A NOVEL MECHANISM OF ALTERNATIVE PATHWAY COMPLEMENT ACTIVATION ACCOUNTS FOR THE DEPOSITION OF C3 FRAGMENTS ON CR-2-EXPRESSING HOMOLOGOUS CELLS

Complement receptor type 2 (CD21, CR2), the receptor for the C3 fragme nt C3dg, activates complement via the alternative pathway and also ser ves as a preferential acceptor site for C3 fragments. The molecular ba sis for this phenomenon, which has recently been demonstrated for B ly mphocytes in vivo, is currently not understood. Here we present a mode l for this CR2-dependent complement activation. The inactive C3 (iC3), which forms spontaneously in serum in low amounts by reaction of nati ve C3 with H2O, binds noncovalently to the N-terminal part of CR2. Sub sequent association of properdin and factor B, and cleavage of factor B by factor D lead to formation of a C3 convertase associated with CR2 , thus focussing covalent C3 deposition to CR2 itself. This model is s upported by the following experimental findings. 1) By FACS analysis a nd radioreceptor assays we showed that iC3, properdin, and factor B bo und to CR2 on Raji B cells, MT2 T cells, and peripheral blood B cells. 2) Both binding of these proteins and complement activation by CR2-ex pressing cells were reduced in parallel by Abs against CR2. 3) I-125-l abeled C3b was covalently deposited on CR2, when hemolytically active I-125-labeled C3 was added to Raji cells preincubated with iC3, factor B, properdin, and factor D, thus proving functionality of CR2-bound C 3 convertase. This model of C3 convertase activity formed on CR2 domai ns inaccessible for decay-accelerating factor offers an explanation fo r the deposition of C3 found on CR2-expressing cells.