A number of structurally different LPS preparations differing in content of lipid A and polysaccharide were examined for their ability to bind and activate the first component of human complement, C1. Lipid A-rich LPS preparations as well as isolated lipid A were found to be orders of magnitude more active in binding highly purified precursor C1 as well as C1 than polysaccharide-rich preparations. This interaction was shown to occur through the C1q portion of the C1 macromolecule. Attachment of the lipid A-rich LPS preparations to C1 is a biologically meaningful event as it was demonstrated to lead to activation of proenzyme C1 reconstituted from highly purified C1q and proenzymes C1r and C1s. Further, an unusual dose response profile was obtained for the lipid A-rich LPS preparation from Salmonella minnesota R 595 in that relatively high doses of LPS bound C1 but activation was inhibited. Lower doses, in contrast, bound and also activated C1. Isolated lipid A, by comparison, bound and activated C1 efficiently at high and low dose ranges.

The lipid A region of the LPS molecule was found to be responsible for classical pathway activation. This conclusion derives from several observations. First, isolated lipid A was more active in binding and activating C1 and LPS containing even minor proportions of carbohydrate. Second, polymyxin B, an antibiotic that binds to the lipid A portion of LPS, abrogated the C1-activating ability of the preparations. Third, the presence of LAP, a protein that is associated with lipid A in certain LPS preparations, interfered with C1 binding by LPS. Finally, alteration of lipid A by mild alkaline hydrolysis abrogated its C1-binding capacity. These studies thus show, in a purified system, that the lipid A region of lipid A-rich LPS preparations isolated from rough strains of bacteria can directly and efficiently activate the classical pathway at the C1 step. This reaction proceeds in the absence of antibody. Thus, in this system C1q fulfills a recognition role normally associated with the antibody molecule.

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