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1.
Front Immunol ; 14: 1046639, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37168853

RESUMO

Cellular immune responses are of pivotal importance to understand SARS-CoV-2 pathogenicity. Using an enzyme-linked immunosorbent spot (ELISpot) interferon-γ release assay with wild-type spike, membrane and nucleocapsid peptide pools, we longitudinally characterized functional SARS-CoV-2 specific T-cell responses in a cohort of patients with mild, moderate and severe COVID-19. All patients were included before emergence of the Omicron (B.1.1.529) variant. Our most important finding was an impaired development of early IFN-γ-secreting virus-specific T-cells in severe patients compared to patients with moderate disease, indicating that absence of virus-specific cellular responses in the acute phase may act as a prognostic factor for severe disease. Remarkably, in addition to reactivity against the spike protein, a substantial proportion of the SARS-CoV-2 specific T-cell response was directed against the conserved membrane protein. This may be relevant for diagnostics and vaccine design, especially considering new variants with heavily mutated spike proteins. Our data further strengthen the hypothesis that dysregulated adaptive immunity plays a central role in COVID-19 immunopathogenesis.


Assuntos
COVID-19 , SARS-CoV-2 , Humanos , Linfócitos T , Imunidade Adaptativa , Proteínas Mutadas de Ataxia Telangiectasia , Interferon gama
2.
Virol J ; 20(1): 85, 2023 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-37138352

RESUMO

Infection with the novel pandemic SARS-CoV-2 virus has been shown to elicit a cross-reactive immune response that could lead to a back-boost of memory recall to previously encountered seasonal (endemic) coronaviruses (eCoVs). Whether this response is associated with a fatal clinical outcome in patients with severe COVID-19 remains unclear. In a cohort of hospitalized patients, we have previously shown that heterologous immune responses to eCoVs can be detected in severe COVID-19. Here, we report that COVID-19 patients with fatal disease have decreased SARS-CoV-2 neutralizing antibody titers at hospital admission, which correlated with lower SARS-CoV-2 spike-specific IgG and was paralleled by a relative abundance of IgG against spike protein of eCoVs of the genus Betacoronavirus. Additional research is needed to assess if eCoV-specific back-boosted IgG is a bystander phenomenon in severe COVID-19, or a factor that influences the development of an efficient anti-viral immune response.


Assuntos
COVID-19 , Humanos , SARS-CoV-2 , Imunoglobulina G , Glicoproteína da Espícula de Coronavírus , Estações do Ano , Anticorpos Antivirais , Anticorpos Neutralizantes
3.
Pathog Dis ; 80(1)2022 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-36089571

RESUMO

Effective vaccination is a key element in the exit strategy from the current severe acute respiratory syndrome-CoV coronavirus-2 (SARS-CoV-2) pandemic, and may also offer protection against severe disease from future variants of concern. Here, we prospectively monitored T-cell responses over time, using ELISpot interferon-γ (INF-y) release assays, and B-cell responses, using serological tests, after vaccination and booster with BioNTech/Pfizer mRNA (Pfizer) and Janssen vector (Janssen/Johnson & Johnson) vaccines in hospital health care workers. Vaccine recipients were divided into seropositive and seronegative individuals at baseline, in order to determine the effect of natural immunity on vaccine-induced immune kinetics. We found that convalescent individuals mounted higher spike-specific INF-y-secreting T-cell responses and B-cell-mediated IgG responses, after receiving the Janssen vaccine or the first dose of the Pfizer vaccine. IgG levels corresponded to the virus neutralization capacity as measured by VNT assay. At 8 months postvaccination, spike-specific cellular immunity waned to low levels in individuals with or without prior natural immunity, whereas waning of humoral immunity occurred predominantly in naive individuals. The booster shot effectively reinduced both cellular and humoral immune responses. To conclude, our data supports the implemented single-dose mRNA booster strategy employed in the Netherlands. Furthermore, the level of pre-existing natural immunity may be factored into determining the optimal time window between future booster vaccines.


Assuntos
COVID-19 , Vacinas Virais , Anticorpos Antivirais , COVID-19/prevenção & controle , Pessoal de Saúde , Humanos , Imunidade Celular , Imunidade Humoral , Imunoglobulina G , Interferon gama , Cinética , RNA Mensageiro , SARS-CoV-2 , Vacinação
4.
Front Immunol ; 13: 839367, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35355988

RESUMO

Defining immune correlates of disease severity is important to better understand the immunopathogenesis in COVID-19. Here we made use of a protein microarray platform to detect IgG- and IgA-reactive antibodies in sera and saliva respectively, and assess cross-reactivity between SARS-CoV-2 and endemic coronaviruses (eCoVs). IgG responses against the full protein of spike, but not the S1 subunit, were significantly higher in convalescent sera of patients with severe disease compared to mild disease and healthy controls. In addition, we detected reactivity of secretory IgA to eCoVs in saliva of patients with severe disease, not present in patients with moderate disease or seropositive healthy controls. These heterologous immune responses are in line with non-protective cross-reactivity, and support a potential role for immune imprinting in the pathogenesis of severe COVID-19.


Assuntos
COVID-19 , Anticorpos Antivirais , COVID-19/terapia , Humanos , Imunidade , Imunização Passiva , Imunoglobulina A , Imunoglobulina A Secretora , Imunoglobulina G , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Soroterapia para COVID-19
6.
Tuberculosis (Edinb) ; 111: 102-108, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-30029893

RESUMO

BACKGROUND: QuantiFERON (QFT) results near the cut-off are subject to debate. We aimed to investigate which borderline QFT results were due to Mycobacterium tuberculosis (Mtb)-specific responses or to test variability. METHODS: In a contact investigation, tuberculin skin test (TST), QFT and T-SPOT.TB (T-SPOT) were performed in 785 BCG-unvaccinated contacts. Contacts with a low-negative (<0.15), borderline (0.15-0.35), low-positive (0.35-0.70) or high-positive QFT (≥0.70 IU/mL) were compared with respect to exposure, TST and T-SPOT results. Development of active tuberculosis was assessed. RESULTS: Borderline QFT results occurred in threefold excess over test variability (p = 0.0027). In contacts with low-negative, borderline or positive QFT results, a positive TST occurred in 24.9%, 62.1% and 91.4% (p < 0.0001) and a positive T-SPOT result in 6.3%, 41.3% and 86.4%, respectively (p < 0.0001). Two-third (20/29) of contacts with a borderline and 14/16 (88%) with a low-positive QFT had a positive TST and/or T-SPOT, indicating probable Mtb-infection. During 12 years of follow-up, seven patients were diagnosed with active tuberculosis, two of whom after a low-positive QFT. CONCLUSIONS: In this study, most borderline and low-positive QFT results were Mtb-specific, showing the biological significance of a borderline QFT. The clinical relevance, however, will be most distinct in patients who are or will be immunocompromised.


Assuntos
ELISPOT , Testes de Liberação de Interferon-gama , Interferon gama/sangue , Tuberculose Latente/diagnóstico , Mycobacterium tuberculosis/imunologia , Tuberculose/diagnóstico , Adolescente , Biomarcadores/sangue , Feminino , Interações Hospedeiro-Patógeno , Humanos , Interferon gama/imunologia , Tuberculose Latente/sangue , Tuberculose Latente/imunologia , Tuberculose Latente/microbiologia , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/patogenicidade , Valor Preditivo dos Testes , Prognóstico , Reprodutibilidade dos Testes , Estudos Retrospectivos , Fatores de Tempo , Teste Tuberculínico , Tuberculose/sangue , Tuberculose/imunologia , Tuberculose/microbiologia , Adulto Jovem
7.
Sarcoidosis Vasc Diffuse Lung Dis ; 31(2): 142-8, 2014 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-25078642

RESUMO

BACKGROUND: The possible association between (tuberculous and nontuberculous) mycobacterial infections and sarcoidosis is still a matter of dispute. Using diagnostic tests for specific T-cell responses, this association can be investigated in an innovative manner. OBJECTIVE: To measure the T-cell responsiveness to the purified protein derivative (PPD) antigen in blood and broncho-alveolar lavage (BAL) fluid in patients with sarcoidosis and patients with other causes of interstitial lung disease. It was hypothesized that if a mycobacterial infection of the lung is of importance for the development of sarcoidosis, T-cell responsiveness towards the PPD antigen would be increased in patients with sarcoidosis when compared to patients with other causes of interstitial lung disease. METHODS: A single-center study was conducted which included patients with and without sarcoidosis. Venous blood was collected and BAL was performed for, inter alia, Interferon Gamma Release Assay´s (IGRA) with different stimulating antigens, including PPD, ESAT-6, CFP-10 and, as a control, Epstein-Barr virus (EBV). RESULTS: A total of 118 patients were included. There is no difference between PPD reactivity in BAL fluid in patients with or without sarcoidosis. In patients without sarcoidosis, ELISpot PPD in blood shows more reactivity compared to patients with sarcoidosis, although this difference is not significant. ELISpot EBV and TB results are not significant different between both groups. CONCLUSION: These results provide no evidence for the involvement of different mycobacteria in the pathogenesis of sarcoidosis.


Assuntos
Mycobacterium/imunologia , Sarcoidose Pulmonar/imunologia , Linfócitos T/imunologia , Tuberculina/imunologia , Adulto , Líquido da Lavagem Broncoalveolar/imunologia , Estudos de Casos e Controles , Células Cultivadas , ELISPOT , Feminino , Humanos , Interferon gama/imunologia , Testes de Liberação de Interferon-gama , Masculino , Pessoa de Meia-Idade , Países Baixos , Valor Preditivo dos Testes , Fatores de Risco , Sarcoidose Pulmonar/sangue , Sarcoidose Pulmonar/diagnóstico , Sarcoidose Pulmonar/microbiologia , Linfócitos T/microbiologia , Tuberculina/sangue
8.
Thorax ; 68(11): 1079-80, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23598710

RESUMO

As part of a prospective study on the safety of TNF-α inhibitor therapy after screening for and treatment of latent tuberculosis infection (LTBI), we report two patients who developed active tuberculosis (TB) infection during TNF-α inhibitor therapy, despite negative screening for LTBI. The clinical history is suggestive of a primary infection acquired during travelling to TB-endemic countries. In this lesson of the month we would like to highlight the risk of travelling to TB-endemic areas in patients treated with TNF-α inhibitor therapy. Screening for latent tuberculosis infection is not enough to prevent tuberculosis in patients treated with TNF-α inhibitor therapy.


Assuntos
Anticorpos Monoclonais/efeitos adversos , Hospedeiro Imunocomprometido , Doenças Inflamatórias Intestinais/tratamento farmacológico , Tuberculose Latente/etiologia , Tuberculose Pulmonar/etiologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Feminino , Humanos , Infliximab , Tuberculose Latente/diagnóstico , Tuberculose Latente/imunologia , Masculino , Pessoa de Meia-Idade , Teste Tuberculínico , Tuberculose Pulmonar/imunologia
9.
Clin Vaccine Immunol ; 19(6): 974-7, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22461529

RESUMO

In this case series, we describe four cases in which the use of gamma interferon release assays with purified protein derivative (PPD) as a stimulating antigen was able to demonstrate PPD-specific immune activation. This may help to improve the adequate diagnosis of (systemic) Mycobacterium bovis BCG infections after intravesical BCG instillations for bladder carcinoma.


Assuntos
Testes de Liberação de Interferon-gama/métodos , Mycobacterium bovis/imunologia , Tuberculina , Tuberculose/diagnóstico , Neoplasias da Bexiga Urinária/terapia , Administração Intravesical , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade , Tuberculina/imunologia , Tuberculose/microbiologia
10.
Expert Opin Med Diagn ; 3(3): 303-12, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-23488465

RESUMO

BACKGROUND: In view of the continuing global epidemic of tuberculosis (TB), adequate diagnosis is crucial for controlling this disease. Two commercial interferon gamma release assays (IGRA) have become available: the QuantiFERON-TB (QFT) and the T-SPOT.TB (TSPOT). They offer an important new tool for detecting both latent and active TB. In particular, the increased specificity as compared with the tuberculin skin test (TST) has resulted in many now (considering) replacing TST with IGRA. OBJECTIVE: This review tries to offer the reader more insight from a clinical perspective into the applicability of IGRA for both latent and active TB. CONCLUSION: Although both IGRA are based on the same principle, they have marked different performance characteristics and it seems likely that both assays will establish their own niche. The increased specificity and sensitivity of IGRA in various settings as compared with TST show us that IGRA are here to stay. QFT might be the preferred tool for large-scale contact tracing, but in most clinical settings TSPOT has to be preferred. Much knowledge on IGRA has already been obtained in a short time; however, many questions remain unresolved, such as likelihood for developing active TB in individuals with a negative IGRA in contact tracing in various subgroups and the applicability of IGRA for detecting active TB.

12.
Clin Vaccine Immunol ; 14(9): 1239-41, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17626157

RESUMO

We report a follow-up study of 29 subjects with negative tuberculin skin test (TST) results in association with positive gamma interferon release assay (IGRA) results, mainly due to responses to CFP-10 in the T-SPOT.TB assay, during a contact investigation. One year later, 12/29 subjects (41%) had converted to positive TST results in association with negative IGRA results.


Assuntos
Interferon gama/imunologia , Teste Tuberculínico/métodos , Tuberculose/diagnóstico , Adulto , Idoso , Proteínas de Bactérias/biossíntese , Proteínas de Bactérias/imunologia , Humanos , Pessoa de Meia-Idade , Tuberculose/imunologia , Tuberculose/transmissão
13.
Am J Respir Crit Care Med ; 175(6): 618-27, 2007 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-17170386

RESUMO

BACKGROUND: The tuberculin skin test (TST) has low specificity. QuantiFERON-TB Gold (QFT-G) and T-SPOT.TB are based on interferon (IFN)-gamma responses to Mycobacterium tuberculosis-specific antigens. A novel in-tube format of QFT-G (QFT-GIT) offers logistical advantages. OBJECTIVE: To compare TST, QFT-GIT, and T-SPOT.TB in bacillus Calmette-Guérin unvaccinated contacts and correlate results with measures of recent exposure. METHODS: When a supermarket employee with smear-positive tuberculosis had infected most close contacts, a contact investigation among more than 20,000 customers was performed. We recruited subjects randomly on the day of TST administration (n = 469) and subjects with TST of more than 0 mm on the day of TST reading (n = 316). QFT-GIT and T-SPOT.TB were performed. Demographic data and measures of exposure were collected. TST results were analyzed at a cutoff of 10 or 15 mm. Blood tests were interpreted following the manufacturers' criteria and by varying cutoff levels. RESULTS: Among 785 study participants, TST results were associated with age, whereas positive IFN-gamma responses were significantly associated with cumulative shopping time, most markedly for QFT-GIT. Among participants with a TST of 15 mm or greater, sensitivity of QFT-GIT and T-SPOT.TB was 42.2 and 51.3%, respectively. Interassay agreement was 89.6% (kappa = 0.59). By varying cutoff values, agreement between the IFN-gamma assays was optimal at 93.6% (kappa = 0.71) using a cutoff of 0.20 IU/ml for QFT-GIT and 13 spots for T-SPOT.TB. CONCLUSIONS: Blood test results were associated with exposure, whereas the TST was not. A possible lack of sensitivity of IFN-gamma assays in detecting individuals with TST of 15 mm or greater, despite negative bacillus Calmette-Guérin vaccination status, warrants further investigation into alternative cutoff values.


Assuntos
Busca de Comunicante , Interferon gama/sangue , Programas de Rastreamento/métodos , Teste Tuberculínico , Tuberculose Pulmonar/transmissão , Adulto , Fatores Etários , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tuberculose Pulmonar/sangue , Tuberculose Pulmonar/diagnóstico
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