Complement: a critical test of its biological importance.

The biological activities of the more than 30 proteins that comprise the complement system have been elucidated in parallel lines of investigation that resulted in the purification of the proteins and studies of their function in vitro. Twenty years ago, the first complement cDNA clones were generated. Subsequently the structure and chromosomal localization of the complement genes and the primary sequences of their gene products were revealed. For some, even their higher order structure was solved. This work, coupled with studies of complement gene expression, biosynthesis, post-synthetic processing and secretion, contributed to an analysis of the relatively rare naturally occurring genetic deficiencies of complement proteins discovered fortuitously in humans sand experimental animals. Not until the past 5 years, with the application of methods for manipulating genes in vivo (targeted deletion and overexpression), has it been possible to definitively assign specific functions to complement proteins and to assess their importance in the intact organism. These relatively recent studies have confirmed the in vitro work or revealed unexpected roles for complement effector and regulatory proteins in host defenses, specific immunity, immunopathology, metabolism and reproductive biology This work is reviewed and the implications for understanding human diseases and the design of novel pharmaceutical agents are discussed. The promise of this line of investigation is certain but the context imposed by gender, developmental stage, other genes and environment must be taken into account before the practical implications of this deeper understanding of complement biology are fully realized.