Abstract
Complement Factor H has recently come to the fore with variant forms implicated in a range of serious disease states. This review aims to bring together recent data concerning the structure and biological activity of this molecule to highlight the way in which a molecular understanding of function may open novel therapeutic possibilities. In particular we examine the evidence for and against the hypothesis that sequence variations in factor H may predispose to disease if they perturb its ability to recognise and respond appropriately to polyanionic carbohydrates on host surfaces that require protection from complement-mediated damage.
Keywords
- Hemolytic Uremic Syndrome
- Retinal Pigment Epithelium
- Dense Deposit Disease
- Polymorphic Residue
- Complement Regulatory Activity
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Abrera-Abeleda, M.A., Nishimura, C., Smith, J.L., Sethi, S., McRae, J.L., Murphy, B.F., Silvestri, G., Skerka, C., Jozsi, M., Zipfel, P.F., et al. (2006)Variations in the complement regulatory genes factor H (CFH) and factor H related 5 (CFHR5) are associated with membranoproliferative glomerulonephritis type II (dense deposit disease). Journal of Medical Genetics 43, 582–589
Alsenz, J., Lambris, J.D., Schulz, T.F., and Dierich, M.P. (1984). Localization of the complement-component-C3b-binding site and the cofactor activity for factor I in the 38kDa tryptic fragment of factor H. The Biochemical Journal 224, 389–398
Alsenz, J., Schulz, T.F., Lambris, J.D., Sim, R.B., and Dierich, M.P. (1985). Structural and functional analysis of the complement component factor H with the use of different enzymes and monoclonal antibodies to factor H. The Biochemical Journal 232, 841–850
Anderson, D.H., Ozaki, S., Nealon, M., Neitz, J., Mullins, R.F., Hageman, G.S., and Johnson, L.V. (2001). Local cellular sources of apolipoprotein E in the human retina and retinal pigmented epithelium: implications for the process of drusen formation. American Journal of Ophthalmology 131, 767–781
Aronen, M., Leijala, M., and Meri, S. (1990). Value of C-reactive protein in reflecting the magnitude of complement activation in children undergoing open heart surgery. Intensive Care Medicine 16, 128–132
Aslam, M. and Perkins, S.J. (2001). Folded-back solution structure of monomeric factor H of human complement by synchrotron X-ray and neutron scattering, analytical ultracentrifugation and constrained molecular modelling. Journal of Molecular Biology 309, 1117–1138
Bao, L., Haas, M., Kraus, D.M., Hack, B.K., Rakstang, J.K., Holers, V.M., and Quigg, R.J. (2003). Administration of a soluble recombinant complement C3 inhibitor protects against renal disease in MRL/lpr mice. Journal of American Society of Nephrology 14, 670–679
Barlow, P.N., Baron, M., Norman, D.G., Day, A.J., Willis, A.C., Sim, R.B., and Campbell, I.D. (1991). Secondary structure of a complement control protein module by two-dimensional 1H NMR. Biochemistry 30, 997–1004
Barlow, P.N., Norman, D.G., Steinkasserer, A., Horne, T.J., Pearce, J., Driscoll, P.C., Sim, R.B., and Campbell, I.D. (1992). Solution structure of the fifth repeat of factor H: a second example of the complement control protein module. Biochemistry 31, 3626–3634
Barlow, P.N., Steinkasserer, A., Norman, D.G., Kieffer, B., Wiles, A.P., Sim, R.B., and Campbell, I.D. (1993). Solution structure of a pair of complement modules by nuclear magnetic resonance. Journal of Molecular Biology 232, 268–284
Blackmore, T.K., Sadlon, T.A., Ward, H.M., Lublin, D.M., and Gordon, D.L. (1996). Identification of a heparin binding domain in the seventh short consensus repeat of complement factor H. Journal of Immunology 157, 5422–5427
Blackmore, T.K., Hellwage, J., Sadlon, T.A., Higgs, N., Zipfel, P.F., Ward, H.M., and Gordon, D.L. (1998). Identification of the second heparin-binding domain in human complement factor H. Journal of Immunology 160, 3342–3348
