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Peter F. Zipfel - One of the best experts on this subject based on the ideXlab platform.
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Standardisation of tHe Factor H autoantibody assay.
Immunobiology, 2014Co-Authors: Rachael Watson, Eva-maria Hunze, Peter F. Zipfel, Susanne Lindner, Pauline Bordereau, Federico Feroze Tak, Stéphanie Ngo, Christina Skerka, Marie-agnès Dragon-durey, Kevin J. MarchbankAbstract:Abstract THe screening of all atypical Haemolytic uraemic syndrome (aHUS) patients for Factor H autoantibodies is best practice. However, tHere is no consensus assay for tHe reporting of Factor H autoantibody titres. In tHis study, tHree European complement laboratories witH expertise in tHe field of autoantibody testing address tHis by systematically evaluating several ELISA metHods used for tHe detection of Factor H autoantibodies. All metHods tested adequately detect HigH titre samples. However, tHis study recommends tHe Paris metHod for tHe detection and reporting of Factor H autoantibodies to be used wHen setting up a Factor H autoantibody screen. THe importance of individual sample background subtraction in tHese ELISA tests was establisHed. THe use of a relative or arbitrary unit index witH a common positive and negative serum allowed for consistent comparison of findings from different test centres. THerefore, it is recommended tHat a standard arbitrary unit scale based on a titration curve from a common positive anti-serum be adopted to allow future establisHment of tHe relative importance of particular titres of Factor H autoantibodies in aHUS. Systematic assay for tHe presence of Factor H autoantibodies in patients using tHe Paris metHod will provide tHe longitudinal analysis needed to fully establisH tHe importance of Factor H autoantibodies in disease. THis will feed into additional researcH to clarify wHetHer additional Factors Have a bearing on tHe pHenotype/outcome of autoimmune aHUS.
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Human complement Factor H and Factor H-like protein 1 are expressed in Human retinal pigment epitHelial cells.
Ophthalmic Research, 2013Co-Authors: Andreas W. A. Weinberger, Peter F. Zipfel, Cordula Eddahabi, Dörthe Carstesen, Peter Walter, Christine SkerkaAbstract:Background: A common Haplotype in tHe gene for tHe regulator of tHe alternative patHway of complement activation Factor H Has been linked to individual predisposi
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glycerol 3 pHospHate deHydrogenase 2 is a novel Factor H Factor H like protein 1 and plasminogen binding surface protein of candida albicans
The Journal of Infectious Diseases, 2013Co-Authors: Shanshan Luo, Peter F. Zipfel, Christine Skerka, Ralf HoffmannAbstract:Candida albicans uses Human complement regulators sucH as Factor H and Factor H-like protein 1 (FHL-1) for immune evasion. To define tHe wHole panel of fungal complement-evasion molecules, C. albicans cell extract was absorbed to a Factor H-coupled matrix. One 52-kDa protein was eluted and identified by mass spectrometry as glycerol-3-pHospHate deHydrogenase 2 (Gpd2). Consequently, Gpd2 was recombinantly expressed and purified. Recombinant Gpd2 binds Factor Hand and FHL-1, mainly via sHort consensus repeat 7; and binds plasminogen, via lysine residues. THe 3 Human complement regulators, wHen attacHed to candida Gpd2, became functionally active, and tHe attacHed Host proteins assist in inactivation of tHe complement cascade or cleave fibrinogen in tHe extracellular matrix component fibrinogen. Polyclonal Gpd2 antiserum was generated and localized Gpd2 at tHe surface of C. albicans. In addition, candida Gpd2 bound to Human nonpHagocytic cells but not to pHagocytic U937 cells. THus, candida Gpd2 is a novel fungal immune evasion protein tHat binds several Human complement regulators and, in addition, binds Human cells.
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Factor H family proteins and Human diseases.
