhibited the development of EAU. Macrophages and dendritic cells from these animals expressed lower levels of pro-inflammatory genes and markers. Macrophages have been implicated in the pathogenesis of AMD. Class A scavenger receptors, SR-A and MARCO, are expressed on macrophages and are associated with macrophage function. The goal of this study is to examine the role of macrophage scavenger receptors in immune cell recruitment and the formation of CNV. We had previously reported that the deficiency of scavenger receptors impairs the formation of CNV and immune cell recruitment and in these experiments that of EAU. Our findings suggest a potential role for scavenger receptors in contributing to CNV formation and inflammation in AMD and uveitis. We had shown previously that C5a promoted IL-22 and IL-17 expression from human CD4+ T cells of AMD patients and normals accompanied by the expression of the transcription factor BATF. This effect was dependent on B7, IL-1beta and IL-6 expression from monocytes. Intriguingly, we found significantly increased levels of IL-22 in the serum of 22 AMD patients as compared to non-AMD controls, strongly suggesting possible roles of IL-22 and IL-17 in the inflammation that contributes to AMD. We wished to further these observations by evaluating macrophage subtypes in ocular inflammatory disease. While human macrophages have been categorized into subtypes they have not be well evaluated in ocular inflammatory disease and autoimmunity. Uveitis patients circulating monocytes were skewed to the CD14++CD16+ type and this was associated with corticosteroid therapy. This subset had an attenuated capacity to promote nave CD4+ T cells to proliferate and polarize into a TH1 phenotype, memory CD4+ memory cell proliferation and IL-17 expression. They also inhibited T cell inhibition induced by other monocyte subsets while increasing CD4 T regulatory cells. We further studied the effect of immunosuppression on human inflammatory cells. A subset of T cells appear to be resistant to corticosteroid therapy but do respond to cyclosporine therapy, thus selectively attenuating TH17 cells. We have also performed whole transcriptome profiling of peripheral CD4+ T cells of AMD patients using RNA-Seq. These data show moderate but significant differences of gene expression levels between AMD patients and controls, with dysregulation of multiple pathways and biofunctions in CD4+ cells. These data support the profound immune dysregulation of AMD and the potential role of immunosenescence. Thus, our data suggest an underlying mechanism of chronic inflammation leading to retinal degeneration which may herald a new approach to treat AMD. Plans are being made based on these observations to begin a randomized study to prevent the expression of late AMD.
| Knickelbein, Jared E; Liu, Baoying; Arakelyan, Anush et al. (2016) Modulation of Immune Responses by Extracellular Vesicles From Retinal Pigment Epithelium. Invest Ophthalmol Vis Sci 57:4101-7 |
| Chen, Ping; Urzua, Cristhian A; Knickelbein, Jared E et al. (2016) Elevated CD1c+ Myeloid Dendritic Cell Proportions Associate With Clinical Activity and Predict Disease Reactivation in Noninfectious Uveitis. Invest Ophthalmol Vis Sci 57:1765-72 |
| 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 |
| Nussenblatt, Robert B; Lee, Richard W J; Chew, Emily et al. (2014) Immune responses in age-related macular degeneration and a possible long-term therapeutic strategy for prevention. Am J Ophthalmol 158:5-11.e2 |
| 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 |
| Lima, Breno R; Mandelcorn, Efrem D; Bakshi, Nupura et al. (2014) Syphilitic outer retinopathy. Ocul Immunol Inflamm 22:4-8 |
| Whitcup, Scott M; Nussenblatt, Robert B; Lightman, Susan L et al. (2013) Inflammation in retinal disease. Int J Inflam 2013:724648 |
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