RESUMO
OBJECTIVES: The role of B cells in COVID-19, beyond the production of specific antibodies against SARS-CoV-2, is still not well understood. Here, we describe the novel landscape of circulating double-negative (DN) CD27- IgD- B cells in COVID-19 patients, representing a group of atypical and neglected subpopulations of this cell lineage. METHODS: Using multiparametric flow cytometry, we determined DN B cell subset amounts from 91 COVID-19 patients, correlated those with cytokines, clinical and laboratory parameters, and segregated them by principal components analysis. RESULTS: We detected significant increments in the DN2 and DN3 B cell subsets, while we found a relevant decrease in the DN1 B cell subpopulation, according to disease severity and patient outcomes. These DN cell numbers also appeared to correlate with pro- or anti-inflammatory signatures, respectively, and contributed to the segregation of the patients into disease severity groups. CONCLUSION: This study provides insights into DN B cell subsets' potential role in immune responses against SARS-CoV-2, particularly linked to the severity of COVID-19.
Assuntos
COVID-19/sangue , COVID-19/imunologia , Imunoglobulina D/sangue , SARS-CoV-2 , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos B/citologia , COVID-19/diagnóstico , COVID-19/virologia , Linhagem da Célula , Biologia Computacional , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Componente Principal , Prognóstico , Respiração Artificial , Índice de Gravidade de Doença , Adulto JovemRESUMO
BACKGROUND: Currently, there is scant information regarding the features associated to the persistence of post-COVID-19 syndrome, which is the main aim of the present study. METHODS: A cohort study of 102 COVID-19 patients was conducted. The post-COVID-19 symptoms were assessed by a standardised questionnaire. Lymphocyte immunophenotyping was performed by flow cytometry and chemokines/cytokines, neutrophil extracellular traps, the tripartite motif 63, anti-cellular, and anti-SARS-CoV-2 IgG antibodies were addressed in serum. The primary outcome was the persistence of post-COVID-19 syndrome after six months follow-up. RESULTS: Thirteen patients (12.7%) developed the primary outcome and had a more frequent history of post-COVID-19 syndrome 3 months after infection onset (p = .044), increased levels of IL-1α (p = .011) and IP-10 (p = .037) and increased CD57 expression in CD8+ T cells (p = .003). There was a trend towards higher levels of IFN-γ (p = .051), IL-1ß (p = .062) and IL-6 (p = .087). The history of post COVID-19 in the previous 3 months, obesity, baseline serum MIP-1α and IP-10, and CD57 expression in CD8+ T cells were independently associated with the persistence of post-COVID-19 syndrome. CONCLUSION: Our data suggest an important relationship between a pro-inflammatory state mediated through metabolic pathways related to obesity and increased cellular senescence as a key element in the persistence of post-COVID-19 syndrome at six months of follow-up.
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COVID-19 , Humanos , COVID-19/complicações , Projetos Piloto , Síndrome de COVID-19 Pós-Aguda , Linfócitos T CD8-Positivos , Estudos de Coortes , Quimiocina CXCL10 , ObesidadeRESUMO
Background: Until now, most of the research addressing long-term humoral responses in coronavirus disease 2019 (COVID-19) had only evaluated the serum titers of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgGs, without the assessment of the baseline antiviral clinical and immune profile, which is the aim of this study and may be the key factor leading to a broad and sustained antibody response. Methods: We included 103 patients with COVID-19. When the patients sought medical attention (baseline), a blood sample was drawn to perform immunophenotype of lymphocytes by flow cytometry. The patients were assessed 15 days after baseline and then every month until the third month, followed by a last visit 6 months after recruitment. We evaluated the anti-SARS-COV-2 IgG at all time points, and the serum levels of cytokines, chemokines, anti-cellular (AC) antibodies and neutrophil extracellular traps were also assessed during the follow-up. The primary outcome of the study was the presence of a sustained immune humoral response, defined as an anti-SARS-CoV-2 IgG titer >4.99 arbitrary units/mL in at least two consecutive measures. We used generalized lineal models to assess the features associated with this outcome and to assess the effect of the changes in the cytokines and chemokines throughout time on the development of a sustained humoral immune response. Results: At baseline the features associated to a sustained immune humoral response were the diagnosis of critical disease, absolute number of lymphocytes, serum IP-10, IL-4, IL-2, regulatory T cells, CD8+ T cells, and positive AC antibodies. Critical illness and the positivity of AC antibodies were associated with a sustained humoral immune response after 3 months, whilst critical illness and serum IL-13 were the explanatory variables after 6 months. Conclusion: A sustained immune humoral response is strongly related to critical COVID-19, which is characterized by the presence of AC antibodies, quantitative abnormalities in the T cell compartment, and the serum cytokines and chemokines during acute infection and throughout time.
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COVID-19 , Anticorpos Antivirais , Linfócitos T CD8-Positivos , Quimiocinas , Estudos de Coortes , Estado Terminal , Citocinas , Humanos , Imunoglobulina G , SARS-CoV-2RESUMO
Background: Most of the explanatory and prognostic models of COVID-19 lack of a comprehensive assessment of the wide COVID-19 spectrum of abnormalities. The aim of this study was to unveil novel biological features to explain COVID-19 severity and prognosis (death and disease progression). Methods: A predictive model for COVID-19 severity in 121 patients was constructed by ordinal logistic regression calculating odds ratio (OR) with 95% confidence intervals (95% CI) for a set of clinical, immunological, metabolomic, and other biological traits. The accuracy and calibration of the model was tested with the area under the curve (AUC), Somer's D, and calibration plot. Hazard ratios with 95% CI for adverse outcomes were calculated with a Cox proportional-hazards model. Results: The explanatory variables for COVID-19 severity were the body mass index (BMI), hemoglobin, albumin, 3-Hydroxyisovaleric acid, CD8+ effector memory T cells, Th1 cells, low-density granulocytes, monocyte chemoattractant protein-1, plasma TRIM63, and circulating neutrophil extracellular traps. The model showed an outstanding performance with an optimism-adjusted AUC of 0.999, and Somer's D of 0.999. The predictive variables for adverse outcomes in COVID-19 were severe and critical disease diagnosis, BMI, lactate dehydrogenase, Troponin I, neutrophil/lymphocyte ratio, serum levels of IP-10, malic acid, 3, 4 di-hydroxybutanoic acid, citric acid, myoinositol, and cystine. Conclusions: Herein, we unveil novel immunological and metabolomic features associated with COVID-19 severity and prognosis. Our models encompass the interplay among innate and adaptive immunity, inflammation-induced muscle atrophy and hypoxia as the main drivers of COVID-19 severity.
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COVID-19 , SARS-CoV-2 , Índice de Gravidade de Doença , Adulto , Coagulação Sanguínea , Índice de Massa Corporal , COVID-19/sangue , COVID-19/imunologia , COVID-19/metabolismo , Citocinas/sangue , Armadilhas Extracelulares/imunologia , Feminino , Hemoglobinas/análise , Humanos , Masculino , Metaboloma , Pessoa de Meia-Idade , Atrofia Muscular , Neutrófilos/imunologia , Fenótipo , Prognóstico , Albumina Sérica Humana/análise , Linfócitos T/imunologia , Valeratos/sangueRESUMO
Immune tolerance, both to exogenous antigens and autoantigens, is essential for restraining undesired inflammatory responses that might result in severe damage to body tissues or cause chronic diseases. During the past few decades, different cell populations and molecules by them secreted have been associated with suppressing and regulatory mechanisms of immune responses. Although B cells typically acquire relevance as precursors of antibody-producing cells, they can also develop potent regulatory functions through the production of soluble molecules or by establishing direct cellular interactions mediated by different surface proteins implicated in signal transduction. While most studies of regulatory B cells define the role of these lymphocytes in autoimmune diseases, evidence of their importance and mechanisms of action in allergic diseases has accumulated in recent years. As a result, regulatory B cells appear to be relevant elements for the establishment or loss of allergen tolerance in different allergic diseases, although they still have been little explored.
La tolerancia inmunológica, tanto a los antígenos exógenos como a los autoantígenos, es esen-cial para restringir las respuestas inflamatorias no deseadas que pudieran derivar en daño grave a los tejidos del organismo o provocar enfermedades crónicas. Durante las últimas décadas, diversas poblaciones celulares y moléculas secretadas por estas se han asociado con mecanismos supresores y reguladores de las respuestas inmunes. Aunque las células B adquieren relevancia típicamente como precursores de células productoras de anticuerpos, también son capaces desarrollar potentes funciones reguladoras a través de la producción de moléculas solubles o mediante el establecimiento de interacciones celulares directas mediadas por diferentes proteínas de superficie implicadas en transducción de señales. Si bien la mayoría de los estudios de células B reguladoras definen el papel de estos linfocitos en enfermedades autoinmunes, en años recientes se ha acumulado evidencia de su importancia y mecanismos de acción en enfer-medades alérgicas. Las células reguladoras B parecen ser elementos relevantes en el establecimiento o pérdida de la tolerancia a alérgenos en diferentes enfermedades alérgicas, si bien aún han sido poco explorados.