Download PDF
Semin Thromb Hemost 2001; 27(3): 191-200
DOI: 10.1055/s-2001-15248
Copyright © 2001 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Complement Factor H: Physiology and Pathophysiology

Peter F. Zipfel
  • Department of Infectious Biology, Hans-Knoell Institute for Natural Products Research, Jena, Germany
Further Information

Publication History

Publication Date:
31 December 2001 (online)

    Permissions and Reprints

ABSTRACT

The human plasma protein factor H, which is a multifunctional, multidomain protein, acts as a central regulator of the complement system. In addition to its complement regulatory activities, factor H has multiple physiological activities and 1) acts as an extracellular matrix component, 2) binds to cellular receptors of the integrin type, and 3) interacts with a wide selection of ligands, such as the C-reactive protein, thrombospondin, bone sialoprotein, osteopontin, and heparin. Recent genetic reports, which show involvement of factor H in the human disease hemolytic-uremic syndrome (HUS), have attracted the attention of both clinicians and basic complement researchers to the role of factor H in the pathophysiology of HUS.

KEYWORD

Hemolytic-uremic syndrome - HUS - complement system - complement factor H - physiological functions of factor H

REFERENCES

  • 1 Kaplan B S, Chesney R W, Drummond K N. Hemolytic uremic syndrome in families.  N Engl J Med . 1975;  292 1090-1093
    CrossrefPubMedGoogle Scholar
  • 2 Remuzzi G, Ruggenenti P, Bertani T. Thrombotic microangiopathy. In: Tisher CC, Brenner BM, eds. Renal Pathology with Clinical and Functional Correlations Philadelphia: JB Lippincott 1994: 1154-1161
    Google Scholar
  • 3 Thompson R A, Winterborn M H. Hypocomplementaemia due to a genetic deficiency of β1H globulin.  Clin Exp Immunol . 1981;  46 110-119
    PubMedGoogle Scholar
  • 4 Pichette V, Querin S, Schürch W. Familial hemolytic-uremic syndrome and homozygous factor H deficiency.  Am J Kidney Dis . 1994;  26 936-941
    PubMedGoogle Scholar
  • 5 Warwicker P, Goodship T HJ, Donne R L. Genetic studies into inherited and sporadic hemolytic uremic syndrome.  Kidney Int . 1998;  53 836-844
    CrossrefPubMedGoogle Scholar
  • 6 Noris M, Ruggenenti P, Perna A. Hypocomplementemia discloses genetic predisposition to hemolytic uremic syndrome and thrombotic thrombocytopenic purpura: role of factor H abnormalities.  J Am Soc Nephrol . 1999;  10 281-293
    PubMedGoogle Scholar
  • 7 Prodinger W M, Hellwage J, Spruth M, Dierich M P, Zipfel P F. The C-terminus of factor-H: monoclonal antibodies inhibit heparin binding and identify epitopes common to factor H and factor H-related proteins.  Biochem J . 1998;  331 41-47
    PubMedGoogle Scholar
  • 8 Jokiranta T S, Hellwage J, Koistinen V, Zipfel P F, Meri S. Each of the three binding sites on complement factor H interacts with a distinct site on C3b.  J Biol Chem . 2000;  275 27657-27662
    PubMedGoogle Scholar
  • 9 Manuelian T, Brandt E, Oppermann, M, Götze O, Zipfel P F. Manuscript in preparation. 
    PubMedGoogle Scholar
  • 10 Nilsson U R, Müller-Eberhard H. Isolation of b1F-globulin from human serum and its characterization as the fifth component of complement.  J Exp Med . 1965;  122 277-282
    CrossrefPubMedGoogle Scholar
  • 11 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 β1H for cleavage of C3b and C4b in solution.  J Exp Med . 1977;  146 247-270
    PubMedGoogle Scholar
  • 12 Whaley K, Ruddy S. Molulation of the alternative complement pathway by β1H globulin.  J Exp Med . 1976;  144 1147-1163