Buddles, M.R., Donne, R.L., Richards, A., Goodship, J., and Goodship, T.H. (2000). Complement factor H gene mutation associated with autosomal recessive atypical hemolytic uremic syndrome. American Journal of Human Genetics 66, 1721–1722
Clark, S.J., Higman, V.A., Mulloy, B., Perkins, S.J., Lea, S.M., Sim, R.B., and Day, A.J. (2006). His-384 allotypic variant of factor H associated with age-related macular degeneration has different heparin binding properties from the non-disease-associated form. The Journal of Biological Chemistry 281, 24713–24720
Coffey, P.J., Gias, C., McDermott, C.J., Lundh, P., Pickering, M.C., Sethi, C., Bird, A., Fitzke, F.W., Maass, A., Chen, L.L., et al. (2007)Complement factor H deficiency in aged mice causes retinal abnormalities and visual dysfunction. Proceedings of the National Academy of Sciences of the United States of America 104, 16651–16656
Crabb, J.W., Miyagi, M., Gu, X., Shadrach, K., West, K.A., Sakaguchi, H., Kamei, M., Hasan, A., Yan, L., Rayborn, M.E., et al. (2002)Drusen proteome analysis: an approach to the etiology of age-related macular degeneration. Proceedings of the National Academy of Sciences of the United States of America 99, 14682–14687
de Cordoba, S.R. and de Jorge, E.G. (2008)Translational mini-review series on complement factor H: genetics and disease associations of human complement factor H. Clinical and Experimental Immunology 151, 1–13
Edwards, A.O., Ritter, R., III, Abel, K.J., Manning, A., Panhuysen, C., and Farrer, L.A. (2005). Complement factor H polymorphism and age-related macular degeneration. Science 308, 421–424
Esparza-Gordillo, J., Soria, J.M., Buil, A., Almasy, L., Blangero, J., Fontcuberta, J., and Rodriguez de Cordoba, S. (2004). Genetic and environmental factors influencing the human factor H plasma levels. Immunogenetics 56, 77–82
Estaller, C., Koistinen, V., Schwaeble, W., Dierich, M.P., and Weiss, E.H. (1991). Cloning of the 1.4-kb mRNA species of human complement factor H reveals a novel member of the short consensus repeat family related to the carboxy terminal of the classical 150-kDa molecule. Journal of Immunology 146, 3190–3196
Farries, T.C., Seya, T., Harrison, R.A., and Atkinson, J.P. (1990). Competition for binding sites on C3b by CR1, CR2, MCP, factor B and Factor H. Complement and Inflammation 7, 30–41
Fernando, A.N., Furtado, P.B., Clark, S.J., Gilbert, H.E., Day, A.J., Sim, R.B., and Perkins, S.J. (2007). Associative and structural properties of the region of complement factor H encompassing the Tyr402His disease-related polymorphism and its interactions with heparin. Journal of Molecular Biology 368, 564–581
Ferreira, V.P., Herbert, A.P., Hocking, H.G., Barlow, P.N., and Pangburn, M.K. (2006). Critical role of the C-terminal domains of factor H in regulating complement activation at cell surfaces. Journal of Immunology 177, 6308–6316
Gehrs, K.M., Anderson, D.H., Johnson, L.V., and Hageman, G.S. (2006). Age-related macular degeneration – emerging pathogenetic and therapeutic concepts. Annals of Medicine 38, 450–471
Gerber, A., Kirchhoff-Moradpour, A.H., Obieglo, S., Brandis, M., Kirschfink, M., Zipfel, P.F., Goodship, J.A., and Zimmerhackl, L.B. (2003). Successful (?) therapy of hemolytic-uremic syndrome with factor H abnormality. Pediatric Nephrology (Berlin, Germany) 18, 952–955
Gershov, D., Kim, S., Brot, N., and Elkon, K.B. (2000). C-Reactive protein binds to apoptotic cells, protects the cells from assembly of the terminal complement components, and sustains an antiinflammatory innate immune response: implications for systemic autoimmunity. The Journal of Experimental Medicine 192, 1353–1364
Giannakis, E., Jokiranta, T.S., Male, D.A., Ranganathan, S., Ormsby, R.J., Fischetti, V.A., Mold, C., and Gordon, D.L. (2003). A common site within factor H SCR 7 responsible for binding heparin, C-reactive protein and streptococcal M protein. European Journal of Immunology 33, 962–969
