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1.
Thorax ; 77(9): 865-872, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35086913

RESUMO

OBJECTIVE: Mucosal-associated invariant T (MAIT) cells are a subset of innate-like T cells that are engaged in a number of diseases, but their roles in acute respiratory distress syndrome (ARDS) are not fully examined yet. This study aimed to examine levels and functions of MAIT cells in patients with ARDS. METHODS: Peripheral blood samples from patients with ARDS (n=50) and healthy controls (HCs, n=50) were collected. Levels of MAIT cells, cytokines, CD69, programmed cell death-1 (PD-1) and lymphocyte-activation gene 3 (LAG-3) were measured by flow cytometry. RESULTS: Circulating MAIT cell levels were significantly reduced in patients with ARDS than in HCs. MAIT cell levels were inversely correlated with disease severity and mortality. Cytokine production profiles in MAIT cells showed that percentages of interleukin (IL)-17 producing MAIT cell were significantly higher in patients with ARDS than in HCs. Patients with ARDS exhibited higher expression levels of CD69, PD-1 and LAG-3 in circulating MAIT cells. Moreover, levels of MAIT cells and expression levels of CD69, PD-1 and IL-17 in MAIT cells were higher in bronchoalveolar lavage fluid samples than in peripheral blood samples. Our in vitro experiments showed that MAIT cells triggered macrophages to produce proinflammatory cytokines such as tumour necrosis factor-α, IL-1ß and IL-8. CONCLUSIONS: This study demonstrates that circulating MAIT cells are numerically deficient in patients with ARDS. In addition, MAIT cells were found to be activated, migrate into lung, secrete IL-17 and then stimulate macrophages. These findings suggest that MAIT cells contribute to the worsening of inflammation in the lung of patients with ARDS.


Assuntos
Células T Invariantes Associadas à Mucosa , Síndrome do Desconforto Respiratório , Citocinas/metabolismo , Humanos , Interleucina-17/metabolismo , Ativação Linfocitária , Células T Invariantes Associadas à Mucosa/metabolismo , Receptor de Morte Celular Programada 1/metabolismo
2.
J Clin Periodontol ; 49(7): 706-716, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35569027

RESUMO

AIM: Mucosal-associated invariant T (MAIT) cells are known to be resident in oral mucosal tissue, but their roles in periodontitis are unknown. This study aimed to examine the level and function of MAIT cells in periodontitis patients. MATERIALS AND METHODS: Frequency, activation, and function of MAIT cells from 28 periodontitis patients and 28 healthy controls (HCs) were measured by flow cytometry. RESULTS: Circulating MAIT cells were numerically reduced in periodontitis patients. Moreover, they exhibited higher expression of CD69 and annexin V, together with more increased production of interleukin (IL)-17 and tumour necrosis factor (TNF)-α, in periodontitis patients than in HCs. Interestingly, periodontitis patients had higher frequencies of MAIT cells in gingival tissue than in peripheral blood. In addition, circulating MAIT cells had elevated expression of tissue-homing chemokine receptors such as CCR6 and CXCR6, and the corresponding chemokines (i.e., CCL20 and CXCL16) were more strongly expressed in inflamed gingiva than in healthy gingiva. CONCLUSIONS: This study demonstrates that circulating MAIT cells are numerically deficient with an activated profile toward the production of IL-17 and TNF-α in periodontitis patients. Furthermore, circulating MAIT cells have the potential to migrate to inflamed gingival tissues.


Assuntos
Interleucina-17/biossíntese , Células T Invariantes Associadas à Mucosa , Periodontite , Fator de Necrose Tumoral alfa/biossíntese , Citometria de Fluxo , Humanos , Interleucina-17/metabolismo , Ativação Linfocitária , Células T Invariantes Associadas à Mucosa/metabolismo , Periodontite/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
3.
Rheumatology (Oxford) ; 59(8): 2124-2134, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32087015

