Because of its precedence in phylogeny and its freedom from the requirement for an adaptive immune response (i.e., specific antibody), the alternative pathway for complement activation must be an important mechanism for host defense. Similarly, the prevalence of cells bearing high-affinity receptors for fragments of complement proteins and the effects of complement-receptor interactions which have already been discovered make clear the biologic importance of these receptors. This is a request for continued support to study the interactions between plasma proteins of the complement or properdin system and cells. Two parallel lines of investigation will be pursued. In the first, cells (or particles simulating cells) will be used as targets in model systems to elucidate the mechanisms leading to activation of the alternative (properdin) pathway. The capacity of properdin to discriminate among activators or non-activators will be examined in studies of the kinetics and stoichiometry of binding or purified native or activated properdin in various microenvironments. Antibody immunoglobulins, either murine monoclonals specific for defined antigens on particles, or polyclonal monomeric and polymeric IgA specific for blood group antigens, will be examined for differential effects on classic and alternative pathway activation, and then on interaction of the six alternative pathway factors with defined surfaces. In the second line of investigation the biologic consequences of interactions between activated complement proteins or fragments and their corresponding cell surface receptors will be examined. Using monoclonal antibodies specific for CR1(C3b), CR2(C3d), CR3(iC3b), or Fc receptors and bispecific hybrids of such monoclonals, receptors on human polymophonuclear neutrophils or rat mast cells will be cross-linked and effects on receptor display, endocytosis, oxidative metabolism, enzyme secretion and phagocytosis examined. The receptor on mast cells that is specific for C3a will be studied in terms of binding characteristics and biologic function.
