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. 1981 Jul 1;154(1):1–12. doi: 10.1084/jem.154.1.1

Mechanism of action of the C4 nephritic factor. Deregulation of the classical pathway of C3 convertase

PMCID: PMC2186394  PMID: 7019379

Abstract

Three mechanisms that regulate the formation and function of the classical pathway C3 convertase (C4b2a) have been elucidated: (a) an intrinsic decay of the enzyme that is temperature dependent; (b) an extrinsic decay mediated by the effect of the serum protein C4b binding protein (C4-bp); and (c) inactivation of C4b by the proteolytic action of C4b/C3b inactivator (C4b/C3bINA), which cleaves that alpha' chain of C4b to yield C4d (alpha 2) and C4c (alpha 3, alpha 4, beta, and gamma chains). A fourth mechanism described here is based on the observation that the IgG fraction of the serum of certain patients with glomerulonephritis contains a protein termed C4 nephritic factor (NFc), which prevents the intrinsic decay of C4b2a. This protein, which prolongs the half-life of surface-bound C4b2a from 7.5 min to greater than 5 h, increases the use of C3 and C5. It also inhibits the decay produced by C4-bp by preventing the dissociation of C2a from the C4b2a complex. Additionally, the C2b/C3bINA alone, or in the presence of C4- bp, fails to cleave the alpha' chain of C4b in the surface-bound stabilized C4b2a complex. This protective property of NFc requires the presence of C2a, because C4b was not protected unless it was bound to C2a. Thus in the presence of NFc, the three natural controls of the function of the classical pathway convertase, intrinsic decay, extrinsic decay, and proteolytic cleavage, are bypassed.

