Sj""""""""gren'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 Sj""""""""gren's syndrome. The mechanisms responsible for this autoimmune lacrimal keratoconjunctivitis, as well as the specific role of inflammation in the LFU dysfunction in Sj""""""""gren's syndrome remain to be determined. We have developed murine models with features mimicking the autoimmune lacrimal keratoconjunctivitis (ALKC) in human Sj""""""""gren's syndrome that appear relevant to answer these unresolved questions. We have observed that exposure of the ocular surface to desiccating environmental stress exposes an autoantigen in the surface epithelia that 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 Sj""""""""gren's syndrome-like ALKC in na?ve T cell deficient (nude) mice following adoptive transfer of CD4+ T cells isolated from the spleens or superficial cervical lymph nodes of mice exposed to desiccating environmental stress. We have found that regulatory T cells protect against the development of ALKC. These models will allow us to elucidate the mechanism of the immune based dysfunction of the LFU in Sj""""""""gren's syndrome. Our central hypothesis is that desiccating ocular surface stress reveals autoantigens in the ocular surface epithelia that initiate a tissue specific T cell response which causes dysfunction and death of the critical secretory cells in the LFU. We further propose that the severity of this ALKC is worsened by defective self tolerance mechanisms.
Our central hypothesis is that desiccating ocular surface stress reveals autoantigens in the ocular surface epithelia that initiate a tissue specific T cell response which causes dysfunction and death of the critical secretory cells in the LFU. We further propose that the severity of this ALKC is worsened by defective self tolerance mechanisms.
