Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 4.063
Filtrar
1.
Front Immunol ; 11: 599417, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33362783

RESUMO

The complement system comprises the frontline of the innate immune system. Triggered by pathogenic surface patterns in different pathways, the cascade concludes with the formation of a membrane attack complex (MAC; complement components C5b to C9) and C5a, a potent anaphylatoxin that elicits various inflammatory signals through binding to C5a receptor 1 (C5aR1). Despite its important role in pathogen elimination, priming and recruitment of myeloid cells from the immune system, as well as crosstalk with other physiological systems, inadvertent activation of the complement system can result in self-attack and overreaction in autoinflammatory diseases. Consequently, it constitutes an interesting target for specialized therapies. The paradigm of safe and efficacious terminal complement pathway inhibition has been demonstrated by the approval of eculizumab in paroxysmal nocturnal hematuria. In addition, complement contribution in rare kidney diseases, such as lupus nephritis, IgA nephropathy, atypical hemolytic uremic syndrome, C3 glomerulopathy, or antineutrophil cytoplasmic antibody-associated vasculitis has been demonstrated. This review summarizes the involvement of the terminal effector agents of the complement system in these diseases and provides an overview of inhibitors for complement components C5, C5a, C5aR1, and MAC that are currently in clinical development. Furthermore, a link between increased complement activity and lung damage in severe COVID-19 patients is discussed and the potential for use of complement inhibitors in COVID-19 is presented.


Assuntos
Complemento C5a/antagonistas & inibidores , Inativadores do Complemento/uso terapêutico , Complexo de Ataque à Membrana do Sistema Complemento/antagonistas & inibidores , Nefropatias/tratamento farmacológico , Receptor da Anafilatoxina C5a/antagonistas & inibidores , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/patologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Ativação do Complemento/imunologia , Proteínas do Sistema Complemento/metabolismo , Glomerulonefrite por IGA/tratamento farmacológico , Glomerulonefrite por IGA/patologia , Humanos , Rim/patologia , Nefropatias/imunologia , Nefropatias/patologia , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/patologia
2.
J Renin Angiotensin Aldosterone Syst ; 21(4): 1470320320979097, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33283602

RESUMO

Because of the current COVID-19-pandemic, the world is currently being held hostage in various lockdowns. ACE2 facilitates SARS-CoV-2 cell-entry, and is at the very center of several pathophysiological pathways regarding the RAAS, CS, KKS, T2DM, and IL-6. Their interactions with severe COVID-19 complications (e.g. ARDS and thrombosis), and potential therapeutic targets for pharmacological intervention, will be reviewed.


Assuntos
/metabolismo , Proteínas do Sistema Complemento/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/virologia , Interleucina-6/metabolismo , Sistema Calicreína-Cinina , /complicações , Diabetes Mellitus Tipo 2/complicações , Humanos , /fisiologia
4.
Mediators Inflamm ; 2020: 6914878, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33061829

RESUMO

Background: COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has threatened every civilian as a global pandemic. The immune system poses the critical interactive chain between the human body and the virus. Here, we make efforts to examine whether comorbidity with type 2 diabetes (T2D) affects the immunological response in COVID-19 patients. Methods: We conducted a retrospective pilot study investigating immunological characteristics of confirmed cases of COVID-19 with or without comorbid T2D. Two subcohorts of sex- and age-matched participants were eligible for data analysis, of which 33 participants were with T2D and the remaining 37 were nondiabetic (NDM). Cellular immunity was assessed by flow cytometric determination of surface markers including CD3, CD4, CD8, CD19, CD16, and CD56 in peripheral blood. Levels of C reactive protein, immunoglobulin (IgG, IgM, IgA, and IgE), and complements (C3, C4) were detected by rate nephelometry immunoassay. And Th1/Th2 cytokines (IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ) were detected by Cytometric Bead Array. Results: Neutrophil counts were found to be significantly higher in the T2D group than in the NDM group and had a significant relevance with clinical severity. Lymphocyte frequencies showed no significant differences in the two groups. However, the proportions and absolute counts of T, Tc, Th, and NK cells decreased in both groups to different degrees. An abnormal increase in neutrophil count and a decrease in lymphocyte subpopulations may represent risk factors of COVID-19 severity. The level of IgG, IgM, IgA, C3, and C4 showed no significant difference between the two groups, while the IgE levels were higher in the T2D group than in the NDM group (p < 0.05). Th1 cytokines including IFN-γ, TNF-α, and IL-6, as well as CRP, appeared significantly higher in the T2D group. Conclusions: The COVID-19 patients comorbid with T2D demonstrated distinguishable immunological parameters, which represented clinical relevancies with the predisposed disease severity in T2D.


