Factor H

  • D. P. Vik
  • P. MuñOz-Cánoves
  • D. D. Chaplin
  • B. F. Tack
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 153)


Complement component factor H (H) is a 155-kDa plasma protein. It was first observed by NILSSON and MüLLER-EBERHARD (1965) as a minor component in C3 preparations, and its function was not known. They termed this protein β1 H globulin because of its β-electrophoretic mobility in agarose gels. The first function for this protein was recognized by WHALEY and RUDDY (1976a). They isolated a protein from human serum based on its ability to accelerate the activity of C3b inactivator (now termed factor I) and found that this protein was biochemically and immunologically identical to β1 H globulin. At the time, it was thought that I alone cleaved C3b into two fragments, C3c and C3d. Addition of H synergistically enhanced the activity of I-mediated cleavage of C3b. H not only enhanced the activity of I (termed its cofactor activity) but was also able to accelerate the decay of the C3 convertases of the alternative pathway of complement activation C3b, Bb or C3b, Bb, P (Fig. 1) and to inhibit the formation of these convertases (WHALEY and RUDDY 1976 a).


Human Complement Alternative Complement Pathway Membrane Cofactor Protein Human Complement Component Human Complement Factor 
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  1. Aegerter-Shaw M, Cole JL, Klickstein LB, Wong WW, Fearon DT, Lalley PA, Weis JH (1987) Expansion of the complement receptor gene family. Identification in the mouse of two new genes related to the CR1 and CR2 gene family. J Immunol 138: 3488–3493PubMedGoogle Scholar
  2. Angel P, Imagawa M, Chiu R, Stein B, Imbra RJ, Rahmsdorf HJ, Jonat C, Herrlich P, Karin M (1987) Phorbol ester-inducible genes contain a common ci. element recognized by a TPA-modulated trans-acting factor. Cell 49: 729–739PubMedCrossRefGoogle Scholar
  3. Alper CA, Abramson N, Johnston RB, Jandl JH, Rosen FS (1970) Increased susceptibility to infection associated with abnormalities of complement-mediated functions and of the third component of complement (C3). N Engl J Med 282: 349–353CrossRefGoogle Scholar
  4. Alsenz J, Lambris JD, Schulz TF, Dierich MP (1984) Localization of the complement-component-C3b-binding site and the cofactor activity for factor I in the 38 kDa tryptic fragment of factor H. Biochem J 224: 389–398PubMedGoogle Scholar
  5. Alsenz J, Schulz TF, Lambris JD, Sim RB, Dierich MP (1985) Structural and functional analysis of the complement component factor H with the use of different enzymes and monoclonal antibodies to factor H. Biochem J 232: 841–850PubMedGoogle Scholar
  6. Bentley DR (1986) Primary structure of human complement component C2. Homology to two unrelated protein families. Biochem J 239: 339–345PubMedGoogle Scholar
  7. Bitter-Suermann D, Burger R, Hadding U (1981) Activation of the alternative pathway of complement: efficient fluid-phase amplification by blockade of the regulatory complement protein β1 H through sulfated polyanions. Eur J Immunol 11: 291–295PubMedCrossRefGoogle Scholar
  8. Brai M, Misiano G, Maringhini S, Cutaja I, Hauptmann G (1988) Combined homozygous factor H and heterozygous C2 deficiency in an Italian family. J Clin Immunol 8: 50–56PubMedCrossRefGoogle Scholar
  9. Caras IW, Davitz MA, Rhee L, Weddell G, Martin DW, Nussenzweig V (1987) Cloning of decay-accelerating factor suggests novel use of splicing to generate two proteins. Nature 325: 545–549PubMedCrossRefGoogle Scholar
