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  1 / 2089 MEDLINE  
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[PMID]:28460033
[Au] Autor:Ram S; Shaughnessy J; de Oliveira RB; Lewis LA; Gulati S; Rice PA
[Ad] Endereço:Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
[Ti] Título:Gonococcal lipooligosaccharide sialylation: virulence factor and target for novel immunotherapeutics.
[So] Source:Pathog Dis;75(4), 2017 Jun 01.
[Is] ISSN:2049-632X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Gonorrhea has become resistant to most conventional antimicrobials used in clinical practice. The global spread of multidrug-resistant isolates of Neisseria gonorrhoeae could lead to an era of untreatable gonorrhea. New therapeutic modalities with novel mechanisms of action that do not lend themselves to the development of resistance are urgently needed. Gonococcal lipooligosaccharide (LOS) sialylation is critical for complement resistance and for establishing infection in humans and experimental mouse models. Here we describe two immunotherapeutic approaches that target LOS sialic acid: (i) a fusion protein that comprises the region in the complement inhibitor factor H (FH) that binds to sialylated gonococci and IgG Fc (FH/Fc fusion protein) and (ii) analogs of sialic acid that are incorporated into LOS but fail to protect the bacterium against killing. Both molecules showed efficacy in the mouse vaginal colonization model of gonorrhea and may represent promising immunotherapeutic approaches to target multidrug-resistant isolates. Disabling key gonococcal virulence mechanisms is an effective therapeutic strategy because the reduction of virulence is likely to be accompanied by a loss of fitness, rapid elimination by host immunity and consequently, decreased transmission.
[Mh] Termos MeSH primário: Gonorreia/prevenção & controle
Lipopolissacarídeos/metabolismo
Neisseria gonorrhoeae/fisiologia
Ácidos Siálicos/metabolismo
Fatores de Virulência/metabolismo
[Mh] Termos MeSH secundário: Animais
Fator H do Complemento/genética
Fator H do Complemento/metabolismo
Modelos Animais de Doenças
Feminino
Fragmentos Fc das Imunoglobulinas/genética
Fragmentos Fc das Imunoglobulinas/metabolismo
Camundongos
Neisseria gonorrhoeae/efeitos dos fármacos
Ligação Proteica
Proteínas Recombinantes de Fusão/metabolismo
Vagina/microbiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Immunoglobulin Fc Fragments); 0 (Lipopolysaccharides); 0 (Recombinant Fusion Proteins); 0 (Sialic Acids); 0 (Virulence Factors); 0 (lipid-linked oligosaccharides); 80295-65-4 (Complement Factor H)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180228
[Lr] Data última revisão:
180228
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170502
[St] Status:MEDLINE
[do] DOI:10.1093/femspd/ftx049


  2 / 2089 MEDLINE  
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[PMID]:29308852
[Au] Autor:Demyanova KA; Kozlovskaya NL; Bobrova LA; Kozlov LV; Andina SS; Yurova VA; Kuchieva AM; Roshchupkina SV; Shilov EM
[Ti] Título:Complement System Abnormalities in Patients with Atypical Hemolytic Uremic Syndrome and Catastrophic Antiphospholipid Syndrome.
[So] Source:Vestn Ross Akad Med Nauk;72(1):42-52, 2017.
[Is] ISSN:0869-6047
[Cp] País de publicação:Russia (Federation)
[La] Idioma:eng
[Ab] Resumo:Background: The role of the alternative complement pathway (AP) abnormalities in the pathogenesis of aHUS is well studied. Clinical and morphological manifestations of atypical HUS and catastrophic APS are often similar. However, studies on the state of AP in patients with CAPS are virtually absent. Aims: The aim of our study was to assess the state of AP in patients with CAPS and aHUS. Patients and methods: The study enrolled 67 patients (pts) with a diagnosis of CAPS (28 pts) and aHUS (39 pts). Studies of the complement system are made of 10 pts with CAPS and 20 aHUS. Factor H, I, B, D content, functional activity of factor H, and complement components C3, C4 was determined in serum by ELISA kit. Results: Patients with CAPS and aHUS showed similar changes in complement biomarkers. The factor H level in the serum was significantly higher than the standard value. However, the specific activity of factor H reduced, mean rate 59% for aHUS and 26% for CAPS. The median value of factor D was twice higher than the normal range in both groups, indicating the activation of the AP. Conclusions: There are indications of an AP activation not only in pts with aHUS but in CAPS pts too. We suppose that the activity of factor H is a more sensitive indicator of complement system changes than factor H level. Patients with CAPS and aHUS have similar clinical and laboratory characteristics. However, CAPS is more severe, with the involvement of a larger number of vascular beds. Perhaps this is due to the double damaging effects on the endothelium ­ of antiphospholipid antibodies (aPL) and activated complement. So we hypothesize that CAPS can be called aPL-mediated TMA in pts with a complement system defect.
