Cellular and Molecular Mechanisms that Contribute to Ocular Surface Disease during Severe Allergic Inflammation

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ABSTRACT Inflammatory lid margin disease, which arises in chronic ocular surface inflammation, constitutes a major health problem in the U.S. and abroad. This type of inflammation, also referred to as blepharitis, can affect both the anterior and posterior aspects of the lid margin, and may include meibomian gland dysfunction (MGD). Long-term defects of the tear film and secondary impairments to the conjunctiva and cornea often develop due to MGD, as the meibomian gland is responsible for the oil (or meibum) production required for tear film homeostasis. Such debilitating blepharitis occurs regularly in patients with chronic forms of allergic eye disease, such as in atopic keratoconjunctivitis (AKC). Likewise, blepharitis occurs in ocular rosacea, chronic graft versus host disease, Stevens-Johnson Syndrome, and other chronic inflammatory ocular surface diseases. Our lab has previously established and validated a severe allergic eye disease (AED) mouse model. This AED model reproducibly develops various clinical sequelae consistent with AKC in humans, including corneal involvement, subepithelial fibrosis of the bulbar conjunctiva, and blepharitis (anterior and posterior). The utility of this model has proven to permit identification of unknown pathogenic events that mediate severe eye allergy, which is a disease with an unmet medical need. Along these lines, the aim of this grant is to elucidate the immunologic mechanisms that specifically cause blepharitis in the AED model. Experiments proposed go beyond the examination of classical allergic inflammation, such as mast cell degranulation, T helper 2 responses and eosinophilia. Instead, our preliminary data has led us to focus our efforts on the central role of the T helper 17 pathway. Experiments herein also seek to elucidate upstream mediators, including identification of the bona fide dendritic cell subsets, and their mediators, responsible for eliciting the T helper 17 pathway in this disease model. Our approach involves a myriad of in vivo genetic techniques to enable conditional/inducible depletion of specific dendritic cell subsets in a site specific manner. These strategies and others will empower us to pinpoint the mediators and their mechanisms that cause lid margin disease in the AED model. This timely and novel proposal is poised to catalyze our understanding of eye mucosal dendritic cells in disease and lymphocyte activation in blepharitis. Furthermore, information gleaned from these experiments could be relevant in the broader context of ocular surface inflammatory disease.