  10. Carroll MC, Alicot EM, Katzman PJ, Klickstein LB, Smith JA, Fearon DT (1988) Organization of the genes encoding complement receptors type 1 and 2, decay-accelerating factor, and C4-binding protein in the RCA locus on human chromosome 1. J Exp Med 167:1271–1280PubMedCrossRefGoogle Scholar
  11. Catteral CF, Lyons A, Sim RB, Day AJ, Harris TJR (1987) Characterization of the primary amino acid sequence of human complement control protein factor I from an analysis of cDNA clones. Biochem J 242: 849–856Google Scholar
  12. Charlesworth JA, Scott DM, Pussell BA, Peters DK (1979) Metabolism of human β1 H: studies in man and experimental animals. Clin Exp Immunol 38: 397–404PubMedGoogle Scholar
  13. Chung LP, Bentley DR, Reid KBM (1985) Molecular cloning and characterization of the cDNA coding for C4b-binding protein, a regulatory protein of the classical pathway of the human complement system. Biochem J 230: 133–141PubMedGoogle Scholar
  14. Conrad DH, Carlo JR, Ruddy S (1978) Interaction of βl H globulin with cell-bound C3b: quantitative analysis of binding and influence of alternative pathway components on binding. J Exp Med 147: 1792–1805PubMedCrossRefGoogle Scholar
  15. Day AJ, Willis AC, Ripoche J, Sim RB (1988) Sequence polymorphism of human complement factor H. Immunogenetics 27: 211–214PubMedCrossRefGoogle Scholar
  16. de Bruijn MHL, Fey GH (1985) Human complement component C3: cDNA coding sequence and derived primary structure. Proc Natl Acad Sci USA 82: 708–712PubMedCrossRefGoogle Scholar
  17. D’Eustachio P, Kristensen T, Wetsel RA, Riblet R, Taylor BA, Tack BF (1986) Chromosomal location of the genes encoding complement components C5 and factor H in the mouse. J Immunol 137: 3990–3995PubMedGoogle Scholar
  18. DiScipio RG (1981) The binding of human complement proteins C5, factor B, β1 H and properdin to complement fragment C3b on zymosan. Biochem J 199: 485–496PubMedGoogle Scholar
  19. DiScipio RG, Hugli TE (1982) Circular dichroism studies of human factor H a regulatory component of the complement system. Biochim Biophys Acta 709: 58–64PubMedCrossRefGoogle Scholar
  20. Dorsch-Häsler KDA, Keil GM, Weker F, Jasin M, Schaffner W, Koszinowski UH (1985) A long and complex enhancer activates transcription of the gene coding for the highly abundant immediate early mRNA in murine cytomegalovirus. Proc Natl Acad Sci USA 82:8325–8329PubMedCrossRefGoogle Scholar
  21. Fearon DT (1978) Regulation by membrane sialic acid of β1 H-dependent decay-dissociation of amplification C3 convertase of the alternative complement pathway. Proc Natl Acad Sci USA 75: 1971–1975PubMedCrossRefGoogle Scholar
  22. Fearon DT, Austen KF (1977) Activation of the alternative complement pathway due to resistance of zymosan-bound amplification convertase to endogenous regulatory mechanisms. Proc Natl Acad Sci USA 74: 1683–1687PubMedCrossRefGoogle Scholar
  23. Fischer E, Kazatchkine MD (1983) Surface-dependent modulation by H of C5 cleavage by the cell-bound alternative pathway C5 convertase of human complement. J Immunol 130: 2821–2824PubMedGoogle Scholar
  24. Gardner WD, White PJ, Hoch SO (1980) Identification of a major human serum DNA-binding protein as βiH of the alternative pathway of complement activation. Biochem Biophys Res Commun 94: 61–67PubMedCrossRefGoogle Scholar
  25. Goldberger G, Bruns GAP, Rits M, Edge MD, Kwiatkowski DJ (1987) Human complement factor I: analysis of cDNA-derived primary structure and assignment of its gene to chromosome 4. J Biol Chem 262: 10065–10071PubMedGoogle Scholar
