Discrimination between activators and nonactivators of the alternative pathway of complement: regulation via a sialic acid/polyanion binding site on factor H.

Abstract

The alternative complement pathway is capable of discriminating human cells and tissues from a wide variety of potential pathogens. It has been recently demonstrated that attachment of complement component C3b to activator-derived molecules (e.g., small polysaccharides) restricts inactivation of C3b by factors H and I in a manner similar to activator surfaces. It is now shown that restriction is reversed by certain soluble polyanions (e.g., sialoglycopeptides, heparin, or dextran sulfate) that mimic the effects of sialic acid and glycosaminoglycans on human cells and tissues. Fluid-phase polyanions enhanced binding of factor H to C3b attached to activating particles, indicating that the effect resulted from increased affinity between C3b and factor H. The enhancement was specific for activator-bound C3b since no enhancement was observed on nonactivating particles. While several polyanions could cause this effect, some polyanions could not, indicating specificity. The active polyanions also inhibited lysis of cells via the alternative pathway. The binding site for sialic acid appears to reside on factor H, since factor H bound to heparin-agarose and to sialic acid-bearing fetuinagarose, whereas C3b bound to neither under the same conditions. These observations suggest that occupation of a specific site on factor H by polyanions induces an increase in the C3b-H affinity, resulting in discrimination of host cells and tissues from alternative pathway-activating foreign cells.The alternative pathway of complement (AP) represents a natural defense system for recognition and destruction of foreign organisms in vertebrate species (1-4). It enhances phagocytosis and is cytolytic for many bacteria, parasites, and virus-infected cells and for some tumor cells. This relatively simple system is composed of only six plasma glycoproteins (C3 and factors B, D, H, I, and P) but recognizes a wide variety of foreign organisms without prior contact or memory. The molecular mechanism by which C3b and the regulatory system of complement discriminate (5) between human and foreign particles has yet to be fully described. As an approach to this problem, a fluid-phase model for the AP recognition event has been constructed (6, 7). This paper shows that the recognition process can be fully mimicked with soluble complexes.

Factor H uptake regulates intracellular C3 activation during apoptosis and decreases the inflammatory potential of nucleosomes

“…These are Factor H regulates C3 and nucleosomes in apoptosis M Martin et al inhibitory receptors of the sialic acid-binding Ig-like lectin family, which attenuate immune responses and dampen inflammation. 27 FH binds to sialic acid 28 and seems to facilitate the interaction of cis sialic acids and siglec receptors on the monocytes, which enhances their inhibitory response.…”

Exceptional Resistance of Human H2 Glioblastoma Cells to Complement-Mediated Killing by Expression and Utilization of Factor H and Factor H-Like Protein 1

“…Complement factor H was purified as described (17,18) and radiolabeled with Na 125 I (NEN, Boston, MA), according to the manufacturer's instructions. Free 125 I was separated from the labeled proteins by gel filtration through Sephadex G25 (Pharmacia).…”

“…Isopropyl alcohol-precipitated RNA was dissolved in diethylpyrocarbonate-treated water, and 1 g of RNA was denaturated at 70°C for 10 min and then immediately chilled on ice. Reverse-transcriptase reactions were conducted using RNA in a total volume of 20 l containing 10 mM DTT (Life Technologies), 500 M dNTP mix (Pharmacia), 25 g/ml oligo(dT) [12][13][14][15][16][17][18] (Pharmacia), and 200 U Moloney murine leukemia virus reverse transcriptase (Life Technologies) in a reverse-transcriptase buffer (Life Technologies). The reaction was allowed to occur for 1 h at 37°C.…”

Acquisition of Complement Factor H Is Important for Pathogenesis ofStreptococcus pyogenesInfections: Evidence from Bacterial In Vitro Survival and Human Genetic Association

“…AP attacks any surface that is not specifically protected against it (7); therefore, host cells need downregulation on their surfaces by plasma protein complement factor H (CFH) (8,9). CFH is composed of 20 domains; domains 1-4 mediate inactivation of deposited C3b or prevent C3b generation by accelerating decay of the C3-convertase C3bBb.…”