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[PMID]:29187587
[Au] Autor:Antonioli AH; White J; Crawford F; Renner B; Marchbank KJ; Hannan JP; Thurman JM; Marrack P; Holers VM
[Ad] Endereço:Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045.
[Ti] Título:Modulation of the Alternative Pathway of Complement by Murine Factor H-Related Proteins.
[So] Source:J Immunol;200(1):316-326, 2018 01 01.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Factor H (FH) is a key alternative pathway regulator that controls complement activation both in the fluid phase and on specific cell surfaces, thus allowing the innate immune response to discriminate between self and foreign pathogens. However, the interrelationships between FH and a group of closely related molecules, designated the FH-related (FHR) proteins, are currently not well understood. Whereas some studies have suggested that human FHR proteins possess complement regulatory abilities, recent studies have shown that FHR proteins are potent deregulators. Furthermore, the roles of the FHR proteins have not been explored in any in vivo models of inflammatory disease. In this study, we report the cloning and expression of recombinant mouse FH and three FHR proteins (FHR proteins A-C). Results from functional assays show that FHR-A and FHR-B proteins antagonize the protective function of FH in sheep erythrocyte hemolytic assays and increase cell-surface C3b deposition on a mouse kidney proximal tubular cell line (TEC) and a human retinal pigment epithelial cell line (ARPE-19). We also report apparent values for the binding interaction of mouse C3d with mouse FH (3.85 µM), FHR-A (136 nM), FHR-B (546 nM), and FHR-C (1.04 µM), which directly correlate with results from functional assays. Collectively, our work suggests that similar to their human counterparts, a subset of mouse FHR proteins have an important modulatory role in complement activation. Further work is warranted to define the in vivo context-dependent roles of these proteins and determine whether FHR proteins are suitable therapeutic targets for the treatment of complement-driven diseases.
[Mh] Termos MeSH primário: Proteínas Inativadoras do Complemento C3b/genética
Fator H do Complemento/metabolismo
Via Alternativa do Complemento
Rim/fisiologia
Epitélio Pigmentado da Retina/fisiologia
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Clonagem Molecular
Proteínas Inativadoras do Complemento C3b/metabolismo
Hemólise
Seres Humanos
Imunidade Inata
Imunomodulação
Camundongos
Receptores de Complemento/metabolismo
Tolerância a Antígenos Próprios
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Complement C3b Inactivator Proteins); 0 (Receptors, Complement); 0 (factor H receptors); 80295-65-4 (Complement Factor H)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180131
[Lr] Data última revisão:
180131
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171201
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1602017


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[PMID]:28604974
[Au] Autor:Wang J; Yu W; Xu J; Feng L; Liu X
[Ad] Endereço:Physics and Chemistry Laboratory, Shenzhen Center for Chronic Diseases Prevention and Treatment, Shenzhen, Guangdong 518020, China. liuxl36@126.com.
[Ti] Título:[Study on the CFHR1 level and its genetic polymorphisms in type 2 diabetes mellitus patients].
[So] Source:Zhonghua Yi Xue Yi Chuan Xue Za Zhi;34(3):438-442, 2017 Jun 10.
[Is] ISSN:1003-9406
[Cp] País de publicação:China
[La] Idioma:chi
[Ab] Resumo:OBJECTIVE: To explore the characteristics in CFHR1 concentration and the frequency of CFHR1 gene polymorphisms of patients with type 2 diabetes mellitus (T2DM) based on the high level of complement factor H (CFH) expression among such patients and the similarity between CFHR1 and CFH in terms of sequence and functions. METHODS: Fifty T2DM patients and 30 healthy controls were selected. The plasma samples were separated by pI with OFFGEL electrophoresis following solution digestion. Further separation and identification were carried out on a Nano HPLC-Chip-MS/MS system. Differentially expressed proteins were identified by comparison. Enzyme-linked immunosorbent assay (ELISA) was used to validate the result. Genomic DNA of the two groups was extracted. Polymerase chain reaction and sequencing were used to determine the single nucleotide polymorphisms in the 6 exons of the CFHR1 gene. RESULTS: The CFHR1 level in plasma of T2DM patients were significantly higher than that of the healthy controls (P=2.78× 10 ). A significant difference in allelic frequencies of rs12406079 of the fifth exon of the CFHR1 gene was found between the two groups (χ =5.692, P=0.017). CONCLUSION: The concentration of CFHR1 and frequencies of CFHR1 gene polymorphisms among patients with T2DM differ significantly from healthy subjects. Polymorphisms of the CFHR1 gene are associated with T2DM.
[Mh] Termos MeSH primário: Proteínas Inativadoras do Complemento C3b/genética
Diabetes Mellitus Tipo 2/genética
[Mh] Termos MeSH secundário: Proteínas Inativadoras do Complemento C3b/metabolismo
Diabetes Mellitus Tipo 2/metabolismo
Feminino
Genótipo
Seres Humanos
Masculino
Meia-Idade
Polimorfismo de Nucleotídeo Único
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CFHR1 protein, human); 0 (Complement C3b Inactivator Proteins)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170914
[Lr] Data última revisão:
170914
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170613
[St] Status:MEDLINE
[do] DOI:10.3760/cma.j.issn.1003-9406.2017.03.029


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[PMID]:28533443
[Au] Autor:Csincsi ÁI; Szabó Z; Bánlaki Z; Uzonyi B; Cserhalmi M; Kárpáti É; Tortajada A; Caesar JJE; Prohászka Z; Jokiranta TS; Lea SM; Rodríguez de Córdoba S; Józsi M
[Ad] Endereço:Hungarian Academy of Sciences-Eötvös Loránd University MTA-ELTE Lendület Complement Research Group, Department of Immunology, ELTE Eötvös Loránd University, 1117 Budapest, Hungary.
[Ti] Título:FHR-1 Binds to C-Reactive Protein and Enhances Rather than Inhibits Complement Activation.
[So] Source:J Immunol;199(1):292-303, 2017 Jul 01.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Factor H-related protein (FHR) 1 is one of the five human FHRs that share sequence and structural homology with the alternative pathway complement inhibitor FH. Genetic studies on disease associations and functional analyses indicate that FHR-1 enhances complement activation by competitive inhibition of FH binding to some surfaces and immune proteins. We have recently shown that FHR-1 binds to pentraxin 3. In this study, our aim was to investigate whether FHR-1 binds to another pentraxin, C-reactive protein (CRP), analyze the functional relevance of this interaction, and study the role of FHR-1 in complement activation and regulation. FHR-1 did not bind to native, pentameric CRP, but it bound strongly to monomeric CRP via its C-terminal domains. FHR-1 at high concentration competed with FH for CRP binding, indicating possible complement deregulation also on this ligand. FHR-1 did not inhibit regulation of solid-phase C3 convertase by FH and did not inhibit terminal complement complex formation induced by zymosan. On the contrary, by binding C3b, FHR-1 allowed C3 convertase formation and thereby enhanced complement activation. FHR-1/CRP interactions increased complement activation via the classical and alternative pathways on surfaces such as the extracellular matrix and necrotic cells. Altogether, these results identify CRP as a ligand for FHR-1 and suggest that FHR-1 enhances, rather than inhibits, complement activation, which may explain the protective effect of FHR-1 deficiency in age-related macular degeneration.
[Mh] Termos MeSH primário: Proteína C-Reativa/imunologia
Proteína C-Reativa/metabolismo
Ativação do Complemento
Proteínas Inativadoras do Complemento C3b/imunologia
Proteínas Inativadoras do Complemento C3b/metabolismo
[Mh] Termos MeSH secundário: Sítios de Ligação
Proteína C-Reativa/química
Proteína C-Reativa/farmacologia
Convertases de Complemento C3-C5
Complemento C3b/imunologia
Complemento C3b/farmacologia
Proteínas Inativadoras do Complemento C3b/farmacologia
Fator H do Complemento
Matriz Extracelular/efeitos dos fármacos
Matriz Extracelular/imunologia
Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos
Células Endoteliais da Veia Umbilical Humana/imunologia
Seres Humanos
Ligantes
Degeneração Macular/imunologia
Ligação Proteica
Componente Amiloide P Sérico/imunologia
Componente Amiloide P Sérico/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CFHR1 protein, human); 0 (Complement C3b Inactivator Proteins); 0 (Ligands); 0 (Serum Amyloid P-Component); 0 (complement factor H, human); 148591-49-5 (PTX3 protein); 80295-43-8 (Complement C3b); 80295-65-4 (Complement Factor H); 9007-41-4 (C-Reactive Protein); EC 3.4.21.- (Complement C3-C5 Convertases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170927
[Lr] Data última revisão:
170927
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170524
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1600483


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[PMID]:28121931
[Au] Autor:Song RH; Shao XQ; Li L; Wang W; Zhang JA
[Ad] Endereço:Department of Endocrinology, Jinshan Hospital of Fudan University, Jinshan District, Shanghai, China.
[Ti] Título:Copy number variations exploration of multiple genes in Graves' disease.
[So] Source:Medicine (Baltimore);96(4):e5866, 2017 Jan.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Few previous published papers reported copy number variations of genes could affect the predisposition of Graves' disease (GD). Herein, the aim of this study was to explore the association between copy number variations (CNV) profile and GD. METHODS: The preliminary copy number microarray used to screen copy number variant genes was performed in 6 GD patients. Five CNV candidate genes (CFH, CFHR1, KIAA0125, UGT2B15, and UGT2B17) were then validated in an independent set of samples (50 GD patients and 50 matched healthy ones) by the Accucopy assay method. The CNV of the other 2 genes TRY6 and CCL3L1 was investigated in 144 GD patients and 144 healthy volunteers by the definitive genotyping technique using the Taqman quantitative polymerase-chain-reaction (Taqman qPCR). TRY6 gene-associated single nucleotide polymorphism (SNP), rs13230029, was genotyped by the PCR-ligase detection reaction (LDR) in 675 GD patients and 898 healthy controls. RESULTS: There were no correlation of the gene copy number (GCN) of CFH, CFHR1, KIAA0125, UGT2B15, and UGT2B17 with GD. In comparison with that of controls, the GCN distribution of TRY6 and CCL3L1 in GD patients did not show significantly differ (P > 0.05). Furthermore, TRY6-related polymorphism (rs13230029) showed no difference between GD patients and controls. No correlation was found between CNV or SNP genotype and clinical phenotypes. Generally, there were no link of the copy numbers of several genes, including CFH, CFHR1, KIAA0125, UGT2B15, UGT2B17, TRY6, and CCL3L1 to GD. CONCLUSION: Our results clearly indicated that the copy number variations of multiple genes, namely CFH, CFHR1, KIAA0125, UGT2B15, UGT2B17, TRY6, and CCL3L1, were not associated with the development of GD.
[Mh] Termos MeSH primário: Variações do Número de Cópias de DNA
Predisposição Genética para Doença
Doença de Graves/genética
[Mh] Termos MeSH secundário: Adulto
Estudos de Casos e Controles
Quimiocinas CC/genética
Proteínas Inativadoras do Complemento C3b/genética
Fator H do Complemento/genética
Proteínas de Ligação a DNA/genética
Feminino
Genótipo
Glucuronosiltransferase/genética
Seres Humanos
Masculino
Meia-Idade
Antígenos de Histocompatibilidade Menor/genética
Reação em Cadeia da Polimerase
Polimorfismo de Nucleotídeo Único
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CCL3L1 protein, human); 0 (CFHR1 protein, human); 0 (Chemokines, CC); 0 (Complement C3b Inactivator Proteins); 0 (DNA-Binding Proteins); 0 (Minor Histocompatibility Antigens); 80295-65-4 (Complement Factor H); EC 2.4.1.17 (Glucuronosyltransferase); EC 2.4.1.17 (UDP-glucuronosyltransferase 2B15, human); EC 2.4.1.17 (UGT2B17 protein, human)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170224
[Lr] Data última revisão:
170224
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170126
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000005866


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[PMID]:28104134
[Au] Autor:Dedhia P; Govil A; Mogilishetty G; Alloway RR; Woodle ES; Abu Jawdeh BG
[Ad] Endereço:Division of Nephrology and Hypertension, University of Cincinnati, Cincinnati, Ohio, United States. Electronic address: drparasdedhia@gmail.com.
[Ti] Título:Eculizumab and Belatacept for De Novo Atypical Hemolytic Uremic Syndrome Associated With CFHR3-CFHR1 Deletion in a Kidney Transplant Recipient: A Case Report.
[So] Source:Transplant Proc;49(1):188-192, 2017 Jan - Feb.
[Is] ISSN:1873-2623
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is associated with significant morbidity and mortality and occurs due to genetic or acquired abnormalities that result in the dysregulation of the alternative complement pathway. CASE REPORT: We report a case of post-living kidney transplantation de novo aHUS in a setting of heterozygous deletion in the complement factor H-related protein (CFHR)3-CFHR1 gene. The aHUS episode was possibly triggered by antibody-mediated rejection or tacrolimus. The patient responded well to eculizumab and substituting belatacept for tacrolimus. Her serum creatinine level was stable at 1.5 mg/dL after 2.5 years of follow-up. CONCLUSION: This case highlights the success of using a strategy that combines eculizumab and belatacept, as an alternative to calcineurin inhibitors, in treating aHUS in a patient with heterozygous deletion in the CFHR3-CFHR1 gene.
[Mh] Termos MeSH primário: Abatacepte/uso terapêutico
Anticorpos Monoclonais Humanizados/uso terapêutico
Síndrome Hemolítico-Urêmica Atípica/tratamento farmacológico
Inativadores do Complemento/uso terapêutico
Rejeição de Enxerto/tratamento farmacológico
Imunossupressores/uso terapêutico
Transplante de Rim
Complicações Pós-Operatórias/tratamento farmacológico
[Mh] Termos MeSH secundário: Adulto
Síndrome Hemolítico-Urêmica Atípica/etiologia
Síndrome Hemolítico-Urêmica Atípica/genética
Proteínas Sanguíneas/genética
Proteínas Inativadoras do Complemento C3b/genética
Feminino
Rejeição de Enxerto/complicações
Rejeição de Enxerto/prevenção & controle
Heterozigoto
Seres Humanos
Complicações Pós-Operatórias/genética
Tacrolimo/efeitos adversos
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Monoclonal, Humanized); 0 (Blood Proteins); 0 (CFHR1 protein, human); 0 (CFHR3 protein, human); 0 (Complement C3b Inactivator Proteins); 0 (Complement Inactivating Agents); 0 (Immunosuppressive Agents); 7D0YB67S97 (Abatacept); A3ULP0F556 (eculizumab); WM0HAQ4WNM (Tacrolimus)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170817
[Lr] Data última revisão:
170817
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170121
[St] Status:MEDLINE


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[PMID]:27814381
[Au] Autor:Hannan JP; Laskowski J; Thurman JM; Hageman GS; Holers VM
[Ad] Endereço:Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, United States of America.
[Ti] Título:Mapping the Complement Factor H-Related Protein 1 (CFHR1):C3b/C3d Interactions.
[So] Source:PLoS One;11(11):e0166200, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Complement factor H-related protein 1 (CFHR1) is a complement regulator which has been reported to regulate complement by blocking C5 convertase activity and interfering with C5b surface association. CFHR1 also competes with complement factor H (CFH) for binding to C3b, and may act as an antagonist of CFH-directed regulation on cell surfaces. We have employed site-directed mutagenesis in conjunction with ELISA-based and functional assays to isolate the binding interaction that CFHR1 undertakes with complement components C3b and C3d to a single shared interface. The C3b/C3d:CFHR1 interface is identical to that which occurs between the two C-terminal domains (SCR19-20) of CFH and C3b. Moreover, we have been able to corroborate that dimerization of CFHR1 is necessary for this molecule to bind effectively to C3b and C3d, or compete with CFH. Finally, we have established that CFHR1 competes with complement factor H-like protein 1 (CFHL-1) for binding to C3b. CFHL-1 is a CFH gene splice variant, which is almost identical to the N-terminal 7 domains of CFH (SCR1-7). CFHR1, therefore, not only competes with the C-terminus of CFH for binding to C3b, but also sterically blocks the interaction that the N-terminus of CFH undertakes with C3b, and which is required for CFH-regulation.
[Mh] Termos MeSH primário: Proteínas Inativadoras do Complemento C3b/metabolismo
Complemento C3b/metabolismo
Complemento C3d/metabolismo
Proteínas do Sistema Complemento/metabolismo
[Mh] Termos MeSH secundário: Sítios de Ligação/fisiologia
Membrana Celular/metabolismo
Convertases de Complemento C3-C5/metabolismo
Seres Humanos
Mutagênese Sítio-Dirigida/métodos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CFHR1 protein, human); 0 (Complement C3b Inactivator Proteins); 80295-43-8 (Complement C3b); 80295-45-0 (Complement C3d); 9007-36-7 (Complement System Proteins); EC 3.4.21.- (Complement C3-C5 Convertases)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170626
[Lr] Data última revisão:
170626
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161105
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0166200


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[PMID]:27671112
[Au] Autor:Shi K; Wang Z; Liu Y; Gong Y; Fu Y; Li S; Wood K; Hao J; Zhang GX; Shi FD; Yan Y
[Ad] Endereço:Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, China.
[Ti] Título:CFHR1-Modified Neural Stem Cells Ameliorated Brain Injury in a Mouse Model of Neuromyelitis Optica Spectrum Disorders.
[So] Source:J Immunol;197(9):3471-3480, 2016 Nov 01.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A major hurdle for effective stem cell therapy is ongoing inflammation in the target organ. Reconditioning the lesion microenvironment may be an effective way to promote stem cell therapy. In this study, we showed that engineered neural stem cells (NSCs) with complement factor H-related protein 1, a complement inhibitor protein, can attenuate inflammatory infiltration and immune-mediated damage of astrocytes, an important pathogenic progress in patients with neuromyelitis optica spectrum disorders. Furthermore, we demonstrated that transplantation of the complement factor H-related protein 1-modified NSCs effectively blocked the complement activation cascade and inhibited formation of the membrane attack complex, thus contributing to the protection of endogenous and transplanted NSC-differentiated astrocytes. Therefore, manipulation of the lesion microenvironment contributes to a more effective cell replacement therapeutic strategy for autoimmune diseases of the CNS.
[Mh] Termos MeSH primário: Astrócitos/fisiologia
Proteínas Inativadoras do Complemento C3b/metabolismo
Células-Tronco Neurais/fisiologia
Neuromielite Óptica/imunologia
Neuroproteção
Transplante de Células-Tronco
[Mh] Termos MeSH secundário: Adulto
Animais
Aquaporina 4/imunologia
Autoanticorpos/metabolismo
Autoantígenos/imunologia
Células Cultivadas
Ativação do Complemento
Proteínas Inativadoras do Complemento C3b/genética
Modelos Animais de Doenças
Feminino
Terapia Genética
Seres Humanos
Camundongos
Camundongos Endogâmicos C57BL
Meia-Idade
Células-Tronco Neurais/transplante
Neuromielite Óptica/terapia
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aquaporin 4); 0 (Autoantibodies); 0 (Autoantigens); 0 (CFHR1 protein, human); 0 (Complement C3b Inactivator Proteins)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170814
[Lr] Data última revisão:
170814
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:160928
[St] Status:MEDLINE


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[PMID]:27490940
[Au] Autor:Xiao X; Ghossein C; Tortajada A; Zhang Y; Meyer N; Jones M; Borsa NG; Nester CM; Thomas CP; de Córdoba SR; Smith RJ
[Ad] Endereço:Molecular Otolaryngology and Renal Research Laboratories, Caver College of Medicine, University of Iowa, Iowa City, IA, USA; Interdepartmental PhD Program in Genetics, Caver College of Medicine, University of Iowa, Iowa City, IA, USA.
[Ti] Título:Familial C3 glomerulonephritis caused by a novel CFHR5-CFHR2 fusion gene.
[So] Source:Mol Immunol;77:89-96, 2016 Sep.
[Is] ISSN:1872-9142
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:C3 glomerulopathy (C3G) is an ultra-rare complement-mediated renal disease characterized histologically by the predominance of C3 deposition within in the glomerulus. Familial cases of C3G are extremely uncommon and offer unique insight into the genetic drivers of complement dysregulation. In this report, we describe a patient who presented with C3G. Because a relative carried the same diagnosis, we sought an underlying genetic commonality to explain the phenotype. As part of a comprehension genetic screen, we completed multiplex ligation-dependent probe amplification across the complement factor H related region and identified amplification alterations consistent with a genomic rearrangement. Using comparative genomic hybridization, we narrowed and then cloned the rearrangement breakpoints thereby defining a novel fusion gene that is translated into a serum protein comprised of factor H related-5 (short consensus repeats 1 and 2) and factor H-related-2 (short consensus repeats 1-4). These data highlight the role of factor H related proteins in the control of complement activity and illustrate how perturbation of that control leads to C3G.
[Mh] Termos MeSH primário: Proteínas Inativadoras do Complemento C3b/genética
Proteínas do Sistema Complemento/genética
Glomerulonefrite Membranoproliferativa/genética
[Mh] Termos MeSH secundário: Adulto
Western Blotting
Hibridização Genômica Comparativa
Feminino
Seres Humanos
Masculino
Reação em Cadeia da Polimerase Multiplex
Linhagem
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CFHR2 protein, human); 0 (Complement C3b Inactivator Proteins); 0 (FHR5 protein, human); 9007-36-7 (Complement System Proteins)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170821
[Lr] Data última revisão:
170821
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160805
[St] Status:MEDLINE


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[PMID]:26940089
[Au] Autor:Xie J; Kiryluk K; Li Y; Mladkova N; Zhu L; Hou P; Ren H; Wang W; Zhang H; Chen N; Gharavi AG
[Ad] Endereço:Institute of Nephrology, Department of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Medicine, Division of Nephrology, College of Physicians and Surgeons, Columbia University, New York, New York; and.
[Ti] Título:Fine Mapping Implicates a Deletion of CFHR1 and CFHR3 in Protection from IgA Nephropathy in Han Chinese.
[So] Source:J Am Soc Nephrol;27(10):3187-3194, 2016 Oct.
[Is] ISSN:1533-3450
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:An intronic variant at the complement factor H (CFH) gene on chromosome 1q32 (rs6677604) associates with risk of IgA nephropathy (IgAN), but the association signal has not been uniformly replicated in Han Chinese populations. We investigated whether the causal sequence variant resides in the CFH gene or the neighboring complement factor H-related 1 (CFHR1) gene and CFHR3, which harbor an 84-kb combined deletion (CFHR3,1Δ) in linkage disequilibrium with rs6677604. Imputation of 1000 Genomes Project data did not suggest new causal single-nucleotide variants within the CFH cluster. We next performed copy number analysis across the CFH locus in two independent Han Chinese case-control cohorts (combined n=3581). The CFHR3,1Δ and rs6677604-A alleles were rare (4.4% in patients and 7.1% in controls) and in strong linkage disequilibrium with each other (r =0.95); of these alleles, CFHR3,1Δ associated more significantly with decreased risk of IgAN (odds ratio [OR], 0.56; 95% confidence interval [95% CI], 0.46 to 0.70; P=8.5 × 10 versus OR, 0.61; 95% CI, 0.50 to 0.75; P=1.6 × 10 for rs6677604-A). Moreover, CFHR3,1Δ explained all of the association signal at rs6677604 and remained significant after conditioning on rs6677604 genotype (P=0.01). Exploratory analyses of clinical and histopathologic parameters using the Oxford classification criteria revealed a suggestive association of CFHR3,1Δ with reduced tubulointerstitial injury (OR, 0.46; 95% CI, 0.25 to 0.79). These data indicate that dysregulated activity of the alternative complement pathway contributes to IgAN pathogenesis in both Asians and Europeans and implicate CFHR3,1Δ as the functional allele at this locus.
[Mh] Termos MeSH primário: Proteínas Sanguíneas/genética
Proteínas Inativadoras do Complemento C3b/genética
Deleção de Genes
Glomerulonefrite por IGA/genética
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Idoso de 80 Anos ou mais
Grupo com Ancestrais do Continente Asiático/genética
Criança
Mapeamento Cromossômico
Feminino
Genótipo
Seres Humanos
Masculino
Meia-Idade
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Blood Proteins); 0 (CFHR1 protein, human); 0 (CFHR3 protein, human); 0 (Complement C3b Inactivator Proteins)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171001
[Lr] Data última revisão:
171001
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160305
[St] Status:MEDLINE


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[PMID]:26643478
[Au] Autor:Harder MJ; Anliker M; Höchsmann B; Simmet T; Huber-Lang M; Schrezenmeier H; Ricklin D; Lambris JD; Barlow PN; Schmidt CQ
[Ad] Endereço:Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, 89081 Ulm, Germany;
[Ti] Título:Comparative Analysis of Novel Complement-Targeted Inhibitors, MiniFH, and the Natural Regulators Factor H and Factor H-like Protein 1 Reveal Functional Determinants of Complement Regulation.
[So] Source:J Immunol;196(2):866-76, 2016 Jan 15.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The serum proteins factor H (FH), consisting of 20 complement control protein modules (CCPs), and its splice product FH-like protein 1 (FHL-1; consisting of CCPs 1-7) are major regulators of the alternative pathway (AP) of complement activation. The engineered version of FH, miniFH, contains only the N- and C-terminal portions of FH linked by an optimized peptide and shows ∼ 10-fold higher ex vivo potency. We explored the hypothesis that regulatory potency is enhanced by unmasking of a ligand-binding site in the C-terminal CCPs 19-20 that is cryptic in full-length native FH. Therefore, we produced an FH variant lacking the central domains 10-15 (FHΔ10-15). To explore how avidity affects regulatory strength, we generated a duplicated version of miniFH, termed midiFH. We compared activities of FHΔ10-15 and midiFH to miniFH, FH, and FHL-1. Relative to FH, FHΔ10-15 exhibited an altered binding profile toward C3 activation products and a 5-fold-enhanced complement regulation on a paroxysmal nocturnal hemoglobinuria patient's erythrocytes. Contrary to dogma, FHL-1 and FH exhibited equal regulatory activity, suggesting that the role of FHL-1 in AP regulation has been underestimated. Unexpectedly, a substantially increased avidity for complement opsonins, as seen in midiFH, did not potentiate the inhibitory potential on host cells. In conclusion, comparisons of engineered and native FH-based regulators have identified features that determine high AP regulatory activity on host cells. Unrestricted availability of FH CCPs 19-20 and an optimal spatial orientation between the N- and C-terminal FH regions are key.
[Mh] Termos MeSH primário: Proteínas Inativadoras do Complemento C3b/imunologia
Fator H do Complemento/imunologia
Inativadores do Complemento/farmacologia
Via Alternativa do Complemento/imunologia
Proteínas Recombinantes/farmacologia
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Fator H do Complemento/química
Inativadores do Complemento/síntese química
Inativadores do Complemento/imunologia
Eletroforese em Gel de Poliacrilamida
Ensaio de Imunoadsorção Enzimática
Citometria de Fluxo
Seres Humanos
Dados de Sequência Molecular
Reação em Cadeia da Polimerase
Ligação Proteica
Proteínas Recombinantes/síntese química
Proteínas Recombinantes/imunologia
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (CFHR1 protein, human); 0 (Complement C3b Inactivator Proteins); 0 (Complement Inactivating Agents); 0 (Recombinant Proteins); 80295-65-4 (Complement Factor H)
[Em] Mês de entrada:1605
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:151209
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1501919



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