Assuntos
Betacoronavirus , Infecções por Coronavirus/imunologia , Diabetes Mellitus Tipo 2/imunologia , Pneumonia Viral/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , China/epidemiologia , Estudos de Coortes , Comorbidade , Proteínas do Sistema Complemento/metabolismo , Infecções por Coronavirus/complicações , Infecções por Coronavirus/epidemiologia , Citocinas/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Humanos , Imunidade Celular , Imunoglobulinas/sangue , Mediadores da Inflamação/sangue , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Pandemias , Projetos Piloto , Pneumonia Viral/complicações , Pneumonia Viral/epidemiologia , Estudos Retrospectivos , Células Th1/imunologia , Células Th2/imunologia
5.
J Vis Exp ; (162)2020 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-32894265

RESUMO

In this study, the hemocompatibility of tubes with an inner diameter of 5 mm made of polyvinyl chloride (PVC) and coated with different bioactive conjugates was compared to uncoated PVC tubes, latex tubes, and a stent for intravascular application that was placed inside the PVC tubes. Evaluation of hemocompatibility was done using an in vitro hemodynamic loop model that is recommended by the ISO standard 10993-4. The tubes were cut into segments of identical length and closed to form loops avoiding any gap at the splice, then filled with human blood and rotated in a water bath at 37 °C for 3 hours. Thereafter, the blood inside the tubes was collected for the analysis of whole blood cell count, hemolysis (free plasma hemoglobin), complement system (sC5b-9), coagulation system (fibrinopeptide A), and leukocyte activation (polymorphonuclear elastase, tumor necrosis factor and interleukin-6). Host cell activation was determined for platelet activation, leukocyte integrin status and monocyte platelet aggregates using flow cytometry. The effect of inaccurate loop closure was examined with x-ray microtomography and scanning electron microscopy, that showed thrombus formation at the splice. Latex tubes showed the strongest activation of both plasma and cellular components of the blood, indicating a poor hemocompatibility, followed by the stent group and uncoated PVC tubes. The coated PVC tubes did not show a significant decrease in platelet activation status, but showed an increased in complement and coagulation cascade compared to uncoated PVC tubes. The loop model itself did not lead to the activation of cells or soluble factors, and the hemolysis level was low. Therefore, the presented in vitro hemodynamic loop model avoids excessive activation of blood components by mechanical forces and serves as a method to investigate in vitro interactions between donor blood and vascular medical devices.


Assuntos
Células Sanguíneas/metabolismo , Prótese Vascular , Materiais Revestidos Biocompatíveis/química , Hemodinâmica/fisiologia , Teste de Materiais/métodos , Células Sanguíneas/citologia , Coagulação Sanguínea , Proteínas do Sistema Complemento/metabolismo , Humanos , Teste de Materiais/normas , Modelos Biológicos , Plasma/metabolismo , Ativação Plaquetária , Cloreto de Polivinila/química
6.
PLoS Pathog ; 16(8): e1008754, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32776975

RESUMO

Arbovirus infection of Aedes aegypti salivary glands (SGs) determines transmission. However, there is a dearth of knowledge on SG immunity. Here, we characterized SG immune response to dengue, Zika and chikungunya viruses using high-throughput transcriptomics. We also describe a transcriptomic response associated to apoptosis, blood-feeding and lipid metabolism. The three viruses differentially regulate components of Toll, Immune deficiency (IMD) and c-Jun N- terminal Kinase (JNK) pathways. However, silencing of the Toll and IMD pathway components showed variable effects on SG infection by each virus. In contrast, regulation of the JNK pathway produced consistent responses in both SGs and midgut. Infection by the three viruses increased with depletion of the activator Kayak and decreased with depletion of the negative regulator Puckered. Virus-induced JNK pathway regulates the complement factor, Thioester containing protein-20 (TEP20), and the apoptosis activator, Dronc, in SGs. Individual and co-silencing of these genes demonstrate their antiviral effects and that both may function together. Co-silencing either TEP20 or Dronc with Puckered annihilates JNK pathway antiviral effect. Upon infection in SGs, TEP20 induces antimicrobial peptides (AMPs), while Dronc is required for apoptosis independently of TEP20. In conclusion, we revealed the broad antiviral function of JNK pathway in SGs and showed that it is mediated by a TEP20 complement and Dronc-induced apoptosis response. These results expand our understanding of the immune arsenal that blocks arbovirus transmission.