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Selected References

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  1. Daha M. R., Austen K. F., Fearon D. T. The incorporation of C3 nephritic factor (C3NeF) into a stabilized C3 convertase, C3bBb(C3NeF), and its release after decay of convertase function. J Immunol. 1977 Sep;119(3):812–817. [PubMed] [Google Scholar]
  2. Daha M. R., Hazevoet H. M., Vanes L. A., Cats A. Stabilization of the classical pathway C3 convertase C42, by a factor F-42, isolated from serum of patients with systemic lupus erythematosus. Immunology. 1980 Jul;40(3):417–424. [PMC free article] [PubMed] [Google Scholar]
  3. Daha M. R., van Es L. A. Relative resistance of the F-42-stabilized classical pathway C3 convertase to inactivation by C4-binding protein. J Immunol. 1980 Nov;125(5):2051–2054. [PubMed] [Google Scholar]
  4. David G. S., Reisfeld R. A. Protein iodination with solid state lactoperoxidase. Biochemistry. 1974 Feb 26;13(5):1014–1021. doi: 10.1021/bi00702a028. [DOI] [PubMed] [Google Scholar]
  5. Davis A. E., 3rd, Ziegler J. B., Gelfand E. W., Rosen F. S., Alper C. A. Heterogeneity of nephritic factor and its identification as an immunoglobulin. Proc Natl Acad Sci U S A. 1977 Sep;74(9):3980–3983. doi: 10.1073/pnas.74.9.3980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Fearon D. T., Austen K. F. Properdin: binding to C3b and stabilization of the C3b-dependent C3 convertase. J Exp Med. 1975 Oct 1;142(4):856–863. doi: 10.1084/jem.142.4.856. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Fearon D. T., Austen K. F., Ruddy S. Formation of a hemolytically active cellular intermediate by the interaction between properdin factors B and D and the activated third component of complement. J Exp Med. 1973 Dec 1;138(6):1305–1313. doi: 10.1084/jem.138.6.1305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Fujita T., Gigli I., Nussenzweig V. Human C4-binding protein. II. Role in proteolysis of C4b by C3b-inactivator. J Exp Med. 1978 Oct 1;148(4):1044–1051. doi: 10.1084/jem.148.4.1044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gigli I., Fujita T., Nussenzweig V. Modulation of the classical pathway C3 convertase by plasma proteins C4 binding protein and C3b inactivator. Proc Natl Acad Sci U S A. 1979 Dec;76(12):6596–6600. doi: 10.1073/pnas.76.12.6596. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Gigli I., Porter R. R., Sim R. B. The unactivated form of the first component of human complement, C1. Biochem J. 1976 Sep 1;157(3):541–548. doi: 10.1042/bj1570541. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Gigli I., von Zabern I., Porter R. R. The isolation and structure of C4, the fourth component of human complement. Biochem J. 1977 Sep 1;165(3):439–446. doi: 10.1042/bj1650439. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Halbwachs L., Leveillé M., Lesavre P., Wattel S., Leibowitch J. Nephritic factor of the classical pathway of complement: immunoglobulin G autoantibody directed against the classical pathway C3 convetase enzyme. J Clin Invest. 1980 Jun;65(6):1249–1256. doi: 10.1172/JCI109787. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kerr M. A., Porter R. R. The purification and properties of the second component of human complement. Biochem J. 1978 Apr 1;171(1):99–107. doi: 10.1042/bj1710099. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  15. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  16. McLean R. H., Siegel N. J., Kashgarian M. Activation of the classic complement pathway in patients with the C3 nephritic factor. Nephron. 1980;25(2):57–64. doi: 10.1159/000181754. [DOI] [PubMed] [Google Scholar]
  17. Müller-Eberhard H. J., Götze O. C3 proactivator convertase and its mode of action. J Exp Med. 1972 Apr 1;135(4):1003–1008. doi: 10.1084/jem.135.4.1003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Müller-Eberhard H. J., Polley M. J., Calcott M. A. Formation and functional significance of a molecular complex derived from the second and the fourth component of human complement. J Exp Med. 1967 Feb 1;125(2):359–380. doi: 10.1084/jem.125.2.359. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Nagasawa S., Stroud R. M. Mechanism of action of the C3b inactivator: requirement for a high molecular weight cofactor (C3b-C4bINA cofactor) and production of a new C3b derivative (C3b'). Immunochemistry. 1977 Nov-Dec;14(11-12):749–756. doi: 10.1016/0019-2791(77)90345-7. [DOI] [PubMed] [Google Scholar]
  20. 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]
  21. 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]
  22. Polley M. J., Müller-Eberhard H. J. The second component of human complement: its isolation, fragmentation by C'1 esterase, and incorporation into C'3 convertase. J Exp Med. 1968 Sep 1;128(3):533–551. doi: 10.1084/jem.128.3.533. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Schreiber R. D., Götze O., Müller-Eberhard H. J. Nephritic factor: its structure and function and its relationship to initiating factor of the alternative pathway. Scand J Immunol. 1976;5(6-7):705–713. doi: 10.1111/j.1365-3083.1976.tb03020.x. [DOI] [PubMed] [Google Scholar]
  24. Schreiber R. D., Medicus R. G., Gïtze O., Müller-Eberhard H. J. Properdin- and nephritic factor-dependent C3 convertases: requirement of native C3 for enzyme formation and the function of bound C3b as properdin receptor. J Exp Med. 1975 Sep 1;142(3):760–772. doi: 10.1084/jem.142.3.760. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Tack B. D., Prahl J. W. Third component of human complement: purification from plasma and physicochemical characterization. Biochemistry. 1976 Oct 5;15(20):4513–4521. doi: 10.1021/bi00665a028. [DOI] [PubMed] [Google Scholar]
  26. Thompson R. A. C3 inactivating factor in the serum of a patient with chronic hypocomplementaemic proliferative glomerulo-nephritis. Immunology. 1972 Jan;22(1):147–158. [PMC free article] [PubMed] [Google Scholar]
  27. Vallota E. H., Götze O., Spiegelberg H. L., Forristal J., West C. D., Müller-Eberhard H. J. A serum factor in chronic hypocomplementemic hephritis distinct from immunoglobulins and activating the alternate pathway of complement. J Exp Med. 1974 May 1;139(5):1249–1261. doi: 10.1084/jem.139.5.1249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Weiler J. M., Daha M. R., Austen K. F., Fearon D. T. Control of the amplification convertase of complement by the plasma protein beta1H. Proc Natl Acad Sci U S A. 1976 Sep;73(9):3268–3272. doi: 10.1073/pnas.73.9.3268. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Whaley K., Ruddy S. Modulation of C3b hemolytic activity by a plasma protein distinct from C3b inactivator. Science. 1976 Sep 10;193(4257):1011–1013. doi: 10.1126/science.948757. [DOI] [PubMed] [Google Scholar]
  30. Whaley K., Ruddy S. Modulation of the alternative complement pathways by beta 1 H globulin. J Exp Med. 1976 Nov 2;144(5):1147–1163. doi: 10.1084/jem.144.5.1147. [DOI] [PMC free article] [PubMed] [Google Scholar]

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