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2.
Nat Immunol ; 21(6): 605-614, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32367037

RESUMO

Impressive progress has been made over the last several years toward understanding how almost every aspect of the immune system contributes to the expression of systemic autoimmunity. In parallel, studies have shed light on the mechanisms that contribute to organ inflammation and damage. New approaches that address the complicated interaction between genetic variants, epigenetic processes, sex and the environment promise to enlighten the multitude of pathways that lead to what is clinically defined as systemic lupus erythematosus. It is expected that each patient owns a unique 'interactome', which will dictate specific treatment.


Assuntos
Autoimunidade , Suscetibilidade a Doenças/imunologia , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/etiologia , Animais , Diagnóstico Diferencial , Exposição Ambiental , Predisposição Genética para Doença , Variação Genética , Humanos , Imunidade Inata , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Especificidade de Órgãos , Fatores Sexuais
3.
BMC Cancer ; 20(1): 173, 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32131750

RESUMO

BACKGROUND: Alterations in peripheral blood lymphocytes in cervical cancer have been reported, although conflicting views exist. The present study investigated the distributions of lymphocyte subsets in tumor tissue and peripheral blood samples from cervical cancer patients and precancerous lesion patients, and evaluated the correlations of lymphocyte subsets with clinicopathological and prognostic variables. METHODS: A total of 44 patients with stage IB1-IIA2 cervical cancer and 13 precancerous lesion patients were included. Lymphocytes were collected from the tumor tissue and the peripheral blood, and isolated by Lymphoprep density gradient centrifugation. The percentages of lymphocyte subsets were quantified by flow cytometry analysis, and the differences between lymphocyte subsets in the tumor tissue and peripheral blood were compared by SPSS. In addition, the relationships between lymphocyte subsets and clinicopathological and prognostic variables were analyzed. RESULTS: Our results revealed that the amount of total T lymphocytes, CD8+ T cells, granulocytes, pDCs, CD16+ monocytes and CD56high NK cells were significantly higher in the tumor tissue than in the peripheral blood in the cervical cancer patients, while those of CD4+ T cells, CD4+/CD8+ cell ratio, rdT cells, BDCA1+ mDCs, total monocytes, CD14+ monocytes, NK cells and CD56low NK cells exhibited the opposite trend (p < 0.05). The levels of total pDCs and BDCA1+ mDCs in the peripheral blood were significantly lower in the cervical cancer patients than in the precancerous lesion patients, while the proportion of CD16+ monocytes was elevated (p < 0.05). In addition, some lymphocyte subsets, especially CD4+ cells and CD8+ cells, and the CD4+/CD8+ cell ratio were closely associated with clinicopathological and prognostic parameters. CONCLUSIONS: These results suggested that distinct alterations in infiltrating lymphocyte subsets occurred in the tumor and were associated with clinicopathological and prognostic parameters. Systemic impairment of the immune system may occur in the antitumor response of cervical cancer patients.


Assuntos
Leucócitos Mononucleares/imunologia , Subpopulações de Linfócitos/metabolismo , Neoplasias do Colo do Útero/patologia , Adulto , Idoso , Feminino , Humanos , Contagem de Linfócitos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Neoplasias do Colo do Útero/imunologia , Adulto Jovem
4.
J Nutr Health Aging ; 24(3): 325-329, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32115615

RESUMO

OBJECTIVES: Lymphocytes can affect the proliferation and migration of muscle satellite cells, which may be associated with reduced muscle mass in patients with sarcopenia. The present study aimed to further enrich understandings of the changes of blood lymphocytes and explore the relationship between peripheral lymphocyte subsets and muscle mass in patients with sarcopenia. DESIGN: A cross-sectional study. SETTING: Geriatrics department of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. METHODS: Eighty-five subjects were enrolled in this study, and were divided into two groups: the sarcopenia group (n=60) and the non-sarcopenia group (n=25). The diagnosis of sarcopenia was based on the diagnostic criteria updated by the Asian Working Group for Sarcopenia (AWGS) in 2014. Complete blood count, peripheral lymphocyte subsets, and body composition of all patients were measured. RESULTS: Skeletal muscle mass index (SMI) was negatively correlated with CD4+CD28null T lymphocytes in peripheral blood in patients with sarcopenia. CONCLUSION: The result of our study may point out the role of CD4+CD28null T lymphocytes in the pathogenesis of sarcopenia.