    CrossrefPubMedGoogle Scholar
  • 13 Vik D P, Munoz-Canoves P, Chaplin D D, Tack B F. Factor H.  Curr Top Microbiol Immunol . 1990;  153 147-162
    PubMedGoogle Scholar
  • 14 Friese M A, Hellwage J, Jokiranta T S. Different regulation of factor H and FHL-1/reconectin by inflammatory mediators and expression of the two proteins in rheumatoid arthritis (RA).  Clin Exp Immunol . 2000;  121 406-415
    CrossrefPubMedGoogle Scholar
  • 15 Lambris J D, Ross G D. Characterization of the lymphocyte membrane receptor for factor H (beta1H-globulin) with an antibody to anti-factor H idiotype.  J Exp Med . 1982;  155 1400-1411
    CrossrefPubMedGoogle Scholar
  • 16 Avery V M, Gordon D L. Characterization of factor H binding to human polymorphonuclear leukocytes.  J Immunol . 1993;  151 5545-5553
    PubMedGoogle Scholar
  • 17 DiScipio R G, Daffern P J, Schraufstatter I U, Sriramarao P. Human polymorphonuclear leukocytes adhere to complement factor H through an interaction that involves alphaMbeta2 (CD11b/CD18).  J Immunol . 1998;  160 4057-4066
    PubMedGoogle Scholar
  • 18 Nabil K, Rihn B, Jaurand M C. Identification of human complement factor H as a chemotactic protein for monocytes.  Biochem J . 1997;  326 377-383
    PubMedGoogle Scholar
  • 19 Meri S, Pangburn M K. Discrimination between activator and nonactivators of the alternative pathway of complement: regulation via sialic acid/polyanion binding sites on factor H.  Proc Natl Acad Sci USA . 1990;  87 3982-3986
    PubMedGoogle Scholar
  • 20 Carron J A, Bates R C, Smith A I. Factor H co-purifies with thrombospondin isolated from platelet secretate.  Biochim Biophys Acta . 1996;  1289 305-311
    PubMedGoogle Scholar
  • 21 Jarva H, Jokiranta T S, Hellwage J, Zipfel P F, Meri S. Regulation of complement activation by C-reactive protein: targeting the complement inhibitory activity of factor H by an interaction with short consensus repeat domains 7 and 8-11.  J Immunol . 1999;  163 3957-3962
    PubMedGoogle Scholar
  • 22 Fedarko N S, Fohr B, Robey P G, Young M F, Fisher L W. Factor H binding to bone sialoprotein and osteopontin enables tumor cell evasion of complement-mediated attack.  J Biol Chem . 2000;  275 16666-16672
    CrossrefPubMedGoogle Scholar
  • 23 Zipfel P F, Hellwage J, Friese M A. Factor H and disease: a complement regulator affects vital body functions.  Mol Immunol . 1999;  36 241-248
    CrossrefPubMedGoogle Scholar
  • 24 Lindahl G, Sjobring U, Johnsson E. Human complement regulators: a major target for pathogenic microorganisms.  Curr Opin Immunol . 2000;  12 44-51
    CrossrefPubMedGoogle Scholar
  • 25 Zipfel P F, Skerka C. FHL-1/reconectin: a human complement and immune regulator with cell-adhesive function.  Immunol Today . 1999;  20 135-140
    CrossrefPubMedGoogle Scholar
  • 26 Zipfel P F, Jokiranta T S, Hellwage J, Koistinen V, Meri S. The factor H protein family.  Immunopharmacology . 1999;  42 53-60
    CrossrefPubMedGoogle Scholar
  • 27 Male D A, Ormsby R J, Ranganathan S, Giannakis E, Gordon D L. Complement factor H: sequence analysis of 221 kb of human genomic DNA containing the entire fH, fHR-1 and fHR-3 genes.  Mol Immunol . 2000;  37 41-52
    CrossrefPubMedGoogle Scholar
  • 28 Zipfel P F, Skerka C. Complement factor H and related proteins: an expanding family of complement-regulatory proteins?.  Immunol Today . 1994;  15 121-126
    CrossrefPubMedGoogle Scholar