Gold, B., Merriam, J.E., Zernant, J., Hancox, L.S., Taiber, A.J., Gehrs, K., Cramer, K., Neel, J., Bergeron, J., Barile, G.R., et al. (2006)Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nature Genetics 38, 458–462
Gordon, D.L., Kaufman, R.M., Blackmore, T.K., Kwong, J., and Lublin, D.M. (1995). Identification of complement regulatory domains in human factor H. Journal of Immunology 155, 348–356
Hageman, G.S., Mullins, R.F., Russell, S.R., Johnson, L.V., and Anderson, D.H. (1999). Vitronectin is a constituent of ocular drusen and the vitronectin gene is expressed in human retinal pigmented epithelial cells. FASEB J 13, 477–484
Hageman, G.S., Luthert, P.J., Victor Chong, N.H., Johnson, L.V., Anderson, D.H., and Mullins, R.F. (2001). An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch’s membrane interface in aging and age-related macular degeneration. Progress in Retinal and Eye Research 20, 705–732
Hageman, G.S., Anderson, D.H., Johnson, L.V., Hancox, L.S., Taiber, A.J., Hardisty, L.I., Hageman, J.L., Stockman, H.A., Borchardt, J.D., Gehrs, K.M., et al. (2005)A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proceedings of the National Academy of Sciences of the United States of America 102, 7227–7232
Hageman, G.S., Hancox, L.S., Taiber, A.J., Gehrs, K.M., Anderson, D.H., Johnson, L.V., Radeke, M.J., Kavanagh, D., Richards, A., Atkinson, J., et al. (2006)Extended haplotypes in the complement factor H (CFH) and CFH-related (CFHR) family of genes protect against age-related macular degeneration: characterization, ethnic distribution and evolutionary implications. Annals of Medicine 38, 592–604
Haines, J.L., Hauser, M.A., Schmidt, S., Scott, W.K., Olson, L.M., Gallins, P., Spencer, K.L., Kwan, S.Y., Noureddine, M., Gilbert, J.R., et al. (2005)Complement factor H variant increases the risk of age-related macular degeneration. Science (New York, NY)308, 419–421
Hakobyan, S., Harris, C.L., van den Berg, C., Pepys, M.B., Morgan, B.P. (2007). Binding of factor H to C-reactive protein occurs only when the latter has undergone non-physiologic denaturation. Molecular Immunology 44, 3983–3984
Hamilton, G., Proitsi, P., Williams, J., O’Donovan, M., Owen, M., Powell, J., and Lovestone, S. (2007). Complement factor H Y402H polymorphism is not associated with late-onset Alzheimer’s disease. Neuromolecular Medicine 9, 331–334
Hegasy, G.A., Manuelian, T., Hogasen, K., Jansen, J.H., and Zipfel, P.F. (2002). The molecular basis for hereditary porcine membranoproliferative glomerulonephritis type II: point mutations in the factor H coding sequence block protein secretion. The American Journal of Pathology 161, 2027–2034
Heinen, S., Sanchez-Corral, P., Jackson, M.S., Strain, L., Goodship, J.A., Kemp, E.J., Skerka, C., Jokiranta, T.S., Meyers, K., Wagner, E., et al. (2006)De novo gene conversion in the RCA gene cluster (1q32) causes mutations in complement factor H associated with atypical hemolytic uremic syndrome. Human Mutation 27, 292–293
Herbert, A.P., Uhrin, D., Lyon, M., Pangburn, M.K., and Barlow, P.N. (2006). Disease-associated sequence variations congregate in a polyanion recognition patch on human factor H revealed in three-dimensional structure. The Journal of Biological Chemistry 281, 16512–16520
Herbert, A.P., Deakin, J.A., Schmidt, C.Q., Blaum, B.S., Egan, C., Ferreira, V.P., Pangburn, M.K., Lyon, M., Uhrin, D., and Barlow, P.N. (2007). Structure shows that a glycosaminoglycan and protein recognition site in factor H is perturbed by age-related macular degeneration-linked single nucleotide polymorphism. The Journal of Biological Chemistry 282, 18960–18968
Holers, V.M. (2003). The complement system as a therapeutic target in autoimmunity. Clinical Immunology (Orlando, Fla)107, 140–151
Holers, V.M., Girardi, G., Mo, L., Guthridge, J.M., Molina, H., Pierangeli, S.S., Espinola, R., Xiaowei, L.E., Mao, D., Vialpando, C.G., et al. (2002)Complement C3 activation is required for antiphospholipid antibody-induced fetal loss. The Journal of Experimental Medicine 195, 211–220
