Evidence is presented that cobra venom factor, the anticomplementary protein in Naja naja venom, is modified cobra C3 (the third component of complement). Antiserum to the cobra venom factor cross reacts with human C3. A protein in cobra serum reacts strongly with antiserum to the venom factor and the former protein, like human C3, is converted by incubation of cobra serum with endotoxin, hydrazine, or simple storage at 37 degrees C. Incubation of cobra venom factor with cobra serum destroys the C3 cleaving activity of the venom factor in human serum, whereas human C3b inactivator is ineffective. Thus, the cobra venom factor appears to be a form of C3 (perhaps C3b); its potent action in human serum probably derives from its lack of sensitivity to human C3b inactivator.

A B S T R A C T Using isoelectric focusing in polyacrylamide gel and a hemolytic assay for development of patterns, extensive structural polymorphism in human C8 has been delineated. Two C8 allotypes have been determined for two previously studied familes, each with a homozygous C8-deficient propositus. This study suggests that C8 deficiency is a silent or null allele of the C8 structural locus, and that half normal levels of C8 cannot be used as a single criterion for the establishment of heterozygous C8 deficiency. C8 allotypes, as well as 18 other autosomal markers, were also determined for 24 familes. The C8 structural locus is not closely linked to these markers, including the human histocompatibility loci complex.

The presence in cobra venom of an anticomplementary activity has been known for over 80 years. More recent studies have demonstrated that purified CoF incubated with mammalian sera results in an alternative pathway mediated attack on C3. Lachmann and Nicol have pointed out that CoF is “C3b-like” in its ability to activate C3 and later components. The present studies strongly suggest that CoF is, in fact, altered cobra C3. Potent rabbit antiserum to CoF cross-reacts with human C3. On immunofixation of cobra serum after prolonged agarose gel electrophoresis, a single reactive band was found in the β1-region. Multiple slower bands were found in cobra venom or purified CoF, suggesting that CoF is an altered form of the serum molecule. When cobra serum was incubated at 37°C, slow conversion to a more rapidly migrating form was observed in immunoelectrophoresis. Much more rapid conversion occurred when cobra serum was incubated with endotoxin at 37°C.

Four families have been studied, some members of which have inherited deficiency of the sixth component of complement. The genetically determined electrophoretic variants of C6 were evaluated in all family members. Seven individuals were found who did not have the variant found in the serum of the parent from whom they inherited the deficiency. It is inferred that the isolated low levels of C6 in these individuals results from the heterozygous state of a normal C6 variant gene and a silent or null C6 gene; the genes determining electrophoretic variants and the low serum levels of C6 are allelic.