The role of the mast cell in seasonal allergic conjunctivitis

Evidence is presented of conjunctival mast cell accumulation in SAC in the absence of increased numbers of eosinophils or neutrophils. By examining thin sections of conjunctiva using immunohistochemistry and in-situ hybridisation, immunoreactivity for a range of cytokines known to play key roles in the pathophysiology of allergic diseases is demonstrated. Furthermore, these cytokines are well recognized to selectivity upregulate cell adhesion molecules critical to the recruitment of leucocytes to areas of allergic inflammation. These findings support the hypothesis that mast cell degranulation can drive the conjunctival late phase response (LPR) in the absence of the activation of other inflammatory cells and thus provide a link between the type I hypersensitivity reaction to pollen and the clinical disease of SAC. This hypothesis was tested using conjunctival allergen challenge to generate a LPR in human subjects followed by the recording of symptom scores and study of the tissue cell and cytokine changes. These data provide evidence that the conjunctival mast cell is well positioned to orchestrate the early immune response to allergen prior to leukocyte recruitment and activation. Mast cells, however, are heterogeneous and in man, are typically described according to their content of serine proteases. To determine whether this distinction extended to a functional heterogeneity based on cytokine content, the distribution of the TH2-like cytokines, IL-4, IL-13, IL-5 and IL-6 between mast cell subtypes was investigated. The tissue regulation of mast cell growth, development, function and survival is poorly understood, but stem cell factor (SCF) is known to play a major role. This thesis reports that human mast cells are themselves a source of this cytokine. This key finding provides novel evidence that a mechanism exists to regulate the biology of this important and ubiquitous cell in an autocrine manner.