RESUMO

OBJECTIVE: This study was designed to investigate the role of mucosal-associated invariant T (MAIT) cells in gouty arthritis (GA) and their effects on osteoclastogenesis. METHODS: Patients with GA (n = 61), subjects with hyperuricaemia (n = 11) and healthy controls (n = 30) were enrolled in this study. MAIT cells, cytokines, CD69, programmed death-1 (PD-1) and lymphocyte-activation gene 3 (LAG-3) levels were measured by flow cytometry. In vitro osteoclastogenesis experiments were performed using peripheral blood mononuclear cells in the presence of M-CSF and RANK ligand. RESULTS: Circulating MAIT cell levels were significantly reduced in GA patients. However, their capacities for IFN-γ, IL-17 and TNF-α production were preserved. Expression levels of CD69, PD-1 and LAG-3 in MAIT cells were found to be elevated in GA patients. In particular, CD69 expression in circulating MAIT cells was increased by stimulation with MSU crystals, suggesting that deposition of MSU crystals might contribute to MAIT cell activation. Interestingly, MAIT cells were found to be accumulated in synovial fluid and infiltrated into gouty tophus tissues within joints. Furthermore, activated MAIT cells secreted pro-resorptive cytokines (i.e. IL-6, IL-17 and TNF-α) and facilitated osteoclastogenesis. CONCLUSION: This study demonstrates that circulating MAIT cells are activated and numerically deficient in GA patients. In addition, MAIT cells have the potential to migrate to inflamed tissues and induce osteoclastogenesis. These findings provide an important role of MAIT cells in the pathogenesis of inflammation and bone destruction in GA patients.


Assuntos
Artrite Gotosa/metabolismo , Hiperuricemia/metabolismo , Células T Invariantes Associadas à Mucosa/metabolismo , Osteogênese/fisiologia , Adulto , Idoso , Movimento Celular/fisiologia , Citocinas/metabolismo , Feminino , Citometria de Fluxo , Humanos , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade
4.
J Infect Dis ; 218(11): 1813-1821, 2018 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-29982731

RESUMO

Background: Human natural killer T (NKT) cells are known to serve as regulatory and/or effector cells in infectious diseases. However, little is known about the role of NKT cells in Orientia tsutsugamushi infection. Accordingly, the objective of this study was to examine the level and function of NKT cells in patients with scrub typhus. Methods: This study included 62 scrub typhus patients and 62 healthy controls (HCs). NKT cell level and function in peripheral blood samples were measured by flow cytometry. Results: Proliferation of NKT cells and their ability to produce interferon-γ and interleukin-4 (IL-4) were significantly lower in scrub typhus patients compared to those in HCs. However, circulating NKT cell levels were comparable between patients and HCs. Expression levels of CD69, programmed death-1 (PD-1), lymphocyte activation gene-3 (LAG-3), and T-cell immunoglobulin domain and mucin domain-containing molecule-3 (TIM-3) were significantly increased in scrub typhus patients. Elevated expression of CD69, PD-1, LAG-3, and TIM-3, impaired proliferation, and decreased IL-4 production by NKT cells were recovered in the remission phase. Conclusions: This study demonstrates that circulating NKT cells are numerically preserved but functionally impaired in scrub typhus patients. In addition, NKT cell dysfunction is recovered in the remission phase.


Assuntos
Células T Matadoras Naturais , Tifo por Ácaros , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Proliferação de Células , Citocinas/sangue , Citocinas/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/metabolismo , Orientia tsutsugamushi/imunologia , Tifo por Ácaros/imunologia , Tifo por Ácaros/metabolismo , Tifo por Ácaros/fisiopatologia
5.
J Korean Med Sci ; 32(5): 750-756, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28378547

RESUMO

Mucosal-associated invariant T (MAIT) cells and natural killer T (NKT) cells are known to play important roles in autoimmunity, infectious diseases and cancers. However, little is known about the roles of these invariant T cells in multiple trauma. The purposes of this study were to examine MAIT and NKT cell levels in patients with multiple trauma and to investigate potential relationships between these cell levels and clinical parameters. The study cohort was composed of 14 patients with multiple trauma and 22 non-injured healthy controls (HCs). Circulating MAIT and NKT cell levels in the peripheral blood were measured by flow cytometry. The severity of injury was categorised according to the scoring systems, such as Acute Physiology and Chronic Health Evaluation (APACHE) II score, Simplified Acute Physiology Score (SAPS) II, and Injury Severity Score (ISS). Circulating MAIT and NKT cell numbers were significantly lower in multiple trauma patients than in HCs. Linear regression analysis showed that circulating MAIT cell numbers were significantly correlated with age, APACHE II, SAPS II, ISS category, hemoglobin, and platelet count. NKT cell numbers in the peripheral blood were found to be significantly correlated with APACHE II, SAPS II, and ISS category. This study shows numerical deficiencies of circulating MAIT cells and NKT cells in multiple trauma. In addition, these invariant T cell deficiencies were found to be associated with disease severity. These findings provide important information for predicting the prognosis of multiple trauma.


