This proposed research represents a continuation of work on the biochemistry and biology of human C1, the first complement component and its substrates. C1 is activated by a variety of biological materials and initiates a cascade reaction beginning with the proteolytic cleavage of its natural substrates C4 and C2. Cleavage of C4 and C2 lead to convertase formation with the ability to cleave C3. Generation of capillary permeability, chemotactic, opsonic and lytic activities result and these reactions appear to play fundamental roles in acute and probably in chronic inflammation, irrespective of its cause. C1 also has a role in the alternative pathway and our initial aim will be to search for its substrate in this pathway. These studies initially aim to increase our ability to (1) understand the precise role that the early C components of both pathways play in human disease, (2) to uncover the activators, and (3) to eventually develop pharmacological inhibitors.