Assuntos
Subpopulações de Linfócitos/metabolismo , Músculo Esquelético/fisiologia , Sarcopenia/diagnóstico , China , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
5.
Immunohorizons ; 4(2): 82-92, 2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32071067

RESUMO

Although the consequences of splenectomy are well understood in mice, much less is known about the immunologic changes that occur following splenectomy in humans. We sought to characterize the circulating immune cell populations of patients before and after elective splenectomy to determine if these changes are related to postsplenectomy survival outcomes. Retrospective clinical information was collected from 95 patients undergoing elective splenectomy compared with 91 patients undergoing pancreaticoduodenectomy (Whipple procedure). We further analyzed peripheral blood from five patients in the splenectomy group, collected before and after surgery, using single-cell cytometry by time-of-flight mass spectrometry. We compared pre- and postsplenectomy data to characterize both the major and minor immune cell populations in significantly greater detail. Compared with patients undergoing a Whipple procedure, splenectomized patients had significant and long-lasting elevated counts of lymphocytes, monocytes, and basophils. Cytometry by time-of-flight mass spectroscopy analysis demonstrated that the elevated lymphocytes primarily consisted of naive CD4+ T cells and a population of activated CD25+CD56+CD4+ T cells, whereas the elevated monocyte counts were mainly mature, activated monocytes. We also observed a significant increase in the expression of the chemokine receptors CCR6 and CCR4 on several cellular populations. Taken together, these data indicate that significant immunological changes take place following splenectomy. Whereas other groups have compared splenectomized patients to healthy controls, this study compared patients undergoing elective splenectomy to those undergoing a similar major abdominal surgery. Overall, we found that splenectomy results in significant long-lasting changes in circulating immune cell populations and function.


Assuntos
Esplenectomia/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Basófilos/metabolismo , Basófilos/patologia , Biomarcadores/metabolismo , Feminino , Humanos , Contagem de Leucócitos , Subpopulações de Linfócitos/metabolismo , Subpopulações de Linfócitos/patologia , Linfócitos/metabolismo , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Monócitos/patologia , Células Mieloides/metabolismo , Células Mieloides/patologia , Pancreaticoduodenectomia/efeitos adversos , Pancreaticoduodenectomia/mortalidade , Contagem de Plaquetas , Período Pós-Operatório , Receptores CCR/metabolismo , Estudos Retrospectivos , Esplenectomia/mortalidade , Análise de Sobrevida
6.
Nat Immunol ; 21(2): 168-177, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31873294

RESUMO

Group 3 innate lymphoid cell (ILC3)-mediated production of the cytokine interleukin-22 (IL-22) is critical for the maintenance of immune homeostasis in the gastrointestinal tract. Here, we find that the function of ILC3s is not constant across the day, but instead oscillates between active phases and resting phases. Coordinate responsiveness of ILC3s in the intestine depended on the food-induced expression of the neuropeptide vasoactive intestinal peptide (VIP). Intestinal ILC3s had high expression of the G protein-coupled receptor vasoactive intestinal peptide receptor 2 (VIPR2), and activation by VIP markedly enhanced the production of IL-22 and the barrier function of the epithelium. Conversely, deficiency in signaling through VIPR2 led to impaired production of IL-22 by ILC3s and increased susceptibility to inflammation-induced gut injury. Thus, intrinsic cellular rhythms acted in synergy with the cyclic patterns of food intake to drive the production of IL-22 and synchronize protection of the intestinal epithelium through a VIP-VIPR2 pathway in ILC3s.


Assuntos
Imunidade nas Mucosas/imunologia , Subpopulações de Linfócitos/imunologia , Linfócitos/imunologia , Periodicidade , Peptídeo Intestinal Vasoativo/imunologia , Animais , Ingestão de Alimentos/imunologia , Imunidade Inata/imunologia , Subpopulações de Linfócitos/metabolismo , Linfócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Peptídeo Intestinal Vasoativo/metabolismo
7.
Sci Rep ; 9(1): 19997, 2019 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-31882709