Assuntos
Células T Invariantes Associadas à Mucosa/citologia , Traumatismo Múltiplo/patologia , Células T Matadoras Naturais/citologia , Adulto , Idoso , Plaquetas/citologia , Estudos de Casos e Controles , Feminino , Citometria de Fluxo , Hemoglobinas/metabolismo , Humanos , Leucócitos Mononucleares/citologia , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Células T Invariantes Associadas à Mucosa/imunologia , Traumatismo Múltiplo/sangue , Traumatismo Múltiplo/imunologia , Células T Matadoras Naturais/imunologia , Índice de Gravidade de Doença
6.
J Immunol ; 193(8): 3891-901, 2014 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-25225673

RESUMO

Mucosal-associated invariant T (MAIT) cells contribute to protection against certain microorganism infections and play an important role in mucosal immunity. However, the role of MAIT cells remains enigmatic in autoimmune diseases. In this study, we examined the level and function of MAIT cells in patients with rheumatic diseases. MAIT cell, cytokine, and programmed death-1 (PD-1) levels were measured by flow cytometry. Circulating MAIT cell levels were significantly reduced in systemic lupus erythematosus (SLE) and rheumatoid arthritis patients. In particular, this MAIT cell deficiency was more prominent in CD8(+) and double-negative T cell subsets, and significantly correlated with disease activity, such as SLE disease activity index and 28-joint disease activity score. Interestingly, MAIT cell frequency was significantly correlated with NKT cell frequency in SLE patients. IFN-γ production in MAIT cells was impaired in SLE patients, which was due to an intrinsic defect in the Ca(2+)/calcineurin/NFAT1 signaling pathway. In SLE patients, MAIT cells were poorly activated by α-galactosylceramide-stimulated NKT cells, thereby showing the dysfunction between MAIT cells and NKT cells. Notably, an elevated expression of PD-1 in MAIT cells and NKT cells was associated with SLE. In rheumatoid arthritis patients, MAIT cell levels were significantly higher in synovial fluid than in peripheral blood. Our study primarily demonstrates that MAIT cells are numerically and functionally deficient in SLE. In addition, we report a novel finding that this MAIT cell deficiency is associated with NKT cell deficiency and elevated PD-1 expression. These abnormalities possibly contribute to dysregulated mucosal immunity in SLE.


Assuntos
Imunidade nas Mucosas/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Células T Matadoras Naturais/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Transporte Ativo do Núcleo Celular , Adulto , Artrite Reumatoide/imunologia , Doenças Autoimunes/imunologia , Linfócitos T CD8-Positivos/imunologia , Calcineurina/metabolismo , Sinalização do Cálcio , Citocinas/metabolismo , Escherichia coli/imunologia , Infecções por Escherichia coli/imunologia , Feminino , Galactosilceramidas , Humanos , Interferon gama/biossíntese , Ativação Linfocitária/imunologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Fatores de Transcrição NFATC/metabolismo , Líquido Sinovial/citologia , Subpopulações de Linfócitos T/imunologia
7.
COPD ; 13(2): 196-202, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26552490

RESUMO

Mucosal-associated invariant T (MAIT) cells have been reported to play an important role in mucosal immunity. However, little is known about the roles of MAIT cells in chronic obstructive pulmonary disease (COPD). The aims of this study were to examine the levels of circulating MAIT cells and their subsets in COPD patients and to investigate the potential relationship between clinical parameters and MAIT cell levels. Forty-five COPD patients and 57 healthy control subjects were enrolled in the study. Circulating MAIT cells and their subset levels in the peripheral blood were measured by flow cytometry. Disease grades were classified according to the GOLD criteria for the assessment of severity of COPD. Circulating MAIT cell levels were found to be significantly reduced in COPD patients. In particular, this MAIT cell deficiency was more prominent in CD8+ and double-negative T cell subsets. Interestingly, elevated serum C-reactive protein level and reduced FEV1/FVC ratio were associated with MAIT cell deficiency in COPD patients. Furthermore, the circulating MAIT levels were found to be significantly lower in patients with moderate to severe COPD than in patients with mild COPD. Our data shows that MAIT cells are numerically deficient in the peripheral blood of patients with COPD. In addition, this MAIT cell deficiency was found to reflect inflammatory activity and disease severity. These findings provide important information for monitoring the changes in MAIT cell levels and for predicting the prognosis during the disease course.


