Human complement receptor type one (CR1; CD35; C3b/C4b receptor) clears immune complexes (IC) and prevents their deposition in tissues, regulates Complement ~ activation and participates in immune regulation. Soluble CR1 has been used successfully to inhibit C mediated tissue injury in animal models of glomerulonephritis, ischemia reperfusion and transplantation and is in early stages of human clinical trials. A better understanding of the biology of its structure and function will help in identifying its pathophysiological significance in autoimmune conditions such as SLE and in generation of more effective C inhibitors. Compared to humans, other primates express 10-50 fold higher copies of CR1 analogues of smaller size (55-77 kDa or 120-150 kDa compared to 220 kDa human CR1) on their erythrocytes (E). In many species, being the only CR1 analogues on E, thee short proteins process IC. Preliminary studies suggest that short CR1 proteins, lacking one or more functional domains, make key structural adjustments to preserve full function. This unique heterogeneity in size within primate CR1 and accompanying functional adaptation provides a good model system to characterize structural determinants involved in IC clearance and C regulation as well as the molecular basis and evolutionary reasons for these alterations in size and function of this protein. CR1 analogues from four primate have been identified as potentially most informative in this regard. Their cDNA derived primary structure and IC binding and regulatory functions will be compared to human CR1. Amino acid changes identified as likely to be important will be assessed by substitution in active sites of human CR1 for gain or loss of function. Understanding the physiological advantage of the selected primates vs. The human system (high copy numbers of short proteins vs. Fewer copies of large proteins with multiple active domains) in IC processing and C regulation and investigating the immune regulatory and cell signaling functions of CR1 are longer term objectives.
