A new disease, C1 esterase inhibitor deficiency, associated with the formation of a monoclonal antibody to the C1 inhibitor was described. Seven patients have now been collected who are making this antibody of extremely restricted heterogeneity to one plasma protein. The antibody inactivates the plasma protein causing disease. Demonstration of this antibody has been difficult because of its low affinity and the fact that it does not precipitate with the antigen. Those difficulties have now been surmounted. The mechanism of action of the antibody has been studied. In its normal function C1 inhibitor presents a bait sequence to the enzyme to be inhibited and is cleaved. It then forms a covalent bond with the enzyme to be inhibited. The antibody does not appear to function to prevent cleavage of the C1 inhibitor but rather prevents the covalent bond from being formed when the C1 inhibitor is cleaved. In these patients the C1 inhibitor circulates as a fragment and has no functional activity. Methods of therapy are currently being developed. C5a has been purified and C5a des arg are continuing to be studied for their effects in man. It has been shown that in human beings the wheel and flare response to C5a injections in the skin is attenuated if one studies patients with reduced polymorphonuclear neutrophils. These data are taken to indicate, in a preliminary way, that the C5a causes its effect on mast cells via a neutrophil effect; that is, it triggers neutrophils to release a factor which causes mast cells to degranulate. This is under further study at the present time. As one increases the amount of antibody on the target it becomes impossible for complement to lyse the target. The basis for this phenomena, known since the turn of the century, has been examined. The step in which prozone occurs in the complement sequence has been identified and has to do with the binding of C2 to C4. The chemical reason why, as one increases the C4 concentration on the cell, C2 binding falls off is under investigation. The effect may have to do with the presence of regulatory proteins but this may not be the entire story.