[Mh] Termos MeSH primário: Síndrome Antifosfolipídica
Síndrome Hemolítico-Urêmica Atípica
Fator H do Complemento
Proteínas do Sistema Complemento
Microangiopatias Trombóticas/metabolismo
[Mh] Termos MeSH secundário: Adulto
Anticorpos Antifosfolipídeos/sangue
Síndrome Antifosfolipídica/diagnóstico
Síndrome Antifosfolipídica/metabolismo
Síndrome Antifosfolipídica/fisiopatologia
Síndrome Hemolítico-Urêmica Atípica/diagnóstico
Síndrome Hemolítico-Urêmica Atípica/metabolismo
Síndrome Hemolítico-Urêmica Atípica/fisiopatologia
Fator H do Complemento/análise
Fator H do Complemento/metabolismo
Via Alternativa do Complemento
Proteínas do Sistema Complemento/análise
Proteínas do Sistema Complemento/metabolismo
Endotélio Vascular/metabolismo
Endotélio Vascular/fisiopatologia
Feminino
Seres Humanos
Masculino
Estatística como Assunto
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Antiphospholipid); 80295-65-4 (Complement Factor H); 9007-36-7 (Complement System Proteins)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180220
[Lr] Data última revisão:
180220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180109
[St] Status:MEDLINE
[do] DOI:10.15690/vramn769


  3 / 2089 MEDLINE  
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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


  4 / 2089 MEDLINE  
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[PMID]:29243465
[Au] Autor:Kaartinen K; Martola L; Meri S
[Ti] Título:Atypical hemolytic-uremic syndrome.
[So] Source:Duodecim;133(6):539-47, 2017.
[Is] ISSN:0012-7183
[Cp] País de publicação:Finland
[La] Idioma:eng
[Ab] Resumo:Atypical hemolytic-uremic syndrome (aHUS) is a rare form of thrombotic microagiopathy caused dysregulation of the alternative pathway of the complement resulting in tissue. In aHUS, activation of the alternative pathway of the complement is in an aberrant way directed against endothelial cells and blood cells. This is either due to a mutation in a complement factor, most commonly factor H, or an autoantibody against a complement regulator. In some patients the underlying disorder is not identified despite thorough examinations. Typical aHUS-patients have acute kidney injury and microangiopathic hemolysis and, to a varying degree, disturbances of other organs. An effective inhibitor of the final product of complement, eculizumab, has revolutionized the treatment of these patients.
[Mh] Termos MeSH primário: Anticorpos Monoclonais Humanizados/uso terapêutico
Síndrome Hemolítico-Urêmica Atípica/complicações
Síndrome Hemolítico-Urêmica Atípica/tratamento farmacológico
[Mh] Termos MeSH secundário: Lesão Renal Aguda/etiologia
Autoanticorpos
Fator H do Complemento
Seres Humanos
Microangiopatias Trombóticas/etiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antibodies, Monoclonal, Humanized); 0 (Autoantibodies); 0 (complement factor H, human); 80295-65-4 (Complement Factor H); A3ULP0F556 (eculizumab)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180115
[Lr] Data última revisão:
180115
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171216
[St] Status:MEDLINE


  5 / 2089 MEDLINE  
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[PMID]:28859202
[Au] Autor:Kersten E; Geerlings MJ; den Hollander AI; de Jong EK; Fauser S; Peto T; Hoyng CB
[Ad] Endereço:Department of Ophthalmology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
[Ti] Título:Phenotype Characteristics of Patients With Age-Related Macular Degeneration Carrying a Rare Variant in the Complement Factor H Gene.
[So] Source:JAMA Ophthalmol;135(10):1037-1044, 2017 Oct 01.
[Is] ISSN:2168-6173
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Importance: Rare variants in the complement factor H (CFH) gene and their association with age-related macular degeneration (AMD) have been described. However, there is limited literature on the phenotypes accompanying these rare variants. Phenotypical characteristics could help ophthalmologists select patients for additional genetic testing. Objective: To describe the phenotypical characteristics of patients with AMD carrying a rare variant in the CFH gene. Design, Setting, and Participants: In this cross-sectional study, we searched the genetic database of the department of ophthalmology at the Radboudumc (tertiary ophthalmologic referral center) and the European Genetic Database for patients with AMD with a rare genetic variant in the CFH gene. Patient recruitment took place from March 30, 2006, to February 18, 2013, and data were analyzed from November 30, 2015, to May 8, 2017. Phenotypical features on fundus photographs of both eyes of patients were graded by 2 independent reading center graders masked for carrier status. Main Outcomes and Measures: Differences in phenotypical characteristics between rare variant carriers and noncarriers were analyzed using univariable generalized estimated equations logistic regression models accounting for intereye correlation. Results: Analyses included 100 eyes of 51 patients with AMD carrying a CFH variant (mean [SD] age, 66.7 [12.1] years; 64.7% female) and 204 eyes of 102 age-matched noncarriers (mean [SD] age, 67.1 [11.8] years; 54.9% female). Carrying a rare pathogenic CFH variant was associated with larger drusen area (odds ratio range, 6.98 [95% CI, 2.04-23.89] to 18.50 [95% CI, 2.19-155.99]; P = .002), presence of drusen with crystalline appearance (odds ratio, 3.24; 95% CI, 1.24-8.50; P = .02), and drusen nasal to the optic disc (odds ratio range, 4.03 [95% CI, 1.70-9.56] to 7.42 [95% CI, 0.65-84.84]; P = .003). Conclusions and Relevance: Identification of rare CFH variant carriers may be important for upcoming complement-inhibiting therapies. Patients with an extensive drusen area, drusen with crystalline appearance, and drusen nasal to the optic disc are more likely to have a rare variant in the CFH gene. However, it is not likely that carriers can be discriminated from noncarriers based solely on phenotypical characteristics from color fundus images. Therefore, ophthalmologists should consider genetic testing in patients with these phenotypic characteristics in combination with other patient characteristics, such as early onset, cuticular drusen on fluorescein angiography, and family history of AMD.
[Mh] Termos MeSH primário: Degeneração Macular/genética
Fenótipo
Polimorfismo de Nucleotídeo Único
Drusas Retinianas/genética
[Mh] Termos MeSH secundário: Adulto
Idoso
Fator H do Complemento/genética
Estudos Transversais
Bases de Dados Factuais
Feminino
Angiofluoresceinografia
Testes Genéticos
Técnicas de Genotipagem
Seres Humanos
Degeneração Macular/diagnóstico
Masculino
Meia-Idade
Drusas Retinianas/patologia
Estudos Retrospectivos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (complement factor H, human); 80295-65-4 (Complement Factor H)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171023
[Lr] Data última revisão:
171023
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170901
[St] Status:MEDLINE
[do] DOI:10.1001/jamaophthalmol.2017.3195


  6 / 2089 MEDLINE  
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[PMID]:28846925
[Au] Autor:Wu L; Uldahl KB; Chen F; Benasutti H; Logvinski D; Vu V; Banda NK; Peng X; Simberg D; Moghimi SM
[Ad] Endereço:Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, People's Republic of China.
[Ti] Título:Interaction of extremophilic archaeal viruses with human and mouse complement system and viral biodistribution in mice.
[So] Source:Mol Immunol;90:273-279, 2017 Oct.
