Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Complement factor H binds malondialdehyde epitopes and protects from oxidative stress


Oxidative stress and enhanced lipid peroxidation are linked to many chronic inflammatory diseases, including age-related macular degeneration (AMD). AMD is the leading cause of blindness in Western societies, but its aetiology remains largely unknown. Malondialdehyde (MDA) is a common lipid peroxidation product that accumulates in many pathophysiological processes, including AMD. Here we identify complement factor H (CFH) as a major MDA-binding protein that can block both the uptake of MDA-modified proteins by macrophages and MDA-induced proinflammatory effects in vivo in mice. The CFH polymorphism H402, which is strongly associated with AMD, markedly reduces the ability of CFH to bind MDA, indicating a causal link to disease aetiology. Our findings provide important mechanistic insights into innate immune responses to oxidative stress, which may be exploited in the prevention of and therapy for AMD and other chronic inflammatory diseases.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: CFH specifically binds to MDA modifications.
Figure 2: The SCR7 domain of CFH is critical for MDA binding.
Figure 3: CFH binds to MDA epitopes present in AMD lesions, on necrotic cells and apoptotic blebs.
Figure 4: CFH inactivates complement on MDA-bearing surfaces.
Figure 5: CFH neutralizes proinflammatory effects of MDA.


  1. Chou, M. Y. et al. Oxidation-specific epitopes are important targets of innate immunity. J. Intern. Med. 263, 479–488 (2008)

    Article  CAS  ADS  Google Scholar 

  2. Esterbauer, H., Schaur, R. J. & Zollner, H. Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic. Biol. Med. 11, 81–128 (1991)

    Article  CAS  Google Scholar 

  3. Chang, M. K. et al. Monoclonal antibodies against oxidized low-density lipoprotein bind to apoptotic cells and inhibit their phagocytosis by elicited macrophages: evidence that oxidation-specific epitopes mediate macrophage recognition. Proc. Natl Acad. Sci. USA 96, 6353–6358 (1999)

    Article  CAS  ADS  Google Scholar 

  4. Miller, Y. I. et al. Oxidation-specific epitopes are danger-associated molecular patterns recognized by pattern recognition receptors of innate immunity. Circ. Res. 108, 235–248 (2011)

    Article  CAS  Google Scholar 

  5. Hollyfield, J. G. et al. Oxidative damage-induced inflammation initiates age-related macular degeneration. Nature Med. 14, 194–198 (2008)

    Article  CAS  Google Scholar 

  6. Suzuki, M. et al. Oxidized phospholipids in the macula increase with age and in eyes with age-related macular degeneration. Mol. Vis. 13, 772–778 (2007)

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Jager, R. D., Mieler, W. F. & Miller, J. W. Age-related macular degeneration. N. Engl. J. Med. 358, 2606–2617 (2008)

    Article  CAS  Google Scholar 

  8. Schutt, F., Bergmann, M., Holz, F. G. & Kopitz, J. Proteins modified by malondialdehyde, 4-hydroxynonenal, or advanced glycation end products in lipofuscin of human retinal pigment epithelium. Invest. Ophthalmol. Vis. Sci. 44, 3663–3668 (2003)

    Article  Google Scholar 

  9. Thiele, G. M. et al. Malondialdehyde-acetaldehyde (MAA) modified proteins induce pro-inflammatory and pro-fibrotic responses by liver endothelial cells. Comp. Hepatol. 3 (suppl. 1). S25 (2004)

    Article  Google Scholar 

  10. Shanmugam, N. et al. Proinflammatory effects of advanced lipoxidation end products in monocytes. Diabetes 57, 879–888 (2008)

    Article  CAS  Google Scholar 

  11. Shechter, I. et al. The metabolism of native and malondialdehyde-altered low density lipoproteins by human monocyte-macrophages. J. Lipid Res. 22, 63–71 (1981)

    CAS  PubMed  ADS  Google Scholar 

  12. Chou, M. Y. et al. Oxidation-specific epitopes are dominant targets of innate natural antibodies in mice and humans. J. Clin. Invest. 119, 1335–1349 (2009)

    Article  CAS  Google Scholar 

  13. Xu, D. et al. Epitope characterization of malondialdehyde-acetaldehyde adducts using an enzyme-linked immunosorbent assay. Chem. Res. Toxicol. 10, 978–986 (1997)

