Autoimmune dry eye - Molecular mechanisms and novel therapies

One of the most debilitating forms of dry eye or keratoconjunctivitis sicca (KCS)) results from autoimmune-mediated destruction of the lacrimal gland. Despite powerful immunosuppressive and immunomodulatory therapy, KCS associated with autoimmune disease can provoke corneal opacification and even blindness through a process known as squamous metaplasia. Little is known about the pathogenesis of squamous metaplasia and there is no cure. The goal of our research is to decipher how chronic inflammation in autoimmune disease provokes KCS and vision-threatening squamous metaplasia. Our approach includes three model systems, (i) human patients with Sjögren's syndrome (the second leading cause of autoimmune disease); (ii) a validated mouse model that mimics the clinical characteristics of Sjögren's syndrome; and (iii) in vitro studies of cultured corneal epithelial cells. We have demonstrated an essential role for autoreactive CD4+ T cells and their interplay with the proinflammatory cytokine interleukin (IL)-1 in the pathogenesis of autoimmune KCS. We show squamous metaplasia begins at the stem cell level through the aberrant activation of basal progenitor cells. Altered stem cell activation promotes a shift from the moist mucosal surface of the eye to one that is pathologically keratinized and skin-like. These studies have improved our understanding of the underlying mechanisms in autoimmune KCS and have allowed us to identify novel drug targets to prevent its devastating consequences.

Room 489