  26. Harrison RA, Lachmann PJ (1979) An improved purification procedure for the third component of complement and β1 H globulin from human serum. Mol Immunol 16: 767–776PubMedCrossRefGoogle Scholar
  27. Hearing P, Shenk T (1983) The adenovirus type 5 E1A transcriptional control region contains a duplicated enhancer element. Cell 33: 695–703PubMedCrossRefGoogle Scholar
  28. Hong K, Kinoshita T, Dohi Y, Inoue K (1982) Effect of trysinization on the activity of human factor H. J Immunol 129: 647–652PubMedGoogle Scholar
  29. Ichinose A, McMullen BA, Fujikawa K, Davie EW (1986) Amino acid sequence of the b subunit of human factor XIII, a protein composed of ten repetitive segments. Biochemistry 25: 4633–4638PubMedCrossRefGoogle Scholar
  30. Isenman DE, Podack ER, Cooper NR (1980) The interaction of C5 with C3b in free solution: a sufficient condition for cleavage by a fluid phase C3/C5 convertase. J Immunol 124:326–331PubMedGoogle Scholar
  31. Ito S, Tamura N (1983) Inhibition of classical C5 convertase in the complement system by factor H. Immunology 50: 631–635PubMedGoogle Scholar
  32. Journet A, Tosi M (1986) Cloning and sequencing of full-length cDNA encoding the precursor of human complement component C1r. Biochem J 240: 783–787PubMedGoogle Scholar
  33. Jouvin M-H, Kazatchkine MD, Cahour A, Bernard N (1984) Lysine residues, but not carbohydrates, are required for the regulatory function of H on the amplification C3 convertase of complement. J Immunol 133: 3250–3254PubMedGoogle Scholar
  34. Katz Y, Strunk RC (1988) Synthesis and regulation of complement protein factor H in human skin fibroblasts. J Immunol 141: 559–563PubMedGoogle Scholar
  35. Kazatchkine MD, Fearon DT, Austen KF (1979) Human alternative complement pathway: membrane-associated sialic acid regulates the competition between B and β1 H for cell-bound C3b. J Immunol 122: 75–81PubMedGoogle Scholar
  36. Kingsmore SF, Vik DP, Kurtz CB, Leroy P, Tack BF, Weis JH, Scidin MF (1989) Genetic organization of complement receptor related genes in the mouse. J Exp Med 169:1479–1484PubMedCrossRefGoogle Scholar
  37. Klickstein LB, Wong WW, Smith JA, Weis JH, Wilson JG, Fearon DT (1987) Human C3b/C4b receptor (CR1). Demonstration of long homologous repeating domains that are composed of the short consensus repeats characteristic of C3/C4 binding proteins. J Exp Med 165: 1095–1112PubMedCrossRefGoogle Scholar
  38. Kotwal GJ, Moss B (1988) Vaccinia virus encodes a secretory polypeptide structurally related to complement control proteins. Nature 335: 176–178PubMedCrossRefGoogle Scholar
  39. Kristensen T, Tack BF (1986) Murine protein H is comprised of 20 repeating units, 61 amino acids in length. Proc Natl Acad Sci USA 83: 3963–3967PubMedCrossRefGoogle Scholar
  40. Kristensen T, Wetsel RA, Tack BF (1986) Structural analysis of human complement protein H: homology with C4b binding protein, β2-glycoprotein I, and the Ba fragment of B. J Immunol 136: 3407–3411PubMedGoogle Scholar
  41. Kristensen T, Ogata RT, Chung LP, Reid KBM, Tack BF (1987a) cDNA structure of murine C4b-binding protein, a regulatory component of the serum complement system. Biochemistry 26: 4668–4674PubMedCrossRefGoogle Scholar
  42. Kristensen T, D’Eustachio P, Ogata RT, Chung LP, Reid KBM, Tack BF (1987b) The superfamily of C3b/C4b-binding proteins. Fed Proc 46: 2463–2469PubMedGoogle Scholar
