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Modulation of the Antigenicity of C1 and C1 by C Inactivator¹

From the Department of Molecular Immunology, Research Institute of Scripps Clinic, La Jolla, California 92037

Abstract

The first complement component, C1, was activated in normal human sera by addition of aggregated IgG, immune complexes, and lipopolysaccharide, after which the concentrations of the C1 subcomponents, C1r and C1s, were measured by single radial immunodiffusion. A progressive reduction in C1r antigen content was observed as greater amounts of activator were added to normal human sera. Three lines of evidence proved that the apparent disappearance of C1r was due to interaction of C1 with C Inactivator (C In). First, no loss of C1r antigen was detected in sera from patients with hereditary angioneurotic edema, which lack functional C Inactivator. Second, reconstitution of these patients' sera with physiologic concentrations of purified C In resulted in the disappearance of C1r antigen. Third, purified C In greatly reduced the intensity of the precipitin line formed between purified C1 and anti-C1.

In parallel experiments, certain antisera to C1s were found to show a comparable disappearance of C1s antigenic content in activated human sera. This antigenic loss was similarly shown to be due to the interaction of C1 with C In. However, it should be noted that the detection of changes of C1 antigenicity was dependent on the specificity of the C1s antisera employed, since antisera with antigenic specificities apparently directed to determinants on the C1s molecule distant from the region of interaction with C In did not show changes with activation.

Ultracentrifugal studies demonstrated that C1 and C1 formed soluble complexes with C In in activated serum, thus precluding the possibility that C1 and C1 escape immunochemical detection in activated serum by being present in large aggregated complexes. Also ruled out, in the case of C1, is the possibility that the binding of C In leads to a major conformational rearrangement of C1 with resulting changes in exposed antigens of the molecule. It is most likely that the loss in C1 and C1 antigenic content with activation of C1 in serum occurs because of simple physical masking of the relevant antigens of C1 and C1 by the relatively large C In molecule.

Footnotes

¹ This is publication Number 1559 from the Research Institute of Scripps Clinic. This work was supported by Public Health Service Grants CA 14692, AI 07007, AI 14502, and I S07 RR-05514 from the National Institutes of Health and Grant-in-Aid 77-941 from the American Heart Association.