Dennis E. Hourcade, Ph.D.

DEPARTMENT OF Internal Medicine
Keywords: inflammation, immunology, complement, proteases

Complement consists of about 30 soluble and membrane-bound proteins that together constitute an important part of immunity. Complement recognizes immune complexes and foreign substances and marks them for adhesion and phagocytosis or lysis, and initiates pro-inflammatory and vasoactive reactions. As a result, complement is a powerful defense against many pathogens. Complement also helps to direct the antibody repertoire that is expressed, plays a role in host/pathogen relationships, and accounts for substantial tissue damage in a wide variety of autoimmune/immune complex mediated syndromes and tissue injury brought about by vascular injury. A deeper understanding of complement could form a basis for the control of antibiotic-resistant microbes, the modulation of acquired immunity, and the abatement of complement-mediated injury and disease. Our long-range goal is to discover new approaches to the therapeutic control of complement.

The complement convertases are serine proteases that are assembled at sites of foreign objects and immune complexes. There they cleave C3, an abundant serum component, and the resulting C3 derivatives direct the major effects of the complement response: antigen selection, inflammation, immune clearance, and cell lysis. We are investigating the mechanism of convertase assembly and regulation. Our approach has emphasized a structure/function analysis of the convertase catalytic subunits, factor B and C2. These studies are revealing the interactions which control convertase activation and identifying targets for new complement inhibitors.