Trends in Immunology, 2008Co-Authors: Mihály Józsi, Peter F. ZipfelAbstract:Complement is a major defense system of innate immunity and aimed to destroy microbes. One of tHe central complement regulators is Factor H, wHicH belongs to a protein family tHat includes CFHL1 and five Factor H-related (CFHR) proteins. Recent evidence sHows tHat Factor H family proteins (Factor H and CFHRs) are associated witH diverse and severe Human diseases and are also used by Human patHogenic microbes for complement evasion. THerefore, dissecting tHe exact functions of tHe individual CFHR proteins will provide insigHts into tHe patHopHysiology of sucH inflammatory and infectious diseases and will define tHe tHerapeutic potential of tHese proteins.
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Hemolytic uremic syndrome a Factor H mutation e1172stop causes defective complement control at tHe surface of endotHelial cells
Journal of The American Society of Nephrology, 2007Co-Authors: Stefan Heinen, Mihály Józsi, Christine Skerka, Marina Noris, Giuseppe Remuzzi, Andrea Hartmann, Peter F. ZipfelAbstract:Defective complement regulation results in Hemolytic uremic syndrome (HUS), a disease tHat is cHaracterized by microangiopatHy, tHrombocytopenia, and acute renal failure and tHat causes endotHelial cell damage. For cHaracterization of How defective complement regulation relates to tHe patHopHysiology, tHe role of tHe complement regulator Factor H and also of a mutant Factor H protein was studied on tHe surface of Human umbilical vein endotHelial cells. THe mutant 145-kD Factor H protein was purified to Homogeneity, from plasma of a patient witH HUS, wHo is Heterozygous for a Factor H gene mutation G3587T, wHicH introduces a stop codon at position 1172. Functional analyses sHow tHat tHe lack of tHe most C-terminal domain sHort consensus repeats 20 severely affected recognition functions (i.e., binding to Heparin, C3b, C3d, and tHe surface of endotHelial cells). Wild-type Factor H as well as tHe mutant protein formed dimers in solution as sHown by cross-linking studies and mass spectroscopy. WHen assayed in fluid pHase, tHe complement regulatory activity of tHe mutant protein was normal and comparable to wild-type Factor H. However, on tHe surface of endotHelial cells, tHe mutant Factor H protein sHowed severely reduced regulatory activities and lacked protective functions. Similarly, witH tHe use of sHeep erytHrocytes, tHe mutant protein lacked tHe protective activity and caused increased Hemolysis wHen it was added to Factor H-depleted plasma. THis study sHows How a mutation tHat affects tHe C-terminal region of tHe Factor H protein leads to defective complement control on cell surfaces and damage to endotHelial cells in patients witH HUS. THese effects explain How mutant Factor H causes defective complement control and in HUS-particularly under condition of inflammation and complement activation-causes endotHelial cell damage.
Mihály Józsi - One of the best experts on this subject based on the ideXlab platform.
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Regulation of regulators: Role of tHe complement Factor H-related proteins.
Seminars in Immunology, 2019Co-Authors: Marcell Cserhalmi, Alexandra Papp, Bianca Brandus, Barbara Uzonyi, Mihály JózsiAbstract:THe complement system, wHile being an essential and very efficient effector component of innate immunity, may cause damage to tHe Host and result in various inflammatory, autoimmune and infectious diseases or cancer, wHen it is improperly activated or regulated. Factor H is a serum glycoprotein and tHe main regulator of tHe activity of tHe alternative complement patHway. Factor H, togetHer witH its splice variant Factor H-like protein 1 (FHL-1), inHibits complement activation at tHe level of tHe central complement component C3 and beyond. In Humans, tHere are also five Factor H-related (FHR) proteins, wHose function is poorly cHaracterized. WHile data indicate complement inHibiting activity for some of tHe FHRs, tHere is increasing evidence tHat FHRs Have an opposite role compared witH Factor H and FHL-1, namely, tHey enHance complement activation directly and also by competing witH tHe regulators FH and FHL-1. THis review summarizes tHe current stand and recent data on tHe roles of Factor H family proteins in HealtH and disease, witH focus on tHe function of FHR proteins.
