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The decision of the acquired immune system to respond to an antigen may be based not only on what is non-self, but also on what is infectious and of potential danger to the host (1). How the immune system makes this latter determination is not clear because the antigen receptors that are distributed among different lymphocyte clones generally cannot distinguish between noxious and innocuous antigens.
Systems of innate resistance to infection evolved before acquired immunity and are triggered by certain biochemical characteristics that are shared by microorganisms but not by higher forms of life. Complement is a plasma protein system of innate immunity that is activated by microorganisms in the absence of antibody (2). One consequence of activation is the covalent attachment of fragments of the third complement protein, C3, to the activator, and two of these fragments, C3dg and C3d, bind to CR2 (CD21) on B lymphocytes. CD21 may have B cell-stimulating functions because it assaciates with CD19, a B cell membrane protein that amplifies B cell activation (3) and is required for normal T cell-dependent, B cell responses (4). In support of this, depleting mice of C3 or blocking the binding of ligand to CD21 raises by approximately 10-fold the threshold dose of antigen required to elicit antibody (5, 6). Therefore, the complement system may be an innate immune system that provides information to the acquired immune system in an attempt to classify antigens according to their potential hazard.
To determine whether the immunity-enhancing function of complement is mediated solely by the attachment of C3d to antigen and, if so, the magnitude of this effect of C3d, we prepared recombinant model antigens of hen egg lysozyme (HEL) alone and of HEL fused to one, two, or three copies of murine C3d (7) (Fig. 1). (Fig. 1 omitted) The recombinant proteins were bound with equivalent affinities by HyHEL-9 (8), a conformation-sensitive monoclonal antibody to HEL, and by HEL-specific B cells from transgenic mice (9) expressing an HEL antibody (anti-HEL) (HyHEL-10) that binds to a distinct epitope. Thus, fusion to C3d did not alter at least two epitopes of HEL. The ability of the C3d components of the fusion proteins to bind to CD21 was determined by competitive binding assays with Raji B lymphoblastoid cells...