    Article  CAS  Google Scholar 

  14. Zipfel, P. F. & Skerka, C. Complement regulators and inhibitory proteins. Nature Rev. Immunol. 9, 729–740 (2009)

    Article  CAS  Google Scholar 

  15. Józsi, M. & Zipfel, P. F. Factor H family proteins and human diseases. Trends Immunol. 29, 380–387 (2008)

    Article  Google Scholar 

  16. Haines, J. L. et al. Complement factor H variant increases the risk of age-related macular degeneration. Science 308, 419–421 (2005)

    Article  CAS  ADS  Google Scholar 

  17. Klein, R. J. et al. Complement factor H polymorphism in age-related macular degeneration. Science 308, 385–389 (2005)

    Article  CAS  ADS  Google Scholar 

  18. Edwards, A. O. et al. Complement factor H polymorphism and age-related macular degeneration. Science 308, 421–424 (2005)

    Article  CAS  ADS  Google Scholar 

  19. Hageman, G. S. et al. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc. Natl Acad. Sci. USA 102, 7227–7232 (2005)

    Article  CAS  ADS  Google Scholar 

  20. Hughes, A. E. et al. A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration. Nature Genet. 38, 1173–1177 (2006)

    Article  CAS  Google Scholar 

  21. Takizawa, F., Tsuji, S. & Nagasawa, S. Enhancement of macrophage phagocytosis upon iC3b deposition on apoptotic cells. FEBS Lett. 397, 269–272 (1996)

    Article  CAS  Google Scholar 

  22. Amarilyo, G. et al. iC3b-opsonized apoptotic cells mediate a distinct anti-inflammatory response and transcriptional NF-κB-dependent blockade. Eur. J. Immunol. 40, 699–709 (2010)

    Article  CAS  Google Scholar 

  23. Higgins, G. T., Wang, J. H., Dockery, P., Cleary, P. E. & Redmond, H. P. Induction of angiogenic cytokine expression in cultured RPE by ingestion of oxidized photoreceptor outer segments. Invest. Ophthalmol. Vis. Sci. 44, 1775–1782 (2003)

    Article  Google Scholar 

  24. de Jong, P. T. Age-related macular degeneration. N. Engl. J. Med. 355, 1474–1485 (2006)

    Article  CAS  Google Scholar 

  25. Binder, C. J. et al. Innate and acquired immunity in atherogenesis. Nature Med. 8, 1218–1226 (2002)

    Article  CAS  Google Scholar 

  26. Flierman, R. & Daha, M. R. The clearance of apoptotic cells by complement. Immunobiology 212, 363–370 (2007)

    Article  CAS  Google Scholar 

  27. Trouw, L. A. et al. C4b-binding protein and factor H compensate for the loss of membrane-bound complement inhibitors to protect apoptotic cells against excessive complement attack. J. Biol. Chem. 282, 28540–28548 (2007)

    Article  CAS  Google Scholar 

  28. Meri, S. & Pangburn, M. K. Discrimination between activators and nonactivators of the alternative pathway of complement: regulation via a sialic acid/polyanion binding site on factor H. Proc. Natl Acad. Sci. USA 87, 3982–3986 (1990)

    Article  CAS  ADS  Google Scholar 

  29. Leffler, J. et al. Annexin-II, DNA, and histones serve as factor H ligands on the surface of apoptotic cells. J. Biol. Chem. 285, 3766–3776 (2010)

    Article  CAS  Google Scholar 

  30. Savill, J., Dransfield, I., Gregory, C. & Haslett, C. A blast from the past: clearance of apoptotic cells regulates immune responses. Nature Rev. Immunol. 2, 965–975 (2002)

    Article  CAS  Google Scholar 

  31. Chang, M. K. et al. Apoptotic cells with oxidation-specific epitopes are immunogenic and proinflammatory. J. Exp. Med. 200, 1359–1370 (2004)

    Article  CAS  Google Scholar 

  32. Mihlan, M., Stippa, S., Jozsi, M. & Zipfel, P. F. Monomeric CRP contributes to complement control in fluid phase and on cellular surfaces and increases phagocytosis by recruiting factor H. Cell Death Differ. 16, 1630–1640 (2009)

    Article  CAS  Google Scholar 

  33. Thakkinstian, A. et al. Systematic review and meta-analysis of the association between complement factor H Y402H polymorphisms and age-related macular degeneration. Hum. Mol. Genet. 15, 2784–2790 (2006)

    Article  CAS  Google Scholar 

  34. Donoso, L. A., Vrabec, T. & Kuivaniemi, H. The role of complement factor H in age-related macular degeneration: a review. Surv. Ophthalmol. 55, 227–246 (2010)