  • 29 Hellwage J, Jokiranta T S, Koistinen V. Functional properties of complement factor H-related proteins FHR-3 and FHR-4: binding to the C3d region of C3b and differential regulation by heparin.  FEBS Lett . 1999;  462 345-352
    CrossrefPubMedGoogle Scholar
  • 30 Gordon D L, Kaufman R M, Blackmore T K, Kwong J, Lublin D M. Identification of complement regulatory domains in human factor H.  J Immunol . 1995;  155 348-356
    PubMedGoogle Scholar
  • 31 Kuhn S, Skerka C, Zipfel P F. Mapping of the complement regulatory domains in the human factor H-like protein 1 and in factor H1.  J Immunol . 1995;  155 5663-5670
    PubMedGoogle Scholar
  • 32 Kuhn S, Zipfel P F. Mapping of the domains required for decay acceleration activity of the human factor H-like protein 1 and factor H.  Eur J Immunol . 1996;  26 2383-2387
    PubMedGoogle Scholar
  • 33 Sharma A K, Pangburn M K. Identification of three physically and functionally distinct binding sites for C3b in human complement factor H by deletion mutagenesis.  Proc Natl Acad Sci USA . 1996;  93 10996-11001
    CrossrefPubMedGoogle Scholar
  • 34 Identification of a heparin binding domain in the seventh short consensus repeat of complement factor H. J Immunol .  1996;  157 5422-5427
    PubMedGoogle Scholar
  • 35 Blackmore T K, Hellwage J, Sadlon T A. Identification of the second heparin-binding domain in human complement factor H.  J Immunol . 1998;  160 3342-33348
    PubMedGoogle Scholar
  • 36 Pangburn M K, Atkinson M A, Meri S. Localization of the heparin-binding site on complement factor H.  J Biol Chem . 1991;  266 16847-16853
    PubMedGoogle Scholar
  • 37 DiScipio R. Ultrastructures and interactions of complement factor H and I.  J Immunol . 1989;  149 2592-2599
    PubMedGoogle Scholar
  • 38 Högasen K, Jansen J H, Mollnes T E, Hovdenes J, Harboe M. Hereditary porcine membranoproliferative glomerulonephritis type II is caused by factor H deficiency.  J Clin Invest . 1995;  95 1054-1061
    PubMedGoogle Scholar
  • 39 Ault B H, Schmidt B Z, Fowler N L. Human factor H deficiency: mutations in framework cysteine residues block H protein secretion and intracellular catabolism.  J Biol Chem . 1997;  272 25168-25175
    CrossrefPubMedGoogle Scholar
  • 40 Meri S, Koistinen V, Miettinen A, Törnroth T, Seppälä I JT. Activation of the alternative pathway of complement by monoclonal light chains in membranoproliferative glomerulonephritis.  J Exp Med . 1992;  175 939-950
    CrossrefPubMedGoogle Scholar
  • 41 Jokiranta S T, Solomon A, Pangburn M K, Zipfel P F, Meri S. Nephritogenic lambda-light chain dimer: a unique human miniautoantibody against complement factor H.  J Immunol . 1999;  163 4590-4596
    PubMedGoogle Scholar
  • 42 Schmidt B Z, Fowler N L, Hidvegi T, Perlmutter D H, Colten H R. Disruption of disulfide bonds is responsible for impaired secretion in human complement factor H deficiency.  J Biol Chem . 1999;  274 11782-11788
    CrossrefPubMedGoogle Scholar
  • 43 Kotarsky H, Hellwage J, Johnsson E. Identification of a domain in human factor H and factor H-like protein-1 required for the interaction with streptococcal M proteins.  J Immunol . 1998;  160 3349-3354
    PubMedGoogle Scholar
  • 44 Kraiczy P, Skerka C, Kirschfink M, Brade V, Zipfel P F. Immune evasion of Borrelia burgdorferi by acquisition of human complement regulators FHL-1/reconectin and factor H.  Europ J Immunol (in press).
    PubMedGoogle Scholar
  • 45 Ram S, McQuillen D P, Gulati S. Binding of complement factor H to loop 5 of porin protein 1A: a molecular mechanism of serum resistance of nonsialylated Neisseria gonorrhoeae J Exp Med .  1998;  188 671-680
