Dry eye disease (DED), a chronic immune-mediated disorder of the ocular surface, is characterized by sustained ocular surface inflammation and disruption of the ocular surface epithelium, which in severe cases can lead to corneal scarring and blindness. DED has a very high prevalence, almost triple that of age-related macular degeneration, affecting many millions of individuals in the United States alone, and its prevalence is set to increase considerably with the aging of the population. Current expenditures for treating DED surpass $2 billion dollars annually, and because it often affects visual function in working adults, it leads to lost productivity by impacting job performance. While the role of immunity in amplifying DED severity has been known for some time, it is only recently that we have gained insights into the immunopathogenic mechanisms that drive DED. Evidence from several laboratories, including the Principal Investigator's, has established strong evidence for the critical role of T helper-17 (Th17) cells, in driving immune-mediated damage to the ocular surface in DED. More recent evidence from the PI's lab shows that DED can be maintained chronically for months, even after termination of desiccating stress to the eye, by memory Th17 cells, which are distinct from the effector T cells that mediate disease after acute ocular desiccating stress. In addition, data from the PI's lab demonstrate that in DED the regulatory T cells (Tregs), which are normally highly effective in suppressing T cell-mediated inflammation, are particularly defective in suppressing the Th17 response. While these data provide new insights into DED immunopathogenesis, numerous important questions remain unanswered. We hypothesize that DED is characterized by a microenvironment that promotes the generation and maintenance of Th17 immunity, which in turn leads to suppressed function of Tregs that normally maintain immune quiescence. The principal objectives of this project are to (i) define the factors that influence the generation and maintenance of immunologic memory, and characterize precisely the dysfunction of (ii) the corneal epithelium and (iii) Tregs in maintaining immune homeostasis in DED. To achieve these major objectives, three specific aims have been defined to answer the following questions:
Aim 1 : What are the critical cytokine mechanisms that lead to induction and maintenance of Th17 immunological memory in chronic dry eye disease? Aim 2: How does epithelial damage affect the immunomodulatory function of the corneal epithelium in DED? And, Aim 3: Which among the Th17- associated cytokines interact directly with Tregs to suppress their regulatory function? It is anticipated that this research will have significant translational impact given the high prevalence of DED, the still limited knowledge we have regarding its precise immunopathogenesis, and the relative dearth of effective treatments.
Dry eye disease is an extremely common inflammatory disorder of the ocular surface associated with visual dysfunction, with as of yet incompletely understood immunopathogenic mechanisms. We propose to determine the specific immune-based cellular and molecular pathogenic elements that amplify dry eye disease severity and promote chronic immune based inflammation. The hope is that better understanding of these pathogenic mechanisms will yield important therapeutic targets that could be used in better management of the many millions of Americans suffering from dry eye disease.
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