Hughes, A.E., Orr, N., Esfandiary, H., Diaz-Torres, M., Goodship, T., and Chakravarthy, U. (2006). A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration. Nature Genetics 38, 1173–1177
Jakobsdottir, J., Conley, Y.P., Weeks, D.E., Mah, T.S., Ferrell, R.E., and Gorin, M.B. (2005). Susceptibility genes for age-related maculopathy on chromosome 10q26. American Journal of Human Genetics 77, 389–407
Jansen, J.H., Hogasen, K., Harboe, M., and Hovig, T. (1998). In situ complement activation in porcine membranoproliferative glomerulonephritis type II. Kidney International 53, 331–349
Jarva, H., Jokiranta, T.S., Hellwage, J., Zipfel, P.F., and Meri, S. (1999). 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. Journal of Immunology 163, 3957–3962
Johnson, L.V., Ozaki, S., Staples, M.K., Erickson, P.A., and Anderson, D.H. (2000). A potential role for immune complex pathogenesis in drusen formation. Experimental Eye Research 70, 441–449
Johnson, L.V., Leitner, W.P., Staples, M.K., and Anderson, D.H. (2001). Complement activation and inflammatory processes in Drusen formation and age related macular degeneration. Experimental Eye Research 73, 887–896
Johnson, P.T., Betts, K.E., Radeke, M.J., Hageman, G.S., Anderson, D.H., and Johnson, L.V. (2006). Individuals homozygous for the age-related macular degeneration risk-conferring variant of complement factor H have elevated levels of CRP in the choroid. Proceedings of the National Academy of Sciences of the United States of America 103, 17456–17461
Jokiranta, T.S., Hellwage, J., Koistinen, V., Zipfel, P.F., and Meri, S. (2000). Each of the three binding sites on complement factor H interacts with a distinct site on C3b. The Journal of Biological Chemistry 275, 27657–27662
Jokiranta, T.S., Jaakola, V.P., Lehtinen, M.J., Parepalo, M., Meri, S., and Goldman, A. (2006). Structure of complement factor H carboxyl-terminus reveals molecular basis of atypical haemolytic uremic syndrome. The EMBO Journal 25, 1784–1794
Jouvin, M.H., Kazatchkine, M.D., Cahour, A., and Bernard, N. (1984). Lysine residues, but not carbohydrates, are required for the regulatory function of H on the amplification C3 convertase of complement. Journal of Immunology 133, 3250–3254
Kardys, I., Klaver, C.C., Despriet, D.D., Bergen, A.A., Uitterlinden, A.G., Hofman, A., Oostra, B.A., Van Duijn, C.M., de Jong, P.T., and Witteman, J.C. (2006). A common polymorphism in the complement factor H gene is associated with increased risk of myocardial infarction: the Rotterdam Study. Journal of the American College of Cardiology 47, 1568–1575
Kavanagh, D., Richards, A., Fremeaux-Bacchi, V., Noris, M., Goodship, T., Remuzzi, G., and Atkinson, J.P. (2007). Screening for complement system abnormalities in patients with atypical hemolytic uremic syndrome. Clinical Journal of American Society of Nephrology 2, 591–596
Kinoshita, T. (1991). Biology of complement: the overture. Immunology today 12, 291–295
Klein, R.J., Zeiss, C., Chew, E.Y., Tsai, J.Y., Sackler, R.S., Haynes, C., Henning, A.K., SanGiovanni, J.P., Mane, S.M., Mayne, S.T., et al. (2005)Complement factor H polymorphism in age-related macular degeneration. Science 308, 385–389
Kuhn, S. and Zipfel, P.F. (1996). Mapping of the domains required for decay acceleration activity of the human factor H-like protein 1 and factor H. European Journal of Immunology 26, 2383–2387
Kuhn, S., Skerka, C., and Zipfel, P.F. (1995). Mapping of the complement regulatory domains in the human factor H-like protein 1 and in factor H1. Journal of Immunology 155, 5663–5670
Laine, M., Jarva, H., Seitsonen, S., Haapasalo, K., Lehtinen, M.J., Lindeman, N., Anderson, D.H., Johnson, P.T., Jarvela, I., Jokiranta, T.S., et al. (2007). Y402H polymorphism of complement factor H affects binding affinity to C-reactive protein. Journal of Immunology 178, 3831–3836
Li, M., Atmaca-Sonmez, P., Othman, M., Branham, K.E., Khanna, R., Wade, M.S., Li, Y., Liang, L., Zareparsi, S., Swaroop, A., et al. (2006). CFH haplotypes without the Y402H coding variant show strong association with susceptibility to age-related macular degeneration. Nature Genetics 38, 1049–1054
