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1.
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
/imunologia , Diabetes Mellitus Tipo 2/imunologia , Adulto , Idoso , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , /complicações , 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 , /fisiologia , Células Th1/patologia , Células Th2/patologia
2.
Signal Transduct Target Ther ; 6(1): 113, 2021 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-33686064

RESUMO

The adaptive immunity that protects patients from coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is not well characterized. In particular, the asymptomatic patients have been found to induce weak and transient SARS-CoV-2 antibody responses, but the underlying mechanisms remain unknown; meanwhile, the protective immunity that guide the recovery of these asymptomatic patients is elusive. Here, we characterized SARS-CoV-2-specific B-cell and T-cell responses in 10 asymptomatic patients and 64 patients with other disease severity (mild, n = 10, moderate, n = 32, severe, n = 12) and found that asymptomatic or mild symptomatic patients failed to mount virus-specific germinal center (GC) B cell responses that result in robust and prolonged humoral immunity, assessed by GC response indicators including follicular helper T (TFH) cell and memory B cell responses as well as serum CXCL13 levels. Alternatively, these patients mounted potent virus-specific TH1 and CD8+ T cell responses. In sharp contrast, patients of moderate or severe disease induced vigorous virus-specific GC B cell responses and associated TFH responses; however, the virus-specific TH1 and CD8+ T cells were minimally induced in these patients. These results, therefore, uncovered the protective immunity in asymptomatic patients and also revealed the strikingly dichotomous and incomplete humoral and cellular immune responses in COVID-19 patients with different disease severity, providing important insights into rational design of effective COVID-19 vaccines.


Assuntos
Imunidade Adaptativa , Linfócitos B/imunologia , Linfócitos T CD8-Positivos/imunologia , /imunologia , Células Th1/imunologia , Adulto , Linfócitos B/patologia , Linfócitos T CD8-Positivos/patologia , Feminino , Humanos , Masculino , Índice de Gravidade de Doença , Células Th1/patologia
3.
J Immunol ; 206(7): 1478-1482, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33558375

RESUMO

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has become pandemic. Cytokine release syndrome occurring in a minority of SARS-CoV-2 infections is associated with severe disease and high mortality. We profiled the composition, activation, and proliferation of T cells in 20 patients with severe or critical COVID-19 and 40 matched healthy controls by flow cytometry. Unsupervised hierarchical cluster analysis based on 18 T cell subsets resulted in separation of healthy controls and COVID-19 patients. Compared to healthy controls, patients suffering from severe and critical COVID-19 had increased frequencies of activated and proliferating CD38+Ki67+ CD4+ and CD8+ T cells, suggesting active antiviral T cell defense. Frequencies of CD38+Ki67+ Th1 and CD4+ cells correlated negatively with plasma IL-6. Thus, our data suggest that patients suffering from COVID-19 have a distinct T cell composition that is potentially modulated by IL-6.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Imunidade Celular , Células Th1/imunologia , ADP-Ribosil Ciclase 1/imunologia , Adulto , Linfócitos T CD8-Positivos/patologia , /patologia , Feminino , Humanos , Imunofenotipagem , Interleucina-6/imunologia , Antígeno Ki-67/imunologia , Masculino , Glicoproteínas de Membrana/imunologia , Pandemias , Estudos Retrospectivos , Células Th1/patologia
4.
Methods Mol Biol ; 2223: 217-236, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33226598

RESUMO

Cellular inflammation, with elevated levels of Th1/Th2 cytokines, airway mucus hypersecretion, and thickening of the airway smooth muscle, are characteristic features of the allergic lung. Assessment of pathophysiological changes in allergic lungs serves as an important tool to determine disease progression and understand the underlying mechanisms of pathogenesis. This can be achieved by evaluating the lung tissue for inflammation and airway structural changes along with the measurement of important pro-inflammatory mediators such as Th1/Th2 cytokines and eotaxins. This chapter describes procedures to histologically evaluate inflammatory and pathological changes observed during allergic airway inflammation using lung tissue from mice.


Assuntos
Alérgenos/administração & dosagem , Asma/imunologia , Pulmão/imunologia , Hipersensibilidade Respiratória/imunologia , Coloração e Rotulagem/métodos , Equilíbrio Th1-Th2 , Animais , Asma/induzido quimicamente , Asma/metabolismo , Asma/patologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/biossíntese , Citocinas/imunologia , Progressão da Doença , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Microtomia/métodos , Muco/imunologia , Miócitos de Músculo Liso/imunologia , Miócitos de Músculo Liso/patologia , Inclusão em Parafina/métodos , Hipersensibilidade Respiratória/induzido quimicamente , Hipersensibilidade Respiratória/metabolismo , Hipersensibilidade Respiratória/patologia , Células Th1/imunologia , Células Th1/patologia , Células Th2/imunologia , Células Th2/patologia
5.
Sci Rep ; 10(1): 7396, 2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32355188