[Is] ISSN:1872-9142
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Archaeal viruses offer exceptional biophysical properties for modification and exploration of their potential in bionanotechnology, bioengineering and nanotherapeutic developments. However, the interaction of archaeal viruses with elements of the innate immune system has not been explored, which is a necessary prerequisite if their potential for biomedical applications to be realized. Here we show complement activation through lectin (via direct binding of MBL/MASPs) and alternative pathways by two extremophilic archaeal viruses (Sulfolobus monocaudavirus 1 and Sulfolobus spindle-shaped virus 2) in human serum. We further show some differences in initiation of complement activation pathways between these viruses. Since, Sulfolobus monocaudavirus 1 was capable of directly triggering the alternative pathway, we also demonstrate that the complement regulator factor H has no affinity for the viral surface, but factor H deposition is purely C3-dependent. This suggests that unlike some virulent pathogens Sulfolobus monocaudavirus 1 does not acquire factor H for protection. Complement activation with Sulfolobus monocaudavirus 1 also proceeds in murine sera through MBL-A/C as well as factor D-dependent manner, but C3 deficiency has no overall effect on viral clearance by organs of the reticuloendothelial system on intravenous injection. However, splenic deposition was significantly higher in C3 knockout animals compared with the corresponding wild type mice. We discuss the potential application of these viruses in biomedicine in relation to their complement activating properties.
[Mh] Termos MeSH primário: Vírus de Archaea/imunologia
Ativação do Complemento/imunologia
Via Alternativa do Complemento/imunologia
Imunidade Inata/imunologia
[Mh] Termos MeSH secundário: Adulto
Animais
Complemento C3/genética
Complemento C3/imunologia
Fator H do Complemento/imunologia
Extremófilos/imunologia
Feminino
Seres Humanos
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Microscopia Eletrônica de Transmissão
Sulfolobus/virologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Complement C3); 80295-65-4 (Complement Factor H)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170829
[St] Status:MEDLINE


  7 / 2089 MEDLINE  
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[PMID]:28671664
[Au] Autor:Xue X; Wu J; Ricklin D; Forneris F; Di Crescenzio P; Schmidt CQ; Granneman J; Sharp TH; Lambris JD; Gros P
[Ad] Endereço:Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, the Netherlands.
[Ti] Título:Regulator-dependent mechanisms of C3b processing by factor I allow differentiation of immune responses.
[So] Source:Nat Struct Mol Biol;24(8):643-651, 2017 Aug.
[Is] ISSN:1545-9985
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The complement system labels microbes and host debris for clearance. Degradation of surface-bound C3b is pivotal to direct immune responses and protect host cells. How the serine protease factor I (FI), assisted by regulators, cleaves either two or three distant peptide bonds in the CUB domain of C3b remains unclear. We present a crystal structure of C3b in complex with FI and regulator factor H (FH; domains 1-4 with 19-20). FI binds C3b-FH between FH domains 2 and 3 and a reoriented C3b C-terminal domain and docks onto the first scissile bond, while stabilizing its catalytic domain for proteolytic activity. One cleavage in C3b does not affect its overall structure, whereas two cleavages unfold CUB and dislodge the thioester-containing domain (TED), affecting binding of regulators and thereby determining the number of cleavages. These data explain how FI generates late-stage opsonins iC3b or C3dg in a context-dependent manner, to react to foreign, danger or healthy self signals.
[Mh] Termos MeSH primário: Complemento C3b/química
Complemento C3b/metabolismo
Fator H do Complemento/química
Fator H do Complemento/metabolismo
Fator I do Complemento/química
Fator I do Complemento/metabolismo
[Mh] Termos MeSH secundário: Cristalografia por Raios X
Seres Humanos
Modelos Moleculares
Ligação Proteica
Conformação Proteica
Proteólise
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
80295-43-8 (Complement C3b); 80295-65-4 (Complement Factor H); EC 3.4.21.45 (Complement Factor I)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170814
[Lr] Data última revisão:
170814
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170704
[St] Status:MEDLINE
[do] DOI:10.1038/nsmb.3427


  8 / 2089 MEDLINE  
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[PMID]:28658265
[Au] Autor:Winkler MT; Bushey RT; Gottlin EB; Campa MJ; Guadalupe ES; Volkheimer AD; Weinberg JB; Patz EF
[Ad] Endereço:Department of Radiology, Duke University Medical Center, Durham, North Carolina, United States of America.
[Ti] Título:Enhanced CDC of B cell chronic lymphocytic leukemia cells mediated by rituximab combined with a novel anti-complement factor H antibody.
