title: Desiccating stress-induced disruption of ocular surface immune tolerance drives dry eye disease.
abstract: Dry eye is an allegedly autoimmune disorder for which the initiating mechanisms and the targeted antigens in the ocular surface are not known, yet there is extensive evidence that a localized T helper type 1 (Th1)/Th17 effector T cell response is responsible for its pathogenesis. In this work, we explore the reconciling hypothesis that desiccating stress, which is usually considered an exacerbating factor, could actually be sufficient to skew the ocular surface's mucosal response to any antigen and therefore drive the disease. Using a mouse model of dry eye, we found that desiccating stress causes a nuclear factor kappa B (NF-κB)- and time-dependent disruption of the ocular surface's immune tolerance to exogenous ovalbumin. This pathogenic event is mediated by increased Th1 and Th17 T cells and reduced regulatory T cells in the draining lymph nodes. Conversely, topical NF-κB inhibitors reduced corneal epithelial damage and interleukin (IL)-1β and IL-6 levels in the ocular surface of mice under desiccating stress. The observed effect was mediated by an augmented regulatory T cell response, a finding that highlights the role of mucosal tolerance disruption in dry eye pathogenesis. Remarkably, the NF-κB pathway is also involved in mucosal tolerance disruption in other ocular surface disorders. Together, these results suggest that targeting of mucosal NF-κB activation could have therapeutic potential in dry eye.
authors.affiliation: Immunology Laboratory, Institute of Experimental Medicine, National Academy of Medicine/CONICET, Buenos Aires, Argentina.
authors.forename: M
authors.initials: M
authors.lastname: Guzmán
authors.affiliation: Immunology Laboratory, Institute of Experimental Medicine, National Academy of Medicine/CONICET, Buenos Aires, Argentina.
authors.forename: I
authors.initials: I
authors.lastname: Keitelman
authors.affiliation: Immunology Laboratory, Institute of Experimental Medicine, National Academy of Medicine/CONICET, Buenos Aires, Argentina.
authors.forename: F
authors.initials: F
authors.lastname: Sabbione
authors.affiliation: Immunology Laboratory, Institute of Experimental Medicine, National Academy of Medicine/CONICET, Buenos Aires, Argentina.
authors.forename: A S
authors.initials: AS
authors.lastname: Trevani
authors.affiliation: Immunology Laboratory, Institute of Experimental Medicine, National Academy of Medicine/CONICET, Buenos Aires, Argentina.
authors.forename: M N
authors.initials: MN
authors.lastname: Giordano
authors.affiliation: Immunology Laboratory, Institute of Experimental Medicine, National Academy of Medicine/CONICET, Buenos Aires, Argentina.
authors.forename: J G
authors.initials: JG
authors.lastname: Galletti
mesh_terms: D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D015352:Dry Eye Syndromes / Q000276:immunology*; D019573:Epithelium, Corneal / Q000276:immunology / Q000293:injuries / Q000503:physiopathology*; D007108:Immune Tolerance / Q000276:immunology*; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D018655:Lymphocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010047:Ovalbumin / Q000276:immunology; D013312:Stress, Physiological / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology
chemical_list: C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D015850:Interleukin-6; D016328:NF-kappa B; D010047:Ovalbumin
keywords: conjunctival tolerance; desiccating stress; dry eye; mucosal tolerance; ocular surface