Assuntos
Imunidade nas Mucosas , Células T Invariantes Associadas à Mucosa/imunologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Subpopulações de Linfócitos T/imunologia , Idoso , Proteína C-Reativa/metabolismo , Citocinas/metabolismo , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/metabolismo
8.
J Korean Med Sci ; 30(5): 606-11, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25931792

RESUMO

Mucosal-associated invariant T (MAIT) cells and natural killer T (NKT) cells are known to play crucial roles in a variety of diseases, including autoimmunity, infectious diseases, and cancers. However, little is known about the roles of these invariant T cells in acute cholecystitis. The purposes of this study were to examine the levels of MAIT cells and NKT cells in patients with acute cholecystitis and to investigate potential relationships between clinical parameters and these cell levels. Thirty patients with pathologically proven acute cholecystitis and 47 age- and sex-matched healthy controls were enrolled. Disease grades were classified according to the revised Tokyo guidelines (TG13) for the severity assessment for acute cholecystitis. Levels of MAIT and NKT cells in peripheral blood were measured by flow cytometry. Circulating MAIT and NKT cell numbers were significantly lower in acute cholecystitis patients than in healthy controls, and these deficiencies in MAIT cells and NKT cell numbers were associated with aging in acute cholecystitis patients. Notably, a reduction in NKT cell numbers was found to be associated with severe TG13 grade, death, and high blood urea nitrogen levels. The study shows numerical deficiencies of circulating MAIT and NKT cells and age-related decline of these invariant T cells. In addition, NKT cell deficiency was associated with acute cholecystitis severity and outcome. These findings provide an information regarding the monitoring of these changes in circulating MAIT and NKT cell numbers during the course of acute cholecystitis and predicting prognosis.


Assuntos
Colecistite Aguda/diagnóstico , Células T Matadoras Naturais/citologia , Subpopulações de Linfócitos T/citologia , Idoso , Anticorpos Monoclonais/imunologia , Estudos de Casos e Controles , Colecistite Aguda/imunologia , Colecistite Aguda/patologia , Feminino , Citometria de Fluxo , Humanos , Leucócitos Mononucleares/citologia , Masculino , Pessoa de Meia-Idade , Células T Matadoras Naturais/imunologia , Pacientes , Prognóstico , Índice de Gravidade de Doença , Subpopulações de Linfócitos T/imunologia
9.
Gynecol Oncol ; 132(3): 551-5, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24440470

RESUMO

OBJECTIVE: Preoperative leukocytosis is known to be a negative prognostic factor for several gynecologic malignancies, but its relationship with epithelial ovarian carcinoma (EOC) is unknown. We sought to evaluate the prognostic implications of preoperative leukocytosis for women with EOC. METHODS: We retrospectively reviewed the medical records of patients who underwent primary debulking surgery and adjuvant platinum-based chemotherapy for EOC between January 1993 and October 2011. Associations between leukocytosis and recurrence-free survival (RFS) and overall survival (OS) were determined by univariate analyses. Multivariate Cox proportional hazards regression was used to identify independent prognostic factors for RFS and OS. RESULTS: Of 155 women, 23 (14.8%) had leukocytosis and 132 (85.2%) did not have leukocytosis. RFS and OS were significantly shorter for women with leukocytosis than for women without leukocytosis (P=0.009 and P<0.0001, respectively). The mortality rate was also higher among women with leukocytosis (P<0.0001). Multivariate analysis revealed that preoperative leukocytosis (hazard ratio [HR]: 2.15; 95% confidence interval [CI]: 1.55-4.41; P=0.009), advanced stage (HR: 3.12; 95% CI: 1.44-6.75; P=0.004), and optimal cytoreduction (HR: 0.38; 95% CI: 0.14-0.70; P=0.031) were independent prognostic factors for RFS. Additionally, preoperative leukocytosis was independently associated with decreased OS (HR: 7.66; 95% CI: 2.78-21.16; P<0.0001). CONCLUSIONS: Among women with EOC, preoperative leukocytosis might be an independent prognostic factor for RFS and OS. A larger-scaled, prospective study is needed to verify these results.