  43. Kurosky A, Barnett DR, Lee T-H, Touchstone B, Hay RE, Arnott MS, Bowman BH, Fitch WM (1980) Covalent structure of human haptoglobin: a serine protease homolog. Proc Natl Acad Sci USA 77: 3388–3392PubMedCrossRefGoogle Scholar
  44. Lambris JD, Avila D, Becherer JD, Müller-Eberhard HJ (1988) A discontinuous factor H binding site in the third component of complement as delineated by synthetic peptides. J Biol Chem 263: 12147–12150PubMedGoogle Scholar
  45. Levy M, Halbwachs-Mecarelli L, Gubler M-C, Kohout G, Bensenouci A, Niaudet P, Hauptmann G, Lesavre P (1986) H deficiency in two brothers with atypical dense intramembranous deposit disease. Kidney Int 30: 949–956PubMedCrossRefGoogle Scholar
  46. Leytus SP, Kurachi K, Sakariassen KS, Davie EW (1986) Nucleotide sequence of the cDNA coding for human complement Clr. Biochemistry 25: 4855–4863PubMedCrossRefGoogle Scholar
  47. Lozier J, Takahashi N, Putnam FW (1984) Complete amino acid sequence of human plasma β2-glyeoprotein I. Proc Natl Acad Sci USA 81: 3640–3644PubMedCrossRefGoogle Scholar
  48. Lublin DM, Lemons RS, Le Beau MM, Holers VM, Tykocinski ML, Medof ME, Atkinson JP (1987) The gene encoding decay-accelerating factor (DAF) is located in the complement-regulatory locus on the long arm of chromosome 1. J Exp Med 165: 1731–1736PubMedCrossRefGoogle Scholar
  49. Lublin DM, Liszewski MK, Post TW, Arce MA, Le Beau MM, Rebentisch MB, Lemons RS, Seya T, Atkinson JP (1988) Molecular cloning and chromosomal localization of human membrane cofactor protein (MCP). Evidence for inclusion in the multigene family of complement-regulatory proteins. J Exp Med 168: 181–194PubMedCrossRefGoogle Scholar
  50. Mole JE, Anderson JK, Davison EA, Woods DE (1984) Complete primary structure for the zymogen of human complement factor B. J Biol Chem 259: 3407–3412PubMedGoogle Scholar
  51. Moore MD, Cooper NR, Tack BF, Nemerow GR (1987) Molecular cloning of the cDNA encoding the Epstein-Barr virus/C3d receptor (complement receptor type 2) of human B lymphocytes. Proc Natl Acad Sci USA 84: 9194–9198PubMedCrossRefGoogle Scholar
  52. Morley BJ, Campbell RD (1984) Internal homologies of the Ba fragment from human complement component factor B, a class III MHC antigen. EMBO J 3: 153–157PubMedGoogle Scholar
  53. Nagaki K, Iida K, Okubo M, Inai S (1978) Reaction mechanisms of β1 H globulin. Int Arch Allergy Appl Immunol 87: 221–232CrossRefGoogle Scholar
  54. Nilsson B, Nilsson UR (1986) Antigens of complement factor C3 involved in the interactions with factors I and H. Scand J Immunol 23: 357–363PubMedCrossRefGoogle Scholar
  55. Nilsson UR, Müller-Eberhard HJ (1965) Isolation of βIF-globulin from human serum and its characterization as the fifth component of complement. J Exp Med 122: 277–298PubMedCrossRefGoogle Scholar
  56. Pangburn MK (1986) Differences between the binding sites of the complement regulatory proteins DAF, CR1 and factor H on C3 convertases. J Immunol 136: 2216–2221PubMedGoogle Scholar
  57. Pangburn MK, Schreiber RD, Müller-Eberhard HJ (1977) Human complement C3b inactivator: isolation, characterization, and demonstration of an absolute requirement for the serum protein β1 H for cleavage of C3b and C4b in solution. J Exp Med 146: 257–270PubMedCrossRefGoogle Scholar
  58. Pangburn MK, Müller-Eberhard HJ (1978) Complement C3 convertase: cell surface restriction of β1 H control and generation of restriction on neuraminidase-treated cells. Proc Natl Acad Sci USA 75: 2416–2420PubMedCrossRefGoogle Scholar
