Fibroblasts as local immune modulators in ocular allergic disease

Vernal keratoconjunctivitis (VKC), a severe form of ocular allergic disease, is characterized by the formation of giant papillae at the upper tarsal conjunctiva and corneal lesions that threaten vision. Recent evidence indicates that resident fibroblasts function as immune modulators in the pathogenesis of the chronic allergic inflammation associated with VKC. The T helper 2 (Th2) cell-derived cytokines interleukin (IL)-4 and IL-13 stimulate the migration and proliferation of conjunctival fibroblasts as well as protecting these cells from apoptotic cell death, effects that likely underlie the hyperplasia of fibroblasts that contributes to the formation of giant papillae. Conjunctival fibroblasts also synthesize extracellular matrix proteins and tissue inhibitors of metalloproteinases as well as down-regulate the expression of matrix metalloproteinases in response to these cytokines, effects that likely contribute to the excessive deposition of extracellular matrix that is characteristic of giant papillae. Stimulation of fibroblasts in the corneal stroma with the combination of a proinflammatory cytokine and either IL-4 or IL-13 results in up-regulation of the expression of the chemokine eotaxin and thymus- and activation-regulated chemokine as well as of vascular cell adhesion molecule-1, which together mediate the infiltration and activation of eosinophils and Th2 cells. Fibroblasts therefore appear to play a central role in the induction and amplification of ocular allergic inflammation and the consequent development of giant papillae and corneal disorders in individuals with VKC. Fibroblasts and fibroblast-derived factors thus represent new and potentially important therapeutic targets for treatment of the giant papillae and corneal disorders associated with VKC.