Assuntos
Aedes/imunologia , Apoptose , Febre de Chikungunya/imunologia , Proteínas do Sistema Complemento/imunologia , Dengue/imunologia , Sistema de Sinalização das MAP Quinases , Glândulas Salivares/imunologia , Infecção por Zika virus/imunologia , Aedes/virologia , Animais , Febre de Chikungunya/metabolismo , Febre de Chikungunya/prevenção & controle , Febre de Chikungunya/virologia , Vírus Chikungunya/imunologia , Proteínas do Sistema Complemento/metabolismo , Dengue/metabolismo , Dengue/prevenção & controle , Dengue/virologia , Vírus da Dengue/imunologia , Feminino , Interações Hospedeiro-Patógeno , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Insetos Vetores/imunologia , Insetos Vetores/virologia , Glândulas Salivares/virologia , Transcriptoma , Replicação Viral , Zika virus/imunologia , Infecção por Zika virus/metabolismo , Infecção por Zika virus/prevenção & controle , Infecção por Zika virus/virologia
7.
PLoS Pathog ; 16(6): e1008606, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32569291

RESUMO

An important effector function of the human complement system is to directly kill Gram-negative bacteria via Membrane Attack Complex (MAC) pores. MAC pores are assembled when surface-bound convertase enzymes convert C5 into C5b, which together with C6, C7, C8 and multiple copies of C9 forms a transmembrane pore that damages the bacterial cell envelope. Recently, we found that bacterial killing by MAC pores requires local conversion of C5 by surface-bound convertases. In this study we aimed to understand why local assembly of MAC pores is essential for bacterial killing. Here, we show that rapid interaction of C7 with C5b6 is required to form bactericidal MAC pores on Escherichia coli. Binding experiments with fluorescently labelled C6 show that C7 prevents release of C5b6 from the bacterial surface. Moreover, trypsin shaving experiments and atomic force microscopy revealed that this rapid interaction between C7 and C5b6 is crucial to efficiently anchor C5b-7 to the bacterial cell envelope and form complete MAC pores. Using complement-resistant clinical E. coli strains, we show that bacterial pathogens can prevent complement-dependent killing by interfering with the anchoring of C5b-7. While C5 convertase assembly was unaffected, these resistant strains blocked efficient anchoring of C5b-7 and thus prevented stable insertion of MAC pores into the bacterial cell envelope. Altogether, these findings provide basic molecular insights into how bactericidal MAC pores are assembled and how bacteria evade MAC-dependent killing.


Assuntos
Atividade Bactericida do Sangue , Membrana Celular/metabolismo , Parede Celular/metabolismo , Complemento C5/metabolismo , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Escherichia coli/metabolismo , Proteínas do Sistema Complemento/metabolismo , Células HEK293 , Humanos
8.
Int J Lab Hematol ; 42 Suppl 1: 33-40, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32543063

RESUMO

Thrombotic microangiopathies (TMA) are a heterogeneous group of red cell fragmentation syndromes characterized by a tendency for thrombosis and pathognomonic red cell fragments in peripheral blood, which results in thrombosis in the microvasculature due to endothelial damage. Genomic investigations into inherited TMAs are of diagnostic, prognostic and therapeutic value. Here, we present two cases that capture the importance of performing genomic testing in rare disorders. Treatment options for these conditions, such as plasma exchange and monoclonal antibodies against complement factors, are intensive and expensive health care interventions. The results of genomic investigation into rare TMAs can better inform the clinicians and their patients of prognosis and suitable personalized treatment options.


Assuntos
Testes Genéticos , Genômica , Microangiopatias Trombóticas/genética , Anticorpos Monoclonais/uso terapêutico , Proteínas do Sistema Complemento/genética , Proteínas do Sistema Complemento/metabolismo , Eritrócitos/metabolismo , Humanos , Troca Plasmática , Microangiopatias Trombóticas/sangue , Microangiopatias Trombóticas/terapia
9.
EBioMedicine ; 56: 102822, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32535547

RESUMO

Immunosuppression and immunomodulation are valuable therapeutic approaches for managing neuroimmunological diseases. In times of the Coronavirus disease 2019 (COVID-19) pandemic, clinicians must deal with the question of whether immunotherapy should currently be initiated or discontinued in neurological patients. Uncertainty exists especially because different national medical associations publish different recommendations on the extent to which immunotherapies must be continued, monitored, or possibly switched during the current pandemic. Based on the most recently available data both about the novel coronavirus and the approved immunotherapies for neurological diseases, we provide an updated overview that includes current treatment strategies and the associated COVID-19 risk, but also the potential of immunotherapies to treat COVID-19.


