title: Complement Factor H Binds to Human Serum Apolipoprotein E and Mediates Complement Regulation on High Density Lipoprotein Particles.
abstract: The alternative pathway of complement is an important part of the innate immunity response against foreign particles invading the human body. To avoid damage to host cells, it needs to be efficiently down-regulated by plasma factor H (FH) as exemplified by various diseases caused by mutations in its domains 19-20 (FH19-20) and 5-7 (FH5-7). These regions are also the main interaction sites for microbial pathogens that bind host FH to evade complement attack. We previously showed that inhibition of FH binding by a recombinant FH5-7 construct impairs survival of FH binding pathogens in human blood. In this study we found that upon exposure to full blood, the addition of FH5-7 reduces survival of, surprisingly, also those microbes that are not able to bind FH. This effect was mediated by inhibition of complement regulation and subsequently enhanced neutrophil phagocytosis by FH5-7. We found that although FH5-7 does not reduce complement regulation in the actual fluid phase of plasma, it reduces regulation on HDL particles in plasma. Using affinity chromatography and mass spectrometry we revealed that FH interacts with serum apolipoprotein E (apoE) via FH5-7 domains. Furthermore, binding of FH5-7 to HDL was dependent on the concentration of apoE on the HDL particles. These findings explain why the addition of FH5-7 to plasma leads to excessive complement activation and phagocytosis of microbes in full anticoagulated blood. In conclusion, our data show how FH interacts with apoE molecules via domains 5-7 and regulates alternative pathway activation on plasma HDL particles.
authors.affiliation: From the Department of Bacteriology and Immunology, Haartman Institute, and Research Programs Unit, Immunobiology, University of Helsinki, FIN-00014 Helsinki, Finland, Medical Microbiology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands, K.J.Haapasalo-Tuomainen@umcutrecht.nl.
authors.forename: Karita
authors.initials: K
authors.lastname: Haapasalo
authors.affiliation: Medical Microbiology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
authors.forename: Kok
authors.initials: K
authors.lastname: van Kessel
authors.affiliation: From the Department of Bacteriology and Immunology, Haartman Institute, and Research Programs Unit, Immunobiology, University of Helsinki, FIN-00014 Helsinki, Finland.
authors.forename: Eija
authors.initials: E
authors.lastname: Nissilä
authors.affiliation: Department of Molecular Medicine, National Institute for Health and Welfare, Biomedicum, FI-00290 Helsinki, Finland.
authors.forename: Jari
authors.initials: J
authors.lastname: Metso
authors.affiliation: From the Department of Bacteriology and Immunology, Haartman Institute, and Research Programs Unit, Immunobiology, University of Helsinki, FIN-00014 Helsinki, Finland.
authors.forename: Tiira
authors.initials: T
authors.lastname: Johansson
authors.affiliation: University of Helsinki, Institute of Biotechnology, 00014 Helsinki, Finland.
authors.forename: Sini
authors.initials: S
authors.lastname: Miettinen
authors.affiliation: University of Helsinki, Institute of Biotechnology, 00014 Helsinki, Finland.
authors.forename: Markku
authors.initials: M
authors.lastname: Varjosalo
authors.affiliation: HUSLAB, Helsinki University Central Hospital Laboratory, 00290 Helsinki, Finland, and.
authors.forename: Juha
authors.initials: J
authors.lastname: Kirveskari
authors.affiliation: HUSLAB, Helsinki University Central Hospital Laboratory, 00290 Helsinki, Finland, and.
authors.forename: Pentti
authors.initials: P
authors.lastname: Kuusela
authors.affiliation: Institute of Biosciences and Applications, National Center for Scientific Research "Demokritos," 15310 Athens, Greece.
authors.forename: Angelika
authors.identifier: http://orcid.org/0000-0003-3107-1189
authors.initials: A
authors.lastname: Chroni
authors.affiliation: Department of Molecular Medicine, National Institute for Health and Welfare, Biomedicum, FI-00290 Helsinki, Finland.
authors.forename: Matti
authors.initials: M
authors.lastname: Jauhiainen
authors.affiliation: Medical Microbiology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
authors.forename: Jos
authors.identifier: http://orcid.org/0000-0001-6253-0830
authors.initials: J
authors.lastname: van Strijp
authors.affiliation: From the Department of Bacteriology and Immunology, Haartman Institute, and Research Programs Unit, Immunobiology, University of Helsinki, FIN-00014 Helsinki, Finland.
authors.forename: T Sakari
authors.identifier: http://orcid.org/0000-0003-3125-9640
authors.initials: TS
authors.lastname: Jokiranta
mesh_terms: D001057:Apolipoproteins E / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D002846:Chromatography, Affinity; D017242:Complement Factor H / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008075:Lipoproteins, HDL / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D013058:Mass Spectrometry; D011485:Protein Binding; D017434:Protein Structure, Tertiary
chemical_list: D001057:Apolipoproteins E; D008075:Lipoproteins, HDL; D017242:Complement Factor H
keywords: apolipoprotein E (ApoE); complement; complement system; factor H; high density lipoprotein (HDL); inflammation