title: Mucosal tolerance disruption favors disease progression in an extraorbital lacrimal gland excision model of murine dry eye.
abstract: Dry eye is a highly prevalent immune disorder characterized by a dysfunctional tear film and a Th1/Th17 T cell response at the ocular surface. The specificity of these pathogenic effector T cells remains to be determined, but auto-reactivity is considered likely. However, we have previously shown that ocular mucosal tolerance to an exogenous antigen is disrupted in a scopolamine-induced murine dry eye model and that it is actually responsible for disease progression. Here we report comparable findings in an entirely different murine model of dry eye that involves resection of the extraorbital lacrimal glands but no systemic muscarinic receptor blockade. Upon ocular instillation of ovalbumin, a delayed breakdown in mucosal tolerance to this antigen was observed in excised but not in sham-operated mice, which was mediated by interferon γ- and interleukin 17-producing antigen-specific T cells. Consistently, antigen-specific regulatory T cells were detectable in sham-operated but not in excised mice. As for other models of ocular surface disorders, epithelial activation of the NF-κB pathway by desiccating stress was determinant in the mucosal immune outcome. Underscoring the role of mucosal tolerance disruption in dry eye pathogenesis, its prevention by a topical NF-κB inhibitor led to reduced corneal damage in excised mice. Altogether these results show that surgically originated desiccating stress also initiates an abnormal Th1/Th17 T cell response to harmless exogenous antigens that reach the ocular surface. This event might actually contribute to corneal damage and challenges the conception of dry eye as a strictly autoimmune disease.
authors.affiliation: Immunology Laboratory, Institute of Experimental Medicine, National Academy of Medicine/CONICET, Buenos Aires, Argentina.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Guzmán
authors.affiliation: Immunology Laboratory, Institute of Experimental Medicine, National Academy of Medicine/CONICET, Buenos Aires, Argentina.
authors.forename: Irene
authors.initials: I
authors.lastname: Keitelman
authors.affiliation: Immunology Laboratory, Institute of Experimental Medicine, National Academy of Medicine/CONICET, Buenos Aires, Argentina.
authors.forename: Florencia
authors.initials: F
authors.lastname: Sabbione
authors.affiliation: Immunology Laboratory, Institute of Experimental Medicine, National Academy of Medicine/CONICET, Buenos Aires, Argentina.
authors.forename: Analía 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: Mirta N
authors.initials: MN
authors.lastname: Giordano
authors.affiliation: Immunology Laboratory, Institute of Experimental Medicine, National Academy of Medicine/CONICET, Buenos Aires, Argentina. Electronic address: jeremiasg@gmx.net.
authors.forename: Jeremías G
authors.initials: JG
authors.lastname: Galletti
mesh_terms: D000818:Animals; D003228:Conjunctiva / Q000276:immunology / Q000473:pathology; D003315:Cornea / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D015352:Dry Eye Syndromes / Q000175:diagnosis* / Q000276:immunology / Q000601:surgery; D007108:Immune Tolerance; D007111:Immunity, Cellular; D007765:Lacrimal Apparatus / Q000276:immunology* / Q000473:pathology / Q000601:surgery; D051379:Mice; D009092:Mucous Membrane / Q000276:immunology / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
keywords: Animal models; Conjunctiva; Cornea; Desiccating stress; Dry eye; Mucosal immunology; Mucosal tolerance; Ocular surface