    PubMedGoogle Scholar
  • 46 China B, Sory M P, N'Guyen B T, De Bruyere M, Cornelis G R. Role of the YadA protein in prevention of opsonization of Yersinia enterocolitica by C3b molecules.  Infect Immun . 1993;  61 3129-3136
    PubMedGoogle Scholar
  • 47 Diaz A, Ferreira A, Sim R B. Complement evasion by Echinococcus granulosus: sequestration of host factor H in the hydatid cyst wall.  J Immunol . 1997;  158 3779-3786
    PubMedGoogle Scholar
  • 48 Meri T, Zipfel P F, Meri S. manuscript submitted. 
    PubMedGoogle Scholar
  • 49 Stoiber H, Pinter C, Siccardi A G, Clivio A, Dierich M P. Efficient destruction of human immunodeficiency virus in human serum by inhibiting the protective action of complement factor H and decay accelerating factor (DAF,CD55).  J Exp Med . 1996;  183 307-310
    CrossrefPubMedGoogle Scholar
  • 50 Johnsson E, Berggard K, Kotarsky H. Role of the hypervariable region in streptococcal M proteins: binding of a human complement inhibitor.  J Immunol . 1998;  161 4894-4901
    PubMedGoogle Scholar
  • 51 Ram S, Sharma A K, Simpson S D. A novel sialic acid binding site on factor H mediates serum resistance of sialylated Neisseria gonorrhoeae J Exp Med .  1998;  187 743-752
    PubMedGoogle Scholar
  • 52 Junnikkala S, Jokiranta S T, Friese M A. Resistance of human H2 glioblastoma cells to complement-mediated killing by expression and utilization of factor H and factor H-like protein 1.  J Immunol . 2000;  164 6075-6081
    PubMedGoogle Scholar
  • 53 Gorter A, Meri S. Immune evasion of tumor cells using membrane-bound complement regulatory proteins.  Immunol Today . 2000;  20 576-582
    PubMedGoogle Scholar
  • 54 Kinders R, Jones T, Root R. Complement factor H or a related protein is a marker for transitional cell cancer of the bladder.  Clin Cancer Res . 1998;  4 2511-2520
    PubMedGoogle Scholar
  • 55 Bogdanovic R, Cvoric A, Nikolic V, Sindjic M. Recurrent haemolytic-uraemic syndrome with hypocomplementaemia: a case report.  Pediatr Nephrol . 1988;  2 236-238
    CrossrefPubMedGoogle Scholar
  • 56 Carreras L, Romero R, Requesens C. Familial hypocomplementemic hemolytic uremic syndrome with HLA-A3,B7 haplotype.  JAMA . 1981;  245 602-604
    CrossrefPubMedGoogle Scholar
  • 57 Ohali M, Shalev H, Schlesinger M. Hypocomplementemic autosomal recessive hemolytic uremic syndrome with decreased factor H.  Pediatr Nephrol . 1998;  12 619-624
    CrossrefPubMedGoogle Scholar
  • 58 Rougier N, Kazatchkine M D, Rougier J P. Human complement factor H deficiency associated with hemolytic uremic syndrome.  J Am Soc Nephrol . 1998;  9 2318-2326
    PubMedGoogle Scholar
  • 59 Hourcade D, Garcia A D, Post T W. Analysis of the human regulators of complement activation (RCA) gene cluster with yeast artificial chromosomes (YACs).  Genomics . 1992;  12 289-300
    CrossrefPubMedGoogle Scholar
  • 60 Caprioli J, Bettingalio P, Zipfel P F. Mutations of factor H (HF) in familial hemolytic uremic syndrome (HUS)/ thrombotic thrombocytopenic purpura (TTP).  J Am Soc Nephrol . 2001;  12 297-307
    PubMedGoogle Scholar
  • 61 Buddels M RH, Donne R L, Richards A, Goodship J, Goodship THJ.Complement factor H gene mutation associated with autosomal recessive atypical hemolytic uremic syndrome (Letter). Am J Genet .  2000;  66 1721-1722
    PubMedGoogle Scholar
  • 62 Ying L, Katz Y, Schlesinger M. Complement factor H gene mutation associated with autosomal recessive atypical hemolytic uremic syndrome.  Am J Hum Genet . 1999;  65 1538-1546
    CrossrefPubMedGoogle Scholar
      >