Guinea pigs with a genetically determined total deficiency of the fourth component of complement have been studied for various in vivo immunological functions. Passive cutaneous anaphylaxsis, contact and delayed hypersensitivity, and the cellular exudative response to a foreign body were normal. These animals also have normal direct and reverse passive Arthus reactions which suggest that they possess a mechanism to bypass C4 and directly activate late-acting complement components. This would appear to be an unequivocal demonstration of an alternate pathway in the complement sequence. Immune clearance of guinea pig erythrocytes sensitized with rabbit antibody was impaired in the deficient animals. Antibody production in C4-deficient animals was impaired for two of the three antigens studied.

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