The importance of the complement system of innate immunity as an adjuvant for B cell responses is becoming increasingly apparent. Complement is thought to """"""""instruct"""""""" the B cell response by covalent attachment of C3 to pathogens. Recent studies have identified the classical pathway as required for an efficient humoral response to peripheral infections with type 1 herpes simplex virus (HSV-1). Notably, local (extra-hepatic) synthesis of complement C3 and C4 by myeloid cells is sufficient for enhancement of B cell immunity. These observations raised the question of a general concept, namely that macrophage-produced complement could be essential for linking innate and adaptive immunity. We propose the following three specific aims to test this hypothesis. The first specific aim will test the hypothesis that macrophage-produced C3 and C4 are not only sufficient but also necessary, for complement-enhancement of the humoral response to peripheral infection with HSV- 1. The second specific aim will examine at what stage myeloid-derived complement enhances the humoral response to peripheral infection with HSV. Specifically, it will attempt to distinguish between the roles of complement in transport of antigen from the site of infection versus within the draining LN. The third specific aim will test the hypothesis that macrophage synthesis of complement C3 and C4 within pLNs is regulated by cytokines such as IFN-y, TNF-c_ and IL-6. Identification of macrophages as a critical source of early complement in vivo is a novel concept. Elucidating this pathway has important implications for furthering our understanding of how innate immunity """"""""instructs"""""""" adaptive immune responses. Moreover, it could lead to rational design of improved vaccines to pathogenic viruses, such as HSV, for which there is currently no cure.
| Yalcindag, Ali; He, Rui; Laouini, Dhafer et al. (2006) The complement component C3 plays a critical role in both Th1 and Th2 responses to antigen. J Allergy Clin Immunol 117:1455-61 |
| Banda, Nirmal K; Thurman, Joshua M; Kraus, Damian et al. (2006) Alternative complement pathway activation is essential for inflammation and joint destruction in the passive transfer model of collagen-induced arthritis. J Immunol 177:1904-12 |
| Carroll, Michael C (2004) The complement system in regulation of adaptive immunity. Nat Immunol 5:981-6 |