RESUMO

A vaccine based on outer membrane vesicles of pertussis (omvPV) is protective in a mouse-challenge model and induces a broad antibody and mixed Th1/Th2/Th17 response against multiple antigens following subcutaneous immunization. However, this route did not result in mucosal immunity and did not prevent nasopharyngeal colonization. In this study, we explored the potential of intranasal immunization with omvPV. Only intranasal immunization induced strong mucosal immune responses that encompasses enhanced pulmonary and nasal IgA antibody levels, mainly directed against Vag8 and LPS. Furthermore, high numbers of IgA- and IgG-producing plasma cells were detected as well as lung-resident IgA memory B-cells. Finally, only intranasal immunization induced pulmonary Th1/Th17-related cytokine responses. The magnitude and type of systemic immunity was comparable between both routes and included high systemic IgG antibody levels, strong IgG-producing plasma cell responses, memory B-cells residing in the spleen and systemic Th1/Th2/Th17-related cytokine responses. Importantly, only intranasal immunization prevented colonization in both the lungs and the nasal cavity. In conclusion, intranasal omvPV immunization induces mucosal IgA and Th17-mediated responses without influencing the systemic immunity profile. These responses resulted in prevention of Bordetella pertussis colonization in the respiratory tract, including the nasal cavity, thereby potentially preventing transmission.


Assuntos
Anticorpos Antibacterianos/imunologia , Bordetella pertussis/imunologia , Micropartículas Derivadas de Células/imunologia , Imunidade nas Mucosas , Imunoglobulina A/imunologia , Vacina contra Coqueluche/imunologia , Células Th17/imunologia , Coqueluche/prevenção & controle , Administração Intranasal , Animais , Linfócitos B/imunologia , Linfócitos B/patologia , Feminino , Memória Imunológica , Camundongos , Camundongos Endogâmicos BALB C , Células Th1/imunologia , Células Th1/patologia , Células Th17/patologia , Coqueluche/imunologia , Coqueluche/patologia
6.
Nat Immunol ; 21(6): 671-683, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32424366

RESUMO

Urinary tract infections (UTIs) typically evoke prompt and vigorous innate bladder immune responses, including extensive exfoliation of the epithelium. To explain the basis for the extraordinarily high recurrence rates of UTIs, we examined adaptive immune responses in mouse bladders. We found that, following each bladder infection, a highly T helper type 2 (TH2)-skewed immune response directed at bladder re-epithelialization is observed, with limited capacity to clear infection. This response is initiated by a distinct subset of CD301b+OX40L+ dendritic cells, which migrate into the bladder epithelium after infection before trafficking to lymph nodes to preferentially activate TH2 cells. The bladder epithelial repair response is cumulative and aberrant as, after multiple infections, the epithelium was markedly thickened and bladder capacity was reduced relative to controls. Thus, recurrence of UTIs and associated bladder dysfunction are the outcome of the preferential focus of the adaptive immune response on epithelial repair at the expense of bacterial clearance.


Assuntos
Cistite/etiologia , Cistite/metabolismo , Ativação Linfocitária/imunologia , Membrana Mucosa/imunologia , Membrana Mucosa/metabolismo , Células Th2/imunologia , Células Th2/metabolismo , Animais , Carga Bacteriana , Biomarcadores , Linhagem Celular , Cistite/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Knockout , Membrana Mucosa/patologia , Células Th1/imunologia , Células Th1/metabolismo , Células Th1/patologia , Infecções Urinárias/etiologia , Infecções Urinárias/metabolismo , Infecções Urinárias/microbiologia , Cicatrização/genética , Cicatrização/imunologia
7.
J Virol ; 94(15)2020 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-32461311

RESUMO

Cellular immunotherapy is a proven approach against Epstein-Barr virus (EBV)-driven lymphoproliferation in recipients of hematopoietic stem cells. Extending the applicability and improving the response rates of such therapy demands improving the knowledge base. We studied 23 healthy donors for specific CD4+ T cell responses against the viral tegument protein BNRF1 and found such T cells in all seropositive donors, establishing BNRF1 as an important immune target in EBV. We identified 18 novel immune epitopes from BNRF1, all of them generated by natural processing of the full-length protein from virus-transformed lymphoblastoid cell lines (LCL). BNRF1-specific CD4+ T cells were measured directly ex vivo by a cytokine-based method, thus providing a tool to study the interaction between immunity and infection in health and disease. T cells of the cytotoxic Th1 type inhibited the proliferation of autologous LCL as well as virus-driven transformation. We infer that they are important in limiting reactivations to subclinical levels during health and reducing virus propagation during disease. The information obtained from this work will feed into data sets that are indispensable in the design of patient-tailored immunotherapeutic approaches, thereby enabling the stride toward broader application of T cell therapy and improving clinical response rates.IMPORTANCE Epstein-Barr virus is carried by most humans and can cause life-threatening diseases. Virus-specific T cells have been used in different clinical settings with variable success rates. One way to improve immunotherapy is to better suit T cell generation protocols to viral targets available in different diseases. BNRF1 is present in viral particles and therefore likely available as a target for T cells in diseases with virus amplification. Here, we studied healthy Epstein-Barr virus (EBV) carriers for BNRF1 immunogenicity and report our results indicating BNRF1 to be a dominant target of the EBV-specific CD4+ T cell response. BNRF1-specific CD4+ T cells were found to be cytotoxic and capable of limiting EBV-driven B cell transformation in vitro The findings of this work contribute to forwarding our understanding of host-virus interactions during health and disease and are expected to find direct application in the generation of specific T cells for immunotherapy.


