Isolated Deficiencies of the Fifth and Eighth Components of Complement (C) in two Families: Clinical, Genetic and Biological Correlations

Rapid advances in our understanding of the biochemistry and biology of C are being made, but the precise role of C in vivo is still poorly defined. The correlation of isolated deficiencies of C components in humans with clinical status, inheritance, and biological activity in vitro will better elucidate the function of C in vivo. In the past year we have identified two patients with isolated C component deficiencies. A severe deficiency of C5 (<2% of normal) was found in a previously healthy 21-year-old women with disseminated gonococcemia. Antibodies to DNA or to nucleoprotein were undetectable. In one year, despite vigorous antibiotic therapy and counseling, she had five recurrences of gonococcemia. Her twin sister (C5 <2% of normal) had one episode of suspected gonococcemia but has been otherwise healthy. Neither of the twins had any C5 protein detectable by radial immunodiffusion. The mother, a brother, and his son had C5 levels of ca. half normal. HLA typing revealed no linkage disequilibrium between the C5 deficiency and either the A or B locus of the major histocompatibility complex (MHC). Chemotactic activity for human PMNs could not be generated in the serum of either sister upon activation of either the classical or the alternative C pathways. Since C3 levels were normal in these sera, it is clear that C3 plays little if any role as a chemotactinogen in vitro. This family demonstrates that severe deficiency of C5 can be associated with heightened susceptibility to gonococcal infections. Recently, a 27-year-old man with a history of gonococcal endocarditis was admitted with staphylococcal sepsis. His hemolytic C8 level was <1% of normal. His mother also had <1% of normal hemolytic C8 but no history of infections. The hemolytic C8 levels of five siblings and half-siblings ranged from 62 to 92% of normal. No linkage disequilibrium between the C8 deficiency and either the A or B locus of the MHC was found. Studies of this family now in progress can help to clarify the genetics of C8 deficiency in man.