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Complement Factor H family proteins in tHeir non-canonical role as modulators of cellular functions.
Seminars in Cell & Developmental Biology, 2019Co-Authors: Mihály Józsi, Andrea E. Schneider, Éva Kárpáti, Noémi SándorAbstract:Complement Factor H is a major regulator of tHe alternative patHway of tHe complement system. THe Factor H-related proteins are less cHaracterized, but recent data indicate tHat tHey ratHer promote complement activation. THese proteins Have some common ligands witH Factor H and Have botH overlapping and distinct functions depending on domain composition and tHe degree of conservation of amino acid sequence. Factor H and some of tHe Factor H-related proteins also appear in a non-canonical function tHat is beyond tHeir role in tHe modulation of complement activation. THis review covers our current understanding on tHis emerging role of Factor H family proteins in modulating tHe activation and function of various cells by binding to receptors or receptor ligands.
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Factor H Family Proteins in Complement Evasion of Microorganisms.
Frontiers in Immunology, 2017Co-Authors: Mihály JózsiAbstract:Human-patHogenic microbes possess various means to avoid destruction by our immune system. THese include interactions witH tHe Host complement system tHat may facilitate patHogen entry into cells and tissues, expression of molecules tHat defuse tHe effector complement components and complexes, and acquisition of Host complement inHibitors to down-regulate complement activity on tHe surface of tHe patHogen. A growing number of patHogenic microorganisms Have acquired tHe ability to bind tHe complement inHibitor Factor H from body fluids and tHus Hijack its Host protecting function. In addition to Factor H, binding of Factor H-related proteins was also demonstrated for several microbes. Initial studies assumed tHat tHese proteins are complement inHibitors similar to Factor H. However, recent evidence suggest tHat Factor H-related proteins may ratHer enHance complement activation botH directly and also by competing witH tHe inHibitor Factor H for binding to certain ligands and surfaces. THis mini review focusses on tHe role of tHe main alternative patHway regulator Factor H in Host-patHogen interactions, as well as on tHe emerging role of tHe Factor H-related proteins as enHancers of complement activation.
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Atypical Hemolytic Uremic Syndrome-Associated Variants and Autoantibodies Impair Binding of Factor H and Factor H-Related Protein 1 to Pentraxin 3
The Journal of Immunology, 2012Co-Authors: Anne Kopp, Stefanie Strobel, Pilar Sánchez-corral, Agustín Tortajada, Santiago Rodríguez De Córdoba, Zoltán Prohászka, Margarita López-trascasa, Mihály JózsiAbstract:Atypical Hemolytic uremic syndrome (aHUS) is a renal disease associated witH complement alternative patHway dysregulation and is cHaracterized by endotHelial injury. Pentraxin 3 (PTX3) is a soluble pattern recognition molecule expressed by endotHelial cells and upregulated under inflammatory conditions. PTX3 activates complement, but it also binds tHe complement inHibitor Factor H. In tHis study, we sHow tHat native Factor H, Factor H-like protein 1, and Factor H-related protein 1 (CFHR1) bind to PTX3 and tHat PTX3-bound Factor H and Factor H-like protein 1 maintain tHeir complement regulatory activities. PTX3, wHen bound to extracellular matrix, recruited functionally active Factor H. Residues witHin sHort consensus repeat 20 of Factor H tHat are relevant for PTX3 binding were identified using a peptide array. aHUS-associated Factor H mutations witHin tHis binding site caused a reduced Factor H binding to PTX3. Similarly, seven of nine analyzed anti-Factor H autoantibodies isolated from aHUS patients inHibited tHe interaction between Factor H and PTX3, and five autoantibodies also inHibited PTX3 binding to CFHR1. Moreover, tHe aHUS-associated CFHR1*B variant sHowed reduced binding to PTX3 in comparison witH CFHR1*A. THus, tHe interactions of PTX3 witH complement regulators are impaired by certain mutations and autoantibodies affecting Factor H and CFHR1, wHicH could result in an enHanced local complement-mediated inflammation, endotHelial cell activation, and damage in aHUS.
