Interactions of C-reactive protein with the complement system. II. C-reactive protein-mediated consumption of complement by poly-L-lysine polymers and other polycations.

Abstract

Cationic homopolymers of poly-L-lysine were found to activate complement (C) via C-reactive protein (CRP) and deplete C3 and C5 as well as early-acting C components. Maximum C consumption was obtained with polymers of 2,000-8,000 daltons; polymers of 1,700, 11,000, and 23,000 daltons were intermediate in reactivity, while L-lysine, lysyl-L-lysine, tetra-L-lysine, and polymers of 70,000-400,000 daltons lacked significant C-consuming activity. Naturally occurring polycations which consumed C in the presence of CRP included myelin basic proteins, cationic proteins of rabbit leukocytes, and both lysine- and arginine-rich histones; poly-L-arginine polymers of 17,000 but not 65,000 daltons also were C-consuming. Polycations without such reactivity included poly-L-orithine (5,000 and 165,000 daltons), egg white and human lysozymes, and Polybrene. The polycations which failed to induce C consumption via CRP, inhibited its consumption by both active polycations and by C-polysaccharide (CPS). The relative inhibitory capacity of phosphorylcholine and polycations in CPS- and polycations-CRP systems was consistent with the concept that phosphate esters and polycations react at the same or an overlapping combining site. The ability of certain polycations to activate C via CRP increases the potential for initiation of host reactions via C. The capacity of other polycations to inhibit C activation via CRP introduces a potential for physiologic or pharmacologic manipulation. These considerations would seem to expand the potential role of CRP in the initiation and modulation of the inflammatory response.

Localization of C‐reactive protein in synovium of patients with rheumatoid arthritis

“…When CRP binds to an appropriate ligand in vitro, it can activate the complement system (8)(9)(10)(11)(12)(13). In the present study CRP was found bound to certain synovial nuclei in patients with rheumatoid arthritis.…”

Systemic circulation of poly(l-lysine)/DNA vectors is influenced by polycation molecular weight and type of DNA: differential circulation in mice and rats and the implications for human gene therapy

“…The influence of molecular weight of polycations on complement activation by pLL and pLL/DNA complexes has been reported previously. Siegal et al 19 have shown, in acute-phase human serum in vitro, that low-molecular-weight pLL (4 and 23 kd) activates complement significantly more than high-molecular-weight pLL (70 kd). In contrast, in normal serum, complement is activated independently of the molecular weight of pLL used.…”

“…Plank et al 18 have also shown that pLL activates complement in normal human serum in vitro, but, in their study, high-molecularweight pLL (approximately 50 kd) and corresponding pLL/DNA complexes were shown to activate complement to a greater extent than low-molecular-weight pLL (1, 4, 6, and 25 kd). The apparent contradiction between these 2 studies may reflect the different methods used to determine complement activation, with Siegal et al 19 using a direct measure of complement protein depletion and Plank et al 18 using an indirect sensitized sheep erythrocyte hemolysis assay. Despite the discrepancies between these 2 studies, which were both performed with human and not mouse serum, they do show that complement is readily activated by pLL and that molecular weight can influence the level of activation achieved.…”

“…Although it is well known that pLL/DNA complexes activate human complement in vitro, 18,19 no studies have correlated immune stimulation by pLL/DNA complexes with circulatory half-lives in rodent models. Indeed, evidence shows that pLL/DNA complexes do not stimulate the immune system in mice, 11 thus confusing the factors involved in the removal of complexes from the circulation.…”

Characterization of C-reactive protein and the complement subcomponent C1t as homologous proteins displaying cyclic pentameric symmetry (pentraxins).

“…However, one of these agents, C-reactive protein (CRP), would appear to act in a manner entirely analogous to immunoglobulin. It has been found that upon interaction with a variety of substances, CRP can activate the C cascade and initiate both the opsonic and lytic potentials of this system through an activation of the primary C pathway (3)(4)(5)(6). CRP has been described as being comprised of probably identical subunits, ca 23,000 daltons, noncovalently linked to form an oligomer of molecular weight 120,000-140,000 (7,8).…”