Innate immunity recognizes infectious organisms, quickly restricts the infection, and stimulates the adaptive immune system. The host's innate immune response is particularly important in young children who have not yet developed a mature adaptive immune system. The lectin pathway, a more recently defined branch of the complement system, constitutes one of the body's innate immune responses to infection. Activation of complement via this pathway depends on the binding of mannan binding lectin (MBL) to mannose residues on the cell surface of microorganisms. Although, MBL has a structure similar to C1q, it activates complement independent of antibodies. Until recently, it was assumed that the activation process was similar to that of the classical pathway. However, our own studies of the lectin pathway suggest that the formation, activity, and regulation of C3/C5 convertases on an activator differ significantly from those of the classical pathway. Mutations in the collagen region of MBL result in natural allelic forms of MBL that are associated with serious infections in children and adults. The allelic forms of MBL occur frequently in certain populations, and MBL replacement therapy has been effective for treatment of infections in MBL deficient patients. These findings underscore the importance of MBL for health and suggest a potential for therapy of MBL deficiency. Our overall goal in the proposed studies is to establish the mechanisms of activation and regulation of the lectin pathway. Studies that address Aim 1 will test the hypothesis that mutations in the collagen region of MBL alter binding interactions with MASP1 or MASP2 and result in dysfunctional complement activation and/or disruption of MBL-mediated phagocytosis. Studies that address Aim 2 will test the hypothesis that the processes of activation and regulation of the lectin pathway differ from those of the classical pathway, which has been the accepted model for lectin-induced complement activation.