Licht, C., Weyersberg, A., Heinen, S., Stapenhorst, L., Devenge, J., Beck, B., Waldherr, R., Kirschfink, M., Zipfel, P.F., and Hoppe, B. (2005). Successful plasma therapy for atypical hemolytic uremic syndrome caused by factor H deficiency owing to a novel mutation in the complement cofactor protein domain 15. American Journal of Kidney Disease 45, 415–421
Licht, C., Heinen, S., Jozsi, M., Loschmann, I., Saunders, R.E., Perkins, S.J., Waldherr, R., Skerka, C., Kirschfink, M., Hoppe, B., et al. (2006). Deletion of Lys224 in regulatory domain 4 of Factor H reveals a novel pathomechanism for dense deposit disease (MPGN II). Kidney International 70, 42–50
Lindahl, G., Sjobring, U., and Johnsson, E. (2000). Human complement regulators: a major target for pathogenic microorganisms. Current Opinion in Immunology 12, 44–51
Liszewski, M.K., and Atkinson, J.P. (1998). Novel complement inhibitors. Expert Opinion on Investigational Drugs 7, 323–331
Male, D.A., Ormsby, R.J., Ranganathan, S., Giannakis, E., and Gordon, D.L. (2000). Complement factor H: sequence analysis of 221 kb of human genomic DNA containing the entire fH, fHR-1 and fHR-3 genes. Molecular Immunology 37, 41–52
Maller, J.B., Fagerness, J.A., Reynolds, R.C., Neale, B.M., Daly, M.J., and Seddon, J.M. (2007). Variation in complement factor 3 is associated with risk of age-related macular degeneration. Nature Genetics 39, 1200–1201
Markiewski, M.M. and Lambris, J.D. (2007). The role of complement in inflammatory diseases from behind the scenes into the spotlight. The American Journal of Pathology 171, 715–727
Meng, W., Hughes, A., Patterson, C.C., Belton, C., Kamaruddin, M.S., Horan, P.G., Kee, F., and McKeown, P.P. (2007). Genetic variants of complement factor H gene are not associated with premature coronary heart disease: a family-based study in the Irish population. BMC Medical Genetics 8, 62
Meri, S. and Pangburn, M.K. (1990). Discrimination between activators and nonactivators of the alternative pathway of complement: regulation via a sialic acid/polyanion binding site on factor H. Proceedings of the National Academy of Sciences of the United States of America 87, 3982–3986
Misasi, R., Huemer, H.P., Schwaeble, W., Solder, E., Larcher, C., and Dierich, M.P. (1989). Human complement factor H: an additional gene product of 43 kDa isolated from human plasma shows cofactor activity for the cleavage of the third component of complement. European Journal of Immunology 19, 1765–1768
Mooijaart, S.P., Koeijvoets, K.M., Sijbrands, E.J., Daha, M.R., and Westendorp, R.G. (2007). Complement Factor H polymorphism Y402H associates with inflammation, visual acuity, and cardiovascular mortality in the elderly population at large. Experimental Gerontology 42, 1116–1122
Mullins, R.F., Russell, S.R., Anderson, D.H., and Hageman, G.S. (2000). Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease. FASEB J 14, 835–846
Mullins, R.F., Aptsiauri, N., and Hageman, G.S. (2001). Structure and composition of drusen associated with glomerulonephritis: implications for the role of complement activation in drusen biogenesis. Eye (London, England)15, 390–395
Nan, R., Gor, J., and Perkins, S.J. (2008). Implications of the progressive self-association of wild-type human factor H for complement regulation and disease. Journal of Molecular Biology 375, 891–900
Nicaud, V., Francomme, C., Ruidavets, J.B., Luc, G., Arveiler, D., Kee, F., Evans, A., Morrison, C., Blankenberg, S., Cambien, F., et al. (2007). Lack of association between complement factor H polymorphisms and coronary artery disease or myocardial infarction. Journal of Molecular Medicine 85, 771–775
Norman, D.G., Barlow, P.N., Baron, M., Day, A.J., Sim, R.B., and Campbell, I.D. (1991). Three-dimensional structure of a complement control protein module in solution. Journal of Molecular Biology 219, 717–725
