Two functions of the complement system related to autoimmune diseases are the induction of an inflammatory response and the augmentation of an immune response. Studies of two complement receptors are proposed that address both functions. A group of plasma and membrane proteins sharing a structural motif inhibit the C3/C5 convertase step of the classical and alternative pathways. One member of this family, complement receptor type 1 (CR1; CD35) normally serves as a receptor but is uniquely suited for complement inhibition. CRI binds bivalently to dimers of C3b and C4b, promotes their cleavage by I, dissociates the catalytic subunits from the C3/C5 convertases of both pathways, and is not restricted by alternative pathway activating surfaces. A soluble form of CR1, sCR1 lacking the transmembrane and cytoplasmic domains was prepared to take advantage of these inhibitory activities. The sCRI was at least 100-fold more inhibitory than C4-binding protein and H in vitro and suppressed complement activation and tissue necrosis in vivo in a model of myocardial ischemia/reperfusion injury. These studies will be extended by determining the SCRs required for the inhibitory functions of CRI, preparing soluble CR1/IgG constructs having improved half-lives and tissue distribution and suppressing a complement-dependent model of autoimmune disease, experimental allergic myasthenia gravis. The capacity of complement to enhance the humoral immune response is mediated in part by the B cell receptor, complement receptor type 2 (CR2; CD21) which augments activation of phospholipase C (PLC) by mIgM. CR2 forms a 1:1 complex with CD19, a membrane protein that is expressed at all stages of B cell development except that of the plasma cell, is a member of the immunoglobulin superfamily, has an extended cytoplasmic domain of 247 amino acids, and releases intracellular Ca++ following ligation, all characteristics of a membrane constituent important in the biology of the B cell. In the mature B cell the CR2/CD19 complex may represent a functional signal transducing unit. The proposed studies will demonstrate that CR2 is a ligand binding subunit and CD19 the signal transducing subunit in the complex, that CD19 utilizes a pathway to PLC activation that is distinct from that of mIgM, and that CD19 is coupled to a protein tyrosine kinase. Through the CR2/CD19 complex, complement may trigger B cells by a pathway fundamental to the biology of this cell type.
Showing the most recent 10 out of 40 publications