RESUMO

The anti-tumour immune response is critical to patient prognosis in colorectal cancer (CRC). The aim of this study was to investigate infiltration of B lymphocytes into CRC tumours, and their clinical relevance, prognostic value and relation to other immune cell subsets. We used multiplexed immunohistochemistry and multispectral imaging to assay the amount of infiltrating CD20+ B lymphocytes along with infiltration of CD8+ cytotoxic T cells, FOXP3+ T regulatory cells, CD68+ macrophages and CD66b+ neutrophils, in 316 archival CRC tissue specimens. A higher density of infiltrating CD20+ B lymphocytes was associated with tumours of the right colon (P = 0.025) and of lower stages (P = 0.009). Furthermore, patients whose tumours were highly infiltrated by CD20+ B lymphocytes had a significantly improved disease-specific survival (HR = 0.45, 95% CI 0.28-0.73, P = 0.001), which remained significant in multivariable analysis. CD20+ B lymphocytes were highly and positively associated with CD8+ T lymphocytes (P < 0.001), and part of the prognostic role was found to be a cooperative effect between these lymphocyte subsets. Our results support a favourable prognostic value of tumour-infiltrating CD20+ B lymphocytes in CRC. Furthermore, a cooperative prognostic effect between CD20+ B lymphocytes and CD8+ T lymphocytes is suggested.


Assuntos
Antígenos CD20/metabolismo , Linfócitos B/imunologia , Linfócitos B/metabolismo , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/mortalidade , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Feminino , Humanos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico
8.
PLoS One ; 14(11): e0220542, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31738771

RESUMO

The impact of performing exercise on the immune system presents contrasting effects on health when performed at different intensities. In addition, the consequences of performing chronic exercise have not been sufficiently studied in contrast to the effects of acute bouts of exercise. The porpoise of this work was to determine the effect that a popular exercise regimen (chronic/moderate/aerobic exercise) has on the proportion of different immune cell subsets, their function and if it affects the cannabinoid system with potentially functional implications on the immune system. A marked increase in several immune cell subsets and their expression of cannabinoid receptors was expected, as well as an enhanced proliferative and cytotoxic activity by total splenocytes in exercised animals. For this study male Wistar rats performed treadmill running 5 times a week for a period of 10 weeks, at moderate intensity. Our results showed a significant decrease in lymphocyte subpopulations (CD4+, Tγδ, and CD45 RA+ cells) and an increase in the cannabinoid receptors expression in those same cell. Although functional assays did not reveal any variation in total immunoglobulin production or NK cells cytotoxic activity, proliferative capability of total splenocytes increased in trained rats. Our results further support the notion that exercise affects the immunological system and extends the description of underlying mechanisms mediating such effects. Altogether, our results contribute to the understanding of the benefits of exercise on the practitioner´s general health.


Assuntos
Imunidade Celular , Condicionamento Físico Animal/fisiologia , Receptores de Canabinoides/metabolismo , Animais , Composição Corporal , Proliferação de Células , Corticosterona/sangue , Citotoxicidade Imunológica , Imunoglobulina G/metabolismo , Ativação Linfocitária , Subpopulações de Linfócitos/citologia , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Masculino , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Corrida/fisiologia
9.
Int J Mol Sci ; 20(19)2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31574995

RESUMO

Group 2 innate lymphoid cells (ILC2s) are a member of the ILC family and are involved in protective and pathogenic type 2 responses. Recent research has highlighted their involvement in modulating tissue and immune homeostasis during health and disease and has uncovered critical signaling circuits. While interactions of ILC2s with the bacterial microbiome are rather sparse, other microbial members of our microbiome, including helminths and protozoans, reveal new and exciting mechanisms of tissue regulation by ILC2s. Here we summarize the current field on ILC2 activation by the tissue and immune environment and highlight particularly new intriguing pathways of ILC2 regulation by protozoan commensals in the intestinal tract.


Assuntos
Imunidade Inata , Ativação Linfocitária/imunologia , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Microbiota/imunologia , Parasitos/microbiologia , Animais , Biomarcadores , Citocinas , Humanos , Imunomodulação , Transdução de Sinais
10.
Biol Sex Differ ; 10(1): 44, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477151

RESUMO

BACKGROUND: Cryptococcus neoformans, the causative agent of cryptococcosis, causes ~ 181,000 deaths annually, with males having a higher incidence of disease than females (7M:3F). The reason for this sex bias remains unclear. We hypothesized that this disparity was due to biological differences between the male and female immune response. METHODS: Peripheral blood mononuclear cells (PBMCs) from healthy donors were isolated and infected with C. neoformans ± exogenous testosterone or 17-ß-estradiol. C. neoformans, B, T, and NK cell proliferation was quantified by flow cytometry. Cytokine analysis was conducted via protein array or ELISA. Serological testing was conducted to determine previous exposure to C. neoformans. RESULTS: C. neoformans proliferated more in male PBMCs. T cell percentages in both sexes were lower in infected versus uninfected cells. Male PBMCs had lower CD3+, CD4+, and CD8+ T cells percentages during infection compared to females. Cytokine profiles showed differences in uninfected male and female PBMCs, which subsided during infection. Only one donor was sero-negative for prior C. neoformans exposure. There was an effect of estrogen in one dataset. CONCLUSIONS: These results suggest that males show an inherent deficit in T cell response during infection, which may contribute to the increased incidence of disease in males.


