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2.
Int J Mol Sci ; 22(11)2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070750

RESUMO

The immune system is a fine modulator of the tumor biology supporting or inhibiting its progression, growth, invasion and conveys the pharmacological treatment effect. Tumors, on their side, have developed escaping mechanisms from the immune system action ranging from the direct secretion of biochemical signals to an indirect reaction, in which the cellular actors of the tumor microenvironment (TME) collaborate to mechanically condition the extracellular matrix (ECM) making it inhospitable to immune cells. TME is composed of several cell lines besides cancer cells, including tumor-associated macrophages, cancer-associated fibroblasts, CD4+ and CD8+ lymphocytes, and innate immunity cells. These populations interface with each other to prepare a conservative response, capable of evading the defense mechanisms implemented by the host's immune system. The presence or absence, in particular, of cytotoxic CD8+ cells in the vicinity of the main tumor mass, is able to predict, respectively, the success or failure of drug therapy. Among various mechanisms of immunescaping, in this study, we characterized the modulation of the phenotypic profile of CD4+ and CD8+ cells in resting and activated states, in response to the mechanical pressure exerted by a three-dimensional in vitro system, able to recapitulate the rheological and stiffness properties of the tumor ECM.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Matriz Extracelular/imunologia , Regulação Neoplásica da Expressão Gênica/imunologia , Evasão Tumoral , Microambiente Tumoral/imunologia , 5'-Nucleotidase/genética , 5'-Nucleotidase/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Fibroblastos Associados a Câncer/imunologia , Fibroblastos Associados a Câncer/patologia , Técnicas de Cultura de Células , Módulo de Elasticidade , Matriz Extracelular/química , Feminino , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/imunologia , Humanos , Hidrogéis/química , Interferon gama/genética , Interferon gama/imunologia , Ativação Linfocitária , Mecanotransdução Celular , Modelos Biológicos , NF-kappa B/genética , NF-kappa B/imunologia , Fenótipo , Cultura Primária de Células , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Reologia , Fator de Transcrição Sp1/genética , Fator de Transcrição Sp1/imunologia , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/imunologia , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/patologia , Microambiente Tumoral/genética , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/patologia
3.
Cancer Med ; 10(10): 3403-3412, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33934535

RESUMO

A primary factor in tumor morbidity and mortality, lung adenocarcinoma (LUAD) is known to be a major subtype of lung cancer, having the lowest survival rate among all other cancers. Using The Cancer Genome Atlas (TCGA) database the relationship between the immune infiltrate and the NUP62CL was explored and the value of the NUP62CL expression in the prognosis and diagnosis LUAD was examined. Using the logistic regression and the Wilcoxon signed-rank test the relationship between the NUP62CL and the clinico-pathological features was analyzed. There was a significant correlation between the clinical stage (p = 0.005), the N (p = 0.004), and the decreased expression of NUP62CL. The prognosis of LUAD with high NUP62CL expression was revealed to be worse than that with low NUP62CL expression (p < 0.001) by the Kaplan-Meier survival analysis. The potentiality of NUP62CL to be a significant factor of prognosis for LUAD was indicated by the analyses of the multivariate and the univariate Cox regression models. In LUAD, the crucial role of recombination and maintenance of telomere as a significant pathway for NUP62CL was suggested by the Gene Set Enrichment Analysis (GSEA). To analyze the correlation between the genes and the tumor infiltrating immune cells the CIBERSORT was used. Moreover the positive correlation with the NUP62CL expression in LUAD of the infiltration level of the tumor infiltrating B lymphocytes and memory CD4+ T cells was exhibited by CIBERSORT. Therefore, NUP62CL may be a new valuable prognostic indicator for LUAD.


Assuntos
Adenocarcinoma de Pulmão/genética , Neoplasias Pulmonares/genética , Linfócitos do Interstício Tumoral/patologia , Glicoproteínas de Membrana/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Adenocarcinoma de Pulmão/patologia , Linfócitos B/patologia , Biomarcadores Tumorais/genética , Linfócitos T CD4-Positivos/patologia , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/patologia , Prognóstico , Modelos de Riscos Proporcionais
4.
J Clin Invest ; 131(12)2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33945513

RESUMO

T cells are involved in control of coronavirus disease 2019 (COVID-19), but limited knowledge is available on the relationship between antigen-specific T cell response and disease severity. Here, we used flow cytometry to assess the magnitude, function, and phenotype of SARS coronavirus 2-specific (SARS-CoV-2-specific) CD4+ T cells in 95 hospitalized COVID-19 patients, 38 of them being HIV-1 and/or tuberculosis (TB) coinfected, and 38 non-COVID-19 patients. We showed that SARS-CoV-2-specific CD4+ T cell attributes, rather than magnitude, were associated with disease severity, with severe disease being characterized by poor polyfunctional potential, reduced proliferation capacity, and enhanced HLA-DR expression. Moreover, HIV-1 and TB coinfection skewed the SARS-CoV-2 T cell response. HIV-1-mediated CD4+ T cell depletion associated with suboptimal T cell and humoral immune responses to SARS-CoV-2, and a decrease in the polyfunctional capacity of SARS-CoV-2-specific CD4+ T cells was observed in COVID-19 patients with active TB. Our results also revealed that COVID-19 patients displayed reduced frequency of Mycobacterium tuberculosis-specific CD4+ T cells, with possible implications for TB disease progression. These results corroborate the important role of SARS-CoV-2-specific T cells in COVID-19 pathogenesis and support the concept of altered T cell functions in patients with severe disease.


