BAYLOR COLLEGE OF MEDICINE
The purpose of this grant is to study the regulation of the ocular surface immune response to desiccating stress.Sjögren’s syndrome causes profound dysfunction of the lacrimal functional unit (LFU) that results in decreased secretion of tear fluid and ocular surface supportive factors by the lacrimal glands, loss of reflex tearing and loss of conjunctival goblet cells. These changes lead to a poorly wettable and irregular ocular surface. Immunopathological changes including immune/inflammatory cell infiltration and increased production of inflammatory cytokines and chemokines have been detected in the dysfunctional lacrimal glands and ocular surface tissues in Sjögren’s syndrome. The mechanisms responsible for this autoimmune lacrimal keratoconjunctivitis, as well as the specific role of inflammation in the LFU dysfunction in Sjögren’s syndrome remain to be determined. We have developed mouse models with features that mimic the autoimmune lacrimal keratoconjunctivitis (ALKC) in Sjögren’s syndrome that appear relevant to answer these unresolved questions. We have observed that exposure of the ocular surface to desiccating environmental stress induces a cellular and cytokine mediated immune response that causes specific components of this pathology. We have demonstrated the pivotal role of this immune response by inducing Sjögren’s syndrome-like ALKC in naïve T cell deficient (nude) mice following adoptive transfer of CD4+ T cells isolated from the spleens or lymph nodes of mice exposed to desiccating environmental stress. Regulatory T cells in the ocular surface and systemic immune systems protect against the development of ALKC. A number of experiments performed using our mouse model will be used to investigate the relative contribution of various regulatory T cell subsets in suppressing the immune based dysfunction of the LFU that develops in response to desiccating stress. These experiments will provide important new information regarding the defective self tolerance mechanisms that predispose to development of Sjögren’s syndrome.