Assuntos
Epitopos de Linfócito T/imunologia , Infecções por Vírus Epstein-Barr/imunologia , Herpesvirus Humano 4/imunologia , Células Th1/imunologia , Proteínas do Envelope Viral/imunologia , Linhagem Celular Transformada , Infecções por Vírus Epstein-Barr/patologia , Infecções por Vírus Epstein-Barr/terapia , Feminino , Humanos , Imunoterapia , Masculino , Células Th1/patologia
8.
Biochem Biophys Res Commun ; 526(4): 1157-1163, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32321642

RESUMO

The pathogenesis of inflammation bowel disease (IBD) involves exaggerated effector T cell responses and impaired regulatory T cell functions. We previously found that sauchinone (SAU) ameliorated experimental colitis via facilitating Th17 cell production of IL-10, but how SAU regulated Th17 cell differentiation remains unknown. MicroRNAs (miR) have been recognized as a crucial regulator of T cell biology and play a considerable role in IBD. Here, we demonstrated that SAU significantly suppressed miR-340 expression in Th17 cells, and enforced miR-340 expression abrogated SAU inhibition of Th17 differentiation. miR-340 itself was found to facilitate Th17 differentiation, especially the pathogenic "Th1-like" subset. In human IBD, miR-340 was intimately correlated with the disease severity. SAU markedly decreased miR-340 in the inflamed mucosa tissues from IBD patients. Scaffold/matrix-associated region-binding protein 1 (SMAR1) was identified as a target gene of miR-340. We revealed that blockade of miR-340 significantly reduced mucosal damage and Th17 responses in the lamina propria in a mouse colitis model. Our findings suggest that miR-340 negatively affects SAU inhibition of Th17 differentiation and might play a crucial role in the regulation of pathogenic "Th1-like" Th17 cell generation, which might serve as a novel therapeutic target of IBD.


Assuntos
Benzopiranos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Dioxóis/farmacologia , Inflamação/imunologia , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Intestinos/patologia , MicroRNAs/metabolismo , Células Th17/patologia , Sequência de Bases , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Colite/induzido quimicamente , Colite/imunologia , Colite/patologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Suscetibilidade a Doenças , Regulação para Baixo/efeitos dos fármacos , Fatores de Transcrição Forkhead/metabolismo , Humanos , MicroRNAs/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Índice de Gravidade de Doença , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th1/efeitos dos fármacos , Células Th1/patologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Ácido Trinitrobenzenossulfônico , Regulação para Cima/efeitos dos fármacos
9.
PLoS Pathog ; 16(3): e1008377, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32163525

RESUMO

The recombinant Canarypox ALVAC-HIV/gp120/alum vaccine regimen was the first to significantly decrease the risk of HIV acquisition in humans, with equal effectiveness in both males and females. Similarly, an equivalent SIV-based ALVAC vaccine regimen decreased the risk of virus acquisition in Indian rhesus macaques of both sexes following intrarectal exposure to low doses of SIVmac251. Here, we demonstrate that the ALVAC-SIV/gp120/alum vaccine is also efficacious in female Chinese rhesus macaques following intravaginal exposure to low doses of SIVmac251 and we confirm that CD14+ classical monocytes are a strong correlate of decreased risk of virus acquisition. Furthermore, we demonstrate that the frequency of CD14+ cells and/or their gene expression correlates with blood Type 1 CD4+ T helper cells, α4ß7+ plasmablasts, and vaginal cytocidal NKG2A+ cells. To better understand the correlate of protection, we contrasted the ALVAC-SIV vaccine with a NYVAC-based SIV/gp120 regimen that used the identical immunogen. We found that NYVAC-SIV induced higher immune activation via CD4+Ki67+CD38+ and CD4+Ki67+α4ß7+ T cells, higher SIV envelope-specific IFN-γ producing cells, equivalent ADCC, and did not decrease the risk of SIVmac251 acquisition. Using the systems biology approach, we demonstrate that specific expression profiles of plasmablasts, NKG2A+ cells, and monocytes elicited by the ALVAC-based regimen correlated with decreased risk of virus acquisition.


Assuntos
Células Matadoras Naturais/imunologia , Monócitos/imunologia , Vacinas contra a SAIDS/imunologia , Vírus da Imunodeficiência Símia/imunologia , Células Th1/imunologia , Vacinação , Vagina/imunologia , Vacinas Virais/imunologia , Animais , Feminino , Células Matadoras Naturais/patologia , Macaca mulatta , Monócitos/patologia , Células Th1/patologia
10.
PLoS Pathog ; 16(3): e1008435, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32210480

RESUMO

A striking feature of human visceral leishmaniasis (VL) is chronic inflammation in the spleen and liver, and VL patients present increased production levels of multiple inflammatory mediators, which contribute to tissue damage and disease severity. Here, we combined an experimental model with the transcriptional profile of human VL to demonstrate that the TLR4-IFN-ß pathway regulates the chronic inflammatory process and is associated with the asymptomatic form of the disease. Tlr4-deficient mice harbored fewer parasites in their spleen and liver than wild-type mice. TLR4 deficiency enhanced the Th1 immune response against the parasite, which was correlated with an increased activation of dendritic cells (DCs). Gene expression analyses demonstrated that IRF1 and IFN-ß were expressed downstream of TLR4 after infection. Accordingly, IRF1- and IFNAR-deficient mice harbored fewer parasites in the target organs than wild-type mice due to having an increased Th1 immune response. However, the absence of TLR4 or IFNAR increased the serum transaminase levels in infected mice, indicating the presence of liver damage in these animals. In addition, IFN-ß limits IFN-γ production by acting directly on Th1 cells. Using RNA sequencing analysis of human samples, we demonstrated that the transcriptional signature for the TLR4 and type I IFN (IFN-I) pathways was positively modulated in asymptomatic subjects compared with VL patients and thus provide direct evidence demonstrating that the TLR4-IFN-I pathway is related to the nondevelopment of the disease. In conclusion, our results demonstrate that the TLR4-IRF1 pathway culminates in IFN-ß production as a mechanism for dampening the chronic inflammatory process and preventing immunopathology development.


Assuntos
Fator Regulador 1 de Interferon/imunologia , Interferon beta/imunologia , Leishmania infantum/imunologia , Leishmaniose Visceral/imunologia , Células Th1/imunologia , Receptor 4 Toll-Like/imunologia , Animais , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Fator Regulador 1 de Interferon/genética , Interferon beta/genética , Leishmaniose Visceral/genética , Leishmaniose Visceral/patologia , Camundongos , Camundongos Knockout , Células Th1/patologia , Receptor 4 Toll-Like/genética
11.
Int J Nanomedicine ; 15: 17-29, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32021162

RESUMO

Background: Honokiol has been reported to possess anti-inflammatory and neuroprotective activities. However, the poor aqueous solubility of honokiol limits its clinical application for systemic administration. Purpose: This study aims to develop a novel formulation of nanosome-encapsulated honokiol (NHNK) for intravenous therapy against mouse experimental autoimmune encephalomyelitis (EAE) that mimics human multiple sclerosis. Methods: Nanosomes and NHNK were prepared by using an ultra-high pressure homogenization (UHPH) method. Mice were treated with NHNK or empty nanosomes during the peak phase of EAE symptoms. Symptoms of EAE were monitored and samples of the spinal cord were obtained for histopathological examinations. Results: The stock of NHNK containing honokiol in the nanosome formulation, which showed the structure of single phospholipid bilayer membranes, was well formulated with the particle size of 48.0 ± 0.1 nm and the encapsulation efficiency 58.1 ± 4.2%. Intravenous administration of NHNK ameliorated the severity of EAE accompanied by a significant reduction of demyelination and inflammation in the spinal cord. Furthermore, NHNK decreased the number of IL-6+, Iba-1+TNF +, Iba-1+IL-12 p40+, and CD3+IFN-γ+ cells infiltrating the spinal cord. Conclusion: The UHPH method simplified the preparation of NHNK with uniformly distributed nanosize and high encapsulation efficiency. Intravenous administration of NHNK ameliorated the severity of EAE by suppressing the infiltration of activated microglia and Th1 cells into the spinal cord. Collectively, these results suggest that the formulation of NHNK is a prospective therapeutic approach for inflammatory CNS diseases, such as multiple sclerosis.


Assuntos
Compostos de Bifenilo/administração & dosagem , Encefalomielite Autoimune Experimental/tratamento farmacológico , Lignanas/administração & dosagem , Nanoestruturas/administração & dosagem , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Encefalomielite Autoimune Experimental/etiologia , Feminino , Injeções Intravenosas , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/patologia , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/etiologia , Mielite/tratamento farmacológico , Mielite/etiologia , Nanoestruturas/química , Fármacos Neuroprotetores/farmacologia , Medula Espinal/patologia , Células Th1/efeitos dos fármacos , Células Th1/patologia
12.
J Biomed Sci ; 27(1): 20, 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31906962

RESUMO

BACKGROUND: Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB), affecting approximately one third of the world's population. Development of an adequate immune response will determine disease progression or progress to chronic infection. Risk of developing TB among human immunodeficiency virus (HIV)-coinfected patients (HIV-TB) is 20-30 times higher than those without HIV infection, and a synergistic interplay between these two pathogens accelerates the decline in immunological functions. TB treatment in HIV-TB coinfected persons is challenging and it has a prolonged duration, mainly due to the immune system failure to provide an adequate support for the therapy. Therefore, we aimed to study the role of the hormone 7-oxo-dehydroepiandrosterone (7-OD) as a modulator of anti-tuberculosis immune responses in the context of HIV-TB coinfection. METHODS: A cross-sectional study was conducted among HIV-TB patients and healthy donors (HD). We characterized the ex vivo phenotype of CD4 + T cells and also evaluated in vitro antigen-specific responses by Mtb stimulation of peripheral blood mononuclear cells (PBMCs) in the presence or absence of 7-OD. We assessed lymphoproliferative activity, cytokine production and master transcription factor profiles. RESULTS: Our results show that HIV-TB patients were not able to generate successful anti-tubercular responses in vitro compared to HD, as reduced IFN-γ/IL-10 and IFN-γ/IL-17A ratios were observed. Interestingly, treatment with 7-OD enhanced Th1 responses by increasing Mtb-induced proliferation and the production of IFN-γ and TNF-α over IL-10 levels. Additionally, in vitro Mtb stimulation augmented the frequency of cells with a regulatory phenotype, while 7-OD reduced the proportion of these subsets and induced an increase in CD4 + T-bet+ (Th1) subpopulation, which is associated with clinical data linked to an improved disease outcome. CONCLUSIONS: We conclude that 7-OD modifies the cytokine balance and the phenotype of CD4 + T cells towards a more favorable profile for mycobacteria control. These results provide new data to delineate novel treatment approaches as co-adjuvant for the treatment of TB.


Assuntos
Coinfecção/imunologia , Desidroepiandrosterona/análogos & derivados , Infecções por HIV/imunologia , HIV-1/imunologia , Mycobacterium tuberculosis/imunologia , Células Th1/imunologia , Tuberculose Pulmonar/imunologia , Adulto , Doença Crônica , Coinfecção/patologia , Estudos Transversais , Desidroepiandrosterona/imunologia , Desidroepiandrosterona/farmacologia , Feminino , Infecções por HIV/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Células Th1/patologia , Tuberculose Pulmonar/patologia
13.
FASEB J ; 34(2): 2896-2911, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31908027

RESUMO

Chorioamnionitis (CA, fetal membrane inflammation) predisposes to preterm birth and is associated with increased neonatal infection risk, but the separate effects of prematurity, CA, and postnatal adaptations on this risk are unclear. Using pigs as models for infants, we examined the systemic immune-metabolic status in cesarean-delivered preterm pigs, with and without CA induced by intra-amniotic (IA) LPS exposure. At birth, cord blood of preterm pigs showed neutropenia and low expressions of innate and adaptive immune genes, relative to term pigs. IA LPS induced CA and fetal systemic innate immune activation via complement and neutrophil-related pathways. These were mainly modulated via cellular regulations rather than granulopoiesis, as validated by the in vitro LPS stimulation of cord blood. After birth, IA LPS-exposed preterm pigs did not follow normal immune-metabolic ontogenies found in fetuses or newborns without prenatal insults, but showed consistently high levels of Treg, impaired Th1 polarization, and reduced expressions of multiple genes related to cellular oxidative phosphorylation and ribosomal activities. In conclusion, our results provide cellular and molecular evidence for CA-induced distinct neonatal immune-metabolic status with increased disease tolerance strategy, suggesting mechanisms for the clinical observation of elevated sepsis risks in immune-compromised preterm infants born with CA.


Assuntos
Corioamnionite/imunologia , Feto/imunologia , Família Multigênica/imunologia , Fosforilação Oxidativa , Células Th1/imunologia , Animais , Animais Recém-Nascidos , Corioamnionite/induzido quimicamente , Corioamnionite/patologia , Modelos Animais de Doenças , Feminino , Feto/patologia , Humanos , Recém-Nascido , Inflamação/induzido quimicamente , Inflamação/imunologia , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Gravidez , Suínos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Células Th1/patologia
14.
J Clin Invest ; 130(2): 748-753, 2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-31904583