Assuntos
Linfócitos T CD4-Positivos/imunologia , COVID-19/imunologia , Coinfecção/imunologia , HIV-1/imunologia , Mycobacterium tuberculosis/imunologia , SARS-CoV-2/imunologia , Tuberculose/imunologia , Adulto , Idoso , Linfócitos T CD4-Positivos/patologia , COVID-19/patologia , Coinfecção/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Tuberculose/patologia
5.
Front Immunol ; 12: 627568, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995351

RESUMO

The beta-coronavirus SARS-CoV-2 induces severe disease (COVID-19) mainly in elderly persons with risk factors, whereas the majority of patients experience a mild course of infection. As the circulating common cold coronaviruses OC43 and HKU1 share some homologous sequences with SARS-CoV-2, beta-coronavirus cross-reactive T-cell responses could influence the susceptibility to SARS-CoV-2 infection and the course of COVID-19. To investigate the role of beta-coronavirus cross-reactive T-cells, we analyzed the T-cell response against a 15 amino acid long peptide (SCoV-DP15: DLSPRWYFYYLGTGP) from the SARS-CoV-2 nucleoprotein sequence with a high homology to the corresponding sequence (QLLPRWYFYYLGTGP) in OC43 and HKU1. SCoV-DP15-specific T-cells were detected in 4 out of 23 (17.4%) SARS-CoV-2-seronegative healthy donors. As HIV-1 infection is a potential risk factor for COVID-19, we also studied a cohort of HIV-1-infected patients on antiretroviral therapy. 44 out of these 116 HIV-1-infected patients (37.9%) showed a specific recognition of the SCoV-DP15 peptide or of shorter peptides within SCoV-DP15 by CD4+ T-cells and/or by CD8+ T-cells. We could define several new cross-reactive HLA-I-restricted epitopes in the SARS-CoV-2 nucleoprotein such as SPRWYFYYL (HLA-B*07, HLA-B*35), DLSPRWYFYY (HLA-A*02), LSPRWYFYY (HLA-A*29), WYFYYLGTGP and WYFYYLGT. Epitope specific CD8+ T-cell lines recognized corresponding epitopes within OC43 and HKU1 to a similar degree or even at lower peptide concentrations suggesting that they were induced by infection with OC43 or HKU1. Our results confirm that SARS-CoV-2-seronegative subjects can target SARS-CoV-2 not only by beta-coronavirus cross-reactive CD4+ T-cells but also by cross-reactive CD8+ cytotoxic T-cells (CTL). The delineation of cross-reactive T-cell epitopes contributes to an efficient epitope-specific immunomonitoring of SARS-CoV-2-specific T-cells. Further prospective studies are needed to prove a protective role of cross-reactive T-cells and their restricting HLA alleles for control of SARS-CoV-2 infection. The frequent observation of SARS-CoV-2-reactive T-cells in HIV-1-infected subjects could be a reason that treated HIV-1 infection does not seem to be a strong risk factor for the development of severe COVID-19.


Assuntos
Linfócitos T CD4-Positivos/imunologia , COVID-19/imunologia , Resfriado Comum/imunologia , Epitopos de Linfócito T/imunologia , Nucleoproteínas/imunologia , SARS-CoV-2/imunologia , Linfócitos T Citotóxicos/imunologia , Adulto , Idoso , Linfócitos T CD4-Positivos/patologia , COVID-19/genética , COVID-19/patologia , Linhagem Celular , Resfriado Comum/genética , Resfriado Comum/patologia , Reações Cruzadas , Epitopos de Linfócito T/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nucleoproteínas/genética , SARS-CoV-2/genética , Linfócitos T Citotóxicos/patologia
6.
Int J Mol Sci ; 22(5)2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33803441

RESUMO

Interferon regulatory factor-4 (IRF4) and IRF8 regulate differentiation, growth and functions of lymphoid and myeloid cells. Targeted deletion of irf8 in T cells (CD4-IRF8KO) has been shown to exacerbate colitis and experimental autoimmune uveitis (EAU), a mouse model of human uveitis. We therefore generated mice lacking irf4 in T cells (CD4-IRF4KO) and investigated whether expression of IRF4 by T cells is also required for regulating T cells that suppress autoimmune diseases. Surprisingly, we found that CD4-IRF4KO mice are resistant to EAU. Suppression of EAU derived in part from inhibiting pathogenic responses of Th17 cells while inducing expansion of regulatory lymphocytes that secrete IL-10 and/or IL-35 in the eye and peripheral lymphoid tissues. Furthermore, CD4-IRF4KO T cells exhibit alterations in cell metabolism and are defective in the expression of two Ikaros zinc-finger (IKZF) transcription factors (Ikaros, Aiolos) that are required for lymphocyte differentiation, metabolism and cell-fate decisions. Thus, synergistic effects of IRF4 and IkZFs might induce metabolic reprogramming of differentiating lymphocytes and thereby dynamically regulate relative abundance of T and B lymphocyte subsets that mediate immunopathogenic mechanisms during uveitis. Moreover, the diametrically opposite effects of IRF4 and IRF8 during EAU suggests that intrinsic function of IRF4 in T cells might be activating proinflammatory responses while IRF8 promotes expansion of immune-suppressive mechanisms.


