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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1990 May;87(10):3982–3986. doi: 10.1073/pnas.87.10.3982

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

S Meri 1, M K Pangburn 1
PMCID: PMC54028  PMID: 1692629

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.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Baenziger J. U., Fiete D. Structure of the complex oligosaccharides of fetuin. J Biol Chem. 1979 Feb 10;254(3):789–795. [PubMed] [Google Scholar]
  2. Baker P. J., Lint T. F., McLeod B. C., Behrends C. L., Gewurz H. Studies on the inhibition of C56-induced lysis (reactive lysis). VI. Modulation of C56-induced lysis polyanions and polycations. J Immunol. 1975 Feb;114(2 Pt 1):554–558. [PubMed] [Google Scholar]
  3. Bitter-Suermann D., Burger R., Hadding U. Activation of the alternative pathway of complement: efficient fluid-phase amplification by blockade of the regulatory complement protein beta1H through sulfated polyanions. Eur J Immunol. 1981 Apr;11(4):291–295. doi: 10.1002/eji.1830110405. [DOI] [PubMed] [Google Scholar]
  4. Burger R., Bitter-Suermann D., Hadding U. Activation of the alternative pathway of complement: inhibition by low molecular weight polyanions. Immunochemistry. 1978 Apr;15(4):231–235. doi: 10.1016/0161-5890(78)90060-3. [DOI] [PubMed] [Google Scholar]
  5. Burger R., Bitter-Suermann D., Loos M., Hadding U. Insoluble polyanions as activators of both pathways of complement. Immunology. 1977 Dec;33(6):827–837. [PMC free article] [PubMed] [Google Scholar]
  6. Capel P. J., Groeneboer O., Grosveld G., Pondman K. W. The binding of activated C3 to polysaccharides and immunoglobulins. J Immunol. 1978 Dec;121(6):2566–2572. [PubMed] [Google Scholar]
  7. Carreno M. P., Labarre D., Maillet F., Jozefowicz M., Kazatchkine M. D. Regulation of the human alternative complement pathway: formation of a ternary complex between factor H, surface-bound C3b and chemical groups on nonactivating surfaces. Eur J Immunol. 1989 Nov;19(11):2145–2150. doi: 10.1002/eji.1830191126. [DOI] [PubMed] [Google Scholar]
  8. Curman B., Sandberg-Trägårdh L., Peterson P. A. Chemical characterization of human factor B of the alternate pathway of complement activation. Biochemistry. 1977 Nov 29;16(24):5368–5375. doi: 10.1021/bi00643a031. [DOI] [PubMed] [Google Scholar]
  9. Edwards M. S., Kasper D. L., Jennings H. J., Baker C. J., Nicholson-Weller A. Capsular sialic acid prevents activation of the alternative complement pathway by type III, group B streptococci. J Immunol. 1982 Mar;128(3):1278–1283. [PubMed] [Google Scholar]
  10. Fearon D. T., Austen K. F. Activation of the alternative complement pathway due to resistance of zymosan-bound amplification convertase to endogenous regulatory mechanisms. Proc Natl Acad Sci U S A. 1977 Apr;74(4):1683–1687. doi: 10.1073/pnas.74.4.1683. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Fearon D. T. Regulation by membrane sialic acid of beta1H-dependent decay-dissociation of amplification C3 convertase of the alternative complement pathway. Proc Natl Acad Sci U S A. 1978 Apr;75(4):1971–1975. doi: 10.1073/pnas.75.4.1971. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fries L. F., Gaither T. A., Hammer C. H., Frank M. M. C3b covalently bound to IgG demonstrates a reduced rate of inactivation by factors H and I. J Exp Med. 1984 Dec 1;160(6):1640–1655. doi: 10.1084/jem.160.6.1640. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Gardner W. D., White P. J., Hoch S. O. Identification of a major human serum DNA-binding protein as beta 1H of the alternative pathway of complement activation. Biochem Biophys Res Commun. 1980 May 14;94(1):61–67. doi: 10.1016/s0006-291x(80)80187-2. [DOI] [PubMed] [Google Scholar]
  14. Götze O., Müller-Eberhard H. J. The C3-activator system: an alternate pathway of complement activation. J Exp Med. 1971 Sep 1;134(3 Pt 2):90s–108s. [PubMed] [Google Scholar]
