STRUCTURAL FEATURES OF HUMAN IMMUNOGLOBULIN-G THAT DETERMINE ISOTYPE-SPECIFIC DIFFERENCES IN COMPLEMENT ACTIVATION

Although very similar in sequence, the four subclasses of human immuno globulin G (IgG) differ markedly in their ability to activate compleme nt. Glu318-Lys320-Lys322 has been identified as a key binding motif fo r the first component of complement, C1q, and is present in all isotyp es of Ig capable of activating complement. This motif, however, is pre sent in all subclasses of human IgG, including those that show little (IgG2) or even no (IgG4) complement activity. Using point mutants of c himeric antibodies, we have identified specific residues responsible f or the differing ability of the IgG subclasses to fix complement. In p articular, we show that Ser at position 331 in gamma4 is critical for determining the inability of that isotype to bind C1q and activate com plement. Additionally, we provide further evidence that levels of C1q binding do not necessarily correlate with levels of complement activit y, and that C1q binding alone is not sufficient for complement activat ion.