    Article  Google Scholar 

  35. Clark, S. J. et al. His-384 allotypic variant of factor H associated with age-related macular degeneration has different heparin binding properties from the non-disease-associated form. J. Biol. Chem. 281, 24713–24720 (2006)

    Article  CAS  Google Scholar 

  36. Green, W. R. & Enger, C. Age-related macular degeneration histopathologic studies. The 1992 Lorenz E. Zimmerman Lecture. Ophthalmology 100, 1519–1535 (1993)

    Article  CAS  Google Scholar 

  37. Sun, M. et al. Light-induced oxidation of photoreceptor outer segment phospholipids generates ligands for CD36-mediated phagocytosis by retinal pigment epithelium: a potential mechanism for modulating outer segment phagocytosis under oxidant stress conditions. J. Biol. Chem. 281, 4222–4230 (2006)

    Article  CAS  Google Scholar 

  38. Kaemmerer, E., Schutt, F., Krohne, T. U., Holz, F. G. & Kopitz, J. Effects of lipid peroxidation-related protein modifications on RPE lysosomal functions and POS phagocytosis. Invest. Ophthalmol. Vis. Sci. 48, 1342–1347 (2007)

    Article  Google Scholar 

  39. Goverdhan, S. V. et al. Interleukin-8 promoter polymorphism −251A/T is a risk factor for age-related macular degeneration. Br. J. Ophthalmol. 92, 537–540 (2008)

    Article  CAS  Google Scholar 

  40. Sofat, R. et al. Genetic variation in complement factor H and risk of coronary heart disease: eight new studies and a meta-analysis of around 48,000 individuals. Atherosclerosis 213, 184–190 (2010)

    Article  CAS  Google Scholar 

  41. Scholl, H. P. et al. Systemic complement activation in age-related macular degeneration. PLoS ONE 3, e2593 (2008)

    Article  ADS  Google Scholar 

  42. Binder, C. J. et al. Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL. Nature Med. 9, 736–743 (2003)

    Article  CAS  Google Scholar 

Download references


We are indebted to M. Ozsvar-Kozma for technical assistance, S. Hälbich for performing the surface plasmon resonance analysis, A. Hartmann for purification of CFH variants from patient plasma, C. Mannhalter for help with genotyping, and E. N. Montano. This work was supported by the Austrian Academy of Sciences, a BRIDGE grant from the Austrian Research Promotion Agency, the SFB Lipotox F30 of the Austrian Science Fund (C.J.B.); NIH grants HL088093 (C.J.B., S.T., J.L.W.), RO1 HL086599 (K.H., J.L.W.), EY14005, EY019044 (J.T.H.); the Edward N. & Della L. Thome Memorial Foundation Awards Program in AMD Research, Research to Prevent Blindness (Wilmer Eye institute) (J.T.H.); the Deutsche Forschungsgemeinschaft (P.F.Z., C.S.); the ProRetina Foundation (N.L., P.F.Z., C.S.); the Fondation Leducq (C.J.B., S.T., J.L.W.); the Wynn-Gund Translational Research Acceleration Program Enhanced Research and Clinical Training Award, National Neurovision Research Institute – Foundation Fighting Blindness, Macular Degeneration Research Award, American Health Assistance Foundation (H.P.N.S.); European Commission and the Seventh European Community Framework Program, Marie Curie Intra-European Fellowship (P.C.I.). K.H. was supported by the Scientist Development Grant 0630228N of the American Heart Association. J.T.H. is the Robert Bond Welch Professor. We thank all patients for participation.

Author information

Authors and Affiliations



D.W. and C.J.B. conceived the project and designed and analysed the experiments with contributions from J.L.W., P.F.Z., J.T.H., G.S.-F. and C.S.; D.W. performed most of the experiments, with contributions from K.H., N.L., K.L.B., M.C., S.T. and H.B.; H.P.N.S. and P.C.I. obtained and provided AMD plasma samples; D.W. and C.J.B. wrote the manuscript with contributions from J.L.W., P.F.Z. and J.T.H.

Corresponding author

Correspondence to Christoph J. Binder.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-15 with legends, Supplementary Methods, which includes 3 tables and additional references and Supplementary Table 1. (PDF 1367 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Weismann, D., Hartvigsen, K., Lauer, N. et al. Complement factor H binds malondialdehyde epitopes and protects from oxidative stress. Nature 478, 76–81 (2011).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing