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Pesquisa : D12.776.124.486.274.045.387 [Categoria DeCS]
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[PMID]:29350259
[Au] Autor:Zhu X; Zhang J; Wang Q; Fu H; Chang Y; Kong Y; Lv M; Xu L; Liu K; Huang X; Zhang X
[Ad] Endereço:Peking University People's Hospital, Peking University Institute of Hematology, Beijing, 100044, China.
[Ti] Título:Diminished expression of ß2-GPI is associated with a reduced ability to mitigate complement activation in anti-GPIIb/IIIa-mediated immune thrombocytopenia.
[So] Source:Ann Hematol;97(4):641-654, 2018 Apr.
[Is] ISSN:1432-0584
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Anti-GPIIb/IIIa-mediated complement activation has been reported to be important in the pathogenesis of immune thrombocytopenia (ITP). However, the role of the complement system and the involved regulatory mechanism remain equivocal. Beta2-glycoprotein I (ß2-GPI), known as the main target for antiphospholipid autoantibodies, has been demonstrated as a complement regulator. Here, we investigated the complement-regulatory role of ß2-GPI in anti-GPIIb/IIIa-mediated ITP. Plasma complement activation and enhanced complement activation capacity (CAC) were found in ITP patients with anti-GPIIb/IIIa antibodies in vivo and in vitro. Diminished plasma levels of ß2-GPI were shown in patients of this group, which was inversely correlated with C5b-9 deposition. C5b-9 generation was inhibited by approximate physiological concentrations of ß2-GPI, in a dose-dependent manner. Inhibition of C3a generation by ß2-GPI and the existence of ß2-GPI/C3 complexes in plasma indicated a regulation on the level of the C3 convertase. Furthermore, ß2-GPI down-regulated the phosphorylation levels of c-Jun N-terminal kinase (JNK) and cleavage of BH3 interacting domain death agonist (Bid) and ultimately harbored platelet lysis. Our findings may provide a novel link between diminished plasma levels of ß2-GPI and enhanced complement activation, indicating ß2-GPI as a potential diagnostic biomarker and therapeutic target in the treatment of anti-GPIIb/IIIa-mediated ITP.
[Mh] Termos MeSH primário: Ativação do Complemento
Regulação para Baixo
Isoanticorpos/metabolismo
Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores
Púrpura Trombocitopênica Idiopática/metabolismo
beta 2-Glicoproteína I/metabolismo
[Mh] Termos MeSH secundário: Adulto
Idoso
Biomarcadores/sangue
Plaquetas/imunologia
Plaquetas/metabolismo
Plaquetas/patologia
China/epidemiologia
Convertases de Complemento C3-C5/metabolismo
Complemento C3a/metabolismo
Feminino
Seres Humanos
Masculino
Meia-Idade
Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo
Complexo Glicoproteico GPIb-IX de Plaquetas/antagonistas & inibidores
Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo
Púrpura Trombocitopênica Idiopática/imunologia
Púrpura Trombocitopênica Idiopática/patologia
Púrpura Trombocitopênica Idiopática/fisiopatologia
Risco
Trombocitopenia/sangue
Trombocitopenia/imunologia
Trombocitopenia/metabolismo
Trombose/epidemiologia
Trombose/etiologia
Adulto Jovem
beta 2-Glicoproteína I/sangue
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Isoantibodies); 0 (Platelet Glycoprotein GPIIb-IIIa Complex); 0 (Platelet Glycoprotein GPIb-IX Complex); 0 (beta 2-Glycoprotein I); 0 (glycoprotein receptor GPIb-IX); 80295-42-7 (Complement C3a); EC 3.4.21.- (Complement C3-C5 Convertases)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180120
[St] Status:MEDLINE
[do] DOI:10.1007/s00277-017-3215-3


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[PMID]:28757372
[Au] Autor:DiScipio RG; Schraufstatter IU
[Ad] Endereço:Torrey Pines Institute for Molecular Studies, 3550 General Atomics Court, San Diego, CA 92122, United States. Electronic address: rdiscipio@ca.tpims.org.
[Ti] Título:Magnetic bead based assays for complement component C5.
[So] Source:J Immunol Methods;450:50-57, 2017 Nov.
[Is] ISSN:1872-7905
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Two novel magnetic agarose bead based assays have been developed to measure complement component C5 interaction with C3b and the Factor I Modules (FIMs) of C7. One innovation was to couple C3b onto the magnetic agarose bead using the alternative pathway C3 convertase, which resulted in a linkage of the ligand by a covalent ester bond. A second innovation was to employ nickel ion charged N,N,N'-tris(carboxymethyl)ethylene-diamine-magnetic agarose to capture recombinantly prepared C7 FIMs that were expressed with an oligo-histidine linker followed by an acidic domain that provided a spacer enabling the C7 modules exposure to C5. Detection was brought about by peroxidase coupled to C5. Both assays exhibited adequate statistics suitable for screening. As examples of the utility of these new methods, we chose to examine influence of natural products on C5 interaction. Fucoidan and ß-glucans were observed to inhibit C3b-C5 interaction, and dextran sulfate was similarly active; however, rosmarinic acid had no measurable effect. In contrast only ß-glucans from two species of macrofungi were able to interfere with interaction of C5 with the FIMs of C7.
[Mh] Termos MeSH primário: Ativação do Complemento
Complemento C3b/imunologia
Complemento C5/imunologia
Complemento C7/imunologia
Técnicas Imunológicas
Magnetismo
[Mh] Termos MeSH secundário: Ativação do Complemento/efeitos dos fármacos
Convertases de Complemento C3-C5/metabolismo
Complemento C3b/metabolismo
Complemento C5/metabolismo
Complemento C7/metabolismo
Ensaio de Atividade Hemolítica de Complemento
Inativadores do Complemento/farmacologia
Sulfato de Dextrana/farmacologia
Hemólise
Seres Humanos
Ferro/química
Polissacarídeos/farmacologia
Ligação Proteica
Sefarose/química
beta-Glucanas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Complement C5); 0 (Complement C7); 0 (Complement Inactivating Agents); 0 (Polysaccharides); 0 (beta-Glucans); 80295-43-8 (Complement C3b); 9012-36-6 (Sepharose); 9042-14-2 (Dextran Sulfate); 9072-19-9 (fucoidan); E1UOL152H7 (Iron); EC 3.4.21.- (Complement C3-C5 Convertases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171002
[Lr] Data última revisão:
171002
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170801
[St] Status:MEDLINE


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[PMID]:28652401
[Au] Autor:Bettoni S; Galbusera M; Gastoldi S; Donadelli R; Tentori C; Spartà G; Bresin E; Mele C; Alberti M; Tortajada A; Yebenes H; Remuzzi G; Noris M
[Ad] Endereço:IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Centro di Ricerche Cliniche per le Malattie Rare "Aldo e Cele Daccò," 24020 Ranica Bergamo, Italy.
[Ti] Título:Interaction between Multimeric von Willebrand Factor and Complement: A Fresh Look to the Pathophysiology of Microvascular Thrombosis.
[So] Source:J Immunol;199(3):1021-1040, 2017 Aug 01.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:von Willebrand factor (VWF), a multimeric protein with a central role in hemostasis, has been shown to interact with complement components. However, results are contrasting and inconclusive. By studying 20 patients with congenital thrombotic thrombocytopenic purpura (cTTP) who cannot cleave VWF multimers because of genetic deficiency, we investigated the mechanism through which VWF modulates complement and its pathophysiological implications for human diseases. Using assays of ex vivo serum-induced C3 and C5b-9 deposits on endothelial cells, we documented that in cTTP, complement is activated via the alternative pathway (AP) on the cell surface. This abnormality was corrected by restoring ADAMTS13 activity in cTTP serum, which prevented VWF multimer accumulation on endothelial cells, or by an anti-VWF Ab. In mechanistic studies we found that VWF interacts with C3b through its three type A domains and initiates AP activation, although assembly of active C5 convertase and formation of the terminal complement products C5a and C5b-9 occur only on the VWF-A2 domain. Finally, we documented that in the condition of ADAMTS13 deficiency, VWF-mediated formation of terminal complement products, particularly C5a, alters the endothelial antithrombogenic properties and induces microvascular thrombosis in a perfusion system. Altogether, the results demonstrated that VWF provides a platform for the activation of the AP of complement, which profoundly alters the phenotype of microvascular endothelial cells. These findings link hemostasis-thrombosis with the AP of complement and open new therapeutic perspectives in cTTP and in general in thrombotic and inflammatory disorders associated with endothelium perturbation, VWF release, and complement activation.
[Mh] Termos MeSH primário: Complemento C3b/metabolismo
Via Alternativa do Complemento
Células Endoteliais/imunologia
Microvasos/patologia
Trombose/fisiopatologia
Fator de von Willebrand/metabolismo
[Mh] Termos MeSH secundário: Proteína ADAMTS13/sangue
Proteína ADAMTS13/deficiência
Proteína ADAMTS13/imunologia
Proteína ADAMTS13/metabolismo
Adolescente
Adulto
Criança
Pré-Escolar
Convertases de Complemento C3-C5/metabolismo
Complemento C3b/imunologia
Complemento C5a/imunologia
Complemento C5a/metabolismo
Complexo de Ataque à Membrana do Sistema Complemento/imunologia
Complexo de Ataque à Membrana do Sistema Complemento/metabolismo
Células Endoteliais/metabolismo
Células Endoteliais/patologia
Feminino
Seres Humanos
Recém-Nascido
Masculino
Microvasos/imunologia
Púrpura Trombocitopênica Trombótica/congênito
Púrpura Trombocitopênica Trombótica/imunologia
Púrpura Trombocitopênica Trombótica/fisiopatologia
Trombose/imunologia
Adulto Jovem
Fator de von Willebrand/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Complement Membrane Attack Complex); 0 (von Willebrand Factor); 80295-43-8 (Complement C3b); 80295-54-1 (Complement C5a); EC 3.4.21.- (Complement C3-C5 Convertases); EC 3.4.24.87 (ADAMTS13 Protein); EC 3.4.24.87 (ADAMTS13 protein, human)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170628
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1601121


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[PMID]:28559202
[Au] Autor:Chen YY; Tsai CF; Tsai MC; Hsu YW; Lu FJ
[Ad] Endereço:Institute of Medicine, College of Medicine, Chung Shan Medical University, Taichung City, Taiwan.
[Ti] Título:Inhibitory effects of rosmarinic acid on pterygium epithelial cells through redox imbalance and induction of extrinsic and intrinsic apoptosis.
[So] Source:Exp Eye Res;160:96-105, 2017 Jul.
[Is] ISSN:1096-0007
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Pterygium is a common tumor-like ocular disease, which may be related to exposure to chronic ultraviolet (UV) radiation. Although the standard treatment for pterygium is surgical intervention, the recurrence rate of pterygium is high when no effective inhibitory drug is used after surgery. Rosmarinic acid (RA) is a polyphenol antioxidant with many biological activities, including anti-UV and anti-tumor properties. This study aimed to examine the inhibitory effects of RA on pterygium epithelial cells (PECs). Methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay was used to examine the cell cytotoxicity of PECs after RA treatment. A fluorescent probe, DCFH-DA (2',7'-dichlorofluorescin diacetate), was stained with PECs to measure intracellular reactive oxygen species (ROS) levels. Antioxidant activity assays were used to measure the levels of superoxide dismutase (SOD) and catalase (CAT) in PECs. Western blot analysis was used to determine the protein expression of nuclear factor E2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), quinone acceptor oxidoreductase 1 (NQO1), and apoptosis-associated proteins. RA significantly reduced the cell viability of the PECs. Treatment with RA remarkably increased the Nrf2 protein expression levels in the nucleus, HO-1 and NQO1 protein expression levels, and the activities of SOD and CAT. As a result, intracellular ROS levels in PECs were decreased. Additionally, the induction of extrinsic apoptosis on PECs by RA was associated with increasing expressions levels of Fas, Fas-associated protein with death domain (FADD), tumor necrosis factor-alpha (TNF-α), and caspase 8 protein. Moreover, the induction of intrinsic apoptotic cell death in PECs was confirmed through upregulation of cytochrome c, Bax, caspase 9, and caspase 3 and downregulation of Bcl-2 and pro-caspase 3. Our study demonstrated that RA could inhibit the viability of PECs through regulation of extrinsic and intrinsic apoptosis pathways. Therefore, RA may have potential as a therapeutic medication for pterygium.
[Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos
Cinamatos/farmacologia
Depsídeos/farmacologia
Células Epiteliais/efeitos dos fármacos
Pterígio/tratamento farmacológico
[Mh] Termos MeSH secundário: Antioxidantes/farmacologia
Western Blotting
Sobrevivência Celular
Células Cultivadas
Convertases de Complemento C3-C5
Células Epiteliais/metabolismo
Células Epiteliais/patologia
Seres Humanos
Oxirredução
Pterígio/metabolismo
Pterígio/patologia
Espécies Reativas de Oxigênio/metabolismo
Transdução de Sinais
Superóxido Dismutase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antioxidants); 0 (Cinnamates); 0 (Depsides); 0 (Reactive Oxygen Species); EC 1.15.1.1 (Superoxide Dismutase); EC 3.4.21.- (Complement C3-C5 Convertases); MQE6XG29YI (rosmarinic acid)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170809
[Lr] Data última revisão:
170809
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170601
[St] Status:MEDLINE


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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]:28366510
[Au] Autor:Riedemann NC; Habel M; Ziereisen J; Hermann M; Schneider C; Wehling C; Kirschfink M; Kentouche K; Guo R
[Ad] Endereço:InflaRx GmbH, Jena, Germany. Electronic address: Niels.Riedemann@inflarx.de.
[Ti] Título:Controlling the anaphylatoxin C5a in diseases requires a specifically targeted inhibition.
[So] Source:Clin Immunol;180:25-32, 2017 Jul.
[Is] ISSN:1521-7035
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The terminal complement split product C5a has been described as an important mediator in inflammatory diseases. C5a is generated upon cleavage of C5 and earlier research suggests that, besides the known C5 convertases formed upon activation of the complement pathways, various enzymes could activate C5 directly. We demonstrate that eculizumab effectively blocks C5 activation when mediated by C5-convertase formation, but fails to block C5a generation resulting from direct enzymatic cleavage by trypsin and thrombin. C5a generated by these enzymes is shown to be fully biologically functional and can be blocked by IFX-1, a specific monoclonal anti-human C5a antibody. We further report clinical cases of atypical hemolytic uremic syndrome (aHUS) and C3 Glomerulonephritis (C3GN) patients under treatment with eculizumab presenting substantially elevated C5a levels. Thus, blocking the C5 convertase mediated activation of C5 may not be efficient to control C5a-mediated effects in human disease and that a targeted approach is warranted.
[Mh] Termos MeSH primário: Anticorpos Monoclonais Humanizados/farmacologia
Síndrome Hemolítico-Urêmica Atípica/imunologia
Complemento C5a/imunologia
Glomerulonefrite/imunologia
[Mh] Termos MeSH secundário: Anticorpos Monoclonais Humanizados/uso terapêutico
Síndrome Hemolítico-Urêmica Atípica/tratamento farmacológico
Convertases de Complemento C3-C5/imunologia
Glomerulonefrite/tratamento farmacológico
Seres Humanos
Trombina/imunologia
Tripsina/imunologia
Zimosan/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Monoclonal, Humanized); 80295-54-1 (Complement C5a); 9010-72-4 (Zymosan); A3ULP0F556 (eculizumab); EC 3.4.21.- (Complement C3-C5 Convertases); EC 3.4.21.4 (Trypsin); EC 3.4.21.5 (Thrombin)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170829
[Lr] Data última revisão:
170829
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170404
[St] Status:MEDLINE


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[PMID]:28264884
[Au] Autor:Pedersen DV; Roumenina L; Jensen RK; Gadeberg TA; Marinozzi C; Picard C; Rybkine T; Thiel S; Sørensen UB; Stover C; Fremeaux-Bacchi V; Andersen GR
[Ad] Endereço:Department of Molecular Biology and Genetics, Center for Structural Biology, Aarhus University, Aarhus, Denmark.
[Ti] Título:Functional and structural insight into properdin control of complement alternative pathway amplification.
[So] Source:EMBO J;36(8):1084-1099, 2017 Apr 13.
[Is] ISSN:1460-2075
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Properdin (FP) is an essential positive regulator of the complement alternative pathway (AP) providing stabilization of the C3 and C5 convertases, but its oligomeric nature challenges structural analysis. We describe here a novel FP deficiency (E244K) caused by a single point mutation which results in a very low level of AP activity. Recombinant FP E244K is monomeric, fails to support bacteriolysis, and binds weakly to C3 products. We compare this to a monomeric unit excised from oligomeric FP, which is also dysfunctional in bacteriolysis but binds the AP proconvertase, C3 convertase, C3 products and partially stabilizes the convertase. The crystal structure of such a FP-convertase complex suggests that the major contact between FP and the AP convertase is mediated by a single FP thrombospondin repeat and a small region in C3b. Small angle X-ray scattering indicates that FP E244K is trapped in a compact conformation preventing its oligomerization. Our studies demonstrate an essential role of FP oligomerization while our monomers enable detailed structural insight paving the way for novel modulators of complement.
[Mh] Termos MeSH primário: Convertases de Complemento C3-C5/química
Via Alternativa do Complemento
Properdina/química
Multimerização Proteica
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Convertases de Complemento C3-C5/genética
Convertases de Complemento C3-C5/metabolismo
Doenças Genéticas Inatas/genética
Doenças Genéticas Inatas/metabolismo
Seres Humanos
Mutação de Sentido Incorreto
Properdina/deficiência
Properdina/genética
Properdina/metabolismo
Domínios Proteicos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
11016-39-0 (Properdin); EC 3.4.21.- (Complement C3-C5 Convertases)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170428
[Lr] Data última revisão:
170428
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170308
[St] Status:MEDLINE
[do] DOI:10.15252/embj.201696173


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[PMID]:28083930
[Au] Autor:Subías Hidalgo M; Yébenes H; Rodríguez-Gallego C; Martín-Ambrosio A; Domínguez M; Tortajada A; Rodríguez de Córdoba S; Llorca O
[Ad] Endereço:Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
[Ti] Título:Functional and structural characterization of four mouse monoclonal antibodies to complement C3 with potential therapeutic and diagnostic applications.
[So] Source:Eur J Immunol;47(3):504-515, 2017 Mar.
[Is] ISSN:1521-4141
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:C3 is the central component of the complement system. Upon activation, C3 sequentially generates various proteolytic fragments, C3a, C3b, iC3b, C3dg, each of them exposing novel surfaces, which are sites of interaction with other proteins. C3 and its fragments are therapeutic targets and markers of complement activation. We report the structural and functional characterization of four monoclonal antibodies (mAbs) generated by immunizing C3-deficient mice with a mixture of human C3b, iC3b and C3dg fragments, and discuss their potential applications. This collection includes three mAbs interacting with native C3 and inhibiting AP complement activation; two of them by blocking the cleavage of C3 by the AP C3-converase and one by impeding formation of the AP C3-convertase. The interaction sites of these mAbs in the target molecules were determined by resolving the structures of Fab fragments bound to C3b and/or iC3b using electron microscopy. A fourth mAb specifically recognizes the iC3b, C3dg, and C3d fragments. It binds to an evolutionary-conserved neoepitope generated after C3b cleavage by FI, detecting iC3b/C3dg deposition over opsonized surfaces by flow cytometry and immunohistochemistry in human and other species. Because well-characterized anti-complement mAbs are uncommon, the mAbs reported here may offer interesting therapeutic and diagnostic opportunities.
[Mh] Termos MeSH primário: Anticorpos Monoclonais/metabolismo
Complexo Antígeno-Anticorpo/metabolismo
Convertases de Complemento C3-C5/metabolismo
Complemento C3/metabolismo
Via Alternativa do Complemento
[Mh] Termos MeSH secundário: Animais
Anticorpos Monoclonais/genética
Complemento C3/genética
Complemento C3/imunologia
Engenharia Genética
Técnica de Placa Hemolítica
Seres Humanos
Hibridomas
Fragmentos Fab das Imunoglobulinas/genética
Camundongos
Camundongos Knockout
Ligação Proteica
Conformação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Monoclonal); 0 (Antigen-Antibody Complex); 0 (Complement C3); 0 (Immunoglobulin Fab Fragments); EC 3.4.21.- (Complement C3-C5 Convertases)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170718
[Lr] Data última revisão:
170718
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170114
[St] Status:MEDLINE
[do] DOI:10.1002/eji.201646758


  9 / 634 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


  10 / 634 MEDLINE  
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[PMID]:27591336
[Au] Autor:Garcia BL; Zwarthoff SA; Rooijakkers SH; Geisbrecht BV
[Ad] Endereço:Department of Biochemistry and Molecular Biophysics, Kansas State University, Manhattan, KS 66506; and.
[Ti] Título:Novel Evasion Mechanisms of the Classical Complement Pathway.
[So] Source:J Immunol;197(6):2051-60, 2016 Sep 15.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Complement is a network of soluble and cell surface-associated proteins that gives rise to a self-amplifying, yet tightly regulated system with fundamental roles in immune surveillance and clearance. Complement becomes activated on the surface of nonself cells by one of three initiating mechanisms known as the classical, lectin, and alternative pathways. Evasion of complement function is a hallmark of invasive pathogens and hematophagous organisms. Although many complement-inhibition strategies hinge on hijacking activities of endogenous complement regulatory proteins, an increasing number of uniquely evolved evasion molecules have been discovered over the past decade. In this review, we focus on several recent investigations that revealed mechanistically distinct inhibitors of the classical pathway. Because the classical pathway is an important and specific mediator of various autoimmune and inflammatory disorders, in-depth knowledge of novel evasion mechanisms could direct future development of therapeutic anti-inflammatory molecules.
[Mh] Termos MeSH primário: Via Clássica do Complemento
Evasão da Resposta Imune
[Mh] Termos MeSH secundário: Animais
Complemento C1/fisiologia
Complemento C1q/fisiologia
Convertases de Complemento C3-C5/antagonistas & inibidores
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Complement C1); 80295-33-6 (Complement C1q); EC 3.4.21.- (Complement C3-C5 Convertases)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170924
[Lr] Data última revisão:
170924
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:160904
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1600863



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