Many of the immunological effects attributed to the third component of complement (C3) are mediated by specific cell membrane complement receptors. Complement receptor 1 (CR1) is the immune adherence receptor and participates in C3b- dependent phagocytosis, lymphocyte function and the regulation of C3 activation. Complement receptor 2 (CR2) is involved in lymphocyte activation, in the primary immune response to antigens and in the generation of immunological memory. In some rheumatologic disorders, such as SLE , the levels of these receptors are abnormal, suggesting a role in the pathophysiology of the disease. CR1/CR2 deficient mice have been developed using gene targeting techniques. These mice are unable to mount a normal humoral immune response to specific antigen stimulation. Since mouse CR1 and 2 are the alternatively spliced product of the same gene, the CR1/CR2 deficient mice lack expression of both proteins. However, previous studies have indicated unique functions for each protein. The relative contributions of CR1 versus CR2 to the immune abnormalities observed in the receptor deficient mice, therefore, are not yet defined. We propose to selectively reconstitute each of these proteins in our CR1/CR2 deficient mice using tansgenic technology. Constructs will be designed containing cDNAs encoding each specific complement receptor under the kappa light chain promoter/enhancer transcriptional control, which will direct receptor expression to B lymphocytes. Other promoters will be considered based on their ability to direct tissue specific expression of these receptors. These constructs will be injected individually to generate transgenic mice that express only one of these receptors. Following backcrossing into CR1/CR2 deficient mice, the immune response to different antigens will then be evaluated. These experiments will clarify the different roles of these proteins in the immune response.
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