Assuntos
Doenças Autoimunes , Linfócitos T CD4-Positivos , Diferenciação Celular , Deleção de Genes , Fatores Reguladores de Interferon/deficiência , Transcrição Genética/imunologia , Uveíte , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Doenças Autoimunes/patologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Fatores Reguladores de Interferon/imunologia , Fatores Reguladores de Interferon/metabolismo , Camundongos , Camundongos Knockout , Uveíte/genética , Uveíte/imunologia , Uveíte/metabolismo , Uveíte/patologia
7.
Int J Mol Sci ; 22(5)2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33807704

RESUMO

Alopecia areata (AA) is regarded as a tissue-specific and cell-mediated autoimmune disorder. Regarding the cytokine balance, AA has been considered a type 1 inflammatory disease. On the other hand, AA often complicates atopic dermatitis (AD) and AD is regarded as type 2 inflammatory disease. However, the immunological aspects of AA in relation to AD are still poorly understood. Therefore, we aim to clarify the immunological properties of AD-associated AA. In this study, we performed comparative analysis of the expression of intracytoplasmic cytokines (IFN-γ, IL-4, and IL-13), chemokine receptors (CXCR3 and CCR4) in peripheral blood which were taken from healthy controls, non-atopic AA patients, AA patients with extrinsic AD, and AA patients with intrinsic AD by flowcytometric analysis. We also compared the scalp skin samples taken from AA patients with extrinsic AD before and after treatment with dupilumab. In non-atopic AA patients, the ratios of CD4+IFN-γ+ cells to CD4+IL-4+ cells and CD4+IFN-γ+ cells to CD4+IL-13+ cells were higher than those in AA patients with extrinsic AD. Meanwhile, the ratio of CD8+IFN-γ+ cells to CD8+IL-13+ cells was significantly higher in the non-atopic AA than in the healthy controls. In AA patients with extrinsic AD, the skin AA lesion showed dense infiltration of not only CXCR3+ cells but also CCR4+ cells around hair bulb before dupilumab treatment. However, after the treatment, the number of CXCR3+ cells had no remarkable change while the number of CCR4+ cells significantly decreased. These results indicate that the immunological condition of AA may be different between atopic and non-atopic patients and between extrinsic and intrinsic AD patients. Our study provides an important notion that type 2 immunity may participate in the development of AA in extrinsic AD patients. It may be considered that the immunological state of non-atopic AA is different from that of atopic AA.


Assuntos
Alopecia em Áreas/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Dermatite Atópica/imunologia , Adulto , Alopecia em Áreas/tratamento farmacológico , Alopecia em Áreas/patologia , Anticorpos Monoclonais Humanizados/administração & dosagem , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Citocinas/imunologia , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/patologia , Feminino , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Masculino , Pessoa de Meia-Idade , Receptores CCR4/imunologia , Receptores CXCR3/imunologia , Adulto Jovem
8.
Isr Med Assoc J ; 23(3): 153-159, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33734627

RESUMO

BACKGROUND: Immune cell counts in blood in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection may be useful prognostic biomarkers of disease severity, mortality, and response to treatment. OBJECTIVES: To analyze sub-populations of lymphocytes at hospital admission in survivors and deceased from severe pneumonia due to coronavirus disease-2019 (COVID-19). METHODS: We conducted a cross-sectional study of healthcare workers confirmed with SARS-CoV-2 in convalescents (control group) and healthy controls (HC) diagnosed with severe COVID-19. Serum samples were taken at hospital admission and after recovery. Serum samples ≥ 25 days after onset of symptoms were analyzed for lymphocyte subpopulations through flow cytometry. Descriptive statistics, Kruskall-Wallis test, receiver operating characteristic curve, calculation of sensitivity, specificity, predictive values, and Kaplan-Meier analysis were performed. RESULTS: We included 337 patients: 120 HC, 127 convalescents, and 90 severe COVID-19 disease patients (50 survivors, 40 deceased). For T cells, total lymphocytes ≥ 800/µL, CD3+ ≥ 400/µL, CD4+ ≥ 180/µL, CD8+ ≥ 150/µL, B cells CD19+ ≥ 80/µL, and NK ≥ 34/µL subsets were associated with survival in severe COVID-19 disease patients. All subtypes of lymphocytes had higher concentrations in survivors than deceased, but similar between HC and convalescents. Leukocytes ≥ 10.150/µL or neutrophils ≥ 10,000/µL were associated with increased mortality. The neutrophil-to-lymphocyte ratio (NLR) ≥ 8.5 increased the probability of death in severe COVID-19 (odds ratio 11.68). CONCLUSIONS: Total lymphocytes; NLR; and levels of CD3+, CD4+, CD8+, and NK cells are useful as biomarkers of survival or mortality in severe COVID-19 disease and commonly reach normal levels in convalescents.


Assuntos
Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , COVID-19 , Linfopenia , Neutrófilos/patologia , Biomarcadores/sangue , COVID-19/sangue , COVID-19/diagnóstico , COVID-19/mortalidade , COVID-19/terapia , Correlação de Dados , Estudos Transversais , Feminino , Humanos , Estimativa de Kaplan-Meier , Células Matadoras Naturais/patologia , Contagem de Leucócitos/métodos , Linfopenia/sangue , Linfopenia/diagnóstico , Linfopenia/etiologia , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Mortalidade , Valor Preditivo dos Testes , Avaliação de Sintomas/métodos
9.
Eur J Immunol ; 51(6): 1449-1460, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33788264

RESUMO

The pathogenesis of autoimmune complications triggered by SARS-CoV2 has not been completely elucidated. Here, we performed an analysis of the cellular immune status, cell ratios, and monocyte populations of patients with COVID-19 treated in the intensive care unit (ICU) (cohort 1, N = 23) and normal care unit (NCU) (cohort 2, n = 10) compared with control groups: patients treated in ICU for noninfectious reasons (cohort 3, n = 30) and patients treated in NCU for infections other than COVID-19 (cohort 4, n = 21). Patients in cohort 1 presented significant differences in comparison with the other cohorts, including reduced frequencies of lymphocytes, reduced CD8+T-cell count, reduced percentage of activated and intermediate monocytes and an increased B/T8 cell ratio. Over time, patients in cohort 1 who died presented with lower counts of B, T, CD4+ T, CD8+ T-lymphocytes, NK cells, and activated monocytes. The B/T8 ratio was significantly lower in the group of survivors. In cohort 1, significantly higher levels of IgG1 and IgG3 were found, whereas cohort 3 presented higher levels of IgG3 compared to controls. Among many immune changes, an elevated B/T8-cell ratio and a reduced rate of activated monocytes were mainly observed in patients with severe COVID-19. Both parameters were associated with death in cohort 1.


Assuntos
Linfócitos B/imunologia , COVID-19/imunologia , Monócitos/imunologia , SARS-CoV-2/imunologia , Idoso , Anticorpos Antivirais/imunologia , Linfócitos B/patologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , COVID-19/patologia , Feminino , Humanos , Imunoglobulina G/imunologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Monócitos/patologia , Estudos Prospectivos , Índice de Gravidade de Doença
10.
Front Endocrinol (Lausanne) ; 12: 596518, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33776910

RESUMO

Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT04365634. Context: Diabetes mellitus was associated with increased severity and mortality of disease in COVID-19 pneumonia. So far the effect of type 2 diabetes (T2DM) or hyperglycemia on the immune system among COVID-19 disease has remained unclear. Objective: We aim to explore the clinical and immunological features of type 2 diabetes mellitus (T2DM) among COVID-19 patients. Design and Methods: In this retrospective study, the clinical and immunological characteristics of 306 hospitalized confirmed COVID-19 patients (including 129 diabetic and 177 non-diabetic patients) were analyzed. The serum concentrations of laboratory parameters including cytokines and numbers of immune cells were measured and compared between diabetic and non-diabetic groups. Results: Compared with non-diabetic group, diabetic cases more frequently had lymphopenia and hyperglycemia, with higher levels of urea nitrogen, myoglobin, D-dimer and ferritin. Diabetic cases indicated the obviously elevated mortality and the higher levels of cytokines IL-2R, IL-6, IL-8, IL-10, and TNF-α, as well as the distinctly reduced Th1/Th2 cytokines ratios compared with non-diabetic cases. The longitudinal assays showed that compared to that at week 1, the levels of IL-6 and IL-8 were significantly elevated at week 2 after admission in non-survivors of diabetic cases, whereas there were greatly reductions from week 1 to week 2 in survivors of diabetic cases. Compared with survival diabetic patients, non-survival diabetic cases displayed distinct higher serum concentrations of IL-2R, IL-6, IL-8, IL-10, TNF-α, and lower Th1/Th2 cytokines ratios at week 2. Samples from a subset of participants were evaluated by flow cytometry for the immune cells. The counts of peripheral total T lymphocytes, CD4+ T cells, CD8+ T cells and NK cells were markedly lower in diabetic cases than in non-diabetic cases. The non-survivors showed the markedly declined counts of CD8+ T cells and NK cells than survivors. Conclusion: The elevated cytokines, imbalance of Th1/Th2 cytokines ratios and reduced of peripheral numbers of CD8+ T cells and NK cells might contribute to the pathogenic mechanisms of high mortality of COVID-19 patients with T2DM.


Assuntos
COVID-19/imunologia , Diabetes Mellitus Tipo 2/imunologia , Adulto , Idoso , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , COVID-19/sangue , COVID-19/complicações , COVID-19/mortalidade , China/epidemiologia , Citocinas/análise , Citocinas/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/mortalidade , Feminino , Humanos , Hiperglicemia/sangue , Hiperglicemia/complicações , Hiperglicemia/imunologia , Hiperglicemia/mortalidade , Sistema Imunitário/metabolismo , Sistema Imunitário/patologia , Células Matadoras Naturais/patologia , Contagem de Linfócitos , Linfopenia/sangue , Linfopenia/complicações , Linfopenia/imunologia , Linfopenia/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , SARS-CoV-2/imunologia , SARS-CoV-2/fisiologia , Células Th1/patologia , Células Th2/patologia
11.
PLoS Pathog ; 17(1): e1009214, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33465157

RESUMO

The precise role of CD4 T cell turnover in maintaining HIV persistence during antiretroviral therapy (ART) has not yet been well characterized. In resting CD4 T cell subpopulations from 24 HIV-infected ART-suppressed and 6 HIV-uninfected individuals, we directly measured cellular turnover by heavy water labeling, HIV reservoir size by integrated HIV-DNA (intDNA) and cell-associated HIV-RNA (caRNA), and HIV reservoir clonality by proviral integration site sequencing. Compared to HIV-negatives, ART-suppressed individuals had similar fractional replacement rates in all subpopulations, but lower absolute proliferation rates of all subpopulations other than effector memory (TEM) cells, and lower plasma IL-7 levels (p = 0.0004). Median CD4 T cell half-lives decreased with cell differentiation from naïve to TEM cells (3 years to 3 months, p<0.001). TEM had the fastest replacement rates, were most highly enriched for intDNA and caRNA, and contained the most clonal proviral expansion. Clonal proviruses detected in less mature subpopulations were more expanded in TEM, suggesting that they were maintained through cell differentiation. Earlier ART initiation was associated with lower levels of intDNA, caRNA and fractional replacement rates. In conclusion, circulating integrated HIV proviruses appear to be maintained both by slow turnover of immature CD4 subpopulations, and by clonal expansion as well as cell differentiation into effector cells with faster replacement rates.


Assuntos
Antirretrovirais/uso terapêutico , Linfócitos T CD4-Positivos/patologia , Diferenciação Celular , Infecções por HIV/virologia , HIV-1/imunologia , Carga Viral , Replicação Viral , Adulto , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/virologia , Estudos de Casos e Controles , DNA Viral/análise , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Infecções por HIV/patologia , HIV-1/efeitos dos fármacos , HIV-1/genética , Humanos , Masculino , Pessoa de Meia-Idade
12.
Cell Biochem Funct ; 39(3): 423-431, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33401342

RESUMO

In this pilot study, we explored the immune phenotype of patients with severe obesity and comorbid depressive symptoms compared to non-depressed patients with obesity and normal-weight controls. Immune cell subsets were analysed by flow cytometry and depressive symptoms assessed using the Patient Health Questionnaire (PHQ-9). Cell frequencies were correlated with depressive symptom scores and waist-to-hip ratio (WHR). Patients with obesity and comorbid depression showed significantly lower numbers of circulating cytotoxic natural killer cells, dendritic cells and CD8+ effector memory T cells, compared to normal-weight controls. Regulatory T cells and CD4+ central memory T cells were increased compared to non-depressed patients with obesity and compared to normal-weight controls, respectively. Frequencies of cytotoxic natural killer cells and CD4+ central memory T cells significantly correlated with PHQ-9 scores, but not with WHR. Reduced numbers of dendritic cells were observed in both patient groups with obesity and correlated with PHQ-9 scores and WHR. These findings provide evidence for an altered immune composition in comorbid obesity and depression, supporting a pathobiological overlap between the two disorders.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Depressão/imunologia , Memória Imunológica , Obesidade Mórbida/imunologia , Adulto , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Células Dendríticas/patologia , Depressão/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade Mórbida/patologia , Projetos Piloto , Inquéritos e Questionários
13.
Scand J Immunol ; 93(4): e13006, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33275792

RESUMO

Tumour-infiltrating mast cells (TIMs) have been reported to play functional roles in the tumour microenvironment. However, controversial evidences exist regarding their impact in different cancers. In order to study their role in metastatic renal cell carcinoma (mRCC), we have investigated the prognostic value of TIMs and their association with tumour-infiltrating lymphocytes (TILs) in patients with mRCC treated with sunitinib or sorafenib. Baseline clinical characteristics and follow-up data were collected from 231 patients with mRCC; TIMs (mast cells density positive to tryptase), along with CD8+ and CD4+ TILs, were evaluated by immunohistochemistry using a tissue microarray. The log-rank test and univariate and multivariate COX regression models were used for survival analyses. Our results revealed that patients with high mast cell density had significantly better overall and progression-free survival (OS, P = .008, and PFS, P = .016, respectively) than those with low mast cell density. Additionally, multivariate COX regression analyses identified TIMs as an independent prognostic factor for OS (HR = 0.624, 95% CI: 0.420-0.927, P = .020) and PFS (HR = 0.658, 95% CI: 0.466-0.930, P = .019). Further, combining TIMs with the International mRCC Database Consortium (IMDC) risk model achieved statistically significant and better predictive ability for one- and two-year OS (P = .002 and P = .004, respectively). Moreover, the cases with high mast cell density were associated with a high density of CD8+ and CD4+ TILs (P = .008 and P = .001, respectively). Thus, better OS in patients with mRCC exhibiting a high mast cell density population may be attributed to the co-existence of CD8+ and CD4+ TILs, which have anti-tumour effects on activation status.


Assuntos
Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Linfócitos do Interstício Tumoral/patologia , Mastócitos/patologia , Antineoplásicos/uso terapêutico , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/patologia , Carcinoma de Células Renais/tratamento farmacológico , Contagem de Células/métodos , Feminino , Humanos , Neoplasias Renais/tratamento farmacológico , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Masculino , Mastócitos/efeitos dos fármacos , Pessoa de Meia-Idade , Prognóstico , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Sorafenibe/uso terapêutico , Sunitinibe/uso terapêutico , Análise de Sobrevida , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/fisiologia
14.
Biochem Biophys Res Commun ; 534: 34-40, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33310185

RESUMO

Abnormal crosstalk between gut immune and the liver was involved in nonalcoholic steatohepatitis (NASH). Mice with methionine choline-deficient (MCD) diet-induced NASH presented an imbalance of pro-(IL-6 and IFN-γ) and anti-inflammatory cytokines (IL-10) in the intestine. We also clarified that the ratio of CD4+ T cells and found that the NASH mesenteric lymph node (MLN) presents decreased numbers of CD4+Th17 cells but increased numbers of CD4+CD8+FoxP3+ regulatory T cells (Tregs). Furthermore, the intestinal immune imbalance in NASH was attributed to impaired gut chemokine receptor 9 (CCR9)/chemokine ligand 25 (CCL25) signalling, which is a crucial pathway for immune cell homing in the gut. We also demonstrated that CD4+CCR9+ T cell homing was dependent on CCL25 and that the numbers and migration abilities of CD4+CCR9+ T cells were reduced in NASH. Interestingly, the analysis of dendritic cell (DC) subsets showed that the numbers and retinal dehydrogenase (RALDH) activity of CD103+CD11b+ DCs were decreased and that the ability of these cells to upregulate CD4+ T cell CCR9 expression was damaged in NASH. Taken together, impaired intestinal CCR9/CCL25 signalling induced by CD103+CD11b+ DC dysfunction contributes to the gut immune imbalance observed in NASH.


Assuntos
Quimiocinas CC/metabolismo , Células Dendríticas/imunologia , Intestinos/imunologia , Hepatopatia Gordurosa não Alcoólica/imunologia , Receptores CCR/metabolismo , Alanina Transaminase/sangue , Animais , Antígenos CD/imunologia , Antígenos CD/metabolismo , Aspartato Aminotransferases/sangue , Antígeno CD11b/imunologia , Antígeno CD11b/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Quimiocinas CC/genética , Deficiência de Colina/complicações , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Cadeias alfa de Integrinas/imunologia , Cadeias alfa de Integrinas/metabolismo , Intestinos/fisiopatologia , Masculino , Metionina/deficiência , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo , Receptores CCR/genética , Transdução de Sinais
15.
Cell Death Dis ; 11(12): 1030, 2020 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-33268822

RESUMO

Telomere erosion and mitochondrial dysfunction are prominent features of aging cells with progressive declines of cellular functions. Whether telomere injury induces mitochondrial dysfunction in human T lymphocytes, the major component of adaptive host immunity against infection and malignancy, remains unclear. We have recently shown that disruption of telomere integrity by KML001, a telomere-targeting drug, induces T cell senescence and apoptosis via the telomeric DNA damage response (DDR). In this study, we used KML001 to further investigate the role and mechanism of telomere injury in mitochondrial dysregulation in aging T cells. We demonstrate that targeting telomeres by KML001 induces mitochondrial dysfunction, as evidenced by increased mitochondrial swelling and decreased mitochondrial membrane potential, oxidative phosphorylation, mitochondrial DNA content, mitochondrial respiration, oxygen consumption, glycolysis, and ATP energy production. Mechanistically, we found that the KML001-induced telomeric DDR activated p53 signaling, which in turn repressed the expression of peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) and nuclear respiratory factor 1 (NRF-1), leading to T cell mitochondrial dysfunction. These results, forging a direct link between telomeric and mitochondrial biology, shed new light on the human T cell aging network, and demonstrate that the p53-PGC-1α-NRF-1 axis contributes to mitochondrial dysfunction in the setting of telomeric DDR. This study suggests that targeting this axis may offer an alternative, novel approach to prevent telomere damage-mediated mitochondrial and T cell dysfunctions to combat a wide range of immune aging-associated human diseases.


