The complement system is important in host defense against infection and autoimmune tissue damage. This grant continues to focus on the complement system and the role it plays in inflammatory diseases of the eye.
Specific aims i nclude the following: 1) Cytokine modulation of complement production by scleral and corneal fibroblasts in tissue culture. Local production of complement by scleral or corneal fibroblasts, especially under the influence of cytokines, may provide complement for participation in inflammatory reactions in the avascular cornea and sclera after tissue levels are depleted and before increases in vascular permeability in adjacent tissues and recruitment of other complement-producing cells occur. The following cytokines will be studied: interferon-gamma, interferon-alpha and beta, tumor necrosis factor, interleukin-1alpha and 1beta, and interleukin-2. We will use hemolytic assays to measure C1, C4, C2, C3, C5, C6, and C7, the C1- inhibitor immunoassay to measure C1-inhibitor, and hemolytic diffusion plates to measure Factor B. These studies may help us understand how cytokines regulate the local biosynthesis of complement components in the cornea and sclera during inflammation. 2) Assessment of the role of complement in corneal injuries using a guinea pig model of corneal decomplementation. The influence of complement on the corneal inflammatory response caused by chemical injuries, immune complexes, and endotoxin will be determined using the myeloperoxidase assay; the influence of complement on bacterial and fungal infections will be determined by measuring the number of colony-forming units surviving in corneal tissue. These kinds of studies should clearly define the role of complement in the acute inflammatory response of the cornea to a number of clinically relevant corneal injuries. 3) Measurement of the membrane attack complex of complement in donor human corneas after injuries with chemicals, immune complexes or endotoxin using an enzyme immunoassay. In this way, it will be possible to determine if the entire complement cascade can be activated in human corneas in any or all of the above clinically relevant injuries.
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