  15. Hammer C. H., Wirtz G. H., Renfer L., Gresham H. D., Tack B. F. Large scale isolation of functionally active components of the human complement system. J Biol Chem. 1981 Apr 25;256(8):3995–4006. [PubMed] [Google Scholar]
  16. Horstmann R. D., Pangburn M. K., Müller-Eberhard H. J. Species specificity of recognition by the alternative pathway of complement. J Immunol. 1985 Feb;134(2):1101–1104. [PubMed] [Google Scholar]
  17. Jarvis G. A., Vedros N. A. Sialic acid of group B Neisseria meningitidis regulates alternative complement pathway activation. Infect Immun. 1987 Jan;55(1):174–180. doi: 10.1128/iai.55.1.174-180.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Joiner K. A. Complement evasion by bacteria and parasites. Annu Rev Microbiol. 1988;42:201–230. doi: 10.1146/annurev.mi.42.100188.001221. [DOI] [PubMed] [Google Scholar]
  19. Kazatchkine M. D., Fearon D. T., Austen K. F. Human alternative complement pathway: membrane-associated sialic acid regulates the competition between B and beta1 H for cell-bound C3b. J Immunol. 1979 Jan;122(1):75–81. [PubMed] [Google Scholar]
  20. Kazatchkine M. D., Fearon D. T., Silbert J. E., Austen K. F. Surface-associated heparin inhibits zymosan-induced activation of the human alternative complement pathway by augmenting the regulatory action of the control proteins on particle-bound C3b. J Exp Med. 1979 Nov 1;150(5):1202–1215. doi: 10.1084/jem.150.5.1202. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Lachmann P. J., Halbwachs L. The influence of C3b inactivator (KAF) concentration on the ability of serum to support complement activation. Clin Exp Immunol. 1975 Jul;21(1):109–114. [PMC free article] [PubMed] [Google Scholar]
  22. Lesavre P. H., Hugli T. E., Esser A. F., Müller-Eberhard H. J. The alternative pathway C3/C5 convertase: chemical basis of factor B activation. J Immunol. 1979 Aug;123(2):529–534. [PubMed] [Google Scholar]
  23. Linhardt R. J., Rice K. G., Kim Y. S., Engelken J. D., Weiler J. M. Homogeneous, structurally defined heparin-oligosaccharides with low anticoagulant activity inhibit the generation of the amplification pathway C3 convertase in vitro. J Biol Chem. 1988 Sep 15;263(26):13090–13096. [PubMed] [Google Scholar]
  24. Maillet F., Kazatchkine M. D., Glotz D., Fischer E., Rowe M. Heparin prevents formation of the human C3 amplification convertase by inhibiting the binding site for B on C3b. Mol Immunol. 1983 Dec;20(12):1401–1404. doi: 10.1016/0161-5890(83)90172-4. [DOI] [PubMed] [Google Scholar]
  25. Maillet F., Petitou M., Choay J., Kazatchkine M. D. Structure-function relationships in the inhibitory effect of heparin on complement activation: independency of the anti-coagulant and anti-complementary sites on the heparin molecule. Mol Immunol. 1988 Sep;25(9):917–923. doi: 10.1016/0161-5890(88)90130-7. [DOI] [PubMed] [Google Scholar]
  26. Michalek M. T., Mold C., Bremer E. G. Inhibition of the alternative pathway of human complement by structural analogues of sialic acid. J Immunol. 1988 Mar 1;140(5):1588–1594. [PubMed] [Google Scholar]
  27. Müller-Eberhard H. J. Molecular organization and function of the complement system. Annu Rev Biochem. 1988;57:321–347. doi: 10.1146/annurev.bi.57.070188.001541. [DOI] [PubMed] [Google Scholar]
  28. Nilsson B., Nordén N. E., Svensson S. Structural studies on the carbohydrate portion of fetuin. J Biol Chem. 1979 Jun 10;254(11):4545–4553. [PubMed] [Google Scholar]
  29. Nilsson B., Svensson K. E., Borwell P., Nilsson U. R. Production of mouse monoclonal antibodies that detect distinct neoantigenic epitopes on bound C3b and iC3b but not on the corresponding soluble fragments. Mol Immunol. 1987 May;24(5):487–494. doi: 10.1016/0161-5890(87)90023-x. [DOI] [PubMed] [Google Scholar]
  30. Okada N., Yasuda T., Okada H. Restriction of alternative complement pathway activation by sialosylglycolipids. Nature. 1982 Sep 16;299(5880):261–263. doi: 10.1038/299261a0. [DOI] [PubMed] [Google Scholar]