Assuntos
Criptococose/imunologia , Cryptococcus neoformans , Leucócitos Mononucleares/microbiologia , Subpopulações de Linfócitos/microbiologia , Adolescente , Proliferação de Células , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Feminino , Humanos , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Contagem de Linfócitos , Subpopulações de Linfócitos/metabolismo , Masculino , Caracteres Sexuais
11.
Immunity ; 51(5): 885-898.e7, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31542340

RESUMO

Graft-versus-host disease (GVHD) in the gastrointestinal (GI) tract is the principal determinant of lethality following allogeneic bone marrow transplantation (BMT). Here, we examined the mechanisms that initiate GVHD, including the relevant antigen-presenting cells. MHC class II was expressed on intestinal epithelial cells (IECs) within the ileum at steady state but was absent from the IECs of germ-free mice. IEC-specific deletion of MHC class II prevented the initiation of lethal GVHD in the GI tract. MHC class II expression on IECs was absent from mice deficient in the TLR adaptors MyD88 and TRIF and required IFNγ secretion by lamina propria lymphocytes. IFNγ responses are characteristically driven by IL-12 secretion from myeloid cells. Antibiotic-mediated depletion of the microbiota inhibited IL-12/23p40 production by ileal macrophages. IL-12/23p40 neutralization prevented MHC class II upregulation on IECs and initiation of lethal GVHD in the GI tract. Thus, MHC class II expression by IECs in the ileum initiates lethal GVHD, and blockade of IL-12/23p40 may represent a readily translatable therapeutic strategy.


Assuntos
Apresentação do Antígeno/imunologia , Células Apresentadoras de Antígenos/imunologia , Microbioma Gastrointestinal/imunologia , Doença Enxerto-Hospedeiro/etiologia , Antígenos de Histocompatibilidade Classe II/imunologia , Mucosa Intestinal/imunologia , Animais , Células Apresentadoras de Antígenos/metabolismo , Biomarcadores , Citocinas/metabolismo , Suscetibilidade a Doenças , Feminino , Expressão Gênica , Doença Enxerto-Hospedeiro/mortalidade , Antígenos de Histocompatibilidade Classe II/genética , Íleo/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Estimativa de Kaplan-Meier , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Prognóstico , Regiões Promotoras Genéticas , Transdução de Sinais
12.
BMC Res Notes ; 12(1): 633, 2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31554512

RESUMO

OBJECTIVE: Capillary blood has been increasingly used in point-of-care setting for clinical monitoring in immunology and infectious diseases. We explored whether percentages of lymphocyte subsets (T-cells; CD3+, helper T-cells; CD4+, cytotoxic T-cells; CD8+, B-cells; CD19+, NK cells; CD56+, gamma delta T-cells, and regulatory T-cells) with regard to total lymphocyte count from capillary and venous blood of healthy volunteers were in good agreement. RESULTS: All percentages of lymphocyte subsets with regard to total lymphocyte count from capillary blood were significantly correlated with those from venous blood (r ≥ 0.9 for every cell type). However, Bland-Altman plots showed high agreement between capillary and venous samples only in those of CD3+, CD4+, and CD8+ cells (limit of agreement percentages from mean venous blood < 20%). However, the agreement of percentages of other lymphocyte subsets from venous and capillary blood was mediocre. We concluded that capillary blood could be used as an alternative for venous blood to determine percentages of CD3+, CD4+, and CD8+ cells with regard to total lymphocyte count.