Okamoto, H., Umeda, S., Obazawa, M., Minami, M., Noda, T., Mizota, A., Honda, M., Tanaka, M., Koyama, R., Takagi, I., et al. (2006). Complement factor H polymorphisms in Japanese population with age-related macular degeneration. Molecular Vision 12, 156–158
Okemefuna, A.I., Gilbert, H.E., Griggs, K.M., Ormsby, R.J., Gordon, D.L., and Perkins, S.J. (2008). The regulatory SCR-1/5 and cell surface-binding SCR-16/20 fragments of factor H reveal partially folded-back solution structures and different self-associative properties. Journal of Molecular Biology 375, 80–101
Oppermann, M., Manuelian, T., Jozsi, M., Brandt, E., Jokiranta, T.S., Heinen, S., Meri, S., Skerka, C., Gotze, O., and Zipfel, P.F. (2006). The C-terminus of complement regulator Factor H mediates target recognition: evidence for a compact conformation of the native protein. Clinical and Experimental Immunology 144, 342–352
Ormsby, R.J., Jokiranta, T.S., Duthy, T.G., Griggs, K.M., Sadlon, T.A., Giannakis, E., and Gordon, D.L. (2006). Localization of the third heparin-binding site in the human complement regulator factor H1. Molecular Immunology 43, 1624–1632
Pai, J.K., Manson, J.E., Rexrode, K.M., Albert, C.M., Hunter, D.J., and Rimm, E.B. (2007). Complement factor H (Y402H) polymorphism and risk of coronary heart disease in US men and women. European Heart Journal 28, 1297–1303
Pangburn, M.K., and Muller-Eberhard, H.J. (1983). Kinetic and thermodynamic analysis of the control of C3b by the complement regulatory proteins factors H and I. Biochemistry 22, 178–185
Pangburn, M.K., Schreiber, R.D., and Muller-Eberhard, H.J. (1977). 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. The Journal of Experimental Medicine 146, 257–270
Pangburn, M.K., Atkinson, M.A., and Meri, S. (1991). Localization of the heparin-binding site on complement factor H. The Journal of Biological Chemistry 266, 16847–16853
Penfold, P.L., Madigan, M.C., Gillies, M.C., and Provis, J.M. (2001). Immunological and aetiological aspects of macular degeneration. Progress in Retinal and Eye Research 20, 385–414
Perkins, S.J., Nealis, A.S., and Sim, R.B. (1991). Oligomeric domain structure of human complement factor H by X-ray and neutron solution scattering. Biochemistry 30, 2847–2857
Perkins, S.J., Gilbert, H.E., Aslam, M., Hannan, J., Holers, V.M., and Goodship, T.H. (2002). Solution structures of complement components by X-ray and neutron scattering and analytical ultracentrifugation. Biochemical Society Transactions 30, 996–1001
Pickering, M.C. and Cook, H.T. (2008). Translational mini-review series on complement factor H: renal diseases associated with complement factor H: novel insights from humans and animals. Clinical and Experimental Immunology 151, 210–230
Pickering, M.C., Cook, H.T., Warren, J., Bygrave, A.E., Moss, J., Walport, M.J., and Botto, M. (2002). Uncontrolled C3 activation causes membranoproliferative glomerulonephritis in mice deficient in complement factor H. Nature Genetics 31, 424–428
Pickering, M.C., de Jorge, E.G., Martinez-Barricarte, R., Recalde, S., Garcia-Layana, A., Rose, K.L., Moss, J., Walport, M.J., Cook, H.T., de Cordoba, S.R., et al. (2007)Spontaneous hemolytic uremic syndrome triggered by complement factor H lacking surface recognition domains. The Journal of Experimental Medicine 204, 1249–1256
Prosser, B.E., Johnson, S., Roversi, P., Clark, S.J., Tarelli, E., Sim, R.B., Day, A.J., and Lea, S.M. (2007a). Expression, purification, cocrystallization and preliminary crystallographic analysis of sucrose octasulfate/human complement regulator factor H SCRs 6-8. Acta Crystallographica 63, 480–483
Prosser, B.E., Johnson, S., Roversi, P., Herbert, A.P., Blaum, B.S., Tyrrell, J., Jowitt, T.A., Clark, S.J., Tarelli, E., Uhrin, D., et al. (2007b). Structural basis for complement factor H linked age-related macular degeneration. The Journal of Experimental Medicine 204, 2277–2283
