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.

Public Health Relevance

Ocular surface inflammatory diseases, which impact quality of life and lead to blindness in advanced forms, constitute a major health problem in the U.S. and abroad. Though the immune system plays a central role, the type of immune cell and the manner in which they mediate this set of conditions is poorly understood. Our project is therefore aimed at identifying these cells and their disease causing mechanisms, which will ultimately help the development of new and effective medicines in the treatment of ocular surface diseases.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY021798-10
Application #
9919560
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mckie, George Ann
Project Start
2012-02-01
Project End
2021-04-30
Budget Start
2020-05-01
Budget End
2021-04-30
Support Year
10
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Duke University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Saban, Daniel R (2018) New concepts in macrophage ontogeny in the adult neural retina. Cell Immunol 330:79-85
Reyes, Nancy J; Mathew, Rose; Saban, Daniel R (2018) Induction and Characterization of the Allergic Eye Disease Mouse Model. Methods Mol Biol 1799:49-57
Poe, Jonathan C; Jia, Wei; Di Paolo, Julie A et al. (2018) SYK inhibitor entospletinib prevents ocular and skin GVHD in mice. JCI Insight 3:
Pastak, Marko; Kleff, Veronika; Saban, Daniel R et al. (2018) Gene Therapy for Modulation of T-Cell-Mediated Immune Response Provoked by Corneal Transplantation. Hum Gene Ther 29:467-479
Reyes, Nancy J; Yu, Chen; Mathew, Rose et al. (2018) Neutrophils cause obstruction of eyelid sebaceous glands in inflammatory eye disease in mice. Sci Transl Med 10:
Reyes, Nancy J; O'Koren, Emily G; Saban, Daniel R (2017) New insights into mononuclear phagocyte biology from the visual system. Nat Rev Immunol 17:322-332
Reyes, Nancy J; Saban, Daniel R (2017) A Commencement for Eye Commensals. Immunity 47:6-8
Ahadome, Sarah D; Abraham, David J; Rayapureddi, Suryanarayana et al. (2016) Aldehyde dehydrogenase inhibition blocks mucosal fibrosis in human and mouse ocular scarring. JCI Insight 1:e87001
Ahadome, Sarah D; Mathew, Rose; Reyes, Nancy J et al. (2016) Classical dendritic cells mediate fibrosis directly via the retinoic acid pathway in severe eye allergy. JCI Insight 1:
O'Koren, E G; Mathew, R; Saban, D R (2016) Fate mapping reveals that microglia and recruited monocyte-derived macrophages are definitively distinguishable by phenotype in the retina. Sci Rep 6:20636

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