Assuntos
Capilares , Voluntários Saudáveis/estatística & dados numéricos , Contagem de Linfócitos , Subpopulações de Linfócitos/citologia , Veias , Adulto , Complexo CD3/metabolismo , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Feminino , Humanos , Subpopulações de Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes
13.
Anticancer Res ; 39(9): 4687-4698, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519568

RESUMO

BACKGROUND/AIM: Propagermanium (PG) inhibits the CCL2/CCR2 axis, and has been shown to function as an immune modulator. This study investigated its anti-tumor mechanism in patients with refractory cancers. MATERIALS AND METHODS: Five healthy volunteers and 23 patients with refractory oral (n=8) or gastric (n=15) cancer received PG (30 mg/day). We performed flow cytometry (FCM) of peripheral blood mononuclear cells and in vitro killing assays. RESULTS: FCM revealed that CD16+/CD56Dim NK cells (i.e., mature, cytolytic subset) increased, and the apoptosis induction rate of cancer cells increased after PG administration. Among gastric cancer patients, median OS was 172.0 days. Two patients showed complete remission of lung or liver metastasis. Survival of patients with oral cancer also tended to be prolonged. CONCLUSION: PG induces NK cell maturation, and may potentiate anti-tumor activity.


Assuntos
Antineoplásicos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Neoplasias/imunologia , Neoplasias/mortalidade , Compostos Organometálicos/farmacologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Humanos , Estimativa de Kaplan-Meier , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Tomografia Computadorizada por Raios X
14.
BMC Bioinformatics ; 20(1): 433, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31438843

RESUMO

BACKGROUND: Host immune response is coordinated by a variety of different specialized cell types that vary in time and location. While host immune response can be studied using conventional low-dimensional approaches, advances in transcriptomics analysis may provide a less biased view. Yet, leveraging transcriptomics data to identify immune cell subtypes presents challenges for extracting informative gene signatures hidden within a high dimensional transcriptomics space characterized by low sample numbers with noisy and missing values. To address these challenges, we explore using machine learning methods to select gene subsets and estimate gene coefficients simultaneously. RESULTS: Elastic-net logistic regression, a type of machine learning, was used to construct separate classifiers for ten different types of immune cell and for five T helper cell subsets. The resulting classifiers were then used to develop gene signatures that best discriminate among immune cell types and T helper cell subsets using RNA-seq datasets. We validated the approach using single-cell RNA-seq (scRNA-seq) datasets, which gave consistent results. In addition, we classified cell types that were previously unannotated. Finally, we benchmarked the proposed gene signatures against other existing gene signatures. CONCLUSIONS: Developed classifiers can be used as priors in predicting the extent and functional orientation of the host immune response in diseases, such as cancer, where transcriptomic profiling of bulk tissue samples and single cells are routinely employed. Information that can provide insight into the mechanistic basis of disease and therapeutic response. The source code and documentation are available through GitHub: https://github.com/KlinkeLab/ImmClass2019 .


Assuntos
Algoritmos , Perfilação da Expressão Gênica , Subpopulações de Linfócitos/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismo , Bases de Dados Genéticas , Regulação da Expressão Gênica , Humanos , Modelos Logísticos , Anotação de Sequência Molecular , Curva ROC , Reprodutibilidade dos Testes , Análise de Sequência de RNA , Software
15.
Immunol Allergy Clin North Am ; 39(3): 345-359, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31284925

RESUMO

Early-life wheezing-associated infections with human rhinovirus (HRV) are strongly associated with the inception of asthma. The immune system of immature mice and humans is skewed toward a type 2 cytokine response. Thus, HRV-infected 6-day-old mice but not adult mice develop augmented type 2 cytokine expression, eosinophilic inflammation, mucous metaplasia, and airway hyperresponsiveness. This asthma phenotype depends on interleukin (IL)-13-producing type 2 innate lymphoid cells, the expansion of which in turn depends on release of the innate cytokines IL-25, IL-33, and thymic stromal lymphopoietin from the airway epithelium. In humans, certain genetic variants may predispose to HRV-induced childhood asthma.


Assuntos
Asma/etiologia , Infecções por Picornaviridae/complicações , Infecções por Picornaviridae/virologia , Rhinovirus , Animais , Asma/diagnóstico , Asma/metabolismo , Asma/terapia , Suscetibilidade a Doenças , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Infecções por Picornaviridae/imunologia , Rhinovirus/fisiologia
16.
Genomics Proteomics Bioinformatics ; 17(2): 129-139, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31229590

