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1.
Nat Rev Rheumatol ; 17(11): 678-691, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34611329

RESUMO

Interferon-γ (IFNγ) is a pleiotropic cytokine with multiple effects on the inflammatory response and on innate and adaptive immunity. Overproduction of IFNγ underlies several, potentially fatal, hyperinflammatory or immune-mediated diseases. Several data from animal models and/or from translational research in patients point to a role of IFNγ in hyperinflammatory diseases, such as primary haemophagocytic lymphohistiocytosis, various forms of secondary haemophagocytic lymphohistiocytosis, including macrophage activation syndrome, and cytokine release syndrome, all of which are often managed by rheumatologists or in consultation with rheumatologists. Given the effects of IFNγ on B cells and T follicular helper cells, a role for IFNγ in systemic lupus erythematosus pathogenesis is emerging. To improve our understanding of the role of IFNγ in human disease, IFNγ-related biomarkers that are relevant for the management of hyperinflammatory diseases are progressively being identified and studied, especially because circulating levels of IFNγ do not always reflect its overproduction in tissue. These biomarkers include STAT1 (specifically the phosphorylated form), neopterin and the chemokine CXCL9. IFNγ-neutralizing agents have shown efficacy in the treatment of primary haemophagocytic lymphohistiocytosis in clinical trials and initial promising results have been obtained in various forms of secondary haemophagocytic lymphohistiocytosis, including macrophage activation syndrome. In clinical practice, there is a growing body of evidence supporting the usefulness of circulating CXCL9 levels as a biomarker reflecting IFNγ production.


Assuntos
Doenças do Sistema Imunitário/imunologia , Inflamação/imunologia , Interferon gama/antagonistas & inibidores , Interferon gama/imunologia , Linfo-Histiocitose Hemofagocítica/imunologia , Animais , Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Biomarcadores/sangue , Quimiocina CXCL9/sangue , Quimiocina CXCL9/imunologia , Doença de Crohn/sangue , Doença de Crohn/tratamento farmacológico , Doença de Crohn/imunologia , Modelos Animais de Doenças , Humanos , Doenças do Sistema Imunitário/sangue , Doenças do Sistema Imunitário/tratamento farmacológico , Imunidade/imunologia , Inflamação/sangue , Inflamação/tratamento farmacológico , Interferon gama/biossíntese , Interferon gama/sangue , Linfo-Histiocitose Hemofagocítica/sangue , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Síndrome de Ativação Macrofágica/sangue , Síndrome de Ativação Macrofágica/tratamento farmacológico , Síndrome de Ativação Macrofágica/imunologia , Camundongos , Neopterina/sangue , Neopterina/imunologia , Fator de Transcrição STAT1/sangue , Fator de Transcrição STAT1/imunologia
2.
Nutrients ; 13(10)2021 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-34684629

RESUMO

Melatonin, the hormone of circadian rhythm regulation, is involved in the modulation of mitochondrial activity through its antioxidant and anti-inflammatory properties. Alteration of circadian rhythms such as sleep is related to obesity and metabolic pathogenesis in adulthood, but studies during childhood are scarce. The present study investigated the association of melatonin with metabolic and inflammatory markers in children with (n = 113) and without obesity (n = 117). Melatonin was measured in saliva four and two hours before bedtime, and after one hour of sleep. Cardiometabolic factors, high sensitivity C-reactive protein, immune markers (monocyte chemoattractant protein-1, plasminogen activator inhibitor-1, tumor necrosis α and interferon-γ), leptin and ghrelin were determined. Sleep duration was recorded by a questionnaire. The melatonin level at 1 h after sleep was found to be increased more than twofold in children with obesity (90.16 (57.16-129.16) pg/mL) compared to controls (29.82 (19.05-61.54) pg/mL, p < 0.001) and was related to fat mass (rho = 0.294, p < 0.001); melatonin levels at 1 h after sleep were inversely correlated with high-density lipoprotein cholesterol. Positive correlation was found with apolipoprotein B, adipokines, high sensitivity C-reactive protein, plasminogen activator inhibitor-1 and tumor necrosis factor-α. Shorter sleep duration and earlier waking times were recorded in children with obesity. In conclusion, melatonin in children with obesity appears to be involved in the global metabolic and inflammatory alteration of this condition.


Assuntos
Inflamação/sangue , Melatonina/análise , Obesidade Pediátrica/sangue , Saliva/química , Sono , Adipocinas/sangue , Adolescente , Proteína C-Reativa/análise , Quimiocina CCL2/sangue , Criança , Ritmo Circadiano , Feminino , Grelina/sangue , Humanos , Inflamação/metabolismo , Interferon gama/sangue , Leptina/sangue , Masculino , Obesidade Pediátrica/metabolismo , Inibidor 1 de Ativador de Plasminogênio/sangue , Fator de Necrose Tumoral alfa/sangue
3.
PLoS One ; 16(9): e0258041, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34591918

RESUMO

Numerous assays evaluating serological and cellular responses have been developed to characterize immune responses against SARS-CoV-2. Serological assays are both cost- and time-effective compared to cellular assays, but cellular immune responses may provide a diagnostic value to determine previous SARS-CoV-2 infection in seronegative individuals. However, potential cross-reactive T cell responses stemming from prior encounters with human coronaviruses (HCoVs) may affect assay specificity. In this study, we evaluated the specificity and sensitivity of a SARS-CoV-2 IFN-γ Release Assay (IGRA) based on the FluoroSpot method employing commercially available SARS-CoV-2-specific peptide pools, as well as an in-house designed SARS-CoV-2 peptide pool restricted to 5 amino acid stretches or less aligning with endemic HCoVs. Blood samples were obtained from healthcare workers (HCW) 5-6 months post SARS-CoV-2 spike (S) IgG and nucleocapsid (N) IgG dual seroconversion (n = 187) and HCW who had been S IgG and N IgG dual seronegative at repeated occasions, including the current sampling time point (n = 102). In addition, samples were obtained 4 to 5 months post infection from 55 polymerase chain reaction (PCR)-confirmed COVID-19 patients. Assay specificity and sensitivity were calculated with serology as a reference standard for HCW. The in-house generated peptide pool displayed a specificity of 96.1%, while the commercially available peptide pools displayed specificities of 80.4% and 85.3%, respectively. Sensitivity was higher in a cohort of previously hospitalized COVID-19 patients (96.4% and 84.0% for the commercially available peptide pools and 92.7% for the in-house generated peptide pool) compared to the HCW cohort (92.0% and 66.8% for the commercially available peptide pools and 76.0% for the in-house generated peptide pool). Based on these findings, the individual diagnostic value of T cell immune responses against SARS-CoV-2 currently appears to be limited but remain an important research tool ahead.


Assuntos
Teste para COVID-19/métodos , COVID-19/imunologia , Imunidade Celular , SARS-CoV-2/imunologia , Linfócitos T/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , COVID-19/sangue , COVID-19/diagnóstico , Pessoal de Saúde , Humanos , Interferon gama/sangue , Interferon gama/imunologia , Sensibilidade e Especificidade , Soroconversão
4.
J Infect Dis ; 224(5): 777-782, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34467988

RESUMO

We analyzed plasma levels of interferons (IFNs) and cytokines, and expression of IFN-stimulated genes in peripheral blood mononuclear cells in patients with coronavirus disease 2019 of varying disease severity. Patients hospitalized with mild disease exhibited transient type I IFN responses, while intensive care unit patients had prolonged type I IFN responses. Type II IFN responses were compromised in intensive care unit patients. Type III IFN responses were induced in the early phase of infection, even in convalescent patients. These results highlight the importance of early type I and III IFN responses in controlling coronavirus disease 2019 progression.


Assuntos
COVID-19/imunologia , Interferon Tipo I/imunologia , Interferon gama/imunologia , Interferons/imunologia , COVID-19/sangue , Quimiocinas/sangue , Citocinas/sangue , Humanos , Interferon Tipo I/sangue , Interferon Tipo I/genética , Interferon gama/sangue , Interferon gama/genética , Interferons/sangue , Leucócitos Mononucleares/imunologia , SARS-CoV-2/isolamento & purificação
5.
Int J Mol Sci ; 22(18)2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34576215

RESUMO

Depressive disorder in childhood and adolescence is a highly prevalent mood disorder that tends to recur throughout life. Untreated mood disorders can adversely impact a patient's quality of life and cause socioeconomic loss. Thus, an accurate diagnosis and appropriate treatment is crucial. However, until now, diagnoses and treatments were conducted according to clinical symptoms. Objective and biological validation is lacking. This may result in a poor outcome for patients with depressive disorder. Research has been conducted to identify the biomarkers that are related to depressive disorder. Cumulative evidence has revealed that certain immunologic biomarkers including brain-derived neurotrophic factor (BDNF) and cytokines, gastrointestinal biomarkers, hormones, oxidative stress, and certain hypothalamus-pituitary axis biomarkers are associated with depressive disorder. This article reviews the biomarkers related to the diagnosis and treatment of pediatric depressive disorders. To date, clinical biomarker tests are not yet available for diagnosis or for the prediction of treatment prognosis. However, cytokines such as Interleukin-2, interferon-gamma, tumor necrosis factor-alpha, and BDNF have shown significant results in previous studies of pediatric depressive disorder. These biomarkers have the potential to be used for diagnosis, prognostic assessment, and group screening for those at high risk.


Assuntos
Biomarcadores/sangue , Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/diagnóstico , Adolescente , Animais , Fator Neurotrófico Derivado do Encéfalo/sangue , Criança , Citocinas/sangue , Citocinas/metabolismo , Transtorno Depressivo Maior/genética , Trato Gastrointestinal/metabolismo , Hormônios/sangue , Humanos , Hipotálamo/metabolismo , Sistema Imunitário , Inflamação , Interferon gama/sangue , Interleucina-2/sangue , Aprendizado de Máquina , Neurônios/patologia , Estresse Oxidativo , Hipófise/metabolismo , Prognóstico , Qualidade de Vida , Fator de Necrose Tumoral alfa/sangue
6.
PLoS One ; 16(9): e0257214, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34506568

RESUMO

Our earlier studies in tuberculosis (TB) patients indicate that in those where the process evolves to a larger pulmonary involvement, the immune endocrine response may promote an unfavorable environment. Chronic infectious diseases, and their persistent proinflammatory response, may affect mucosal barriers integrity favoring the translocation of gastrointestinal bacteria, leading to an increase of circulating lipopolysaccharides (LPS). Consequently, we quantified LPS levels in TB patients, with different degrees of pulmonary involvement, and controls (Co) and analyzed the possible relationship between LPS and inflammatory mediators i.e., C reactive protein (CRP), interleukin 6 (IL-6) and Interferon-gamma (IFN-γ), Erythrocyte Sedimentation Rate (ESR), steroid hormones (Cortisol and Dehydroepiandrosterone, DHEA), and inflammatory transcripts from peripheral blood mononuclear cells (IL-1ß, IL-6, IFN-γ). LPS was assessed by the Limulus amoebocyte lysate assay and the ELISA technique was used to quantify hormones and cytokines in the plasma samples. Cytokine transcripts from PBMC were evaluated by qRT-PCR. Non-parametric tests were used. LPS levels were increased in TB patients, as did levels of CRP, IL-6, IFN-γ, cortisol and ESR. Severe patients had the highest amounts of circulating LPS; with moderate and severe cases showing much higher levels of CRP, ESR, IL-6, IFN-γ and cortisol/DHEA ratio, as an endocrine imbalance. Only in PBMC from severe cases was mRNA for IL-1ß increased. Correlation analysis showed that levels of LPS from severe patients were positively associated with IL-6 and IFN-γ plasma concentrations and with IL-1ß transcripts, while IL-6 had a positive correlation with the cortisol/DHEA ratio. The higher levels of circulating LPS during progressive TB may emerge as a contributing factor for the persistence of the greater immune endocrine imbalance distinctive of advanced disease, which might suggest a vicious cycle among LPS, inflammation and endocrine imbalance.


Assuntos
Lipopolissacarídeos/sangue , Tuberculose/sangue , Adolescente , Adulto , Idoso , Proteína C-Reativa/metabolismo , Humanos , Interferon gama/sangue , Interleucina-1beta/sangue , Interleucina-6/sangue , Leucócitos Mononucleares/metabolismo , Pessoa de Meia-Idade , Mycobacterium tuberculosis/metabolismo , Adulto Jovem
7.
Cells ; 10(8)2021 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-34440721

RESUMO

At the end of 2020, population-based vaccination programs with new generation mRNA-based vaccines began almost all over the world. The aim of the study was to evaluate the titer of anti-SARS-CoV-2 IgG antibodies against the S1 subunit of the virus's spike protein as a marker of the humoral response in 477 patients and the concentration of interferon-gamma as an indicator of cellular response in 28 individuals. In our studies, we used serological enzyme-linked immunosorbent assays. IgG was measured in weeks 2 and 3 after the first dose and 1-5 weeks after the second dose of an mRNA vaccine in seropositive and seronegative individuals as well as in symptomatic and asymptomatic convalescents. High levels of antibodies were observed in 98% of our vaccinated cohort, and the presence of protective T cells was confirmed in the blood samples of all participants. The humoral immune response is diversified and is visible as early as 2-3 weeks after the first dose of the mRNA vaccine. The level of protection increased significantly after the second dose, with the increase being much greater in pre-vaccine healthy subjects and less in convalescents. In the second and third weeks after the second dose, the concentration of IgG antibodies was the highest, and in the following weeks, it decreased gradually. Regular serological measurements on eight subjects show that antibody titers are lower four months after vaccination than before the second dose.


Assuntos
Anticorpos Antivirais/sangue , Vacinas contra COVID-19/farmacologia , Imunoglobulina G/sangue , Interferon gama/sangue , SARS-CoV-2/imunologia , Adulto , Fatores Etários , Idoso , COVID-19/prevenção & controle , Vacinas contra COVID-19/uso terapêutico , Feminino , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Polônia , Fatores Sexuais , Fatores de Tempo
8.
Emerg Microbes Infect ; 10(1): 1807-1818, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34402750

RESUMO

Male sex was repeatedly identified as a risk factor for death and intensive care admission. However, it is yet unclear whether sex hormones are associated with disease severity in COVID-19 patients. In this study, we analysed sex hormone levels (estradiol and testosterone) of male and female COVID-19 patients (n = 50) admitted to an intensive care unit (ICU) in comparison to control non-COVID-19 patients at the ICU (n = 42), non-COVID-19 patients with the most prevalent comorbidity (coronary heart diseases) present within the COVID-19 cohort (n = 39) and healthy individuals (n = 50). We detected significantly elevated estradiol levels in critically ill male COVID-19 patients compared to all control cohorts. Testosterone levels were significantly reduced in critically ill male COVID-19 patients compared to control cohorts. No statistically significant differences in sex hormone levels were detected in critically ill female COVID-19 patients, albeit similar trends towards elevated estradiol levels were observed. Linear regression analysis revealed that among a broad range of cytokines and chemokines analysed, IFN-γ levels are positively associated with estradiol levels in male and female COVID-19 patients. Furthermore, male COVID-19 patients with elevated estradiol levels were more likely to receive ECMO treatment. Thus, we herein identified that disturbance of sex hormone metabolism might present a hallmark in critically ill male COVID-19 patients.


Assuntos
COVID-19/mortalidade , COVID-19/patologia , Estradiol/sangue , Testosterona/sangue , Idoso , Idoso de 80 Anos ou mais , COVID-19/sangue , Cuidados Críticos , Estado Terminal , Oxigenação por Membrana Extracorpórea , Feminino , Humanos , Hipogonadismo/patologia , Unidades de Terapia Intensiva , Interferon gama/sangue , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , SARS-CoV-2 , Índice de Gravidade de Doença , Distribuição por Sexo
9.
PLoS Negl Trop Dis ; 15(8): e0009632, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34351903

RESUMO

BACKGROUND: Visceral leishmaniasis is a disease caused by disseminated Leishmania donovani infection which affects almost half a million people annually. Most of the patients are reported from the Indian sub-continent, Eastern Africa and Brazil. In this study, we aimed to determine the levels of antibodies and cytokines in visceral leishmaniasis patients and to examine associations of parasitemia with the clinical states of patients. A prospective study was carried out, enrolling a total of 48 active VL patients who were evaluated before, during different time points and, three months after treatment. Serum cytokine concentrations, antibody levels, parasitemia, laboratory (hematologic and biochemical) measurements, and clinical parameters were assessed. RESULTS: Counts of WBC and platelets, and measurements of hemoglobin (Hb) increased during treatment (P ≤ 0.05). Elevated levels of circulating IL-10, IFN-γ, and TGF-ß1 were measured before treatment. The observed increase in serum IL-10 remarkably declined within 7 days after the start of treatment. Anti-leishmanial antibody index (AI) was high in all VL patients irrespective of spleen aspirate parasite grade before treatment and at different times during treatment. However, a significant (P ≤ 0.05) decrease of AI was observed 120 days post-treatment. IL-2 serum levels were below the detection limit at all sampling points. CONCLUSIONS: The present results suggest that IL-10, IFN-γ, and TGF-ß1 can be used as markers of active visceral leishmaniasis. In addition, measuring circulating cytokines concentrations, particularly IL-10, in combination with other clinical evaluations, could be used as criteria for the cure. The observation that a high serum concentration of IFN-gamma at baseline was associated with low parasitemia deserves further investigations.


Assuntos
Anticorpos Antiprotozoários/sangue , Interferon gama/sangue , Interleucina-10/sangue , Leishmania donovani/imunologia , Leishmaniose Visceral/sangue , Fator de Crescimento Transformador beta1/sangue , Adolescente , Adulto , Criança , Pré-Escolar , Etiópia , Feminino , Hospitais Gerais , Humanos , Interferon gama/imunologia , Interleucina-10/imunologia , Leishmania donovani/isolamento & purificação , Masculino , Pessoa de Meia-Idade , Parasitemia/sangue , Estudos Prospectivos , Fator de Crescimento Transformador beta1/imunologia , Adulto Jovem
10.
Immunol Res ; 69(6): 576-583, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34417958

RESUMO

The development of vaccines to prevent SARS-CoV-2 infection has mainly relied on the induction of neutralizing antibodies (nAbs) to the Spike protein of SARS-CoV-2, but there is growing evidence that T cell immune response can contribute to protection as well. In this study, an anti-receptor binding domain (RBD) antibody assay and an INFγ-release assay (IGRA) were used to detect humoral and cellular responses to the Pfizer-BioNTech BNT162b2 vaccine in three separate cohorts of COVID-19-naïve patients: 108 healthcare workers (HCWs), 15 elderly people, and 5 autoimmune patients treated with immunosuppressive agents. After the second dose of vaccine, the mean values of anti-RBD antibodies (Abs) and INFγ were 123.33 U/mL (range 27.55-464) and 1513 mIU/mL (range 145-2500) in HCWs and 210.7 U/mL (range 3-500) and 1167 mIU/mL (range 83-2500) in elderly people. No correlations between age and immune status were observed. On the contrary, a weak but significant positive correlation was found between INFγ and anti-RBD Abs values (rho = 0.354, p = 0.003). As to the autoimmune cohort, anti-RBD Abs were not detected in the two patients with absent peripheral CD19+B cells, despite high INFγ levels being observed in all 5 patients after vaccination. Even though the clinical relevance of T cell response has not yet been established as a correlate of vaccine-induced protection, IGRA testing has showed optimal sensitivity and specificity to define vaccine responders, even in patients lacking a cognate antibody response to the vaccine.


Assuntos
Vacinas contra COVID-19/imunologia , Imunidade Celular/imunologia , Imunidade Humoral/imunologia , Hospedeiro Imunocomprometido/imunologia , SARS-CoV-2/imunologia , Adulto , Idoso , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Doenças Autoimunes/imunologia , Linfócitos B/imunologia , COVID-19/imunologia , COVID-19/prevenção & controle , Feminino , Pessoal de Saúde/estatística & dados numéricos , Humanos , Imunogenicidade da Vacina/imunologia , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Interferon gama/sangue , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Domínios Proteicos/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Linfócitos T/imunologia , Vacinação , Adulto Jovem
11.
Nat Commun ; 12(1): 4043, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34193870

RESUMO

Memory T cells contribute to rapid viral clearance during re-infection, but the longevity and differentiation of SARS-CoV-2-specific memory T cells remain unclear. Here we conduct ex vivo assays to evaluate SARS-CoV-2-specific CD4+ and CD8+ T cell responses in COVID-19 convalescent patients up to 317 days post-symptom onset (DPSO), and find that memory T cell responses are maintained during the study period regardless of the severity of COVID-19. In particular, we observe sustained polyfunctionality and proliferation capacity of SARS-CoV-2-specific T cells. Among SARS-CoV-2-specific CD4+ and CD8+ T cells detected by activation-induced markers, the proportion of stem cell-like memory T (TSCM) cells is increased, peaking at approximately 120 DPSO. Development of TSCM cells is confirmed by SARS-CoV-2-specific MHC-I multimer staining. Considering the self-renewal capacity and multipotency of TSCM cells, our data suggest that SARS-CoV-2-specific T cells are long-lasting after recovery from COVID-19, thus support the feasibility of effective vaccination programs as a measure for COVID-19 control.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , COVID-19/imunologia , Memória Imunológica/imunologia , SARS-CoV-2/imunologia , Anticorpos Antivirais/sangue , Vacinas contra COVID-19/imunologia , Ensaio de Imunoadsorção Enzimática , Humanos , Interferon gama/sangue , Vacinação
12.
Front Immunol ; 12: 684014, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34194438

RESUMO

T cells play a fundamental role in the early control and clearance of many viral infections of the respiratory system. In SARS-CoV-2-infected individuals, lymphopenia with drastically reduced CD4+ and CD8+ T cells correlates with Coronavirus disease 2019 (COVID-19)-associated disease severity and mortality. In this study, we characterized cellular and humoral immune responses induced in patients with mild, severe and critical COVID-19. Peripheral blood mononuclear cells of 37 patients with mild, severe and critical COVID-19 and 10 healthy individuals were analyzed by IFNγ ELISpot and multi-color flow cytometry upon stimulation with peptide pools covering complete immunodominant SARS-CoV-2 matrix, nucleocapsid and spike proteins. In addition SARS-CoV-2 antibody levels, neutralization abilities and anaphylatoxin levels were evaluated by various commercially available ELISA platforms. Our data clearly demonstrates a significantly stronger induction of SARS-CoV-2 specific CD8+ T lymphocytes and higher IFNγ production in patients with mild compared to patients with severe or critical COVID-19. In all patients SARS-CoV-2-specific antibodies with similar neutralizing activity were detected, but highest titers of total IgGs were observed in critical patients. Finally, elevated anaphylatoxin C3a and C5a levels were identified in severe and critical COVID-19 patients probably caused by aberrant immune complex formation due to elevated antibody titers in these patients. Crucially, we provide a full picture of cellular and humoral immune responses of COVID-19 patients and prove that robust polyfunctional CD8+ T cell responses concomitant with low anaphylatoxin levels correlate with mild infections. In addition, our data indicates that high SARS-CoV-2 antibody titers are associated with severe disease progression.


Assuntos
Anafilatoxinas/metabolismo , Linfócitos T CD8-Positivos/imunologia , COVID-19/imunologia , SARS-CoV-2/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , COVID-19/fisiopatologia , Progressão da Doença , ELISPOT , Feminino , Citometria de Fluxo , Humanos , Imunidade Humoral , Interferon gama/sangue , Masculino , Pessoa de Meia-Idade , Gravidade do Paciente
13.
BMC Infect Dis ; 21(1): 651, 2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34225667

RESUMO

BACKGROUND: The differential diagnosis of active tuberculosis (ATB) and latent tuberculosis infection (LTBI) remains challenging in clinical practice. We aimed to evaluate the diagnostic accuracy of the IFN-γ/TNF-α FluoroSpot assay for differentiating ATB from LTBI. METHODS: We conducted a pilot study of case-control design, using the FluoroSpot assay to simultaneously detect IFN-γ and TNF-α secretion at the single-cell level. The frequencies of antigen-specific single TNF-α-, total TNF-α-, single IFN-γ-, total IFN-γ- and dual IFN-γ/TNF-α-secreting T cells were detected. The optimal cutoffs value of frequencies for differentiating ATB from LTBI were determined according to receiver operating characteristic curve analysis. The sensitivity, specificity, predictive values (PV) and likelihood ratios (LR) of the FluoroSpot assay were calculated. RESULTS: Thirty patients diagnosed microbiologically with ATB, 36 healthcare workers with LTBI and 36 healthy controls were enrolled. After stimulated by ESAT-6 or CFP-10 peptides, the median frequencies of single TNF-α-, total TNF-α-, single IFN-γ-, total IFN-γ- and dual IFN-γ/TNF-α-secreting T cells in ATB patients were all significantly higher than those in LTBI and HC groups (P < 0.01). The frequencies of total IFN-γ-secreting T cells detected by FluoroSpot assay correlated significantly with those of T-SPOT.TB (r = 0.910 for ESAT-6, P < 0.001, r = 0.845 for CFP-10, P < 0.001). After stimulated by ESAT-6 peptides, with total TNF-α-secreting T cells frequencies at a cut off value of 21 iSFCs/250,000 PBMCs, the sensitivity, specificity, PLR, NLR, PPV, NPV of IFN-γ/TNF-α FluoroSpot assay in differentiating ATB from LTBI were 96.7% (95%CI, 82.8-99.9%), 94.3% (95%CI, 80.8-99.3%), 16.92 (95%CI, 4.40-65.08), 0.04 (95%CI, 0.01-0.24), 93.6% (95%CI,78.6-99.2%) and 97.1% (95%CI, 84.7-99.9%), respectively. With the frequencies of total TNF-α- and total IFN-γ-secreting T cells stimulated by ESAT-6 peptides combined, the specificity was increased to 97.1%, and the positive likelihood ratio to 31.5. The combination with CFP-10 might not improve the diagnostic accuracy of the ESAT-6 for differentiating ATB from LTBI. CONCLUSIONS: IFN-γ/TNF-α FluoroSpot assay might have potential to help differentiate ATB from LTBI, but the findings need to be further verified by cross-sectional or prospective cohort studies.


Assuntos
Testes de Liberação de Interferon-gama , Tuberculose Latente/diagnóstico , Tuberculose/diagnóstico , Fator de Necrose Tumoral alfa/sangue , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Diagnóstico Diferencial , Humanos , Interferon gama/sangue , Tuberculose Latente/imunologia , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Tuberculose/imunologia , Adulto Jovem
15.
Sci Rep ; 11(1): 15107, 2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34302024

RESUMO

COVID-19 outbreak brings intense pressure on healthcare systems, with an urgent demand for effective diagnostic, prognostic and therapeutic procedures. Here, we employed Automated Machine Learning (AutoML) to analyze three publicly available high throughput COVID-19 datasets, including proteomic, metabolomic and transcriptomic measurements. Pathway analysis of the selected features was also performed. Analysis of a combined proteomic and metabolomic dataset led to 10 equivalent signatures of two features each, with AUC 0.840 (CI 0.723-0.941) in discriminating severe from non-severe COVID-19 patients. A transcriptomic dataset led to two equivalent signatures of eight features each, with AUC 0.914 (CI 0.865-0.955) in identifying COVID-19 patients from those with a different acute respiratory illness. Another transcriptomic dataset led to two equivalent signatures of nine features each, with AUC 0.967 (CI 0.899-0.996) in identifying COVID-19 patients from virus-free individuals. Signature predictive performance remained high upon validation. Multiple new features emerged and pathway analysis revealed biological relevance by implication in Viral mRNA Translation, Interferon gamma signaling and Innate Immune System pathways. In conclusion, AutoML analysis led to multiple biosignatures of high predictive performance, with reduced features and large choice of alternative predictors. These favorable characteristics are eminent for development of cost-effective assays to contribute to better disease management.


Assuntos
COVID-19/diagnóstico , COVID-19/metabolismo , Imunidade Inata/imunologia , Aprendizado de Máquina , SARS-CoV-2/metabolismo , Biomarcadores/sangue , COVID-19/genética , COVID-19/patologia , Simulação por Computador , Bases de Dados Factuais , Bases de Dados Genéticas , Bases de Dados de Proteínas , Perfilação da Expressão Gênica , Humanos , Imunidade Inata/genética , Interferon gama/sangue , Metabolômica , Prognóstico , Proteômica , Curva ROC , SARS-CoV-2/genética , Índice de Gravidade de Doença , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Software
16.
PLoS Comput Biol ; 17(7): e1009197, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34319988

RESUMO

The risk of tuberculosis (TB) disease is higher in individuals with recent Mycobacterium tuberculosis (M.tb) infection compared to individuals with more remote, established infection. We aimed to define blood-based biomarkers to distinguish between recent and remote infection, which would allow targeting of recently infected individuals for preventive TB treatment. We hypothesized that integration of multiple immune measurements would outperform the diagnostic performance of a single biomarker. Analysis was performed on different components of the immune system, including adaptive and innate responses to mycobacteria, measured on recently and remotely M.tb infected adolescents. The datasets were standardized using variance stabilizing scaling and missing values were imputed using a multiple factor analysis-based approach. For data integration, we compared the performance of a Multiple Tuning Parameter Elastic Net (MTP-EN) to a standard EN model, which was built to the individual adaptive and innate datasets. Biomarkers with non-zero coefficients from the optimal single data EN models were then isolated to build logistic regression models. A decision tree and random forest model were used for statistical confirmation. We found no difference in the predictive performances of the optimal MTP-EN model and the EN model [average area under the receiver operating curve (AUROC) = 0.93]. EN models built to the integrated dataset and the adaptive dataset yielded identically high AUROC values (average AUROC = 0.91), while the innate data EN model performed poorly (average AUROC = 0.62). Results also indicated that integration of adaptive and innate biomarkers did not outperform the adaptive biomarkers alone (Likelihood Ratio Test χ2 = 6.09, p = 0.808). From a total of 193 variables, the level of HLA-DR on ESAT6/CFP10-specific Th1 cytokine-expressing CD4 cells was the strongest biomarker for recent M.tb infection. The discriminatory ability of this variable was confirmed in both tree-based models. A single biomarker measuring M.tb-specific T cell activation yielded excellent diagnostic potential to distinguish between recent and remote M.tb infection.


Assuntos
Modelos Imunológicos , Tuberculose/imunologia , Imunidade Adaptativa , Adolescente , Algoritmos , Biomarcadores/sangue , Criança , Biologia Computacional , Progressão da Doença , Feminino , Humanos , Imunidade Inata , Interferon gama/sangue , Modelos Logísticos , Estudos Longitudinais , Ativação Linfocitária , Aprendizado de Máquina , Masculino , Linfócitos T/imunologia , Fatores de Tempo , Tuberculose/sangue
17.
J Immunol Res ; 2021: 6657894, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34150910

RESUMO

Background: The 2019 novel coronavirus SARS-CoV-2 caused large outbreaks of COVID-19 worldwide. COVID-19 resembles community-acquired pneumonia (CAP). Our aim was to identify lymphocyte subpopulations to distinguish between COVID-19 and CAP. Methods: We compared the peripheral blood lymphocytes and their subsets in 296 patients with COVID-19 and 130 patients with CAP. Parameters for independent prediction of COVID-19 were calculated by logistic regression. Results: The main lymphocyte subpopulations (CD3+CD4+, CD16+CD56+, and CD4+/CD8+ ratio) and cytokines (TNF-α and IFN-γ) of COVID-19 patients were significantly different from that of CAP patients. CD16+CD56+%, CD4+/CD8+ratio, CD19+, and CD3+CD4+ were identified as predictors of COVID-19 diagnosis by logistic regression. In addition, the CD3+CD4+counts, CD3+CD8+ counts, andTNF-α are independent predictors of disease severity in patients. Conclusions: Lymphopenia is an important part of SARS-CoV-2 infection, and lymphocyte subsets and cytokines may be useful to predict the severity and clinical outcomes of the disease.


Assuntos
Relação CD4-CD8 , COVID-19/sangue , Interferon gama/sangue , Subpopulações de Linfócitos/citologia , Pneumonia/sangue , Fator de Necrose Tumoral alfa/sangue , Adulto , Idoso , COVID-19/imunologia , COVID-19/patologia , Teste para COVID-19 , Infecções Comunitárias Adquiridas/microbiologia , Feminino , Humanos , Subpopulações de Linfócitos/imunologia , Linfopenia/sangue , Linfopenia/patologia , Masculino , Pessoa de Meia-Idade , Pneumonia/imunologia , Pneumonia/patologia , Prognóstico , SARS-CoV-2/imunologia , Índice de Gravidade de Doença
18.
Cell Transplant ; 30: 9636897211024942, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34180719

RESUMO

The aim of this clinical trial was to control the cytokine storm by administering mesenchymal stem cells (MSCs) to critically-ill COVID-19 patients, to evaluate the healing effect, and to systematically investigate how the treatment works. Patients with moderate and critical COVID-19 clinical manifestations were separated as Group 1 (moderate cases, n = 10, treated conventionally), Group 2 (critical cases, n = 10, treated conventionally), and Group 3 (critical cases, n = 10, treated conventionally plus MSCs transplantation therapy of three consecutive doses on treatment days 0, 3, and 6, (as 3 × 106 cells/kg, intravenously). The treatment mechanism of action was investigated with evaluation markers of the cytokine storm, via biochemical parameters, levels of proinflammatory and anti-inflammatory cytokines, analyses of tissue regeneration via the levels of growth factors, apoptosis markers, chemokines, matrix metalloproteinases, and granzyme-B, and by the assessment of the immunomodulatory effects via total oxidant/antioxidant status markers and the levels of lymphocyte subsets. In the assessment of the overall mortality rates of all the cases, six patients in Group-2 and three patients in Group-3 died, and there was no loss in Group-1. Proinflammatory cytokines IFNγ, IL-6, IL-17A, IL-2, IL-12, anti-inflammatory cytokines IL-10, IL-13, IL-1ra, and growth factors TGF-ß, VEGF, KGF, and NGF levels were found to be significant in Group-3. When Group-2 and Group-3 were compared, serum ferritin, fibrinogen and CRP levels in Group-3 had significantly decreased. CD45 +, CD3 +, CD4 +, CD8 +, CD19 +, HLA-DR +, and CD16 + / CD56 + levels were evaluated. In the statistical comparison of the groups, significance was only determined in respect of neutrophils. The results demonstrated the positive systematic and cellular effects of MSCs application on critically ill COVID-19 patients in a versatile way. This effect plays an important role in curing and reducing mortality in critically ill patients.


Assuntos
COVID-19/terapia , Transplante de Células-Tronco Mesenquimais , Adulto , Proteína C-Reativa/análise , COVID-19/patologia , COVID-19/virologia , Estado Terminal , Citocinas/sangue , Feminino , Humanos , Interferon gama/sangue , Interleucina-10/sangue , Interleucina-8/sangue , Antígenos Comuns de Leucócito/metabolismo , Linfócitos/citologia , Linfócitos/metabolismo , Masculino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Pessoa de Meia-Idade , Estudos Prospectivos , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de Doença , Resultado do Tratamento
19.
Front Immunol ; 12: 641447, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34108961

RESUMO

The newly emerged novel coronavirus, SARS-CoV-2, the causative agent of COVID-19 has proven to be a threat to the human race globally, thus, vaccine development against SARS-CoV-2 is an unmet need driving mass vaccination efforts. The receptor binding domain of the spike protein of this coronavirus has multiple neutralizing epitopes and is associated with viral entry. Here we have designed and characterized the SARS-CoV-2 spike protein fragment 330-526 as receptor binding domain 330-526 (RBD330-526) with two native glycosylation sites (N331 and N343); as a potential subunit vaccine candidate. We initially characterized RBD330-526 biochemically and investigated its thermal stability, humoral and T cell immune response of various RBD protein formulations (with or without adjuvant) to evaluate the inherent immunogenicity and immunomodulatory effect. Our result showed that the purified RBD immunogen is stable up to 72 h, without any apparent loss in affinity or specificity of interaction with the ACE2 receptor. Upon immunization in mice, RBD generates a high titer humoral response, elevated IFN-γ producing CD4+ cells, cytotoxic T cells, and robust neutralizing antibodies against live SARS-CoV-2 virus. Our results collectively support the potential of RBD330-526 as a promising vaccine candidate against SARS-CoV-2.


Assuntos
Anticorpos Antivirais/sangue , Vacinas contra COVID-19/administração & dosagem , Imunidade Humoral/efeitos dos fármacos , Imunogenicidade da Vacina , Fragmentos de Peptídeos/administração & dosagem , Glicoproteína da Espícula de Coronavírus/administração & dosagem , Células Th1/efeitos dos fármacos , Adjuvantes Imunológicos/administração & dosagem , Animais , Biomarcadores/sangue , Vacinas contra COVID-19/imunologia , Chlorocebus aethiops , Estabilidade de Medicamentos , Glicosilação , Células HEK293 , Humanos , Imunização , Interferon gama/sangue , Masculino , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos/imunologia , Domínios e Motivos de Interação entre Proteínas , Estabilidade Proteica , Glicoproteína da Espícula de Coronavírus/imunologia , Células Th1/imunologia , Células Th1/metabolismo , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/imunologia , Células Vero
20.
Acta Trop ; 222: 106019, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34157293

RESUMO

This study detected and compared the levels of Il-17A, IFN-gamma and IL-10 in the amniotic fluid (AF) and serum of pregnant women with acute toxoplasmosis in southern Brazil. It also compared the serum levels of these mediators in pregnant women with acute or chronic toxoplasmosis and with uninfected women. The serological investigations of anti-T. gondii IgM and IgG from the 60 pregnant women were determined by chemiluminescence microparticle immunoassay (CMIA). Twenty patients were uninfected, twenty were in the chronic phase and twenty were in the acute phase of toxoplasmosis. The 20 pregnant women in acute phase all agreed with amniocentesis. Serum and AF cytokines were evaluated by sandwich enzyme-linked immunosorbent assay. The analyzed cytokines showed no significant difference in blood versus amniotic fluid levels of pregnant women in the acute toxoplasmosis. Furthermore, we observed that serum IL-17A was significantly higher in pregnant women in the acute phase of infection compared to pregnant women with chronic toxoplasmosis and seronegative pregnant women. T. gondii DNA was not amplified in any of the samples of amniotic fluid by the nested-PCR reaction. Serum IL-10 levels were also higher in negative pregnant women than in infected pregnant women. Our findings indicate the activation of an inflammatory response to infection by T. gondii and suggest that increased production of IL-17A may be a protective factor against infection of the fetus.


Assuntos
Líquido Amniótico/química , Interleucina-17/sangue , Complicações Parasitárias na Gravidez , Toxoplasmose , Anticorpos Antiprotozoários , Brasil , Feminino , Humanos , Imunoglobulina M , Interferon gama/sangue , Interleucina-10/sangue , Gravidez , Complicações Parasitárias na Gravidez/imunologia , Gestantes , Toxoplasma , Toxoplasmose/imunologia
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