  31. PILLEMER L., BLUM L., LEPOW I. H., ROSS O. A., TODD E. W., WARDLAW A. C. The properdin system and immunity. I. Demonstration and isolation of a new serum protein, properdin, and its role in immune phenomena. Science. 1954 Aug 20;120(3112):279–285. doi: 10.1126/science.120.3112.279. [DOI] [PubMed] [Google Scholar]
  32. Pangburn M. K. A fluorimetric assay for native C3. The hemolytically active form of the third component of human complement. J Immunol Methods. 1987 Aug 24;102(1):7–14. doi: 10.1016/s0022-1759(87)80003-0. [DOI] [PubMed] [Google Scholar]
  33. Pangburn M. K. Analysis of recognition in the alternative pathway of complement. Effect of polysaccharide size. J Immunol. 1989 Apr 15;142(8):2766–2770. [PubMed] [Google Scholar]
  34. Pangburn M. K. Analysis of the mechanism of recognition in the complement alternative pathway using C3b-bound low molecular weight polysaccharides. J Immunol. 1989 Apr 15;142(8):2759–2765. [PubMed] [Google Scholar]
  35. Pangburn M. K., Morrison D. C., Schreiber R. D., Müller-Eberhard H. J. Activation of the alternative complement pathway: recognition of surface structures on activators by bound C3b. J Immunol. 1980 Feb;124(2):977–982. [PubMed] [Google Scholar]
  36. Pangburn M. K., Müller-Eberhard H. J. Complement C3 convertase: cell surface restriction of beta1H control and generation of restriction on neuraminidase-treated cells. Proc Natl Acad Sci U S A. 1978 May;75(5):2416–2420. doi: 10.1073/pnas.75.5.2416. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Pangburn M. K., Müller-Eberhard H. J. Kinetic and thermodynamic analysis of the control of C3b by the complement regulatory proteins factors H and I. Biochemistry. 1983 Jan 4;22(1):178–185. doi: 10.1021/bi00270a026. [DOI] [PubMed] [Google Scholar]
  38. Pangburn M. K., Müller-Eberhard H. J. Relation of putative thioester bond in C3 to activation of the alternative pathway and the binding of C3b to biological targets of complement. J Exp Med. 1980 Oct 1;152(4):1102–1114. doi: 10.1084/jem.152.4.1102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Pangburn M. K., Müller-Eberhard H. J. The alternative pathway of complement. Springer Semin Immunopathol. 1984;7(2-3):163–192. doi: 10.1007/BF01893019. [DOI] [PubMed] [Google Scholar]
  40. Pangburn M. K., Schreiber R. D., Müller-Eberhard H. J. Human complement C3b inactivator: isolation, characterization, and demonstration of an absolute requirement for the serum protein beta1H for cleavage of C3b and C4b in solution. J Exp Med. 1977 Jul 1;146(1):257–270. doi: 10.1084/jem.146.1.257. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Pryzdial E. L., Isenman D. E. A reexamination of the role of magnesium in the human alternative pathway of complement. Mol Immunol. 1986 Jan;23(1):87–96. doi: 10.1016/0161-5890(86)90175-6. [DOI] [PubMed] [Google Scholar]
  42. Spiro R. G., Bhoyroo V. D. Structure of the O-glycosidically linked carbohydrate units of fetuin. J Biol Chem. 1974 Sep 25;249(18):5704–5717. [PubMed] [Google Scholar]
  43. Tarr P. I., Hosea S. W., Brown E. J., Schneerson R., Sutton A., Frank M. M. The requirement of specific anticapsular IgG for killing of Haemophilus influenzae by the alternative pathway of complement activation. J Immunol. 1982 Apr;128(4):1772–1775. [PubMed] [Google Scholar]
  44. Weiler J. M., Yurt R. W., Fearon D. T., Austen K. F. Modulation of the formation of the amplification convertase of complement, C3b, Bb, by native and commercial heparin. J Exp Med. 1978 Feb 1;147(2):409–421. doi: 10.1084/jem.147.2.409. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Winkelstein J. A., Tomasz A. Activation of the alternative complement pathway by pneumococcal cell wall teichoic acid. J Immunol. 1978 Jan;120(1):174–178. [PubMed] [Google Scholar]

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