Elsevier

Molecular Immunology

Volume 41, Issue 4, June 2004, Pages 355-367
Molecular Immunology

Review
The human complement factor H: functional roles, genetic variations and disease associations

https://doi.org/10.1016/j.molimm.2004.02.005Get rights and content

Abstract

Factor H is an essential regulatory protein that plays a critical role in the homeostasis of the complement system in plasma and in the protection of bystander host cells and tissues from damage by complement activation. Genetic and structural data generated during recent years have been instrumental to delineate the functional domains responsible for these regulatory activities in factor H, which is helping to understand the molecular basis underlying the different pathologies associated to factor H. This review summarises our current knowledge of the role of factor H in health and disease.

Introduction

The complement system is a crucial component of the innate immunity against microbial infection. It contains several plasma and membrane-associated proteins that are organized in three activation pathways: the classical, the lectin and the alternative pathways. Upon activation by molecules on the surface of the microorganisms, these pathways result in the formation of unstable protease complexes, named C3-convertases. Both, the classical/lectin pathway C3-convertase, named C4b2b, and the alternative pathway C3-convertase, named C3bBb, are able to cleave the α-chain of C3 generating C3b. Cleavage of C3 results in the exposure of an internal thiolester which is extremely reactive with nucleophiles, that provides C3b with the potential of binding covalently to biological surfaces exposing hydroxyl or amino groups (Fig. 1). C3b deposition leads to opsonization for phagocytosis by polymorphonuclear cells and macrophages. In the presence of an additional C3b molecule, the C3-convertases can function as C5-convertases, cleaving C5 and initiating the assembly of the membrane attack complex that leads to complement-mediated lysis.

The efficacy of the complement system as an innate defence mechanism against microbial infections depends on the fine control of the complement system, avoiding the wasteful consumption of its components and preventing non-specific damage to host tissues. Normally, activation of C3 in the blood is kept at a low level and deposition of C3b and further activation of complement is limited to the surface of pathogens. Not surprisingly, many complement components are regulatory proteins that modulate complement activation and protect host tissues. Several of these regulatory proteins interact with C3 or C4 derivatives and are encoded by closely linked genes that constitute the Regulator of Complement Activation (RCA) gene cluster on human chromosome 1q32. It is generally accepted that these complement regulatory genes share a common ancestor from which they originated by multiple events of gene duplication. Factor H, a plasma protein encoded by one of these RCA genes, is essential to regulate complement activation and to restrict the action of complement to activating surfaces.

Section snippets

Structure and function of factor H

Factor H was first identified by Nilsson and Müeller-Eberhard (1965) as β1H globulin. Factor H is a single polypeptide chain plasma glycoprotein (155 kDa) that is present in plasma at a concentration of 110–615 μg/ml. The secreted form of the protein is composed of 20 repetitive units of 60 amino acids (Ripoche et al., 1988), named short consensus repeats (SCR) or complement control protein modules (CCP), arranged in a continuous fashion like a string of 20 beads. The SCRs have a typical

The factor H family: genes and proteins

Factor H is encoded by a single gene (HF1) located on human chromosome 1q32 within the RCA gene cluster (Rodriguez de Cordoba and Rubinstein, 1986, Rodriguez de Cordoba et al., 1999, Weis et al., 1987). HF1 is closely linked to the FHR1, FHR2, FHR3, FHR4 and FHR5 genes encoding five factor H-related human plasma proteins (Zipfel and Skerka, 1994, Zipfel et al., 1999, Diaz-Guillen et al., 1999, Perez-Caballero et al., 2001, McRae et al., 2002) (Fig. 3). Sequence analyses of the HF1/FHR1–5 gene

Factor H mutations and disease associations

In recent years a significant number of mutations has been identified in the HF1 gene (Table 2), which has revealed a very interesting association with two different renal diseases, glomerulonephritis and atypical hemolytic uremic syndrome (aHUS).

Factor H deficiencies have been described both in humans and animals. They are caused by mutations that result in truncations or amino acid substitutions that impair secretion of factor H into circulation (Ault et al., 1997, Sanchez-Corral et al., 2000

Quantitative variations and other polymorphisms

As indicated earlier, levels of factor H in human plasma vary largely (110–615 μg/ml) in the population. This variation is not a consequence of HF1 null alleles, which are extremely rare, but the result of the combined effect of genetic and environmental factors. Using variance-component methods (Almasy and Blangero, 1998) in the analysis to a family-based study including 358 individuals, we have determined that factor H plasma levels show an age-dependent increase and are decreased in smokers.