RESUMO

The activation mechanism of chimeric antigen receptor (CAR)-engineered T cells may differ substantially from T cells carrying native T cell receptor, but this difference remains poorly understood. We present the first comprehensive portrait of single-cell level transcriptional and cytokine signatures of anti-CD19/4-1BB/CD28/CD3ζ CAR-T cells upon antigen-specific stimulation. Both CD4+ helper T (TH) cells and CD8+ cytotoxic CAR-T cells are equally effective in directly killing target tumor cells and their cytotoxic activity is associated with the elevation of a range of TH1 and TH2 signature cytokines, e.g., interferon γ, tumor necrotic factor α, interleukin 5 (IL5), and IL13, as confirmed by the expression of master transcription factor genes TBX21 and GATA3. However, rather than conforming to stringent TH1 or TH2 subtypes, single-cell analysis reveals that the predominant response is a highly mixed TH1/TH2 function in the same cell. The regulatory T cell activity, although observed in a small fraction of activated cells, emerges from this hybrid TH1/TH2 population. Granulocyte-macrophage colony stimulating factor (GM-CSF) is produced from the majority of cells regardless of the polarization states, further contrasting CAR-T to classic T cells. Surprisingly, the cytokine response is minimally associated with differentiation status, although all major differentiation subsets such as naïve, central memory, effector memory, and effector are detected. All these suggest that the activation of CAR-engineered T cells is a canonical process that leads to a highly mixed response combining both type 1 and type 2 cytokines together with GM-CSF, supporting the notion that polyfunctional CAR-T cells correlate with objective response of patients in clinical trials. This work provides new insights into the mechanism of CAR activation and implies the necessity for cellular function assays to characterize the quality of CAR-T infusion products and monitor therapeutic responses in patients.


Assuntos
Diferenciação Celular , Ativação Linfocitária/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Análise de Célula Única/métodos , Células Th1/citologia , Células Th2/citologia , Antígenos/metabolismo , Antígeno CTLA-4/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Citocinas/metabolismo , Citotoxicidade Imunológica/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Humanos , Ativação Linfocitária/efeitos dos fármacos , Subpopulações de Linfócitos/efeitos dos fármacos , Subpopulações de Linfócitos/metabolismo , Fenótipo , Proteômica , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo , Células Th1/efeitos dos fármacos , Células Th2/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
17.
Arch Immunol Ther Exp (Warsz) ; 67(5): 335-349, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31177287

RESUMO

Major causes of chronic kidney disease are primary proliferative and nonproliferative glomerulonephritides (PGN and NPGN). However, the pathogenesis of PGN and NPGN is still not fully understood. Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is a T-cell membrane receptor that plays a key role in T-cell inhibition. Despite its role in autoimmunological diseases, little is known about the involvement of CTLA-4 in the pathogenesis of PGN and NPGN. The objective of this study was to determine the role of CTLA-4 in the pathogenesis of PGN and NPGN by evaluating the frequencies of T and B lymphocytes expressing CTLA-4 and the serum concentration of the sCTLA-4 isoform in patients with PGN and NPGN in relation to clinical parameters. The study included peripheral blood (PB) samples from 40 PGN and NPGN patients and 20 healthy age- and sex-matched volunteers (control group). The viable PB lymphocytes were labeled with fluorochrome-conjugated monoclonal anti-CTLA-4 antibodies and analyzed using flow cytometry. The serum concentration of sCTLA-4 was measured using ELISA. The frequencies and absolute counts of CD4+/CTLA-4+ T lymphocytes, CD8+/CTLA-4+ T lymphocytes and CD19+/CTLA-4+ B lymphocytes and the serum sCTLA-4 concentration were lower in PGN and NPGN patients that in the control group. Reduced sCTLA-4 expression was associated with a lower concentration of serum immunoglobulins. Our results indicate that deregulation of CTLA-4 expression may result in continuous activation of T cells and contribute to the pathogenesis of PGN and NPGN.


Assuntos
Antígeno CTLA-4/genética , Regulação da Expressão Gênica , Glomerulonefrite/imunologia , Glomerulonefrite/fisiopatologia , Imunoglobulinas/sangue , Rim/fisiopatologia , Subpopulações de Linfócitos/metabolismo , Adulto , Idoso , Antígenos CD/metabolismo , Antígeno CTLA-4/sangue , Antígeno CTLA-4/metabolismo , Feminino , Humanos , Ativação Linfocitária , Contagem de Linfócitos , Subpopulações de Linfócitos/imunologia , Masculino , Pessoa de Meia-Idade , Curva ROC , Adulto Jovem
18.
Clin Hemorheol Microcirc ; 73(4): 579-590, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31156149

