Major advances in our understanding of the immunobiology of complement were made within the past 5 years primarily due to the development of gene-targeting technology. New strains of mice bearing specific deficiencies in serum complement proteins or their receptors were developed using this approach. Characterization of these mice has provided new and exciting insights into the biology of the complement system. In this review, we discuss recent results on two important aspects of the complement system, i) host protection and inflammation, and ii) regulation of B lymphocytes of adaptive immunity. While these two roles appear distinct, they are linked. We discuss how natural antibody and classical pathway complement work together in host protection against bacterial infection on the one hand but, on the other, they co-operate to induce inflammation as observed in reperfusion injury. Significantly, the lymphocytes that produce natural antibody, the B-1 lymphocytes, are regulated in part by the complement system.

More than half of patients with X-linked lympho-proliferative disease, which is caused by a defect in the intracellular adapter protein SH2D1A, suffer from an extreme susceptibility to EpsteinBarr virus. One-third of these patients, however, develop dysgammaglobulenemia without an episode of severe mononucleosis. Here we show that in SH2D1A ؊/؊ mice, both primary and secondary responses of all Ig subclasses are severely impaired in response to specific antigens. Because germinal centers were absent in SH2D1A ؊/؊ mice upon primary immunization, and because SH2D1A was detectable in wt germinal center B cells, we examined whether SH2D1A ؊/؊ B cell functions were impaired. Using the adoptive cotransfer of B lymphocytes from hapten-primed SH2D1A ؊/؊ mice with CD4 ؉ T cells from primed wt mice into irradiated wt mice provided evidence that signal transduction events controlled by SH2D1A are essential for B cell activities resulting in antigen specific IgG production. Defects in naïve SH2D1A ؊/؊ B cells became evident upon cotransfer with nonprimed wt CD4 ؉ cells into Rag2 ؊/؊ recipients. Thus, both defective T and B cells exist in the absence of SH2D1A, which may explain the progressive dysgammaglobulinemia in a subset of X-linked lympho-proliferative disease patients without involvement of Epstein-Barr virus.Epstein-Barr virus ͉ germinal center ͉ immunoglobulin ͉ SLAM͞CD150