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[PMID]:29208248
[Au] Autor:Sanghera P; Ghanta M; Ozay F; Ariyamuthu VK; Tanriover B
[Ad] Endereço:Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, Texas.
[Ti] Título:Kidney Diseases Associated With Alternative Complement Pathway Dysregulation and Potential Treatment Options.
[So] Source:Am J Med Sci;354(6):533-538, 2017 12.
[Is] ISSN:1538-2990
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Atypical hemolytic uremic syndrome and C3 glomerulopathy (dense deposit disease and C3 glomerulonephritis) are characterized as inappropriate activation of the alternative complement pathway. Genetic mutations affecting the alternative complement pathway regulating proteins (complement factor H, I, membrane cofactor protein and complement factor H-related proteins) and triggers (such as infection, surgery, pregnancy and autoimmune disease flares) result in the clinical manifestation of these diseases. A decade ago, prognosis of these disease states was quite poor, with most patients developing end-stage renal disease. Furthermore, renal transplantation in these conditions was associated with poor outcomes due to graft loss to recurrent disease. Recent advances in targeted complement inhibitor therapy resulted in significant improvement in disease remission, renal recovery, health-related quality of life and allograft survival.
[Mh] Termos MeSH primário: Via Alternativa do Complemento/fisiologia
Nefropatias/etiologia
[Mh] Termos MeSH secundário: Síndrome Hemolítico-Urêmica Atípica/tratamento farmacológico
Síndrome Hemolítico-Urêmica Atípica/etiologia
Inativadores do Complemento/uso terapêutico
Via Alternativa do Complemento/efeitos dos fármacos
Glomerulonefrite/tratamento farmacológico
Glomerulonefrite/etiologia
Glomerulonefrite Membranoproliferativa/tratamento farmacológico
Glomerulonefrite Membranoproliferativa/etiologia
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Complement Inactivating Agents)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180223
[Lr] Data última revisão:
180223
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171207
[St] Status: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


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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]:28855313
[Au] Autor:Sanchez-Larrayoz AF; Elhosseiny NM; Chevrette MG; Fu Y; Giunta P; Spallanzani RG; Ravi K; Pier GB; Lory S; Maira-Litrán T
[Ad] Endereço:Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; and.
[Ti] Título:Complexity of Complement Resistance Factors Expressed by Needed for Survival in Human Serum.
[So] Source:J Immunol;199(8):2803-2814, 2017 Oct 15.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:is a bacterial pathogen with increasing impact in healthcare settings, due in part to this organism's resistance to many antimicrobial agents, with pneumonia and bacteremia as the most common manifestations of disease. A significant proportion of clinically relevant strains are resistant to killing by normal human serum (NHS), an observation supported in this study by showing that 12 out of 15 genetically diverse strains of are resistant to NHS killing. To expand our understanding of the genetic basis of serum resistance, a transposon (Tn) sequencing (Tn-seq) approach was used to identify genes contributing to this trait. An ordered Tn library in strain AB5075 with insertions in every nonessential gene was subjected to selection in NHS. We identified 50 genes essential for the survival of in NHS, including already known serum resistance factors, and many novel genes not previously associated with serum resistance. This latter group included the maintenance of lipid asymmetry genetic pathway as a key determinant in protecting from the bactericidal activity of NHS via the alternative complement pathway. Follow-up studies validated the role of eight additional genes identified by Tn-seq in resistance to killing by NHS but not by normal mouse serum, highlighting the human species specificity of serum resistance. The identification of a large number of genes essential for serum resistance in indicates the degree of complexity needed for this phenotype, which might reflect a general pattern that pathogens rely on to cause serious infections.
[Mh] Termos MeSH primário: Infecções por Acinetobacter/microbiologia
Acinetobacter baumannii/genética
Atividade Bactericida do Sangue
Pneumonia/microbiologia
Virulência
[Mh] Termos MeSH secundário: Infecções por Acinetobacter/imunologia
Acinetobacter baumannii/imunologia
Acinetobacter baumannii/patogenicidade
Animais
Via Alternativa do Complemento/genética
Elementos de DNA Transponíveis/genética
DNA Bacteriano/análise
Seres Humanos
Metabolismo dos Lipídeos/genética
Camundongos
Pneumonia/imunologia
Fator de Resposta Sérica/genética
Especificidade da Espécie
Transcriptoma
Virulência/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA Transposable Elements); 0 (DNA, Bacterial); 0 (Serum Response Factor)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171101
[Lr] Data última revisão:
171101
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170901
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1700877


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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


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[PMID]:28732131
[Au] Autor:Thurman JM; Frazer-Abel A; Holers VM
[Ad] Endereço:University of Colorado Denver, Aurora.
[Ti] Título:The Evolving Landscape for Complement Therapeutics in Rheumatic and Autoimmune Diseases.
[So] Source:Arthritis Rheumatol;69(11):2102-2113, 2017 Nov.
[Is] ISSN:2326-5205
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The complement system is increasingly understood to play major roles in the pathogenesis of human inflammatory and autoimmune diseases. Because of this situation, there are rapidly expanding commercial efforts to develop novel complement inhibitors and effector pathway-modulating drugs. This review provides insights into the evolving understanding of the complement system components, mechanisms of activation within and across the 3 pathways (classical, alternative, and lectin), how the pathways are normally controlled and then dysregulated in target tissues, and what diseases are known to be, in large part, complement-dependent through the successful development and approval of complement therapeutics in patients. Mechanisms of complement activation in rheumatoid arthritis, lupus, and thrombotic microangiopathies are also illustrated. In addition, the specific therapeutic drugs that are both approved and under development are discussed in the context of both nonrheumatic and rheumatic diseases. Finally, the methods by which the complement system can be assessed in humans through biomarker studies are outlined, with the goal of understanding, in specific patients, how the system is functioning.
[Mh] Termos MeSH primário: Doenças Autoimunes/tratamento farmacológico
Inativadores do Complemento/uso terapêutico
Doenças Reumáticas/tratamento farmacológico
[Mh] Termos MeSH secundário: Doenças Autoimunes/imunologia
Via Alternativa do Complemento/imunologia
Via Clássica do Complemento/imunologia
Lectina de Ligação a Manose da Via do Complemento/imunologia
Proteínas do Sistema Complemento/imunologia
Seres Humanos
Lúpus Eritematoso Sistêmico/tratamento farmacológico
Lúpus Eritematoso Sistêmico/imunologia
Terapia de Alvo Molecular
Doenças Reumáticas/imunologia
Microangiopatias Trombóticas/tratamento farmacológico
Microangiopatias Trombóticas/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Complement Inactivating Agents); 9007-36-7 (Complement System Proteins)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171106
[Lr] Data última revisão:
171106
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170722
[St] Status:MEDLINE
[do] DOI:10.1002/art.40219


  7 / 2469 MEDLINE  
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[PMID]:28724763
[Au] Autor:Kumar J; Yadav VN; Phulera S; Kamble A; Gautam AK; Panwar HS; Sahu A
[Ad] Endereço:Complement Biology Laboratory, National Centre for Cell Science, S. P. Pune University, Ganeshkhind, Pune, India.
[Ti] Título:Species Specificity of Vaccinia Virus Complement Control Protein for the Bovine Classical Pathway Is Governed Primarily by Direct Interaction of Its Acidic Residues with Factor I.
[So] Source:J Virol;91(19), 2017 Oct 01.
[Is] ISSN:1098-5514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Poxviruses display species tropism-variola virus is a human-specific virus, while vaccinia virus causes repeated outbreaks in dairy cattle. Consistent with this, variola virus complement regulator SPICE (smallpox inhibitor of complement enzymes) exhibits selectivity in inhibiting the human alternative complement pathway and vaccinia virus complement regulator VCP (vaccinia virus complement control protein) displays selectivity in inhibiting the bovine alternative complement pathway. In the present study, we examined the species specificity of VCP and SPICE for the classical pathway (CP). We observed that VCP is ∼43-fold superior to SPICE in inhibiting bovine CP. Further, functional assays revealed that increased inhibitory activity of VCP for bovine CP is solely due to its enhanced cofactor activity, with no effect on decay of bovine CP C3-convertase. To probe the structural basis of this specificity, we utilized single- and multi-amino-acid substitution mutants wherein 1 or more of the 11 variant VCP residues were substituted in the SPICE template. Examination of these mutants for their ability to inhibit bovine CP revealed that E108, E120, and E144 are primarily responsible for imparting the specificity and contribute to the enhanced cofactor activity of VCP. Binding and functional assays suggested that these residues interact with bovine factor I but not with bovine C4(H O) (a moiety conformationally similar to C4b). Mapping of these residues onto the modeled structure of bovine C4b-VCP-bovine factor I supported the mutagenesis data. Taken together, our data help explain why the vaccine strain of vaccinia virus was able to gain a foothold in domesticated animals. Vaccinia virus was used for smallpox vaccination. The vaccine-derived virus is now circulating and causing outbreaks in dairy cattle in India and Brazil. However, the reason for this tropism is unknown. It is well recognized that the virus is susceptible to neutralization by the complement classical pathway (CP). Because the virus encodes a soluble complement regulator, VCP, we examined whether this protein displays selectivity in targeting bovine CP. Our data show that it does exhibit selectivity in inhibiting the bovine CP and that this is primarily determined by its amino acids E108, E120, and E144, which interact with bovine serine protease factor I to inactivate bovine C4b-one of the two subunits of CP C3-convertase. Of note, the variola complement regulator SPICE contains positively charged residues at these positions. Thus, these variant residues in VCP help enhance its potency against the bovine CP and thereby the fitness of the virus in cattle.
[Mh] Termos MeSH primário: Ativação do Complemento/imunologia
Via Alternativa do Complemento/imunologia
Via Clássica do Complemento/imunologia
Proteínas da Matriz Viral/imunologia
Proteínas Virais/imunologia
Tropismo Viral/genética
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Bovinos
Proteína de Ligação ao Complemento C4b/imunologia
Fibrinogênio/metabolismo
Seres Humanos
Alinhamento de Sequência
Especificidade da Espécie
Vírus Vaccinia/imunologia
Vírus Vaccinia/patogenicidade
Proteínas da Matriz Viral/genética
Proteínas Virais/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Complement C4b-Binding Protein); 0 (SPICE protein, variola virus); 0 (Viral Matrix Proteins); 0 (Viral Proteins); 0 (complement-control protein, Vaccinia virus); 9001-32-5 (Fibrinogen)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170721
[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


  9 / 2469 MEDLINE  
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[PMID]:28630122
[Au] Autor:Konar M; Granoff DM
[Ad] Endereço:Center for Immunobiology and Vaccine Development, UCSF Benioff Children's Hospital Oakland, Oakland, CA.
[Ti] Título:Eculizumab treatment and impaired opsonophagocytic killing of meningococci by whole blood from immunized adults.
[So] Source:Blood;130(7):891-899, 2017 Aug 17.
[Is] ISSN:1528-0020
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Eculizumab, a humanized anti-complement C5 monoclonal antibody (mAb) for treatment of paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome, blocks the terminal complement pathway required for serum bactericidal activity (SBA). Because treated patients are at >1000-fold increased risk of meningococcal disease, vaccination is recommended; whether vaccination can protect by opsonophagocytic activity in the absence of SBA is not known. Meningococci were added to anticoagulated blood from 12 healthy adults vaccinated with meningococcal serogroup B and serogroup A, C, W, Y vaccines. Bacterial survival was measured after 3-hour incubation in the presence of eculizumab or control complement factor D inhibitor ACH-4471, which blocks the complement alternative pathway (AP) and is in phase 2 development for treatment of PNH. In the absence of inhibitors, colony formation units (CFUs) per milliliter in blood from all 12 immunized subjects decreased from ∼4000 at time 0 to sterile cultures at 3 hours. In the presence of eculizumab, there was a >22-fold increase in geometric mean CFUs per milliliter (90 596 and 114 683 CFU/mL for serogroup B and C strains, respectively; < .0001 compared with time 0). In the presence of ACH-4471, there was a >12-fold decrease (23 and 331 CFU/mL, respectively; < .0001). The lack of meningococci killing by blood containing eculizumab resulted from inhibition of release of C5a, a C5 split product needed for upregulation of phagocytosis. The results provide an explanation for the large number of cases of meningococcal disease in immunized patients being treated with eculizumab and suggest that vaccination may provide better protection against meningococcal disease in patients treated with an AP-specific inhibitor.
[Mh] Termos MeSH primário: Anticorpos Monoclonais Humanizados/farmacologia
Imunização
Viabilidade Microbiana/efeitos dos fármacos
Neisseria meningitidis/efeitos dos fármacos
Proteínas Opsonizantes/metabolismo
Fagocitose/efeitos dos fármacos
[Mh] Termos MeSH secundário: Adulto
Idoso
Via Alternativa do Complemento/efeitos dos fármacos
Proteínas do Sistema Complemento/imunologia
Feminino
Seres Humanos
Masculino
Meia-Idade
Receptor da Anafilatoxina C5a/antagonistas & inibidores
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Monoclonal, Humanized); 0 (C5AR1 protein, human); 0 (Opsonin Proteins); 0 (Receptor, Anaphylatoxin C5a); 9007-36-7 (Complement System Proteins); A3ULP0F556 (eculizumab)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170621
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2017-05-781450