Pulido, J.S., McConnell, J.P., Lennon, R.J., Bryant, S.C., Peterson, L.M., Berger, P.B., Somers, V., and Highsmith, W.E. (2007). Relationship between age-related macular degeneration-associated variants of complement factor H and LOC387715 with coronary artery disease. Mayo Clinic Proceedings 82, 301–307
Richards, A., Buddles, M.R., Donne, R.L., Kaplan, B.S., Kirk, E., Venning, M.C., Tielemans, C.L., Goodship, J.A., and Goodship, T.H. (2001). Factor H mutations in hemolytic uremic syndrome cluster in exons 18–20, a domain important for host cell recognition. American Journal of Human Genetics 68, 485–490
Ricklin, D. and Lambris, J.D. (2007). Complement-targeted therapeutics. Nature Biotechnology 25, 1265–1275
Ripoche, J., Day, A.J., Willis, A.C., Belt, K.T., Campbell, R.D., and Sim, R.B. (1986). Partial characterization of human complement factor H by protein and cDNA sequencing: homology with other complement and non-complement proteins. Bioscience Reports 6, 65–72
Ripoche, J., Erdei, A., Gilbert, D., Al Salihi, A., Sim, R.B., and Fontaine, M. (1988). Two populations of complement factor H differ in their ability to bind to cell surfaces. The Biochemical Journal 253, 475–480
Rivera, A., Fisher, S.A., Fritsche, L.G., Keilhauer, C.N., Lichtner, P., Meitinger, T., and Weber, B.H. (2005). Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk. Human Molecular Genetics 14, 3227–3236
Rodriguez de Cordoba, S., Lublin, D.M., Rubinstein, P., and Atkinson, J.P. (1985). Human genes for three complement components that regulate the activation of C3 are tightly linked. The Journal of Experimental Medicine 161, 1189–1195
Rother, R.P., Rollins, S.A., Mojcik, C.F., Brodsky, R.A., and Bell, L. (2007). Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria. Nature Biotechnology 25, 1256–1264
Ryan, U.S. (1995). Complement inhibitory therapeutics and xenotransplantation. Nature Medicine 1, 967–968
Sahu, A., and Lambris, J.D. (2000). Complement inhibitors: a resurgent concept in anti-inflammatory therapeutics. Immunopharmacology 49, 133–148
Schlaf, G., Demberg, T., Beisel, N., Schieferdecker, H.L., and Gotze, O. (2001). Expression and regulation of complement factors H and I in rat and human cells: some critical notes. Molecular Immunology 38, 231–239
Schmidt, C.Q., Herbert, A.P., Hocking, H.G., Uhrin, D., and Barlow, P.N. (2008). Translational mini-review series on complement factor H: structural and functional correlations for factor H. Clinical and Experimental Immunology 151, 14–24
Schwaeble, W., Zwirner, J., Schulz, T.F., Linke, R.P., Dierich, M.P., and Weiss, E.H. (1987). Human complement factor H: expression of an additional truncated gene product of 43 kDa in human liver. European Journal of Immunology 17, 1485–1489
Seddon, J.M., George, S., Rosner, B., and Klein, M.L. (2006). CFH gene variant, Y402H, and smoking, body mass index, environmental associations with advanced age-related macular degeneration. Human Heredity 61, 157–165
Sharma, A.K. and Pangburn, M.K. (1996). Identification of three physically and functionally distinct binding sites for C3b in human complement factor H by deletion mutagenesis. Proceedings of the National Academy of Sciences of the United States of America 93, 10996–11001
Sivaprasad, S., Chong, N.V., and Bailey, T.A. (2005). Serum elastin-derived peptides in age-related macular degeneration. Investigative Ophthalmology and Visual Science 46, 3046–3051
Sjoberg, A.P., Trouw, L.A., Clark, S.J., Sjolander, J., Heinegard, D., Sim, R.B., Day, A.J., and Blom, A.M. (2007). The factor H variant associated with age-related macular degeneration (His-384) and the non-disease-associated form bind differentially to C-reactive protein, fibromodulin, DNA, and necrotic cells. The Journal of Biological Chemistry 282, 10894–10900
Skerka, C., Lauer, N., Weinberger, A.A., Keilhauer, C.N., Suhnel, J., Smith, R., Schlotzer-Schrehardt, U., Fritsche, L., Heinen, S., Hartmann, A., et al. (2007)Defective complement control of factor H (Y402H) and FHL-1 in age-related macular degeneration. Molecular Immunology 44, 3398–3406
