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Almost 50 years ago, MB Pepys recognized that complement component C3 can influence the functions of murine B cells, and thus it forms a bridge between the innate and the adaptive immune system (Pepys, 1974, 1972). Since then, the role of the complement system in the regulation of B cell functions has been in the focus of several investigations. Studying mice, Dempsey et al. revealed that crosslinking CR2 (CD21) with the BCR through a C3d fragment-opsonized antigen essentially reduces the activation threshold of B cells and causes a dose-dependent enhancement of humoral immune responses (Dempsey et al., 1996). Based on this, it has become a textbook dogma that CR2 is a positive coreceptor of BCR, and C3d is a “molecular adjuvant”(Dempsey et al., 1996) species independently. Despite numerous attempts to demonstrate the positive coreceptor function of human CR2, the BCR mediated antibody production enhancing effect of the C3d molecule has never been proven in the case of human B lymphocytes. No wonder, C3d could not have been utilized as a humoral immune response-boosting molecular adjuvant. Results from earlier studies with human B cells are contradictory, mainly due to the significantly disparate experimental conditions. Nevertheless, the findings regarding mouse CR2 have been extended to human CR2, and consequently, human CR2 is commonly referred to as an activating coreceptor of the BCR, which lowers the activation threshold of B cells upon its coengagement with the BCR.

CR2 had been hypothesized to be part of a complex, which comprises CD19, CD81 (TAPA-1) and Leu-13 in the …