Assuntos
Leucocitose/patologia , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/patologia , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Carcinoma Epitelial do Ovário , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Epiteliais e Glandulares/sangue , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Epiteliais e Glandulares/cirurgia , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/cirurgia , Paclitaxel/administração & dosagem , Valor Preditivo dos Testes , Período Pré-Operatório , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Adulto Jovem
10.
Rheumatol Int ; 34(12): 1711-20, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24816858

RESUMO

Triggers of indeterminate results from interferon-gamma release assays (IGRA) in patients with rheumatic diseases are still elusive. The aim of the present study was to describe predictors of indeterminate results from IGRA in the field of rheumatology. This cross-sectional study was retrospectively performed by using a database of patients with a request for QuantiFERON-TB Gold-In Tube test (QFT-GIT) for screening of latent tuberculosis infection. The study cohort included 631 patients with rheumatic diseases. All variables influencing indeterminate QFT-GIT results were investigated by logistic regression analysis. The overall frequency of indeterminate IGRA results was 6.8 % (43/631). Those with indeterminate results were more likely to be aged ≥70 years, female, visitors in winter, suffering from systemic lupus erythematosus (SLE), and using sulfasalazine or a tumor necrosis factor (TNF)-α inhibitor. In addition, a longer incubation time of >6 h increased the odds ratio of indeterminate IGRA results. In contrast, the automated ELISA processor, ankylosing spondylitis, and the use of a non-steroidal anti-inflammatory drug decreased the likelihood of indeterminate IGRA results. Lymphopenia, thrombocytopenia, anemia, and hypoalbuminemia were significantly associated with indeterminate IGRA results. Multivariate analysis revealed that SLE, use of sulfasalazine or a TNF-α inhibitor, and a manual ELISA system were significantly independent predictors of indeterminate IGRA results. The proportion of indeterminate results in patients with rheumatic diseases is not infrequent. Careful attention to the pre-analytical conditions should minimize the indeterminate results. Automation of the ELISA process seems to be a promising solution to decrease the rate of indeterminate response.


Assuntos
Ensaio de Imunoadsorção Enzimática , Testes de Liberação de Interferon-gama , Interferon gama/sangue , Tuberculose Latente/diagnóstico , Doenças Reumáticas/diagnóstico , Adulto , Idoso , Automação Laboratorial , Biomarcadores/sangue , Estudos Transversais , Bases de Dados Factuais , Ensaio de Imunoadsorção Enzimática/instrumentação , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Humanos , Testes de Liberação de Interferon-gama/instrumentação , Testes de Liberação de Interferon-gama/métodos , Tuberculose Latente/sangue , Tuberculose Latente/imunologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Estudos Retrospectivos , Doenças Reumáticas/sangue , Doenças Reumáticas/imunologia , Fatores de Risco
11.
Front Immunol ; 15: 1433028, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39281681

RESUMO

Objective: Acute respiratory distress syndrome (ARDS) presents a global health challenge, characterized by significant morbidity and mortality. However, the role of natural killer T (NKT) cells in human ARDS remains poorly understood. Therefore, this study explored the numerical and functional status of NKT cells in patients with ARDS, examining their clinical relevance and interactions with macrophages and fibroblasts during various stages of the syndrome. Methods: Peripheral blood from 40 ARDS patients and 30 healthy controls was analyzed, with paired samples of peripheral blood and bronchoalveolar lavage fluid (BALF) from seven ARDS patients. We measured levels of NKT cells, cytokines, CD69, programmed death-1 (PD-1), and annexin-V using flow cytometry, and extracellular matrix (ECM) protein expression using real-time PCR. Results: ARDS patients exhibited decreased circulating NKT cells with elevated CD69 expression and enhanced IL-17 production. The reduction in NKT cells correlated with PaO2/FiO2 ratio, albumin, and C-reactive protein levels. Proliferative responses to α-galactosylceramide (α-GalCer) were impaired, and co-culturing NKT cells with monocytes or T cells from ARDS patients resulted in a reduced α-GalCer response. Increased and activated NKT cells in BALF induced proinflammatory cytokine release by macrophages and ECM protein expression in fibroblasts. Conclusion: ARDS is associated with a numerical deficiency but functional activation of circulating NKT cells, showing impaired responses to α-GalCer and altered interactions with immune cells. The increase in NKT cells within BALF suggests their role in inducing inflammation and remodeling/fibrosis, highlighting the potential of targeting NKT cells as a therapeutic approach for ARDS.