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[PMID]:28621538
[Au] Autor:Lorthiois E; Anderson K; Vulpetti A; Rogel O; Cumin F; Ostermann N; Steinbacher S; Mac Sweeney A; Delgado O; Liao SM; Randl S; Rüdisser S; Dussauge S; Fettis K; Kieffer L; de Erkenez A; Yang L; Hartwieg C; Argikar UA; La Bonte LR; Newton R; Kansara V; Flohr S; Hommel U; Jaffee B; Maibaum J
[Ad] Endereço:Novartis Pharma AG, Novartis Institutes for BioMedical Research , Novartis Campus, CH-4056 Basel, Switzerland.
[Ti] Título:Discovery of Highly Potent and Selective Small-Molecule Reversible Factor D Inhibitors Demonstrating Alternative Complement Pathway Inhibition in Vivo.
[So] Source:J Med Chem;60(13):5717-5735, 2017 Jul 13.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The highly specific S1 serine protease factor D (FD) plays a central role in the amplification of the complement alternative pathway (AP) of the innate immune system. Genetic associations in humans have implicated AP activation in age-related macular degeneration (AMD), and AP dysfunction predisposes individuals to disorders such as paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). The combination of structure-based hit identification and subsequent optimization of the center (S)-proline-based lead 7 has led to the discovery of noncovalent reversible and selective human factor D (FD) inhibitors with drug-like properties. The orally bioavailable compound 2 exerted excellent potency in 50% human whole blood in vitro and blocked AP activity ex vivo after oral administration to monkeys as demonstrated by inhibition of membrane attack complex (MAC) formation. Inhibitor 2 demonstrated sustained oral and ocular efficacy in a model of lipopolysaccharide (LPS)-induced systemic AP activation in mice expressing human FD.
[Mh] Termos MeSH primário: Fator D do Complemento/antagonistas & inibidores
Via Alternativa do Complemento/efeitos dos fármacos
Prolina/análogos & derivados
Prolina/farmacologia
[Mh] Termos MeSH secundário: Administração Oral
Animais
Síndrome Hemolítico-Urêmica Atípica/tratamento farmacológico
Síndrome Hemolítico-Urêmica Atípica/imunologia
Fator D do Complemento/imunologia
Complexo de Ataque à Membrana do Sistema Complemento/antagonistas & inibidores
Complexo de Ataque à Membrana do Sistema Complemento/imunologia
Feminino
Haplorrinos
Seres Humanos
Macaca fascicularis
Degeneração Macular/tratamento farmacológico
Degeneração Macular/imunologia
Masculino
Camundongos
Prolina/administração & dosagem
Prolina/farmacocinética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Complement Membrane Attack Complex); 9DLQ4CIU6V (Proline); EC 3.4.21.46 (Complement Factor D)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170801
[Lr] Data última revisão:
170801
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170617
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00425



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