RESUMO

BACKGROUND: Composition of pericardial fluid (PF) may reveal immunological processes influencing oxidative stress and microcirculation of different tissues of the heart and may play a role in the course of myocardial infarction, atherosclerosis, and aortic stenosis. PATIENTS AND METHODS: We investigated lymphocyte populations, cardiovascular markers and immunoglobulin composition in PF and blood samples of patients undergoing CABG operation and compared them to those who had aortic valve surgery. RESULTS: The amount of CD8 + T, NK, memoT and activated T-cytotoxic cells were elevated in PF compared to blood, but naiveT and activated T-helper cell ratio were lower in PF. Amount of activated T-helper cells and regulatory T-lymphocytes were elevated in CABG participants in both PF and blood. INKT cells represented the only regulatory lymphocyte population reaching significantly higher concentration in PF than in blood. IL-6 and MCP1 level were elevated in PF compared to blood and MCP1 plasma level was markedly elevated in CABG group. CONCLUSIONS: Our study describes a comprehensive immunological analysis of PF in humans for the first time. We showed that the investigated lymphocyte populations and cardiovascular markers in PF have significantly different distribution compared to blood, and lymphocyte populations show different compartmentization in coronary disease and aortic stenosis.


Assuntos
Procedimentos Cirúrgicos Cardíacos/métodos , Doença da Artéria Coronariana/diagnóstico , Subpopulações de Linfócitos/metabolismo , Líquido Pericárdico/química , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
19.
Semin Immunol ; 41: 101276, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-31130471

RESUMO

Group 2 innate lymphoid cells (ILC2s) are critical for the initiation of type 2 inflammatory diseases. However, ILC2s are also involved in the establishment of the immune microenvironment during tumor development, growth and metastasization. In this context, ILC2s have been shown to be either tumor-suppressive or tumor-promoting according to the tumor type, the cytokine secreted and the other immune cells that are, in turn, recruited and/or activated.


Assuntos
Suscetibilidade a Doenças , Imunidade Inata , Linfócitos/imunologia , Linfócitos/metabolismo , Neoplasias/etiologia , Neoplasias/metabolismo , Animais , Citocinas/metabolismo , Humanos , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Neoplasias/patologia , Microambiente Tumoral/imunologia
20.
Immunol Lett ; 210: 55-62, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31059734

RESUMO

Common Variable Immunodeficiency (CVID) and agammaglobulinemia are two of the main types of symptomatic primary antibody deficiencies. The pathogenic origins of these two diseases are different; agammaglobulinemia is a group of inherited disorders that usually are caused by mutations in the gene encoding Bruton Tyrosine Kinase (BTK) protein while CVID is a heterogeneous disorder mainly without monogenic cause. However, both diseases share a characteristic of frequent bacterial infections, a decline in serum immunoglobulin levels, and abnormality in antibody responses. The demographics and immunologic parameters, clinical manifestation, and mortality statistics from 297 patients with CVID and agammaglobulinemia followed up over 2 decades in the Children's Medical Center of Iran. Age at onset of symptom in agammaglobulinemia was earlier than CVID but the course of disease in CVID patients was longer than agammaglobulinemia patients. Pulmonary infections were the most prevalent clinical manifestations in both groups of patients. Lymphadenopathy, hepatomegaly, and splenomegaly were significantly higher in CVID patients than agammaglobulinemia patients and there was a significant association between these complications and mortality in CVID patients. Among 297 patients, 128 patients (88 CVID and 40 agammaglobulinemia) deceased. The predominant causes of death in CVID patients were infections, chronic lung disease, and malignancy while in agammaglobulinemia patients were infections and respiratory failure. Infections, especially respiratory infections were the most common complication and cause of death in both CVID and agammaglobulinemia groups and recent treatment advances even Immunoglobulin replacement cannot completely control these complications. Thus prompt recognition and specific management of these complications are worthwhile.


Assuntos
Agamaglobulinemia/diagnóstico , Agamaglobulinemia/imunologia , Imunodeficiência de Variável Comum/diagnóstico , Imunodeficiência de Variável Comum/imunologia , Adolescente , Adulto , Agamaglobulinemia/mortalidade , Biomarcadores , Criança , Imunodeficiência de Variável Comum/mortalidade , Comorbidade , Suscetibilidade a Doenças , Feminino , Humanos , Imunoglobulinas/sangue , Imunoglobulinas/imunologia , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Masculino , Fenótipo , Prognóstico , Avaliação de Sintomas , Adulto Jovem
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