Assuntos
Arsenitos/toxicidade , Linfócitos T CD4-Positivos/patologia , Mitocôndrias/patologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Transdução de Sinais , Compostos de Sódio/toxicidade , Telômero/patologia , Proteína Supressora de Tumor p53/metabolismo , Linfócitos T CD4-Positivos/efeitos dos fármacos , Dano ao DNA , Reparo do DNA/efeitos dos fármacos , Reparo do DNA/genética , Regulação para Baixo/genética , Redes Reguladoras de Genes/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Humanos , Mitocôndrias/efeitos dos fármacos , Biogênese de Organelas , Transdução de Sinais/efeitos dos fármacos , Telômero/efeitos dos fármacos , Regulação para Cima/genética
16.
Nucleus ; 11(1): 117-131, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33356851

RESUMO

The regulatory circuits that define developmental decisions of thymocytes are still incompletely resolved. SATB1 protein is predominantly expressed at the CD4+CD8+cell stage exerting its broad transcription regulation potential with both activatory and repressive roles. A series of post-translational modifications and the presence of potential SATB1 protein isoforms indicate the complexity of its regulatory potential. The most apparent mechanism of its involvement in gene expression regulation is via the orchestration of long-range chromatin loops between genes and their regulatory elements. Multiple SATB1 perturbations in mice uncovered a link to autoimmune diseases while clinical investigations on cancer research uncovered that SATB1 has a promoting role in several types of cancer and can be used as a prognostic biomarker. SATB1 is a multivalent tissue-specific factor with a broad and yet undetermined regulatory potential. Future investigations on this protein could further uncover T cell-specific regulatory pathways and link them to (patho)physiology.


Assuntos
Doenças Autoimunes/metabolismo , Biomarcadores Tumorais/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Cromatina/metabolismo , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/patologia , Biomarcadores Tumorais/genética , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Cromatina/genética , Cromatina/patologia , Humanos , Proteínas de Ligação à Região de Interação com a Matriz/genética , Camundongos , Proteínas de Neoplasias/genética , Neoplasias/genética , Neoplasias/patologia
17.
Sci Rep ; 10(1): 20363, 2020 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-33230147

RESUMO

Osteoclasts (OCs) and much less dendritic cells (DCs) induce significant expansion and functional activation of NK cells, and furthermore, the OC-expanded NK cells preferentially increase the expansion and activation of CD8+ T cells by targeting CD4+ T cells. When autologous OCs were used to expand patient NK cells much lower percentages of expanded CD8+ T cells, decreased numbers of expanded NK cells and decreased functions of NK cells could be observed, and the addition of allogeneic healthy OCs increased the patients' NK function. Mechanistically, OC-expanded NK cells were found to lyse CD4+ T cells but not CD8+ T cells suggesting potential selection of CD8+ T cells before their expansion by OC activated NK cells. In agreement, Increased IFN-γ secretion, and NK cell-mediated cytotoxicity and higher percentages of CD8+ T cells, in various tissue compartments of oral tumor-bearing hu-BLT mice in response to immunotherapy by OC-expanded NK cells were observed. Thus, our results indicate an important relationship between NK and CD8+ T cells.


Assuntos
Carcinoma de Células Escamosas/terapia , Citotoxicidade Imunológica , Imunoterapia/métodos , Células Matadoras Naturais/imunologia , Neoplasias Bucais/terapia , Osteoclastos/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Comunicação Celular/imunologia , Proliferação de Células , Técnicas de Cocultura , Células Dendríticas/imunologia , Células Dendríticas/patologia , Humanos , Imunofenotipagem , Interferon gama/biossíntese , Interferon gama/imunologia , Células Matadoras Naturais/patologia , Células Matadoras Naturais/transplante , Ativação Linfocitária , Contagem de Linfócitos , Camundongos , Camundongos Transgênicos , Neoplasias Bucais/imunologia , Neoplasias Bucais/patologia , Osteoclastos/patologia , Cultura Primária de Células , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Viruses ; 12(11)2020 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-33182268

RESUMO

BACKGROUND: COVID-19 pathophysiology and the predictive factors involved are not fully understood, but lymphocytes dysregulation appears to play a role. This paper aims to evaluate lymphocyte subsets in the pathophysiology of COVID-19 and as predictive factors for severe disease. PATIENT AND METHODS: A prospective cohort study of patients with SARS-CoV-2 bilateral pneumonia recruited at hospital admission. Demographics, medical history, and data regarding SARS-CoV-2 infection were recorded. Patients systematically underwent complete laboratory tests, including parameters related to COVID-19 as well as lymphocyte subsets study at the time of admission. Severe disease criteria were established at admission, and patients were classified on remote follow-up according to disease evolution. Linear regression models were used to assess associations with disease evolution, and Receiver Operating Characteristic (ROC) and the corresponding Area Under the Curve (AUC) were used to evaluate predictive values. RESULTS: Patients with critical COVID-19 showed a decrease in CD3+CD4+ T cells count compared to non-critical (278 (485 IQR) vs. 545 (322 IQR)), a decrease in median CD4+/CD8+ ratio (1.7, (1.7 IQR) vs. 3.1 (2.4 IQR)), and a decrease in median CD4+MFI (21,820 (4491 IQR) vs. 26,259 (3256 IQR)), which persisted after adjustment. CD3+CD8+ T cells count had a high correlation with time to hospital discharge (PC = -0.700 (-0.931, -0.066)). ROC curves for predictive value showed lymphocyte subsets achieving the best performances, specifically CD3+CD4+ T cells (AUC = 0.756), CD4+/CD8+ ratio (AUC = 0.767), and CD4+MFI (AUC = 0.848). CONCLUSIONS: A predictive value and treatment considerations for lymphocyte subsets are suggested, especially for CD3CD4+ T cells. Lymphocyte subsets determination at hospital admission is recommended.