Assuntos
Infecções por Coronavirus/patologia , Imunoterapia , Doenças do Sistema Nervoso/terapia , Pneumonia Viral/patologia , Anticorpos Monoclonais/uso terapêutico , Betacoronavirus/isolamento & purificação , Betacoronavirus/fisiologia , Proteínas do Sistema Complemento/metabolismo , Infecções por Coronavirus/complicações , Infecções por Coronavirus/virologia , Humanos , Imunidade Ativa , Imunossupressores/uso terapêutico , Doenças do Sistema Nervoso/complicações , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/virologia , Vacinação
10.
Thromb Res ; 194: 36-41, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32569879

RESUMO

Severe acute respiratory syndrome coronavirus 2 is responsible for the current COVID-19 pandemic resulting in an escalating number of cases and fatalities worldwide. Preliminary evidence from these patients, as well as past coronavirus epidemics, indicates that those infected suffer from disproportionate complement activation as well as excessive coagulation, leading to thrombotic complications and poor outcome. In non-coronavirus cohorts, evidence has accumulated of an interaction between the complement and coagulation systems, with one amplifying activation of the other. A pressing question is therefore if COVID-19 associated thrombosis could be caused by overactivation of the complement cascade? In this review, we summarize the literature on thrombotic complications in COVID-19, complement activation in coronavirus infections, and the crosstalk between the complement and coagulation systems. We demonstrate how the complement system is able to activate the coagulation cascade and platelets, inhibit fibrinolysis and stimulate endothelial cells. We also describe how these interactions see clinical relevance in several disorders where overactive complement results in a prothrombotic clinical presentation, and how it could be clinically relevant in COVID-19.


Assuntos
Coagulação Sanguínea , Ativação do Complemento , Tromboembolia/etiologia , Trombose/etiologia , Animais , Plaquetas/imunologia , Plaquetas/metabolismo , /imunologia , Proteínas do Sistema Complemento/metabolismo , Células Endoteliais/imunologia , Células Endoteliais/metabolismo , Fibrinólise , Humanos , Transdução de Sinais , Tromboembolia/sangue , Tromboembolia/imunologia , Trombose/sangue , Trombose/imunologia
11.
Clin Adv Hematol Oncol ; 18(1): 35-44, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32511221

RESUMO

Primary cold agglutinin disease (CAD) is characterized by a very indolent bone marrow clonal B-cell lymphoproliferative disorder that initiates an autoimmune hemolytic anemia. The clonal B cells produce a monoclonal autoantibody termed cold agglutinin, most often of the immunoglobulin (Ig) Mκ class. After binding to its antigen, the IgM initiates a complement classical pathway-driven erythrocyte destruction, predominantly mediated by opsonization with complement protein C3b and extravascular hemolysis in the liver. We review the molecular biology, histopathology, clinical features, and diagnostic procedures in CAD. Some patients are only slightly anemic and do not require treatment, but moderate or severe anemia frequently occurs, and the disease burden has been underestimated. CAD should not be treated with corticosteroids. Several B-cell-directed treatment options are available, and complement-directed approaches are being rapidly developed. Current and possible future therapies are reviewed.


Assuntos
Corticosteroides/uso terapêutico , Anemia Hemolítica Autoimune , Transtornos Linfoproliferativos , Anemia Hemolítica Autoimune/tratamento farmacológico , Anemia Hemolítica Autoimune/metabolismo , Anemia Hemolítica Autoimune/patologia , Linfócitos B/metabolismo , Linfócitos B/patologia , Proteínas do Sistema Complemento/metabolismo , Crioglobulinas/metabolismo , Eritrócitos/metabolismo , Eritrócitos/patologia , Hemólise , Humanos , Transtornos Linfoproliferativos/tratamento farmacológico , Transtornos Linfoproliferativos/metabolismo , Transtornos Linfoproliferativos/patologia
12.
Sci Rep ; 10(1): 7787, 2020 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-32385381

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a lung parenchymal disease of unknown cause usually occurring in older adults. It is a chronic and progressive condition with poor prognosis and diagnosis is largely clinical. Currently, there exist few biomarkers that can predict patient outcome or response to therapies. Together with lack of markers, the need for novel markers for the detection and monitoring of IPF, is paramount. We have performed label-free plasma proteomics of thirty six individuals, 17 of which had confirmed IPF. Proteomics data was analyzed by volcano plot, hierarchical clustering, Partial-least square discriminant analysis (PLS-DA) and Ingenuity pathway analysis. Univariate and multivariate statistical analysis overlap identified haptoglobin-related protein as a possible marker of IPF when compared to control samples (Area under the curve 0.851, ROC-analysis). LXR/RXR activation and complement activation pathways were enriched in t-test significant proteins and oxidative regulators, complement proteins and protease inhibitors were enriched in PLS-DA significant proteins. Our pilot study points towards aberrations in complement activation and oxidative damage in IPF patients and provides haptoglobin-related protein as a new candidate biomarker of IPF.


Assuntos
Proteínas Sanguíneas , Proteínas do Sistema Complemento/imunologia , Haptoglobinas/metabolismo , Fibrose Pulmonar Idiopática/imunologia , Fibrose Pulmonar Idiopática/metabolismo , Estresse Oxidativo , Proteômica , Transdução de Sinais , Idoso , Biomarcadores , Estudos de Casos e Controles , Proteínas do Sistema Complemento/metabolismo , Biologia Computacional/métodos , Feminino , Humanos , Fibrose Pulmonar Idiopática/patologia , Masculino , Proteoma , Proteômica/métodos , Curva ROC
13.
Transl Res ; 220: 1-13, 2020 06.
Artigo em Inglês | MEDLINE | ID: covidwho-60383

RESUMO

Acute respiratory failure and a systemic coagulopathy are critical aspects of the morbidity and mortality characterizing infection with severe acute respiratory distress syndrome-associated coronavirus-2, the etiologic agent of Coronavirus disease 2019 (COVID-19). We examined skin and lung tissues from 5 patients with severe COVID-19 characterized by respiratory failure (n= 5) and purpuric skin rash (n = 3). COVID-19 pneumonitis was predominantly a pauci-inflammatory septal capillary injury with significant septal capillary mural and luminal fibrin deposition and permeation of the interalveolar septa by neutrophils. No viral cytopathic changes were observed and the diffuse alveolar damage (DAD) with hyaline membranes, inflammation, and type II pneumocyte hyperplasia, hallmarks of classic acute respiratory distress syndrome, were not prominent. These pulmonary findings were accompanied by significant deposits of terminal complement components C5b-9 (membrane attack complex), C4d, and mannose binding lectin (MBL)-associated serine protease (MASP)2, in the microvasculature, consistent with sustained, systemic activation of the complement pathways. The purpuric skin lesions similarly showed a pauci-inflammatory thrombogenic vasculopathy, with deposition of C5b-9 and C4d in both grossly involved and normally-appearing skin. In addition, there was co-localization of COVID-19 spike glycoproteins with C4d and C5b-9 in the interalveolar septa and the cutaneous microvasculature of 2 cases examined. In conclusion, at least a subset of sustained, severe COVID-19 may define a type of catastrophic microvascular injury syndrome mediated by activation of complement pathways and an associated procoagulant state. It provides a foundation for further exploration of the pathophysiologic importance of complement in COVID-19, and could suggest targets for specific intervention.


Assuntos
Betacoronavirus , Proteínas do Sistema Complemento/metabolismo , Infecções por Coronavirus/complicações , Microvasos/patologia , Pneumonia Viral/complicações , Insuficiência Respiratória/etiologia , Trombose/etiologia , Adulto , Idoso , Ativação do Complemento/fisiologia , Infecções por Coronavirus/patologia , Feminino , Humanos , Masculino , Microvasos/virologia , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/patologia , Púrpura/etiologia , Púrpura/patologia , Púrpura/virologia , Insuficiência Respiratória/patologia , Trombose/patologia
14.
Scand J Rheumatol ; 49(4): 301-311, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32286129

RESUMO

OBJECTIVE: The complement cascade, especially the alternative pathway of complement, has been shown in basic research to be associated with anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV). We aimed to elucidate relationships between serum complement components and clinical characteristics in AAV. METHOD: In a nationwide prospective cohort study (RemIT-JAV-RPGN), we measured the serum levels of C1q, C2, C3, C3b/iC3b, C4, C4b, C5, C5a, C9, factor B, factor D, factor H, factor I, mannose-binding lectin, and properdin in 52 patients with microscopic polyangiitis (MPA) and 39 patients with granulomatosis with polyangiitis (GPA). RESULTS: The properdin level of MPA and GPA was significantly lower than that of healthy donors. The properdin level was negatively correlated with the Birmingham Vasculitis Activity Score (BVAS) (ρ = -0.2148, p = 0.0409). The factor D level at 6 months was significantly positively correlated with the Vasculitis Damage Index (VDI) at 6, 12, and 24 months (ρ = 0.4207, 0.4132, and 0.3115, respectively). Patients with a higher ratio of C5a to C5 had higher neutrophil percentage and serum immunoglobulin G levels, and significantly lower creatinine levels. Cluster analysis divided the MPA and GPA patients into three subgroups. A principal component (PC) analysis aggregated 15 types of complements into alternative pathway-related PC 1 and complement classical pathway and common pathway-related PC 2. CONCLUSIONS: The serum levels of properdin and factor D were correlated with the BVAS and the VDI in MPA and GPA, respectively. Our analyses suggested the pathological heterogeneity of MPA and GPA from the aspect of complement components.


Assuntos
Proteínas do Sistema Complemento/metabolismo , Granulomatose com Poliangiite/sangue , Poliangiite Microscópica/sangue , Idoso , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , Análise por Conglomerados , Feminino , Granulomatose com Poliangiite/tratamento farmacológico , Granulomatose com Poliangiite/etiologia , Humanos , Imunossupressores/uso terapêutico , Masculino , Poliangiite Microscópica/tratamento farmacológico , Poliangiite Microscópica/etiologia , Pessoa de Meia-Idade , Análise de Componente Principal , Estudos Prospectivos , Recidiva , Indução de Remissão
15.
Transl Res ; 220: 1-13, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32299776

RESUMO

Acute respiratory failure and a systemic coagulopathy are critical aspects of the morbidity and mortality characterizing infection with severe acute respiratory distress syndrome-associated coronavirus-2, the etiologic agent of Coronavirus disease 2019 (COVID-19). We examined skin and lung tissues from 5 patients with severe COVID-19 characterized by respiratory failure (n= 5) and purpuric skin rash (n = 3). COVID-19 pneumonitis was predominantly a pauci-inflammatory septal capillary injury with significant septal capillary mural and luminal fibrin deposition and permeation of the interalveolar septa by neutrophils. No viral cytopathic changes were observed and the diffuse alveolar damage (DAD) with hyaline membranes, inflammation, and type II pneumocyte hyperplasia, hallmarks of classic acute respiratory distress syndrome, were not prominent. These pulmonary findings were accompanied by significant deposits of terminal complement components C5b-9 (membrane attack complex), C4d, and mannose binding lectin (MBL)-associated serine protease (MASP)2, in the microvasculature, consistent with sustained, systemic activation of the complement pathways. The purpuric skin lesions similarly showed a pauci-inflammatory thrombogenic vasculopathy, with deposition of C5b-9 and C4d in both grossly involved and normally-appearing skin. In addition, there was co-localization of COVID-19 spike glycoproteins with C4d and C5b-9 in the interalveolar septa and the cutaneous microvasculature of 2 cases examined. In conclusion, at least a subset of sustained, severe COVID-19 may define a type of catastrophic microvascular injury syndrome mediated by activation of complement pathways and an associated procoagulant state. It provides a foundation for further exploration of the pathophysiologic importance of complement in COVID-19, and could suggest targets for specific intervention.


Assuntos
Betacoronavirus , Proteínas do Sistema Complemento/metabolismo , Infecções por Coronavirus/complicações , Microvasos/patologia , Pneumonia Viral/complicações , Insuficiência Respiratória/etiologia , Trombose/etiologia , Adulto , Idoso , Ativação do Complemento/fisiologia , Infecções por Coronavirus/patologia , Feminino , Humanos , Masculino , Microvasos/virologia , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/patologia , Púrpura/etiologia , Púrpura/patologia , Púrpura/virologia , Insuficiência Respiratória/patologia , Trombose/patologia
16.
Infect Immun ; 88(7)2020 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-32284372

RESUMO

The human respiratory tract pathogen Chlamydia pneumoniae, which causes mild to severe infections, has been associated with the development of chronic inflammatory diseases. To understand the biology of C. pneumoniae infections, several studies have investigated the interaction between C. pneumoniae and professional phagocytes. However, these studies have been conducted under nonopsonizing conditions, making the role of opsonization in C. pneumoniae infections elusive. Thus, we analyzed complement and antibody opsonization of C. pneumoniae and evaluated how opsonization affects chlamydial infectivity and phagocytosis in human monocytes and neutrophils. We demonstrated that IgG antibodies and activation products of complement C3 and C4 are deposited on the surface of C. pneumoniae elementary bodies when incubated in human serum. Complement activation limits C. pneumoniae infectivity in vitro and has the potential to induce bacterial lysis by the formation of the membrane attack complex. Coculture of C. pneumoniae and freshly isolated human leukocytes showed that complement opsonization is superior to IgG opsonization for efficient opsonophagocytosis of C. pneumoniae in monocytes and neutrophils. Neutrophil-mediated phagocytosis of C. pneumoniae was crucially dependent on opsonization, while monocytes retained minor phagocytic potential under nonopsonizing conditions. Complement opsonization significantly enhanced the intracellular neutralization of C. pneumoniae in peripheral blood mononuclear cells and neutrophils and almost abrogated the infectious potential of C. pneumoniae In conclusion, we demonstrated that complements limit C. pneumoniae infection in vitro by interfering with C. pneumoniae entry into permissive cells by direct complement-induced lysis and by tagging bacteria for efficient phagocytosis in both monocytes and neutrophils.