Uptake of factor H by microorganisms and tumour cells

The interaction of factor H with polyanions confers to the host cellular surfaces protection from complement activation. Similarly, factor H binding to surface molecules of pathogens and tumour cells has been demonstrated to restrict alternative pathway activation enhancing the survival and pathogenic capacity of these cells and microorganisms. Pathogenic microorganisms are normally potent activators of the complement system. Not surprisingly, many pathogens have evolved to express surface

Additional roles for factor H

Interaction of factor H with novel ligands and expression of factor H in unusual tissues under physiological or pathological conditions suggest that factor H plays a role in processes as diverse as diabetes mellitus (Pio et al., 2001b, Martinez et al., 2001), Alzheimer’s disease (Strohmeyer et al., 2002), rheumatoid arthritis or atherosclerosis (Oksjoki et al., 2003). Factor H interacts with high affinity in plasma with adrenomedullin (AM), a 52-amino acid peptide belonging to the calcitonin

Concluding remarks

We have reviewed the current knowledge of the structure and function of factor H and illustrated different situations that relate factor H with chronic or infectious disease. Abundant data are now available that define the critical role of factor H in the protection of the host cells and tissues from damage by complement activation. Furthermore, it is now well-established that the C3b/polyanions-binding site located at the C-terminal region of factor H is the most important site for preventing

Acknowledgements

We thank the helpful comments of Drs A. Corbı́ and K. E. Heath. This work was supported by the Spanish MCyT (SAF2002-1083).

References (114)

  • R. Janulczyk et al.

    Hic, a novel surface protein of Streptococcus pneumoniae that interferes with complement function

    J. Biol. Chem.

    (2000)
  • D.E. Male et al.

    Complement factor H: sequence analysis of 221 kb of human genomic DNA containing the entire fH, FHR1 and FHR3 genes

    Mol. Immunol.

    (2000)
  • J.L. McRae et al.

    Human factor H-related protein 5 (FHR5). A new complement-associated protein

    J. Biol. Chem.

    (2001)
  • B. Murphy et al.

    Factor H-related protein-5: a novel component of human glomerular immune deposits

    Am. J. Kidney. Dis.

    (2002)
  • M. Noris et al.

    International Registry of Recurrent and Familial HUS/TTP. Familial haemolytic uraemic syndrome and an MCP mutation

    Lancet

    (2003)
  • M.K. Pangburn et al.

    Localization of the heparin-binding site on complement factor H

    J. Biol. Chem.

    (1991)
  • C.T. Park et al.

    Plasma lipopolysaccharide-binding protein is found associated with a particle containing apolipoprotein A–I, phospholipid, and factor H-related proteins

    J. Biol. Chem.

    (1996)
  • D. Pérez-Caballero et al.

    Clustering of missense mutations in the C-terminal region of factor H in atypical hemolytic uremic syndrome

    Am. J. Hum. Genet.

    (2001)
  • S.J. Perkins et al.

    Molecular modelling of the C-terminal domains of factor H of human complement: a correlation between haemolytic uraemic syndrome and a predicted heparin binding site

    J. Mol. Biol.

    (2002)
  • V. Pichette et al.

    Familial hemolytic-uremic syndrome and homozygous factor H deficiency

    Am. J. Kidney Dis.

    (1994)
  • R. Pı́o et al.

    Complement factor H is a serum-binding protein for adrenomedullin, and the resulting complex modulates the bioactivities of both partners

    J. Biol. Chem.

    (2001)
  • R. Pı́o et al.

    Cancer and diabetes: two pathological conditions in which adrenomedullin may be involved

    Peptides

    (2001)
  • G. Remuzzi et al.

    Combined kidney and liver transplantation for familial haemolytic uraemic syndrome

    Lancet

    (2002)
  • G. Ren et al.

    Isolation and characterization of a novel rat factor H-related protein that is up-regulated in glomeruli under complement attack

    J. Biol. Chem.

    (2002)
  • A. Richards et al.

    Factor H mutations in hemolytic uremic syndrome cluster in exons 18–20, a domain important for host cell recognition

    Am. J. Hum. Genet.

    (2001)
  • S. Rodrı́guez de Córdoba et al.

    An integrated map of the human regulator of complement activation (RCA) gene cluster on 1q32

    Mol. Immunol.

    (1999)
  • P. Sánchez-Corral et al.

    Structural and functional characterization of factor H mutations associated with atypical hemolytic uremic syndrome

    Am. J. Hum. Genet.

    (2002)
  • P. Sánchez-Corral et al.

    Functional analysis in serum from atypical hemolytic uremic syndrome patients reveals impaired protection of host cells associated with mutations in Factor H.

    Mol. Immunol.

    (2004)
  • C. Skerka et al.

    The human factor H-related protein 4 (FHR4). A novel short consensus repeat-containing protein is associated with human triglyceride-rich lipoproteins

    J. Biol. Chem.

    (1997)
  • J. Alsenz et al.

    Structural and functional analysis of the complement component factor H with the use of different enzymes and monoclonal antibodies to factor H

    Biochem. J.

    (1985)
  • P.N. Barlow et al.

    Solution structure of the fifth repeat of factor H: a second example of the complement control protein module

    Biochemistry

    (1992)
  • T.K. Blackmore et al.

    Identification of the second heparin-binding domain in human complement factor H

    J. Immunol.

    (1998)
  • T.K. Blackmore et al.

    M protein of the Group A Streptococcus binds to the seventh short consensus repeat of human complement factor H

    Infect. Immun.

    (1998)
  • T.K. Blackmore et al.

    Identification of a heparin binding domain in the seventh short consensus repeat of complement factor H

    J. Immunol.

    (1996)
  • J. Caprioli et al.

    The molecular basis of familial hemolytic uremic syndrome: mutation analysis of factor H gene reveals a hot spot in short consensus repeat 20

    J. Am. Soc. Nephrol.

    (2001)
  • J. Caprioli et al.

    Complement factor H mutations and gene polymorphisms in haemolytic uraemic syndrome: the C-257T, the A2089G and the G2881T polymorphisms are strongly associated with the disease

    Hum. Mol. Genet.

    (2003)
  • B. China et al.

    Role of the YadA protein in prevention of opsonization of Yersinia enterocolitica by C3b molecules

    Infect. Immun.

    (1993)
  • A. Dı́az et al.

    Complement evasion by Echinococcus granulosus: sequestration of host factor H in the hydatid cyst wall

    J. Immunol.

    (1997)
  • M.A. Dı́az-Guillén et al.

    A radiation hybrid map of complement factor H and factor H-related genes

    Immunogenetics

    (1999)
  • R.G. DiScipio et al.

    Human polymorphonuclear leukocytes adhere to complement factor H through an interaction that involves alphaMbeta2 (CD11b/CD18)

    J. Immunol.

    (1998)
  • T.G. Duthy et al.

    The human complement regulator factor H binds pneumococcal surface protein PspC via short consensus repeats 13 to 15

    Infect. Immun.

    (2002)
  • Esparza-Gordillo, J., Soria, J.M., Buil, A., Almasy, L., Blangero, J., Fontouberta, J., Rodrı́guez de Córdoba, S.,...
  • C. Estaller et al.

    Human complement factor H: two factor H proteins are derived from alternatively spliced transcripts

    Eur. J. Immunol.

    (1991)
  • D.T. Fearon

    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)
  • N.S. Fedarko et al.

    Elevated serum bone sialoprotein and osteopontin in colon, breast, prostate, and lung cancer

    Clin. Cancer Res.

    (2001)
  • V.A. Fischetti et al.

    Location of the complement factor H binding site on streptococcal M6 protein

    Infect. Immun.

    (1995)
  • E. Giannakis et al.

    A common site within factor H SCR 7 responsible for binding heparin, C-reactive protein and streptococcal M protein

    Eur. J. Immunol.

    (2003)
  • D.L. Gordon et al.

    Identification of complement regulatory domains in human factor H

    J. Immunol.

    (1995)
  • G.A. Hegasy et al.

    Pig complement regulator factor H: molecular cloning and functional characterization

    Immunogenetics

    (2003)
  • J. Hellwage et al.

    Complement C3b/C3d and cell surface polyanions are recognized by overlapping binding sites on the most carboxyl-terminal domain of complement factor H

    J. Immunol.

    (2002)
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