Synthesis of complement components in liver and at extrahepatic sites

Complement protein biosynthesis has been a subject of study for over 100 years. In the 1890s, Metchinoff suggested that leukocytes were a source of complement1. Interest in the liver as a site of complement production was first generated by the experiments of Ehrlich and Morgenroth2, who demonstrated that complement, but not antibody, was depressed in sera of animals poisoned with phosphorus. Shortly thereafter, Muller found that perfusion of liver with serum led to an increase in complement activity in the effluate, and concluded that the liver was the site of complement synthesis3. In the late 1960s, Alper and coworkers4‘5 confirmed this observation that the liver was a major site of serum complement synthesis by studying a patient following liver transplantation; the electrophoretic form of C3 shifted from the recipient FS type to the donor SS type. The complete shift of C3 from recipient to donor type indicated that the liver synthesized at least 95% of the C3 found in serum4,5. Also in the 1960s, Thorbecke and her colleagues6-8 suggested that cell types of endodermal, mesodermal and ectodermal origin in several organs were capable of synthesizing proteins of the complement system. Application of modern molecular biological methods has confirmed that complement proteins are synthesized at multiple sites. In addition, studies of complement metabolism and mRNA expression in vivo9~n and in tissue culture12,13 indicate a role for complement produced at extrahepatic sites, especially in the immunopathogenesis of autoimmune injury. The functional importance of this extrahepatic complement production is supported by the elaborate tissue-specific and developmentally regulated controls of complement gene expression now recognized in several species.