[So] Source:PLoS One;12(6):e0179841, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Rituximab therapy for B cell chronic lymphocytic leukemia (B-CLL) has met with mixed success. Among several factors to which resistance can be attributed is failure to activate complement dependent cytotoxicity (CDC) due to protective complement regulatory proteins, including the soluble regulator complement factor H (CFH). We hypothesized that rituximab killing of non-responsive B-CLL cells could be augmented by a novel human monoclonal antibody against CFH. The B cells from 11 patients with B-CLL were tested ex vivo in CDC assays with combinations of CFH monoclonal antibody, rituximab, and a negative control antibody. CDC of rituximab non-responsive malignant B cells from CLL patients could in some cases be augmented by the CFH monoclonal antibody. Antibody-mediated cytotoxicity of cells was dependent upon functional complement. In one case where B-CLL cells were refractory to CDC by the combination of rituximab plus CFH monoclonal antibody, additionally neutralizing the membrane complement regulatory protein CD59 allowed CDC to occur. Inhibiting CDC regulatory proteins such as CFH holds promise for overcoming resistance to rituximab therapy in B-CLL.
[Mh] Termos MeSH primário: Anticorpos/uso terapêutico
Antineoplásicos/uso terapêutico
Fator H do Complemento/imunologia
Leucemia Linfocítica Crônica de Células B/tratamento farmacológico
Rituximab/uso terapêutico
[Mh] Termos MeSH secundário: Idoso
Idoso de 80 Anos ou mais
Anticorpos/imunologia
Ativação do Complemento/efeitos dos fármacos
Ativação do Complemento/imunologia
Feminino
Citometria de Fluxo
Seres Humanos
Masculino
Meia-Idade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies); 0 (Antineoplastic Agents); 4F4X42SYQ6 (Rituximab); 80295-65-4 (Complement Factor H)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170629
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0179841


  9 / 2089 MEDLINE  
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[PMID]:28637873
[Au] Autor:Kerr H; Wong E; Makou E; Yang Y; Marchbank K; Kavanagh D; Richards A; Herbert AP; Barlow PN
[Ad] Endereço:From the Schools of Chemistry and Biological Sciences, Joseph Black Building, University of Edinburgh, David Brewster Road, Edinburgh EH9 3FJ, Scotland, United Kingdom.
[Ti] Título:Disease-linked mutations in factor H reveal pivotal role of cofactor activity in self-surface-selective regulation of complement activation.
[So] Source:J Biol Chem;292(32):13345-13360, 2017 Aug 11.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Spontaneous activation enables the complement system to respond very rapidly to diverse threats. This activation is efficiently suppressed by complement factor H (CFH) on self-surfaces but not on foreign surfaces. The surface selectivity of CFH, a soluble protein containing 20 complement-control protein modules (CCPs 1-20), may be compromised by disease-linked mutations. However, which of the several functions of CFH drives this self-surface selectivity remains unknown. To address this, we expressed human CFH mutants in We found that recombinant I62-CFH (protective against age-related macular degeneration) and V62-CFH functioned equivalently, matching or outperforming plasma-derived CFH, whereas R53H-CFH, linked to atypical hemolytic uremic syndrome (aHUS), was defective in C3bBb decay-accelerating activity (DAA) and factor I cofactor activity (CA). The aHUS-linked CCP 19 mutant D1119G-CFH had virtually no CA on (self-like) sheep erythrocytes ( ) but retained DAA. The aHUS-linked CCP 20 mutant S1191L/V1197A-CFH (LA-CFH) had dramatically reduced CA on but was less compromised in DAA. D1119G-CFH and LA-CFH both performed poorly at preventing complement-mediated hemolysis of PspCN, a CFH-binding protein domain, binds CFH tightly and increases accessibility of CCPs 19 and 20. PspCN did not improve the DAA of any CFH variant on Conversely, PspCN boosted the CA, on , of I62-CFH, R53H-CFH, and LA-CFH and also enhanced hemolysis protection by I62-CFH and LA-CFH. We conclude that CCPs 19 and 20 are critical for efficient CA on self-surfaces but less important for DAA. Exposing CCPs 19 and 20 with PspCN and thus enhancing CA on self-surfaces may reverse deficiencies of some CFH variants.
[Mh] Termos MeSH primário: Síndrome Hemolítico-Urêmica Atípica/genética
Ativação do Complemento
Degeneração Macular/genética
Mutação
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Animais
Síndrome Hemolítico-Urêmica Atípica/metabolismo
Proteínas de Bactérias/química
Proteínas de Bactérias/genética
Proteínas de Bactérias/metabolismo
Sítios de Ligação
C3 Convertase da Via Alternativa do Complemento/química
C3 Convertase da Via Alternativa do Complemento/genética
C3 Convertase da Via Alternativa do Complemento/metabolismo
Complemento C3d/química
Complemento C3d/genética
Complemento C3d/metabolismo
Fator H do Complemento/química
Fator H do Complemento/genética
Fator H do Complemento/metabolismo
Fator I do Complemento/química
Fator I do Complemento/genética
Fator I do Complemento/metabolismo
Eritrócitos/química
Hemólise
Seres Humanos
Proteínas Imobilizadas/química
Proteínas Imobilizadas/genética
Proteínas Imobilizadas/metabolismo
Degeneração Macular/metabolismo
Fragmentos de Peptídeos/química
Fragmentos de Peptídeos/genética
Fragmentos de Peptídeos/metabolismo
Domínios e Motivos de Interação entre Proteínas
Proteínas Recombinantes de Fusão/química
Proteínas Recombinantes de Fusão/metabolismo
Carneiro Doméstico
Solubilidade
Streptococcus pneumoniae/metabolismo
Propriedades de Superfície
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Immobilized Proteins); 0 (Peptide Fragments); 0 (Recombinant Fusion Proteins); 0 (complement factor H, human); 80295-45-0 (Complement C3d); 80295-65-4 (Complement Factor H); EC 3.4.21.45 (CFI protein, human); EC 3.4.21.45 (Complement Factor I); EC 3.4.21.47 (Complement C3 Convertase, Alternative Pathway)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170825
[Lr] Data última revisão:
170825
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170623
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.795088


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[PMID]:28566480
[Au] Autor:Li QY; Li HY; Fu G; Yu F; Wu Y; Zhao MH
[Ad] Endereço:Renal Division, Department of Medicine, Peking University First Hospital, Beijing, People's Republic of China.
[Ti] Título:Autoantibodies against C-Reactive Protein Influence Complement Activation and Clinical Course in Lupus Nephritis.
[So] Source:J Am Soc Nephrol;28(10):3044-3054, 2017 Oct.
[Is] ISSN:1533-3450
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Autoantibodies against the major acute-phase reactant C-reactive protein (CRP) are frequently found in patients with lupus nephritis. Further defining the autoimmune epitopes on CRP may not only improve patient stratification but also, hint at mechanisms of CRP action. Herein, we show that amino acids 35-47 constitute the major epitope recognized by anti-CRP autoantibodies in patients with lupus nephritis. Notably, the presence of autoantibodies against amino acids 35-47 associated with more severe renal damage and predicted worse outcome. This epitope is exposed on CRP only after irreversible structure changes, yielding a conformationally altered form termed modified or monomeric CRP (mCRP). ELISA and surface plasmon resonance assays showed that amino acids 35-47 mediate the interaction of mCRP with complement factor H, an inhibitor of alternative pathway activation, and this interaction greatly enhanced the cofactor activity of complement factor H. In contrast, autoantibodies against amino acids 35-47 inhibited these actions of mCRP. Our results thus provide evidence for the generation of mCRP in a human disease and suggest that mCRP actively controls the pathogenesis of lupus nephritis by regulating complement activation. Therefore, amino acids 35-47 constitute a functional autoimmune epitope on CRP that can be targeted therapeutically and diagnostically.
[Mh] Termos MeSH primário: Proteína C-Reativa/imunologia
Nefrite Lúpica/imunologia
[Mh] Termos MeSH secundário: Adolescente
Adulto
Autoanticorpos/metabolismo
Proteína C-Reativa/metabolismo
Estudos de Casos e Controles
Fator H do Complemento/metabolismo
Mapeamento de Epitopos
Feminino
Seres Humanos
Nefrite Lúpica/diagnóstico
Masculino
Prognóstico
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Autoantibodies); 0 (complement factor H, human); 80295-65-4 (Complement Factor H); 9007-41-4 (C-Reactive Protein)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170602
[St] Status:MEDLINE
[do] DOI:10.1681/ASN.2016070735



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