  59. Parker CJ, Baker PJ, Rosse WF (1983) Comparison of binding characteristics of factors B and H to C3b on normal and paroxysmal nocturnal hemoglobinuria erythrocytes. J Immunol 131:2484–2489PubMedGoogle Scholar
  60. Paul MS, Aegerter M, O’Brien SE, Lurtz CB, Weis JH (1989) The murine complement receptor gene family. Analysis of mCRY gene products and their homology to human CR1. J Immunol 142: 582–589PubMedGoogle Scholar
  61. Pelham HRB (1982) A regulatory upstream promoter element in the Drosophil. hsp 70 heat-shock gene. Cell 30: 517–528PubMedCrossRefGoogle Scholar
  62. Reid KBM, Bentley DR, Campbell RD, Chung LP, Sim RB, Kristensen T, Tack BF (1986) Complement system proteins which interact with C3b or C4b. Immunol Today 7:230–234CrossRefGoogle Scholar
  63. Rey-Campos J, Rubinstein P, Rodriguez de Córdoba S (1988) A physical map of the human regulator of complement activation gene cluster linking the complement genes CRI, CR2, DAF, and C4BP. J Exp Med 167: 664–669PubMedCrossRefGoogle Scholar
  64. Ripoche J, Al Salihi A, Rousseaux J, Fontaine M (1984) Isolation of two molecular populations of human complement factor H by hydrophobic affinity chromatography. Biochem J 221: 89–96PubMedGoogle Scholar
  65. Ripoche J, Day AJ, Moffatt B, Sim RB (1987) mRNA coding for a truncated form of human complement factor H. Biochem Soc Trans 15: 651–652Google Scholar
  66. Ripoche J, Day AJ, Harris TJR, Sim RB (1988) The complete amino acid sequence of human complement factor H. Biochem J 249: 593–602PubMedGoogle Scholar
  67. Rodríguez de Córdoba S, Rubinstein P (1984) Genetic polymorphism of human factor H (β1 H). J Immunol 132: 1906–1908.Google Scholar
  68. Rodríguez de Córdoba S, Rubinstein P (1987) New alleles of C4-binding protein and factor H and further linkage data in the regulator of complement activation (RCA) gene cluster in man. Immunogenetics 25: 267–268CrossRefGoogle Scholar
  69. Rodríguez de Córdoba S, Dykman TR, Ginsberg-Fellner F, Ercilla G, Agua M, Atkinson JP, Rubinstein P (1984) Evidence for linkage between the loci coding for the binding protein for the fourth component of human complement (C4BP) and for the C3b/C4b receptor. Proc Natl Acad Sci USA 81: 7890–7892CrossRefGoogle Scholar
  70. Rodríguez de Córdoba S, Lublin DM, Rubinstein P, Atkinson JP (1985) Human genes for three complement components that regulate the activation of C3 are tightly linked. J Exp Med 161: 1189–1195CrossRefGoogle Scholar
  71. Ross GD, Newman SL, Lambris JD, Devery-Pocius JE, Cain JA, Lachmann PJ (1983) Generation of three different fragments of bound C3 with purified factor I or serum. II. Location of binding sites in the C3 fragments for factors B and H, complement receptors, and bovine conglutinin. J Exp Med 158: 334–352PubMedCrossRefGoogle Scholar
  72. Ross SC, Densen P (1984) Complement deficiency states and infection: epidemiology, pathogene-sis and consequences of neisserial and other infections in an immune deficiency. Medicine 63: 243–273PubMedCrossRefGoogle Scholar
  73. Schulz TF, Schwäble W, Stanley KK, Weiβ E, Dierich MF (1986) Human complement factor H: isolation of cDNA clones and partial cDNA sequence of the 38-kDa tryptic fragment containing the binding site for C3b. Eur J Immunol 16: 1351–1355PubMedCrossRefGoogle Scholar
  74. Schütz G (1988) Control of gene expression by steroid hormones. Biol Chem Hoppe Seyler 369: 77–86PubMedCrossRefGoogle Scholar
  75. Schwäble W, Zwirner J, Schulz TF, Linke RP, Dierich MP, Weiβ EH (1987) Human complement factor H: expression of an additional truncated gene product of 43 kDa in human liver. Eur J Immunol 17: 1485–1489CrossRefGoogle Scholar
  76. Shimuzu A, Kondo S, Takeda S, Yodoi J, Ishida N, Sabe H, Osawa H, Diamantstein T, Nikaido T, Honjo T (1985) Nucleotide sequence of mouse IL-2 receptor cDNA and its comparison with the human IL-2 receptor sequence. Nucleic Acids Res 5: 1505–1516CrossRefGoogle Scholar
  77. Sim RB, DiScipio RG (1982) Purification and structural studies on the complement-system control protein β1 H (factor H). Biochem J 205: 285–293PubMedGoogle Scholar
  78. Smith CA, Pangburn MK, Vogel C-W, Müller-Eberhard HJ (1983) Structural investigations of properdin and factor H of human complement. Immunobiology 164: 298Google Scholar
  79. Thompson RA, Lachmann PJ (1977) A second case of human C3b inhibitor (KAF) deficiency. Clin Exp Immunol 27: 23–39PubMedGoogle Scholar
  80. Thompson RA, Winterborn MH (1981) Hypocomplementaemia due to a genetic deficiency of β1 H globulin. Clin Exp Immunol 46: 110–119PubMedGoogle Scholar
  81. Tosi M, Duponchel C, Meo T, Julier C (1987) Complete cDNA sequence of human complement C1s and close physical linkage of the homologous genes Cls and Clr. Biochemistry 26: 8516–8524PubMedCrossRefGoogle Scholar
  82. Vik DP, Keeney JB, Muñoz-Cánoves P, Chaplin DD, Tack BF (1988) Structure of the murine complement factor H gene. J Biol Chem 263: 16720–16724PubMedGoogle Scholar
  83. Weiler JM, Daha MR, Austen KF, Fearon DT (1976) Control of the amplification convertase of complement by the plasma protein β1 H. Proc Natl Acad Sci USA 73: 3268–3272PubMedCrossRefGoogle Scholar
  84. Weis JH, Morton CC, Bruns GP, Weis JJ, Klickstein LB, Wong WW, Fearon DT (1987) A complement receptor locus: genes encoding C3b/C4b receptor and C3d/Epstein-Barr virus receptor map to 1q32. J Immunol 138: 312–315PubMedGoogle Scholar
  85. Weis JJ, Toothaker LE, Smith JA, Weis JH, Fearon DT (1988) Structure of the human B lymphocyte receptor for C3d and the Epstein-Barr virus and relatedness to other members of the family of C3/C4 binding proteins. J Exp Med 167: 1047–1065PubMedCrossRefGoogle Scholar
  86. Whaley K, Ruddy S (1976a) Modulation of the alternative complement pathway by β1H globulin. J Exp Med 144: 1147–1163PubMedCrossRefGoogle Scholar
  87. Whaley K, Ruddy S (1976b) Modulation of C3b hemolytic activity by a plasma protein distinct from C3b inactivator. Science 193: 1011–1013PubMedCrossRefGoogle Scholar
  88. Wong WW, Cahill JM, Rosen MD, Kennedy CA, Bonaccio ET, Morris MJ, Wilson JG, Klickstein LB, Fearon DT (1989) Structure of the CR1 gene: molecular basis of the structural and quantitative polymorphisms and identification of a new CRl-like allele. J Exp Med 169: 847–863PubMedCrossRefGoogle Scholar
  89. Wyatt RJ, Julian BA, Weistein A, Rothfield NF, McLean RH (1982) Partial H (β1 H) deficiency and glomerulonephritis in two families. J Clin Immunol 2: 110–117PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1990

Authors and Affiliations

  • D. P. Vik
    • 1
  • P. MuñOz-Cánoves
    • 1
  • D. D. Chaplin
    • 2
  • B. F. Tack
    • 1
  1. 1.Department of ImmunologyScripps Clinic and Research FoundationLa JollaUSA
  2. 2.Department of Internal Medicine and the Howard Hughes Medical InstituteWashington University School of MedicineSt. LouisUSA

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