Assuntos
Infecções por Chlamydophila/imunologia , Infecções por Chlamydophila/microbiologia , Chlamydophila pneumoniae/fisiologia , Monócitos/imunologia , Neutrófilos/imunologia , Fagocitose , Anticorpos Antibacterianos/imunologia , Ativação do Complemento/imunologia , Proteínas do Sistema Complemento/imunologia , Proteínas do Sistema Complemento/metabolismo , Humanos , Monócitos/metabolismo , Neutrófilos/metabolismo
17.
J Neurosci ; 40(20): 4042-4058, 2020 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-32291326

RESUMO

Despite the success of reperfusion therapy in significantly reducing the extent of infarct expansion after stroke, the effect of revascularization on poststroke neuroinflammation and the role of anti-inflammatory strategies in postreperfusion era are yet to be explored. Here, we investigate whether the neuroinflammatory response may still contribute to neurologic deficits after reperfused stroke by using targeted complement inhibition to suppress poststroke neuroinflammation in mice with or without concurrent reperfusion therapy. Complement inhibition was achieved using B4Crry, an injury site-targeted inhibitor of C3 activation. Following embolic stroke in male C57bl/6 mice, thrombolysis using tissue-plasminogen activator (t-PA) reduced injury and improved motor deficits, but did not improve cognitive outcomes. After both reperfused and non-reperfused stroke, complement activation and opsonization of hippocampal synapses directed ongoing microglia-dependent phagocytosis of synapses for at least 30 d after stroke, leading to a loss of synaptic density that was associated with cognitive decline. B4Crry treatment, alone or in combination with tPA, limited perilesional complement deposition, reduced microgliosis and synaptic uptake, and improved cognitive outcome without affecting regenerative responses. Furthermore, complement inhibition improved the safety, efficacy, and treatment window of reperfusion therapy with t-PA by limiting hemorrhagic transformation. This work thus demonstrates that poststroke neuroinflammation contributes to hemorrhagic transformation and progression of neurodegenerative responses in the brain even following early and successful revascularization.SIGNIFICANCE STATEMENT This study addresses two major challenges facing the treatment of stroke in the era of reperfusion therapy: hemorrhagic transformation and the disconnect between successful revascularization and functional outcomes. We studied how complement-dependent neuroinflammation drives the pathophysiology behind these challenges using a translationally relevant strategy. Complement inhibition was achieved using B4Crry, an injury site-targeted inhibitor of C3 activation. Following embolic stroke, pharmacological thrombolysis limited infarct size, but did not prevent complement activation. In reperfused and non-reperfused stroke, complement activation and opsonization of hippocampal synapses resulted in synaptic phagocytosis and subsequent cognitive decline. B4Crry treatment limited perilesional complement deposition, reduced microgliosis and synaptic uptake, and improved cognitive outcomes. Complement inhibition also improved the safety, efficacy, and treatment window of thrombolytic therapy.


Assuntos
Disfunção Cognitiva/metabolismo , Proteínas do Sistema Complemento/metabolismo , Acidente Vascular Cerebral/metabolismo , Sinapses/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Disfunção Cognitiva/psicologia , Feminino , Humanos , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Recuperação de Função Fisiológica , Reperfusão , Acidente Vascular Cerebral/psicologia , Acidente Vascular Cerebral/terapia , Reabilitação do Acidente Vascular Cerebral , Trombectomia , Terapia Trombolítica , Ativador de Plasminogênio Tecidual/uso terapêutico , Resultado do Tratamento
18.
Acta Cir Bras ; 35(1): e202000105, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32215465

RESUMO

PURPOSE: To investigate whether heat shock protein 90 (HSP90) is involved in complement regulation in ischemic postconditioning (IPC). METHODS: The left coronary artery of rats underwent 30 min of occlusion, followed by 120 min of reperfusion and treatment with IPC via 3 cycles of 30s reperfusion and 30s occlusion. The rats were injected intraperitoneally with 1 mg/kg HSP90 inhibitor geldanamycin (GA) after anesthesia. Eighty rats were randomly divided into four groups: sham, ischemia-reperfusion (I/R), IPC and IPC + GA. Myocardial infarct size, apoptosis index and the expression of HSP90, C3, C5a, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1ß and c-Jun N-terminal kinase (JNK) were assessed. RESULTS: Compared with the I/R injury, the IPC treatment significantly reduced infarct size, release of troponin T, creatine kinase-MB, and lactate dehydrogenase, and cardiomyocyte apoptosis. These beneficial effects were accompanied by a decrease in TNF-α, IL-1ß, C3, C5a and JNK expression levels. However, all these effects were abrogated by administration of the HSP90 inhibitor GA. CONCLUSION: HSP90 exerts a profound effect on IPC cardioprotection, and may be linked to the inhibition of the complement system and JNK, ultimately attenuating I/R-induced myocardial injury and apoptosis.


Assuntos
Benzoquinonas/farmacologia , Proteínas do Sistema Complemento/metabolismo , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Lactamas Macrocíclicas/farmacologia , Infarto do Miocárdio/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Animais , Creatina Quinase Forma MB/metabolismo , Mediadores da Inflamação , Pós-Condicionamento Isquêmico/métodos , Masculino , RNA Mensageiro/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismo
19.
Invest Ophthalmol Vis Sci ; 61(3): 45, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-32207814

RESUMO

Purpose: Age-related macular degeneration (AMD) is the leading cause of blindness in Western populations. While an overactive complement system has been linked to pathogenesis, mechanisms contributing to its activation are largely unknown. In aged and AMD eyes, loss of the elastin layer (EL) of Bruch's membrane (BrM) has been reported. Elastin antibodies are elevated in patients with AMD, the pathogenic significance of which is unclear. Here we assess the role of elastin antibodies using a mouse model of smoke-induced ocular pathology (SIOP), which similarly demonstrates EL loss. Methods: C57BL/6J mice were immunized with elastin or elastin peptide oxidatively modified by cigarette smoke (ox-elastin). Mice were then exposed to cigarette smoke or air for 6 months. Visual function was assessed by optokinetic response, retinal morphology by spectral-domain optical coherence tomography and electron microscopy, and complement activation and antibody deposition by Western blot. Results: Ox-elastin IgG and IgM antibodies were elevated in ox-elastin immunized mice following 6 months of smoke, whereas elastin immunization had a smaller effect. Ox-elastin immunization exacerbated smoke-induced vision loss, with thicker BrM and more damaged retinal pigment epithelium (RPE) mitochondria compared with mice immunized with elastin or nonimmunized controls. These changes were correlated with increased levels of IgM, IgG2, IgG3, and complement activation products in RPE/choroid. Conclusions: These data demonstrate that SIOP mice generate elastin-specific antibodies and that immunization with ox-elastin exacerbates ocular pathology. Elastin antibodies represented complement fixing isotypes that, together with the increased presence of complement activation seen in immunized mice, suggest that elastin antibodies exert pathogenic effects through mediating complement activation.


Assuntos
Autoanticorpos/sangue , Lâmina Basilar da Corioide/patologia , Modelos Animais de Doenças , Elastina/imunologia , Atrofia Geográfica/etiologia , Epitélio Pigmentado da Retina/patologia , Fumar/efeitos adversos , Animais , Western Blotting , Ativação do Complemento/fisiologia , Proteínas do Sistema Complemento/metabolismo , Sensibilidades de Contraste/fisiologia , Ensaio de Imunoadsorção Enzimática , Atrofia Geográfica/imunologia , Atrofia Geográfica/patologia , Imunização , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Camundongos , Camundongos Endogâmicos C57BL , Nistagmo Optocinético/fisiologia , Oxirredução , Produtos do Tabaco , Acuidade Visual/fisiologia
20.
Mol Immunol ; 121: 99-110, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32199212

RESUMO

The complement cascade consists of cell bound and serum proteins acting together to protect the host from pathogens, remove cancerous cells and effectively links innate and adaptive immune responses. Despite its usefulness in microbial neutralization and clearance of cancerous cells, excessive complement activation causes an immune imbalance and tissue damage in the host. Hence, a series of complement regulatory proteins present at a higher concentration in blood plasma and on cell surfaces tightly regulate the cascade. The complement cascade can be initiated by B-1 B cell production of natural antibodies. Natural antibodies arise spontaneously without any known exogenous antigenic or microbial stimulus and protect against invading pathogens, clear apoptotic cells, provide tissue homeostasis, and modulate adaptive immune functions. Natural IgM antibodies recognize microbial and cancer antigens and serve as an activator of complement mediated lysis. This review will discuss advances in complement activation and regulation in bacterial and viral infections, and cancer. We will also explore the crosstalk of natural antibodies with bacterial populations and cancer.


Assuntos
Infecções Bacterianas/imunologia , Imunidade Humoral , Imunidade Inata , Neoplasias/imunologia , Viroses/imunologia , Antígenos de Bactérias/imunologia , Antígenos de Bactérias/metabolismo , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/metabolismo , Antígenos Virais/imunologia , Antígenos Virais/metabolismo , Apoptose/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Ativação do Complemento , Proteínas do Sistema Complemento/imunologia , Proteínas do Sistema Complemento/metabolismo , Humanos , Imunoglobulina M/imunologia , Imunoglobulina M/metabolismo , Receptores de Complemento/imunologia , Receptores de Complemento/metabolismo , Evasão Tumoral
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA