{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Complement factor H–related protein 1 (CFHR1) is a member of a family of plasma regulators that are structurally related to complement factor H (CFH) and plays a multifaceted role in modulating the alternative pathway of complement activation. In several studies, CFHR1 has been shown to compete with CFH for binding to central complement components such as C3b and its degradation products, thereby influencing the degree and localization of complement regulation on cellular surfaces and in the fluid phase."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": " In addition, genetic studies have identified that deletions encompassing CFHR1 (often together with the adjacent CFHR3 gene) can substantially alter disease susceptibility. For example, in atypical hemolytic uremic syndrome (aHUS) the absence of CFHR1 is frequently associated with the development of autoantibodies against CFH—an acquired defect that impairs efficient complement regulation on cell surfaces—and thereby predisposes individuals to renal injury."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "9"}]}, {"type": "t", "text": " Conversely, in disorders such as age‐related macular degeneration (AMD) and IgA nephropathy, deletions removing CFHR1 (and CFHR3) appear to confer protection, likely by reducing competition with CFH and thereby enabling more effective local complement inhibition."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "13"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Furthermore, several pathogens have evolved to exploit CFHR1 for immune evasion. Microorganisms—including Staphylococcus aureus, Aspergillus fumigatus, and Borrelia burgdorferi—bind CFHR1 (often in conjunction with CFH) via specific surface proteins; once recruited, CFHR1 can contribute to the down‐regulation of complement activation on the pathogen surface, thus aiding in their survival within the host."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "16"}]}, {"type": "t", "text": " In addition, CFHR1 has been implicated in modulating leukocyte function as it can interact with complement receptor 3 on neutrophils, thereby enhancing cell adhesion and amplifying antimicrobial responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Taken together, these findings underline the complexity of CFHR1’s function. As a molecule that can both compete with and modulate CFH activity and that may be appropriated by pathogens to inhibit complement‐mediated clearance, CFHR1 is a critical regulator of the alternative complement pathway. Variations in its gene copy number or functional integrity can tip the delicate balance of complement activation, thereby contributing to a spectrum of complement‐mediated diseases.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Daniel P Gale, Elena Goicoechea de Jorge, H Terence Cook, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Lancet (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/S0140-6736(10)60670-8"}], "href": "https://doi.org/10.1016/S0140-6736(10"}, {"type": "t", "text": "60670-8) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20800271"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20800271"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Lars G Fritsche, Nadine Lauer, Andrea Hartmann, et al. "}, {"type": "b", "children": [{"type": "t", "text": "An imbalance of human complement regulatory proteins CFHR1, CFHR3 and factor H influences risk for age-related macular degeneration (AMD)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddq399"}], "href": "https://doi.org/10.1093/hmg/ddq399"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20843825"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20843825"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Agustín Tortajada, Hugo Yébenes, Cynthia Abarrategui-Garrido, et al. "}, {"type": "b", "children": [{"type": "t", "text": "C3 glomerulopathy-associated CFHR1 mutation alters FHR oligomerization and complement regulation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI68280"}], "href": "https://doi.org/10.1172/JCI68280"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23728178"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23728178"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Mihály Józsi, Christoph Licht, Stefanie Strobel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Factor H autoantibodies in atypical hemolytic uremic syndrome correlate with CFHR1/CFHR3 deficiency."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2007-09-109876"}], "href": "https://doi.org/10.1182/blood-2007-09-109876"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18006700"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18006700"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Peter F Zipfel, Matthew Edey, Stefan Heinen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Deletion of complement factor H-related genes CFHR1 and CFHR3 is associated with atypical hemolytic uremic syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Genet (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pgen.0030041"}], "href": "https://doi.org/10.1371/journal.pgen.0030041"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17367211"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17367211"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Johannes Hofer, Andreas R Janecke, L B Zimmerhackl, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Complement factor H-related protein 1 deficiency and factor H antibodies in pediatric patients with atypical hemolytic uremic syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin J Am Soc Nephrol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2215/CJN.01260212"}], "href": "https://doi.org/10.2215/CJN.01260212"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23243267"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23243267"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Stefanie Strobel, Cynthia Abarrategui-Garrido, Elena Fariza-Requejo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Factor H-related protein 1 neutralizes anti-factor H autoantibodies in autoimmune hemolytic uremic syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Kidney Int (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ki.2011.152"}], "href": "https://doi.org/10.1038/ki.2011.152"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21677636"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21677636"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Beom Hee Lee, Soo Heon Kwak, Jae Il Shin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Atypical hemolytic uremic syndrome associated with complement factor H autoantibodies and CFHR1/CFHR3 deficiency."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pediatr Res (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1203/PDR.0b013e3181b1bd4a"}], "href": "https://doi.org/10.1203/PDR.0b013e3181b1bd4a"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19531976"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19531976"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Dineke Westra, Elena Volokhina, Eefje van der Heijden, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic disorders in complement (regulating) genes in patients with atypical haemolytic uraemic syndrome (aHUS)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nephrol Dial Transplant (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/ndt/gfq010"}], "href": "https://doi.org/10.1093/ndt/gfq010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20106822"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20106822"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Anne E Hughes, Nick Orr, Hossein Esfandiary, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng1890"}], "href": "https://doi.org/10.1038/ng1890"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16998489"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16998489"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Kylee L Spencer, Michael A Hauser, Lana M Olson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Deletion of CFHR3 and CFHR1 genes in age-related macular degeneration."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddm369"}], "href": "https://doi.org/10.1093/hmg/ddm369"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18084039"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18084039"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Morad Ansari, Paul M McKeigue, Christine Skerka, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic influences on plasma CFH and CFHR1 concentrations and their role in susceptibility to age-related macular degeneration."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddt336"}], "href": "https://doi.org/10.1093/hmg/ddt336"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23873044"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23873044"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Nicholas R Medjeral-Thomas, Hannah J Lomax-Browne, Hannah Beckwith, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Circulating complement factor H-related proteins 1 and 5 correlate with disease activity in IgA nephropathy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Kidney Int (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.kint.2017.03.043"}], "href": "https://doi.org/10.1016/j.kint.2017.03.043"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28673452"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28673452"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Katrin Haupt, Michael Reuter, Jean van den Elsen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Staphylococcus aureus protein Sbi acts as a complement inhibitor and forms a tripartite complex with host complement Factor H and C3b."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Pathog (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.ppat.1000250"}], "href": "https://doi.org/10.1371/journal.ppat.1000250"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19112495"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19112495"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Judith Behnsen, Andrea Hartmann, Jeannette Schmaler, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The opportunistic human pathogenic fungus Aspergillus fumigatus evades the host complement system."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Infect Immun (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/IAI.01037-07"}], "href": "https://doi.org/10.1128/IAI.01037-07"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18039838"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18039838"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Katrin Haupt, Peter Kraiczy, Reinhard Wallich, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Binding of human factor H-related protein 1 to serum-resistant Borrelia burgdorferi is mediated by borrelial complement regulator-acquiring surface proteins."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Infect Dis (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1086/518509"}], "href": "https://doi.org/10.1086/518509"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17538892"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17538892"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Josephine Losse, Peter F Zipfel, Mihály Józsi "}, {"type": "b", "children": [{"type": "t", "text": "Factor H and factor H-related protein 1 bind to human neutrophils via complement receptor 3, mediate attachment to Candida albicans, and enhance neutrophil antimicrobial activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.0901702"}], "href": "https://doi.org/10.4049/jimmunol.0901702"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20008295"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20008295"}]}]}]}