Stimulation of a human polymorphonuclear leukocyte oxidative response by the C1q subunit of the first complement component.

Abstract

Activation of the classical complement pathway under physiologic conditions leads to C1 inhibitor-mediated dissociation of the first complement component, C1, and exposure of the collagen-like region of the C1q subunit of C1. Because polymorphonuclear leukocytes (PMN) bind this portion of the C1q molecule the possibility that C1q triggers a biologic response in these cells was investigated. C1q, when particle-bound, mediated the stimulation of an oxidative response in human PMN as measured by a luminol-dependent chemiluminescent assay and by hexose monophosphate shunt activity. The chemiluminescent response of PMN to aggregated IgG was found to be enhanced 2- to 10-fold by purified human C1q. Immunoglobulin and the Fc receptor were not required for the stimulation of PMN by C1q, however, as C1q bound to latex beads enhanced the chemiluminescent response 10-fold over that observed with the un-coated latex beads. Because no chemiluminescent response was detected when PMN from a patient with chronic granulomatous disease were incubated with C1q-coated particles, it is likely the stimulated oxidative activity proceeds via the NADPH-dependent oxidase utilized by other activators of oxidative metabolism in PMN. The importance of multi-site binding for the induction of a chemiluminescent response to C1q was indicated by the following: 1) monomeric C1q free in solution was unable to initiate a response; 2) only high concentrations of monomeric C1q were capable of inhibiting the response effected by C1q-coated beads; and 3) the extent of the response was dependent on the amount of C1q per bead. No response was detected to latex beads coated with macromolecular C1 containing amounts of C1q that alone stimulated PMN chemiluminescence, suggesting it is the collagen-like region of the C1q molecule that interacts with the cell in initiating this response. Although the chemiluminescent response was inhibited by sodium azide, superoxide dismutase was not an effective inhibitor and little if any extracellular superoxide anion was detected during the reaction. Stimulation of the oxidative activity was confirmed by measuring hexose monophosphate shunt activity of PMN incubated with C1q-coated latex beads. These data represent a new activity of the C1q molecule and raise the possibility that C1q participates in the PMN-mediated destruction and clearance of activators of the classical complement pathway.