Assuntos
Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , COVID-19/diagnóstico , Subpopulações de Linfócitos/patologia , SARS-CoV-2/patogenicidade , Idoso , Área Sob a Curva , Biomarcadores/análise , Relação CD4-CD8/estatística & dados numéricos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , COVID-19/imunologia , COVID-19/patologia , COVID-19/virologia , Progressão da Doença , Feminino , Humanos , Pulmão , Contagem de Linfócitos , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/virologia , Masculino , Pessoa de Meia-Idade , Alta do Paciente/estatística & dados numéricos , Prognóstico , Estudos Prospectivos , Curva ROC , SARS-CoV-2/imunologia , Índice de Gravidade de Doença
19.
Front Immunol ; 11: 535784, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33193306

RESUMO

Human CD21low B cells are expanded in autoimmune (AI) diseases and display a unique phenotype with high expression of co-stimulatory molecules, compatible with a potential role as antigen-presenting cells (APCs). Thus, we addressed the co-stimulatory capacity of naïve-like, IgM-memory, switched memory and CD27negIgDneg memory CD21low B cells in allogenic co-cultures with CD4 T cells. CD21low B cells of patients with AI disorders expressed high levels of not only CD86, CD80, and HLA-DR (memory B cells) but also PD-L1 ex vivo and efficiently co-stimulated CD4 T cells of healthy donors (HD), as measured by upregulation of CD25, CD69, inducible co-stimulator (ICOS), and programmed cell death protein 1 (PD-1) and induction of cytokines. While the co-stimulatory capacity of the different CD21low B-cell populations was over all comparable to CD21pos counterparts of patients and HD, especially switched memory CD21low B cells lacked the increased capacity of CD21pos switched memory B-cells to induce high expression of ICOS, IL-2, IL-10, and IFN-γ. Acknowledging the limitation of the in vitro setting, CD21low B cells do not seem to preferentially support a specific Th effector response. In summary, our data implies that CD21low B cells of patients with AI diseases can become competent APCs and may, when enriched for autoreactive B-cell receptors (BCR), potentially contribute to AI reactions as cognate interaction partners of autoreactive T cells at sites of inflammation.


Assuntos
Apresentação do Antígeno , Doenças Autoimunes/imunologia , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Memória Imunológica , Receptores de Complemento 3d/imunologia , Idoso , Doenças Autoimunes/patologia , Linfócitos B/patologia , Linfócitos T CD4-Positivos/patologia , Citocinas/imunologia , Feminino , Regulação da Expressão Gênica/imunologia , Humanos , Masculino , Pessoa de Meia-Idade
20.
Sci Rep ; 10(1): 19927, 2020 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-33199774

RESUMO

Published articles support the effect of chemotherapy in the immune environment of tumors, including lung carcinomas. The role of CD4 + T-cells is crucial for expansion and accumulation of other antigen-specific immune cells, and the participation of CD8 + cells in tumor killing activity has been confirmed by many studies. However, little is known about the effect of chemotherapy on the healthy lung parenchyma from lung cancer patients, and whether there are differences between the different chemotherapy compounds used to treat this patient population. The aim of our study was to explore the effect of chemotherapy on CD4 + and CD8 + cells in the bronchoalveolar lavage fluid (BALF) of the healthy lung in patients treated with standard chemotherapy regimens. Fifteen patients underwent BAL, in the healthy lung before and after six chemotherapy courses. Platinum-based regimens included vinolerbine (VN) in 6 patients, gemcitabine (GEM) in 4 patients and etoposide (EP) in 5 patients. All patients but one were males and smokers (93%). The median age of patients was 56 years (42-75). No significant difference was noted in the patients' age between the three treated groups. Furthermore, between the three groups, no significant changes in the means of CD4 + and CD8 + cells were noted. However, when we compared the mean CD4 + cells before and after chemotherapy within each group, changes were noted when comparing VN before versus after (p = 0.05), GEM before versus after (p = 0.03), and EP before versus after (p = 0.036). In our pilot study, changes were noted in BALF CD4 + cells for the three most applied regimens at the normal lung parenchyma.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Líquido da Lavagem Broncoalveolar/imunologia , Linfócitos T CD4-Positivos/imunologia , Neoplasias Pulmonares/tratamento farmacológico , Pulmão/imunologia , Relação CD4-CD8 , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/patologia , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Etoposídeo/administração & dosagem , Feminino , Seguimentos , Humanos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Prognóstico , Estudos Prospectivos , Vinorelbina/administração & dosagem
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