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Factor H: a complement regulator in HealtH and disease, and a mediator of cellular interactions.
Biomolecules, 2012Co-Authors: Anne Kopp, Mario Hebecker, Eliška Svobodová, Mihály JózsiAbstract:Complement is an essential part of innate immunity as it participates in Host defense against infections, disposal of cellular debris and apoptotic cells, inflammatory processes and modulation of adaptive immune responses. Several soluble and membrane-bound regulators protect tHe Host from tHe potentially deleterious effects of uncontrolled and misdirected complement activation. Factor H is a major soluble regulator of tHe alternative complement patHway, but it can also bind to Host cells and tissues, protecting tHem from complement attack. Interactions of Factor H witH various endogenous ligands, sucH as pentraxins, extracellular matrix proteins and DNA are important in limiting local complement-mediated inflammation. Impaired regulatory as well as ligand and cell recognition functions of Factor H, caused by mutations or autoantibodies, are associated witH tHe kidney diseases: atypical Hemolytic uremic syndrome and dense deposit disease and tHe eye disorder: age-related macular degeneration. In addition, Factor H binds to receptors on Host cells and is involved in adHesion, pHagocytosis and modulation of cell activation. In tHis review we discuss current concepts on tHe pHysiological and patHopHysiological roles of Factor H in ligHt of new data and recent developments in our understanding of tHe versatile roles of Factor H as an inHibitor of complement activation and inflammation, as well as a mediator of cellular interactions. A detailed knowledge of tHe functions of Factor H in HealtH and disease is expected to unravel novel tHerapeutic intervention possibilities and to facilitate tHe development or improvement of tHerapies.
Christine Skerka - One of the best experts on this subject based on the ideXlab platform.
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Human complement Factor H and Factor H-like protein 1 are expressed in Human retinal pigment epitHelial cells.
Ophthalmic Research, 2013Co-Authors: Andreas W. A. Weinberger, Peter F. Zipfel, Cordula Eddahabi, Dörthe Carstesen, Peter Walter, Christine SkerkaAbstract:Background: A common Haplotype in tHe gene for tHe regulator of tHe alternative patHway of complement activation Factor H Has been linked to individual predisposi
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glycerol 3 pHospHate deHydrogenase 2 is a novel Factor H Factor H like protein 1 and plasminogen binding surface protein of candida albicans
The Journal of Infectious Diseases, 2013Co-Authors: Shanshan Luo, Peter F. Zipfel, Christine Skerka, Ralf HoffmannAbstract:Candida albicans uses Human complement regulators sucH as Factor H and Factor H-like protein 1 (FHL-1) for immune evasion. To define tHe wHole panel of fungal complement-evasion molecules, C. albicans cell extract was absorbed to a Factor H-coupled matrix. One 52-kDa protein was eluted and identified by mass spectrometry as glycerol-3-pHospHate deHydrogenase 2 (Gpd2). Consequently, Gpd2 was recombinantly expressed and purified. Recombinant Gpd2 binds Factor Hand and FHL-1, mainly via sHort consensus repeat 7; and binds plasminogen, via lysine residues. THe 3 Human complement regulators, wHen attacHed to candida Gpd2, became functionally active, and tHe attacHed Host proteins assist in inactivation of tHe complement cascade or cleave fibrinogen in tHe extracellular matrix component fibrinogen. Polyclonal Gpd2 antiserum was generated and localized Gpd2 at tHe surface of C. albicans. In addition, candida Gpd2 bound to Human nonpHagocytic cells but not to pHagocytic U937 cells. THus, candida Gpd2 is a novel fungal immune evasion protein tHat binds several Human complement regulators and, in addition, binds Human cells.
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Hemolytic uremic syndrome a Factor H mutation e1172stop causes defective complement control at tHe surface of endotHelial cells
Journal of The American Society of Nephrology, 2007Co-Authors: Stefan Heinen, Mihály Józsi, Christine Skerka, Marina Noris, Giuseppe Remuzzi, Andrea Hartmann, Peter F. ZipfelAbstract:Defective complement regulation results in Hemolytic uremic syndrome (HUS), a disease tHat is cHaracterized by microangiopatHy, tHrombocytopenia, and acute renal failure and tHat causes endotHelial cell damage. For cHaracterization of How defective complement regulation relates to tHe patHopHysiology, tHe role of tHe complement regulator Factor H and also of a mutant Factor H protein was studied on tHe surface of Human umbilical vein endotHelial cells. THe mutant 145-kD Factor H protein was purified to Homogeneity, from plasma of a patient witH HUS, wHo is Heterozygous for a Factor H gene mutation G3587T, wHicH introduces a stop codon at position 1172. Functional analyses sHow tHat tHe lack of tHe most C-terminal domain sHort consensus repeats 20 severely affected recognition functions (i.e., binding to Heparin, C3b, C3d, and tHe surface of endotHelial cells). Wild-type Factor H as well as tHe mutant protein formed dimers in solution as sHown by cross-linking studies and mass spectroscopy. WHen assayed in fluid pHase, tHe complement regulatory activity of tHe mutant protein was normal and comparable to wild-type Factor H. However, on tHe surface of endotHelial cells, tHe mutant Factor H protein sHowed severely reduced regulatory activities and lacked protective functions. Similarly, witH tHe use of sHeep erytHrocytes, tHe mutant protein lacked tHe protective activity and caused increased Hemolysis wHen it was added to Factor H-depleted plasma. THis study sHows How a mutation tHat affects tHe C-terminal region of tHe Factor H protein leads to defective complement control on cell surfaces and damage to endotHelial cells in patients witH HUS. THese effects explain How mutant Factor H causes defective complement control and in HUS-particularly under condition of inflammation and complement activation-causes endotHelial cell damage.
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Factor H family proteins: on complement, microbes and Human diseases.
Biochemical Society Transactions, 2002Co-Authors: Peter F. Zipfel, Seppo Meri, Christine Skerka, Marina Noris, Jens Hellwage, S. T. Jokiranta, V. Brade, Peter Kraiczy, G. RemuzziAbstract:At present, tHe Human Factor H protein family represents seven multidomain, multifunctional serum proteins. THis group includes tHe complement and immune regulators Factor H, tHe Factor H-like protein 1 (FHL-1) and five Factor H-related proteins proteins (FHR-1, -2, -3, -4 and -5). EacH is exclusively composed of individually folded protein domains, termed sHort consensus repeats (SCRs) or complement control modules. Structure-function analyses allowed tHe localization of tHe complement regulatory domain of Factor H and FHL-1 in tHe N-terminal region witHin SCRs 1–4. In addition, multiple binding sites for C3b, Heparin and microbial surface proteins were localized in tHe N-terminus, witHin tHe middle region and also in tHe C-terminus of Factor H and FHL-1. Recent results sHow a central role for tHe C-terminus of Factor H, i.e. SCRs 19–20. THese particular domains are conserved in all FHRs identified so far, include contact points for C3b, Heparin and microbial surface proteins and represent a ‘Hot-spot’ for gene mutations in patients tHat suffer from tHe Factor H-associated form of Haemolytic uraemic syndrome.
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Complement Factor H and Hemolytic uremic syndrome
International Immunopharmacology, 2001Co-Authors: Peter F. Zipfel, Christine Skerka, Jessica Caprioli, Tamara Manuelian, Hartmut H.p. Neumann, Marina Noris, Giuseppe RemuzziAbstract:Factor H is a 150 kDa single cHain plasma glycoprotein tHat plays a pivotal role in tHe regulation of tHe alternative patHway of complement. Primary sequence analysis reveals a structural organization of tHis plasma protein, in 20 Homologous units, called SHort Consensus Repeats (SCRs), eacH about 60 amino acids long. BiocHemical and genetic studies sHow an association between Factor H deficiency and Human diseases, including Systemic Lupus ErytHematosus, susceptibility to pyogenic infection and a form of menbranoproliferative glomerulonepHropatHy. More recently, Factor H deficiency Has also been associated witH susceptibility to Hemolytic Uremic Syndrome (HUS), a disease consisting of microangiopatHic Hemolytic anemia, tHrombocytopenia and acute renal failure, caused by platelet tHrombi wHicH mainly, but not exclusively, form in tHe microcirculation of tHe kidney. In tHis review, we summarize recent genetic and biocHemical data, wHicH indicate a critical role for Factor H in tHe patHogenesis of HUS and suggest an important role of tHe most C-terminal domain, i.e. SCR 20, in tHe disease. In addition, we discuss tHe pHysiological consequences of tHese findings, as novel functional data sHow a particular essential role of SCR 20 of Factor H as tHe central discriminatory and regulatory site of tHis multidomain, multifunctional plasma protein.
Santiago Rodríguez De Córdoba - One of the best experts on this subject based on the ideXlab platform.
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Atypical Hemolytic Uremic Syndrome-Associated Variants and Autoantibodies Impair Binding of Factor H and Factor H-Related Protein 1 to Pentraxin 3
The Journal of Immunology, 2012Co-Authors: Anne Kopp, Stefanie Strobel, Pilar Sánchez-corral, Agustín Tortajada, Santiago Rodríguez De Córdoba, Zoltán Prohászka, Margarita López-trascasa, Mihály JózsiAbstract:Atypical Hemolytic uremic syndrome (aHUS) is a renal disease associated witH complement alternative patHway dysregulation and is cHaracterized by endotHelial injury. Pentraxin 3 (PTX3) is a soluble pattern recognition molecule expressed by endotHelial cells and upregulated under inflammatory conditions. PTX3 activates complement, but it also binds tHe complement inHibitor Factor H. In tHis study, we sHow tHat native Factor H, Factor H-like protein 1, and Factor H-related protein 1 (CFHR1) bind to PTX3 and tHat PTX3-bound Factor H and Factor H-like protein 1 maintain tHeir complement regulatory activities. PTX3, wHen bound to extracellular matrix, recruited functionally active Factor H. Residues witHin sHort consensus repeat 20 of Factor H tHat are relevant for PTX3 binding were identified using a peptide array. aHUS-associated Factor H mutations witHin tHis binding site caused a reduced Factor H binding to PTX3. Similarly, seven of nine analyzed anti-Factor H autoantibodies isolated from aHUS patients inHibited tHe interaction between Factor H and PTX3, and five autoantibodies also inHibited PTX3 binding to CFHR1. Moreover, tHe aHUS-associated CFHR1*B variant sHowed reduced binding to PTX3 in comparison witH CFHR1*A. THus, tHe interactions of PTX3 witH complement regulators are impaired by certain mutations and autoantibodies affecting Factor H and CFHR1, wHicH could result in an enHanced local complement-mediated inflammation, endotHelial cell activation, and damage in aHUS.
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Genetic and environmental Factors influencing tHe Human Factor H plasma levels.
Immunogenetics, 2004Co-Authors: Jorge Esparza-gordillo, Jose Manuel Soria, Alfonso Buil, Laura Almasy, John Blangero, Jordi Fontcuberta, Santiago Rodríguez De CórdobaAbstract:Factor H is a plasma protein tHat plays a critical role in tHe regulation of complement activation in fluid pHase and on cellular surfaces. Over tHe years numerous reports Have illustrated tHe association of Factor H deficiencies witH cHronic renal and infectious diseases. Plasma levels of Factor H sHow a five-fold range of variation in Humans (116–562 μg/ml), wHicH may also be relevant to disease susceptibility. To quantify tHe effects of tHe genetic and environmental Factors responsible for tHe variation in tHe Factor H plasma levels, we Have applied variance-component metHods to a family-based sample. Factor H plasma levels sHow an age-dependent increase (P
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genetic and environmental Factors influencing tHe Human Factor H plasma levels
Immunogenetics, 2004Co-Authors: Jorge Esparzagordillo, Jose Manuel Soria, Alfonso Buil, Laura Almasy, John Blangero, Jordi Fontcuberta, Santiago Rodríguez De CórdobaAbstract:Factor H is a plasma protein tHat plays a critical role in tHe regulation of complement activation in fluid pHase and on cellular surfaces. Over tHe years numerous reports Have illustrated tHe association of Factor H deficiencies witH cHronic renal and infectious diseases. Plasma levels of Factor H sHow a five-fold range of variation in Humans (116–562 μg/ml), wHicH may also be relevant to disease susceptibility. To quantify tHe effects of tHe genetic and environmental Factors responsible for tHe variation in tHe Factor H plasma levels, we Have applied variance-component metHods to a family-based sample. Factor H plasma levels sHow an age-dependent increase (P<0.0001) and are decreased in smokers (P<0.0001). Interestingly, tHe Heritability of tHe Factor H trait is very HigH (H 2=0.62±0.07; P<0.0001), indicating tHat 62% of tHe Factor H pHenotypic variance is due to tHe additive effects of genes. On tHis premise, we conducted a genome-wide linkage screen in order to identify genes regulating tHe Factor H trait. THree genomic regions (1q32, 2p21–24 and 15q22–24) provided suggestive evidence of linkage (LOD scores 2.03, 2.15 and 2.00, respectively) witH tHe plasma levels of Factor H.
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THe Human complement Factor H: functional roles, genetic variations and disease associations.
Molecular Immunology, 2004Co-Authors: Santiago Rodríguez De Córdoba, Margarita López-trascasa, Jorge Esparza-gordillo, Elena Goicoechea De Jorge, Pilar Sánchez-corralAbstract: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.
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Structural and functional cHaracterization of Factor H mutations associated witH atypical Hemolytic uremic syndrome
The American Journal of Human Genetics, 2002Co-Authors: Pilar Sánchez-corral, Margarita López-trascasa, David Pérez-caballero, Olatz Huarte, Ari M. Simckes, Elena Goicoechea, Santiago Rodríguez De CórdobaAbstract:Genetic studies Have demonstrated tHe involvement of tHe complement regulator Factor H in nondiarrHeal, nonverocytotoxin (i.e., atypical) cases of Hemolytic uremic syndrome. Different Factor H mutations Have been identified in 10%–30% of patients witH atypical Hemolytic uremic syndrome (aHUS), and most of tHese mutations alter single amino acids in tHe C-terminal region of Factor H. AltHougH tHese mutations are considered to be responsible for tHe disease, tHe precise role tHat Factor H plays in tHe patHogenesis of aHUS is unknown. We report Here tHe structural and functional cHaracterization of tHree different Factor H proteins purified from tHe plasma of patients witH aHUS wHo carry tHe Factor H mutations W1183L, V1197A, or R1210C. Structural anomalies in Factor H were found only in R1210C carriers; tHese individuals sHow, in tHeir plasma, a cHaracteristic HigH-molecular-weigHt Factor H protein tHat results from tHe covalent interaction between Factor H and Human serum albumin. Most important, all tHree aHUS-associated Factor H proteins Have a normal coFactor activity in tHe proteolysis of fluid-pHase C3b by Factor I but sHow very low binding to surface-bound C3b. THis functional impairment was also demonstrated in recombinant mutant Factor H proteins expressed in COS7 cells. THese data support tHe HypotHesis tHat patients witH aHUS carry a specific dysfunction in tHe protection of cellular surfaces from complement activation, offering new possibilities to improve diagnosis and develop appropriate tHerapies.
Marina Botto - One of the best experts on this subject based on the ideXlab platform.
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Factor i is required for tHe development of membranoproliferative glomerulonepHritis in Factor H deficient mice
Journal of Clinical Investigation, 2008Co-Authors: Kirsten L Rose, Terence H Cook, Anne E Bygrave, M J Walport, Danielle Paixaocavalcante, Jennifer Fish, Anthony P Manderson, Talat H Malik, Steven H Sacks, Marina BottoAbstract:THe inflammatory kidney disease membranoproliferative glomerulonepHritis type II (MPGN2) is associated witH dysregulation of tHe alternative patHway of complement activation. MPGN2 is cHaracterized by tHe presence of complement C3 along tHe glomerular basement membrane (GBM). Spontaneous activation of C3 tHrougH tHe alternative patHway is regulated by 2 plasma proteins, Factor H and Factor I. Deficiency of eitHer of tHese regulators results in uncontrolled C3 activation, altHougH tHe breakdown of activated C3 is dependent on Factor I. Deficiency of Factor H, but not Factor I, is associated witH MPGN2 in Humans, pigs, and mice. To explain tHis discordance, mice witH single or combined deficiencies of tHese Factors were studied. MPGN2 did not develop in mice witH combined Factor H and I deficiency or in mice deficient in Factor I alone. However, administration of a source of Factor I to mice witH combined Factor H and Factor I deficiency triggered botH activated C3 fragments in plasma and GBM C3 deposition. Mouse renal transplant studies demonstrated tHat C3 deposited along tHe GBM was derived from plasma. TogetHer, tHese findings provide wHat we believe to be tHe first evidence tHat Factor I–mediated generation of activated C3 fragments in tHe circulation is a critical determinant for tHe development of MPGN2 associated witH Factor H deficiency.
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uncontrolled c3 activation causes membranoproliferative glomerulonepHritis in mice deficient in complement Factor H
Nature Genetics, 2002Co-Authors: Matthew C. Pickering, Terence H Cook, Joanna Warren, Anne E Bygrave, Jill Moss, M J Walport, Marina BottoAbstract:THe alternative patHway of complement is activated continuously in vivo tHrougH tHe C3 'tick-over' patHway1. THis patHway is triggered by tHe Hydrolysis of C3, resulting in tHe formation of C3 convertase. THis, in turn, generates C3b, wHicH mediates many of tHe biological functions of complement. Factor H, tHe main regulator of tHis activation, prevents formation and promotes dissociation of tHe C3 convertase enzyme2,3, and, togetHer witH Factor I, mediates tHe proteolytic inactivation of C3b4. Factor H deficiency, described in 29 individuals from 12 families5,6,7,8,9,10,11,12,13,14 and in pigs15, allows unHindered activation of fluid-pHase C3 and severe depletion of plasma C3 (ref. 11). Membranoproliferative glomerulonepHritis (MPGN) occurs in Factor H–deficient Humans6,12,13 and pigs15. AltHougH MPGN Has been reported in otHer conditions in wHicH uncontrolled activation of C3 occurs, tHe role of C3 dysregulation in tHe patHogenesis of MPGN is not understood. Here we sHow tHat mice deficient in Factor H (CfH−/− mice) develop MPGN spontaneously and are Hypersensitive to developing renal injury caused by immune complexes. Introducing a second mutation in tHe gene encoding complement Factor B, wHicH prevents C3 turnover in vivo, obviates tHe pHenotype of CfH−/− mice. THus, uncontrolled C3 activation in vivo is essential for tHe development of MPGN associated witH deficiency of Factor H.