Soares, D.C., Gerloff, D.L., Syme, N.R., Coulson, A.F., Parkinson, J., and Barlow, P.N. (2005). Large-scale modelling as a route to multiple surface comparisons of the CCP module family. Protein Engineering Design and Selection 18, 379–388
Stark, K., Neureuther, K., Sedlacek, K., Hengstenberg, W., Fischer, M., Baessler, A., Wiedmann, S., Jeron, A., Holmer, S., Erdmann, J., et al. (2007). The common Y402H variant in complement factor H gene is not associated with susceptibility to myocardial infarction and its related risk factors. Clinical Science (Lond)113, 213–218
Stratton, J.D., and Warwicker, P. (2002). Successful treatment of factor H-related haemolytic uraemic syndrome. Nephrology Dialysis Transplantation 17, 684–685
Thurman, J.M. (2007). Triggers of inflammation after renal ischemia/reperfusion. Clinical Immunology (Orlando, Fla)123, 7–13
Thurman, J.M., and Holers, V.M. (2006). The central role of the alternative complement pathway in human disease. Journal of Immunology 176, 1305–1310
Topol, E.J., Smith, J., Plow, E.F., and Wang, Q.K. (2006). Genetic susceptibility to myocardial infarction and coronary artery disease. Human Molecular Genetics 15 Spec No 2, R117–R123
Turnbull, J., Powell, A., and Guimond, S. (2001). Heparan sulfate: decoding a dynamic multifunctional cell regulator. Trends in Cell Bbiology 11, 75–82
Verdugo, M.E. and Ray, J. (1997). Age-related increase in activity of specific lysosomal enzymes in the human retinal pigment epithelium. Experimental Eye Research 65, 231–240
Warwicker, P., Goodship, T.H., Donne, R.L., Pirson, Y., Nicholls, A., Ward, R.M., Turnpenny, P., and Goodship, J.A. (1998). Genetic studies into inherited and sporadic hemolytic uremic syndrome. Kidney International 53, 836–844
Weeks, D.E., Conley, Y.P., Tsai, H.J., Mah, T.S., Schmidt, S., Postel, E.A., Agarwal, A., Haines, J.L., Pericak-Vance, M.A., Rosenfeld, P.J., et al. (2004). Age-related maculopathy: a genomewide scan with continued evidence of susceptibility loci within the 1q31, 10q26, and 17q25 regions. American Journal of Human Genetics 75, 174–189
Yates, J.R., Sepp, T., Matharu, B.K., Khan, J.C., Thurlby, D.A., Shahid, H., Clayton, D.G., Hayward, C., Morgan, J., Wright, A.F., et al. (2007). Complement C3 variant and the risk of age-related macular degeneration. The New England Journal of Medicine 357, 553–561
Yu, J., Wiita, P., Kawaguchi, R., Honda, J., Jorgensen, A., Zhang, K., Fischetti, V.A., and Sun, H. (2007). Biochemical analysis of a common human polymorphism associated with age-related macular degeneration. Biochemistry 46, 8451–8461
Zarbin, M.A. (2004). Current concepts in the pathogenesis of age-related macular degeneration. Archives of Ophthalmology 122, 598–614
Zetterberg, M., Tasa, G., Palmer, M.S., Juronen, E., Teesalu, P., Blennow, K., and Zetterberg, H. (2007). Apolipoprotein E polymorphisms in patients with primary open-angle glaucoma. American Journal of Ophthalmology 143, 1059–1060
Zipfel, P.F. and Skerka, C. (1994). Complement factor H and related proteins: an expanding family of complement-regulatory proteins? Immunology Today 15, 121–126
Zipfel, P.F., Jokiranta, T.S., Hellwage, J., Koistinen, V., and Meri, S. (1999). The factor H protein family. Immunopharmacology 42, 53–60
Author information
Authors and Affiliations
Corresponding authors
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2008 Springer Science+Business Media, LLC
About this chapter
Cite this chapter
Barlow, P.N., Hageman, G.S., Lea, S.M. (2008). Complement Factor H: Using Atomic Resolution Structure to Illuminate Disease Mechanisms. In: Lambris, J. (eds) Current Topics in Complement II. Advances in Experimental Medicine and Biology, vol 632. Springer, New York, NY. https://doi.org/10.1007/978-0-387-78952-1_10
Download citation
DOI: https://doi.org/10.1007/978-0-387-78952-1_10
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-0-387-78951-4
Online ISBN: 978-0-387-78952-1
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)