The mechanisms which predispose to the development of human systemic lupus erythematosus (SLE) have not been fully defined. Treatment regiments which alter the production or tissue levels of eicosanoids suggest that lipoxygenase metabolites have a permissive effect on the expression of autoimmunity. Macrophages from autoimmune-prone mice demonstrate an age- associated enhancement in 5-lipoxygenase activity, as evidenced by their capacity to spontaneously release high levels of leukotriene C4 in vitro. It is hypothesized herein that augmented synthesis of 5-lipoxygenase products results in chronic inflammation in SLE. In contrast to lipoxygenase metabolites, certain products of the cyclooxygenase pathway have a protective effect on the development of lupus in autoimmune MRL-1pr/1pr and New Zealand mice. These strains, like a subset of patients with lupus, demonstrate aberrations in the expression of class II antigens. Macrophages from MRL-1pr/1pr mice show an age- related decrease in their capacity to produce Ia-downregulating prostanoids. It is proposed herein that an imbalance in the synthesis of, or in the responsiveness to, eicosanoids which regulate Ia expression predisposes to hyperexpression of class II antigens on the macrophages and B cells from MRL-1pr/1pr mice which, in turn, leads to the development of autoimmunity. It is suggested further that central to the derangements in eicosanoid production which occur in lupus is a disturbance in the fatty acid composition of the macrophages plasma membrane and/or in the manner in which fatty acids are remodeled in such membranes. These abnormalities render macrophages proinflammatory. Using a number of analytical systems (high pressure liquid chromatography, thin layer chromatography, gas-liquid chromatography/mass spectrometry, enzyme and radioimmunoassays), this proposal seeks to investigate the basis for, and to further characterize the nature of, the aberrations in eicosanoid production which may contribute to the etiopathogenesis of lupus. MRL-1pr/1pr mice will be used primarily as the experimental model. Since abnormalities in eicosanoids have been implicated in the pathogenesis of a variety of chronic inflammatory states, it is believed that the insights gained through these studies will contribute to a more rational therapeutic approach to the treatment of lupus.
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