The overall goal is to increase the understanding of the specific roles that the complement system plays in the immune response. Complement is centrally important in the innate immune system and linked to acquired immunity by specific receptors. In addition the complement system promotes tissue damage in inflammatory, ischemic and autoimmune diseases. Complement activation is normally regulated by intrinsic membrane proteins which form a family of complement receptors and regulatory proteins. Mouse members of this family include CR2, CR1 and Crry. Recently cDNAs or candidate proteins for additional receptors and regulatory proteins in the mouse have been identified including the platelet immune adherence receptor (IAR) and two proteins with sequence similarity to human decay-accelerating factor (DAF). To further extend the understanding of the biology activities of the RCA family, the following specific aims will be pursued:
Specific Aim 1 : Identify and characterize the specific mechanisms by which CR2 and CR1 ligation initiates, amplifies and regulates the humoral and cellular immune response.
Specific Aim 2 : Determine the impact of altered CR2 and CR1 levels and activities on autoimmune features in murine models of SLE.
Specific Aim 3 : Identify and characterize the functional activities and patterns of expression of the two murine DAF-like proteins in addition to the molecular structures and biologic roles of the immune adherence receptor (IAR).
Specific Aim 4 : Compare and contrast the effects of chronic inhibition at C3 versus C5 activation steps on normal complement physiology, susceptibility to infection, spontaneous development of immune complex deposition, and on specific phenotypic outcomes in chronic autoimmune disease models.
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