The broad, long-term objectives are to elucidate the pathogenesis of onchocercal sclerosing keratitis and to identify antigens that may lead to disease in infected humans. Onchocerciasis is one of the leading causes of blindness in the world today. it is caused by infection with filarial parasite Onchocerca volvulus. The major cause of blindness in onchocerciasis is sclerosing keratitis, but its pathogenesis is unclear. A prerequisite appears to be invasion of the cornea by microfilariae in the setting of chronic infection.
The specific aims of this proposal are: to purify antigens that may be associated with the elicitation of sclerosing keratitis in the guinea pig model and in humans: to investigate in a mouse model immunologic mechanisms associated with sclerosing keratitis, in particular the influence of soluble antigen in the anterior chamber and strain differences on the immune response to antigen an on sclerosing keratitis; to examine the immune response to defined antigens in humans with and without ocular disease including sclerosing keratitis. Definition of the mechanisms involved in the pathogenesis of onchocercal sclerosing keratitis has been hampered by the lack of an animal model and by the difficulty in obtaining sufficient quantities of parasite material. A model of sclerosing keratitis has been developed in which guinea pigs are primed with antigen systemically and then injected intrastromally with soluble O. volvulus antigen. Interstitial keratitis, scarring, and neovascularization, as seen in human onchocerciasis, is found clinically and on histopathologic examination. Antigens from recombinant cDNA clones will be used to examine whether specific antigens may be especially relevant in the elicitation of sclerosing keratitis in the animal model and in humans. Furthermore, by using a mouse model, antigens will be tested for induction of ACAID. The response (cellular and humoral) of infected persons with and without ocular disease to defined antigens will be examined. Strain differences in reactivity will be assessed. This is important information for the understanding of the disease process and essential information for the efforts at vaccine production. Furthermore, the results of these studies should be relevant to corneal inflammatory disease of diverse etiologies such as allograft rejection and Herpes simplex or syphylitic stromal keratitis.
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