RESUMO

Chronic hepatitis C virus (HCV) infection is characterized by persistent high-level viremia and defective cellular immunity, including a lack of functional HCV-specific CD4+ T cells. We previously described an exceptional period of viral control that occurs in some chronically infected women after childbirth. Here, we investigated whether reduced HCV replication after pregnancy is associated with recovery of CD4+ T cell immunity. Class II tetramer analysis revealed significantly greater frequencies of circulating HCV-specific CD4+ T cells at 3 months postpartum in women with concurrent declines in viremia compared with those with stable viremia. These HCV-specific CD4+ T cells had an effector-memory phenotype. Inhibitory coreceptor expression on these cells corresponded to the degree of viral control. Circulating CD4+ T cells produced IL-2 and IFN-γ after HCV antigen stimulation, demonstrating Th1 functionality. These data provide direct evidence that the profound loss of HCV-specific CD4+ T cell help that results in chronic infection is reversible following pregnancy, and this recovery of CD4+ T cells is associated with at least transient control of persistent viral replication.


Assuntos
Hepacivirus/fisiologia , Hepatite C Crônica/imunologia , Parto , Complicações Infecciosas na Gravidez/imunologia , Células Th1/imunologia , Replicação Viral/imunologia , Adulto , Feminino , Hepatite C Crônica/patologia , Humanos , Interferon gama/imunologia , Interleucina-2/imunologia , Gravidez , Complicações Infecciosas na Gravidez/patologia , Células Th1/patologia
15.
Br J Haematol ; 189(1): 133-145, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31724172

RESUMO

Chronic lymphocytic leukaemia (CLL) is associated with alterations in T cell number, subset distribution and function. Among these changes, an increase in CD4+ T cells was reported. CD4+ T cells are a heterogeneous population and distinct subsets have been described to exert pro- and anti-tumour functions. In CLL, controversial reports describing the dominance of IFNγ-expressing Th1 T cells or of IL-4-producing Th2 T cells exist. Our study shows that blood of CLL patients is enriched in Th1 T cells producing high amounts of IFNγ. Moreover, we observed that their frequency remains relatively stable in CLL patients over a time course of five years. Furthermore, we provide evidence for an accumulation of Th1 T cells in the Eµ-TCL1 mouse model of CLL. As TBET (encoded by Tbx21) is a crucial transcription factor for Th1 polarization, we generated Tbx21-/- bone marrow chimaeric mice which showed a lower number of IFNγ-producing Th1 T cells, and used them for adoptive transfer of Eµ-TCL1 leukaemia. Disease development in these mice was, however, comparable to that in wild-type controls, excluding a major role for TBET-expressing Th1 cells in Eµ-TCL1 leukaemia. Collectively, our data highlight that Th1 T cells accumulate in CLL but reducing their number has no impact on disease development.


Assuntos
Regulação Leucêmica da Expressão Gênica/imunologia , Leucemia Linfocítica Crônica de Células B/imunologia , Proteínas de Neoplasias/imunologia , Neoplasias Experimentais/imunologia , Proteínas com Domínio T/imunologia , Células Th1/imunologia , Animais , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Camundongos , Camundongos Knockout , Proteínas de Neoplasias/genética , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Proteínas com Domínio T/genética , Células Th1/patologia
16.
J Clin Invest ; 130(3): 1315-1329, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-31846439

RESUMO

Acute graft-versus-host disease (GVHD) can affect the central nervous system (CNS). The role of microglia in CNS-GVHD remains undefined. In agreement with microglia activation, we found that profound morphological changes and MHC-II and CD80 upregulation occurred upon GVHD induction. RNA sequencing-based analysis of purified microglia obtained from mice with CNS-GVHD revealed TNF upregulation. Selective TNF gene deletion in microglia of Cx3cr1creER Tnffl/- mice reduced MHC-II expression and decreased CNS T cell infiltrates and VCAM-1+ endothelial cells. GVHD increased microglia TGF-ß-activated kinase-1 (TAK1) activation and NF-κB/p38 MAPK signaling. Selective Tak1 deletion in microglia using Cx3cr1creER Tak1fl/fl mice resulted in reduced TNF production and microglial MHC-II and improved neurocognitive activity. Pharmacological TAK1 inhibition reduced TNF production and MHC-II expression by microglia, Th1 and Th17 T cell infiltrates, and VCAM-1+ endothelial cells and improved neurocognitive activity, without blocking graft-versus-leukemia effects. Consistent with these findings in mice, we observed increased activation and TNF production of microglia in the CNS of GVHD patients. In summary, we prove a role for microglia in CNS-GVHD, identify the TAK1/TNF/MHC-II axis as a mediator of CNS-GVHD, and provide a TAK1 inhibitor-based approach against GVHD-induced neurotoxicity.


Assuntos
Doenças do Sistema Nervoso Central/imunologia , Doença Enxerto-Hospedeiro/imunologia , Microglia/imunologia , Fator de Necrose Tumoral alfa/imunologia , Regulação para Cima/imunologia , Doença Aguda , Animais , Receptor 1 de Quimiocina CX3C/genética , Receptor 1 de Quimiocina CX3C/imunologia , Doenças do Sistema Nervoso Central/genética , Doenças do Sistema Nervoso Central/patologia , Modelos Animais de Doenças , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/patologia , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , MAP Quinase Quinase Quinases/genética , MAP Quinase Quinase Quinases/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Microglia/patologia , Células Th1/imunologia , Células Th1/patologia , Células Th17/imunologia , Células Th17/patologia , Fator de Necrose Tumoral alfa/genética , Molécula 1 de Adesão de Célula Vascular/genética , Molécula 1 de Adesão de Célula Vascular/imunologia
17.
J Allergy Clin Immunol ; 145(1): 215-228, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31626841

RESUMO

BACKGROUND: The circulating immune phenotype was defined in adults and young children with early atopic dermatitis (AD), but chronologic changes in the blood of infants and children with AD through adolescence have not been explored. OBJECTIVE: We sought to compare immune activation and cytokine polarization in the blood of 0- to 5-year-old (n = 39), 6- to 11-year-old (n = 26), 12- to 17-year-old (n = 21) and 18-year-old or older (n = 43) patients with AD versus age-matched control subjects. METHODS: Flow cytometry was used to measure IFN-γ, IL-9, IL-13, IL-17, and IL-22 cytokine levels in CD4+/CD8+ T cells, with inducible costimulator molecule and HLA-DR defining midterm and long-term T-cell activation, respectively, within skin-homing/cutaneous lymphocyte antigen (CLA)+ versus systemic/CLA- T cells. Unsupervised clustering differentiated patients based on their blood biomarker frequencies. RESULTS: Although CLA+ TH1 frequencies were significantly lower in infants with AD versus all older patients (P < .01), frequencies of CLA+ TH2 T cells were similarly expanded across all AD age groups compared with control subjects (P < .05). After infancy, CLA- TH2 frequencies were increased in patients with AD in all age groups, suggesting systemic immune activation with disease chronicity. IL-22 frequencies serially increased from normal levels in infants to highly significant levels in adolescents and adults compared with levels in respective control subjects (P < .01). Unsupervised clustering aligned the AD profiles along an age-related spectrum from infancy to adulthood (eg, inducible costimulator molecule and IL-22). CONCLUSIONS: The adult AD phenotype is achieved only in adulthood. Unique cytokine signatures characterizing individual pediatric endotypes might require age-specific therapies. Future longitudinal studies, comparing the profile of patients with cleared versus persistent pediatric AD, might define age-specific changes that predict AD clearance.


Assuntos
Citocinas/imunologia , Dermatite Atópica/imunologia , Antígenos HLA-DR/imunologia , Células Th1/imunologia , Células Th2/imunologia , Adolescente , Adulto , Criança , Pré-Escolar , Dermatite Atópica/patologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Células Th1/patologia , Células Th2/patologia
18.
J Clin Invest ; 130(2): 998-1009, 2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-31697649

RESUMO

BACKGROUNDChronic hepatitis C virus (HCV) infection is characterized by a severe impairment of HCV-specific CD4+ T cell help that is driven by chronic antigen stimulation. We aimed to study the fate of HCV-specific CD4+ T cells after virus elimination.METHODSHCV-specific CD4+ T cell responses were longitudinally analyzed using MHC class II tetramer technology, multicolor flow cytometry, and RNA sequencing in a cohort of patients chronically infected with HCV undergoing therapy with direct-acting antivirals. In addition, HCV-specific neutralizing antibodies and CXCL13 levels were analyzed.RESULTSWe observed that the frequency of HCV-specific CD4+ T cells increased within 2 weeks after initiating direct-acting antiviral therapy. Multicolor flow cytometry revealed a downregulation of exhaustion and activation markers and an upregulation of memory-associated markers. Although cells with a Th1 phenotype were the predominant subset at baseline, cells with phenotypic and transcriptional characteristics of follicular T helper cells increasingly shaped the circulating HCV-specific CD4+ T cell repertoire, suggesting antigen-independent survival of this subset. These changes were accompanied by a decline of HCV-specific neutralizing antibodies and the germinal center activity.CONCLUSIONWe identified a population of HCV-specific CD4+ T cells with a follicular T helper cell signature that is maintained after therapy-induced elimination of persistent infection and may constitute an important target population for vaccination efforts to prevent reinfection and immunotherapeutic approaches for persistent viral infections.FUNDINGDeutsche Forschungsgemeinschaft (DFG, German Research Foundation), the National Institute of Allergy and Infectious Diseases (NIAID), the European Union, the Berta-Ottenstein-Programme for Advanced Clinician Scientists, and the ANRS.


