The long-term objective of the proposed research is to test the hypothesis that in systemic lupus erythematosus (SLE) there is an increase in the antigen driven autoimmune response through delayed clearance of DNA and nuclear-associated proteins due to an abnormally low C-reactive protein (CRP) response. This hypothesis is based on observations that in the SLE the CRP response during inflammatory episodes related to disease is markedly diminished compared to the degree of inflammation and tissue damage present. The mechanisms responsible for this reduced CRP response are not known. In addition, CRP has been shown to localize in the nuclei of damaged cells and to bind to chromatin. Given the inappropriate CRP-response and the characteristic antibody response to DNA and nuclear proteins in SLE, we, and others, hypothesize that CRP reacts with DNA associated components in damaged tissue and aids in their removal through interactions with the complement system and cells of the phagocytic system. We propose to use human CRP-transgenic (NZB X NZW)F1 mice to test our hypothesis. (NZB X NZW) F1 mice have been utilized as a model for SLE and display a well characterized anti-DNA and anti-nuclear antigen response. Therefore, transgenic (NZB X NZW)F1 mice which have the human CRP gene should be an exceptional tool for studying the effects of CRP on the development of anti-DNA and anti-nuclear antibodies in SLE. Specifically, we plan to determine the effects of human CRP on the development of the lupus like disease of (NZB X NZW)F1 autoimmune mice. We will construct transgenic CB6 mice which express human CRP in an acute phase manner, and then transmit the human CRP on the development of the lupus like disease of (NZB X NZW)F1 autoimmune mice. We will construct transgenic CB6 mice which express human CRP in an acute phase manner, and then transmit the human CRP gene to autoimmune mice through selective breeding. If there is a disease associated CRP response, the development of disease in the CRP transgenic (NZB X NZW)F1 mice will be compared to (NZB X NZW)F1 mice. If there is no significant, disease associated-CRP response in the (NZB X NZW)f1 transgenic mice, we will determine whether these mice have normal CRP expression in response to other stimuli and if the low response is due to some disease related phenomenon. In addition, we will examine the effect of constant expression of CRP on the development of disease in (NZW X NZW)F1 transgenic mice by introducing into the mice DNA constructs of CRP genomic DNA and the mouse metallothionein I enhancer/promoter sequences. The data from the proposed experiments will be an important addition to our knowledge of CRP's role in the development of the autoimmune response, as well as the regulation of CRP's expression in SLE. Finally, these studies will also provide valuable information on regulation of CRP expression within a normal background.
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