Assuntos
Hepacivirus/imunologia , Hepatite C Crônica/imunologia , Antivirais/administração & dosagem , Feminino , Citometria de Fluxo , Seguimentos , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Células Th1/patologia
19.
J Virol ; 94(6)2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-31827000

RESUMO

Generating durable humoral immunity through vaccination depends upon effective interactions of follicular helper T (Tfh) cells with germinal center (GC) B cells. Th1 polarization of Tfh cells is an important process shaping the success of Tfh-GC B cell interactions by influencing costimulatory and cytokine-dependent Tfh help to B cells. However, the question remains as to whether adjuvant-dependent modulation of Tfh cells enhances HIV-1 vaccine-induced antienvelope (anti-Env) antibody responses. We investigated whether an HIV-1 vaccine platform designed to increase the number of Th1-polarized Tfh cells enhances the magnitude and quality of anti-Env antibodies. Utilizing a novel interferon-induced protein 10 (IP-10)-adjuvanted HIV-1 DNA prime followed by a monophosphoryl lipid A and QS-21 (MPLA+QS-21)-adjuvanted Env protein boost (DIP-10 PALFQ) in macaques, we observed higher anti-Env serum IgG titers with greater cross-clade reactivity, specificity for V1V2, and effector functions than in macaques primed with DNA lacking IP-10 and boosted with MPLA-plus-alum-adjuvanted Env protein (DPALFA) The DIP-10 PALFQ vaccine regimen elicited higher anti-Env IgG1 and lower IgG4 antibody levels in serum, showing for the first time that adjuvants can dramatically impact the IgG subclass profile in macaques. The DIP-10 PALFQ regimen also increased vaginal and rectal IgA antibodies to a greater extent. Within lymph nodes, we observed augmented GC B cell responses and the promotion of Th1 gene expression profiles in GC Tfh cells. The frequency of GC Tfh cells correlated with both the magnitude and avidity of anti-Env serum IgG. Together, these data suggest that adjuvant-induced stimulation of Th1-Tfh cells is an effective strategy for enhancing the magnitude and quality of anti-Env antibody responses.IMPORTANCE The results of the RV144 trial demonstrated that vaccination could prevent HIV transmission in humans and that longevity of anti-Env antibodies may be key to this protection. Efforts to improve upon the prime-boost vaccine regimen used in RV144 have indicated that booster immunizations can increase serum anti-Env antibody titers but only transiently. Poor antibody durability hampers efforts to develop an effective HIV-1 vaccine. This study was designed to identify the specific elements involved in the immunological mechanism necessary to produce robust HIV-1-specific antibodies in rhesus macaques. By clearly defining immune-mediated pathways that improve the magnitude and functionality of the anti-HIV-1 antibody response, we will have the foundation necessary for the rational development of an HIV-1 vaccine.


Assuntos
Vacinas contra a AIDS/farmacologia , Anticorpos Anti-HIV/imunologia , HIV-1/imunologia , Imunização Secundária , Imunoglobulina G/imunologia , Células Th1/imunologia , Vacinas contra a AIDS/imunologia , Adjuvantes Imunológicos/farmacologia , Animais , Linfócitos B/imunologia , Linfócitos B/patologia , Feminino , Centro Germinativo/imunologia , Centro Germinativo/patologia , Humanos , Lipídeo A/análogos & derivados , Lipídeo A/farmacologia , Macaca mulatta , Saponinas/farmacologia , Células Th1/patologia
20.
Front Immunol ; 10: 2732, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31824509

RESUMO

Avian coccidiosis is caused by Eimeria, which is an intracellular apicomplexan parasite that invades through the intestinal tract to cause devastating disease. Upon invasion through the intestinal epithelial cells, a strong inflammatory response is induced that results in complete villous destruction, diarrhea, hemorrhage, and in severe cases, death. Since the life cycle of Eimeria parasites is complex and comprises several intra- and extracellular developmental stages, the host immune responses are diverse and complex. Interferon-γ-mediated T helper (Th)1 response was originally considered to be the predominant immune response in avian coccidiosis. However, recent studies on other avian T cell lineages such as Th17 and T regulatory cells have implicated their significant involvement in maintaining gut homeostasis in normal and disease states including coccidiosis. Therefore, there is a need to understand better their role in coccidiosis. This review focuses on research findings concerning the host immune response induced by avian coccidiosis in the context of T cell immunity, including expression of T-cell-related cytokines and surface molecules that determine the phenotype of T lymphocytes.


Assuntos
Doenças das Aves , Aves , Coccidiose , Eimeria/imunologia , Células Th1 , Células Th17 , Animais , Proteínas Aviárias/imunologia , Doenças das Aves/imunologia , Doenças das Aves/patologia , Aves/imunologia , Aves/microbiologia , Coccidiose/imunologia , Coccidiose/patologia , Coccidiose/veterinária , Citocinas/imunologia , Células Th1/imunologia , Células Th1/patologia , Células Th17/imunologia , Células Th17/patologia
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