Assuntos
Células T Matadoras Naturais , Síndrome do Desconforto Respiratório , Humanos , Síndrome do Desconforto Respiratório/imunologia , Masculino , Feminino , Pessoa de Meia-Idade , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/metabolismo , Líquido da Lavagem Broncoalveolar/imunologia , Líquido da Lavagem Broncoalveolar/citologia , Adulto , Idoso , Macrófagos/imunologia , Macrófagos/metabolismo , Citocinas/metabolismo , Fibroblastos/metabolismo , Fibroblastos/imunologia , Ativação Linfocitária/imunologia , Antígenos de Diferenciação de Linfócitos T , Antígenos CD , Lectinas Tipo C
12.
Arthritis Rheum ; 64(9): 2868-77, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22605480

RESUMO

OBJECTIVE: To examine the levels and functions of natural killer (NK) and natural killer T (NKT) cells, investigate relationships between NK and NKT cells, and determine the clinical relevance of NKT cell levels in patients with adult-onset Still's disease (AOSD). METHODS: Patients with active untreated AOSD (n = 20) and age- and sex-matched healthy controls (n = 20) were studied. NK and NKT cell levels were measured by flow cytometry. Peripheral blood mononuclear cells were cultured in vitro with α-galactosylceramide (αGalCer). NK cytotoxicity against K562 cells and proliferation indices of NKT cells were estimated by flow cytometry. RESULTS: Percentages and absolute numbers of NKT cells were significantly lower in the peripheral blood of AOSD patients than in that of healthy controls. Proliferative responses of NKT cells to αGalCer were also lower in patients, and this was found to be due to proinflammatory cytokines and NKT cell apoptosis. In addition, NK cytotoxicity was found to be significantly lower in patients than in healthy controls, but NK cell levels were comparable in the 2 groups. Notably, this NKT cell deficiency was found to be correlated with NK cell dysfunction and to reflect active disease status. Furthermore, αGalCer-mediated NK cytotoxicity, showing the interaction between NK and NKT cells, was significantly lower in AOSD patients than in healthy controls. CONCLUSION: These findings demonstrate that NK and NKT cell functions are defective in AOSD patients and suggest that these abnormalities contribute to innate immune dysfunction in AOSD.


Assuntos
Linfopenia/imunologia , Células T Matadoras Naturais/imunologia , Doença de Still de Início Tardio/imunologia , Adolescente , Adulto , Citotoxicidade Imunológica , Feminino , Citometria de Fluxo , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade
13.
Proc Natl Acad Sci U S A ; 107(47): 20281-6, 2010 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-21059944

RESUMO

The receptor activator of nuclear factor-κB (RANK) and its ligand RANKL, which belong to the tumor necrosis factor (TNF) receptor-ligand family, mediate osteoclastogenesis. The crystal structure of the RANKL ectodomain (eRANKL) in complex with the RANK ectodomain (eRANK) combined with biochemical assays of RANK mutants indicated that three RANK loops (Loop1, Loop2, and Loop3) bind to the interface of a trimeric eRANKL. Loop3 is particularly notable in that it is structurally distinctive from other TNF-family receptors and forms extensive contacts with RANKL. The disulfide bond (C125-C127) at the tip of Loop3 is important for determining the unique topology of Loop3, and docking E126 close to RANKL, which was supported by the inability of C127A or E126A mutants of RANK to bind to RANKL. Inhibitory activity of RANK mutants, which contain loops of osteoprotegerin (OPG), a soluble decoy receptor to RANKL, confirmed that OPG shares the similar binding mode with RANK and OPG. Loop3 plays a key role in RANKL binding. Peptide inhibitors designed to mimic Loop3 blocked the RANKL-induced differentiation of osteoclast precursors, suggesting that they could be developed as therapeutic agents for the treatment of osteoporosis and bone-related diseases. Furthermore, some of the RANK mutations associated with autosomal recessive osteopetrosis (ARO) resulted in reduced RANKL-binding activity and failure to induce osteoclastogenesis. These results, together with structural interpretation of eRANK-eRANKL interaction, provided molecular understanding for pathogenesis of ARO.


Assuntos
Osso e Ossos/metabolismo , Modelos Moleculares , Oligopeptídeos/farmacologia , Osteopetrose/metabolismo , Osteoprotegerina/metabolismo , Peptídeos Cíclicos/farmacologia , Ligante RANK/química , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Cristalografia , Camundongos , Mutagênese Sítio-Dirigida , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Osteopetrose/genética , Ligante RANK/antagonistas & inibidores , Receptor Ativador de Fator Nuclear kappa-B/genética
14.
Immune Netw ; 23(3): e22, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37416928

RESUMO

Alcoholic liver cirrhosis (ALC) is caused by chronic alcohol overconsumption and might be linked to dysregulated immune responses in the gut-liver axis. However, there is a lack of comprehensive research on levels and functions of innate lymphocytes including mucosal-associated invariant T (MAIT) cells, NKT cells, and NK (NK) cells in ALC patients. Thus, the aim of this study was to examine the levels and function of these cells, evaluate their clinical relevance, and explore their immunologic roles in the pathogenesis of ALC. Peripheral blood samples from ALC patients (n = 31) and healthy controls (HCs, n = 31) were collected. MAIT cells, NKT cells, NK cells, cytokines, CD69, PD-1, and lymphocyte-activation gene 3 (LAG-3) levels were measured by flow cytometry. Percentages and numbers of circulating MAIT cells, NKT cells, and NK cells were significantly reduced in ALC patients than in HCs. MAIT cell exhibited increased production of IL-17 and expression levels of CD69, PD-1, and LAG-3. NKT cells displayed decreased production of IFN-γ and IL-4. NK cells showed elevated CD69 expression. Absolute MAIT cell levels were positively correlated with lymphocyte count but negatively correlated with C-reactive protein. In addition, NKT cell levels were negatively correlated with hemoglobin levels. Furthermore, log-transformed absolute MAIT cell levels were negatively correlated with the Age, Bilirubin, INR, and Creatinine score. This study demonstrates that circulating MAIT cells, NKT cells, and NK cells are numerically deficient in ALC patients, and the degree of cytokine production and activation status also changed. Besides, some of their deficiencies are related to several clinical parameters. These findings provide important information about immune responses of ALC patients.

15.
Clin Exp Rheumatol ; 30(4): 469-75, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22510234

RESUMO

OBJECTIVES: The aims of this study were to examine immune cell proportions in peripheral blood of patients with ankylosing spondylitis (AS) and to investigate relationships between immune cells, level of bone formation related molecules, and radiographic changes. METHODS: Forty-nine AS patients and 53 age- and sex-matched healthy controls (HCs) were enrolled in this study. Clinical parameters were extensively evaluated in the study subjects. CD4+ T-cells, CD8+ T-cells, CD56+ T-cells, natural killer cells, and natural killer T (NKT) cells in peripheral blood were measured by flow cytometry. Serum levels of Dickkopf-1 and bone morphogenic proteins were determined using enzyme linked immunosorbent assays. Modified Stokes AS spinal scores were used to assess radiographic changes. RESULTS: Patients were found to have a significantly higher percentages of CD56+T-cells than healthy controls (median 1.31% vs. 0.53%, p<0.001), whereas percentages of peripheral blood natural killer T (NKT) cell were lower in patients than in controls (median 0.07 % vs. 0.10%, p=0.010). Moreover, mean CD 56+T to NKT cell ratio was markedly higher in patients. Although no significant correlations were observed between the immune cell percentages and bone formation-related molecule levels, interestingly, patients with a higher CD56+T to NKT cell ratio at baseline were found to develop greater radiographic changes (r=0.79, p=0.007, age and disease duration adjusted) during 3 years of radiographic follow-up. CONCLUSIONS: An altered T-cell compartment, particularly with respect to CD56+ T and NKT cells, was observed in AS patients and could contribute to radiographic changes in AS.


Assuntos
Antígeno CD56/imunologia , Osteogênese/imunologia , Espondilite Anquilosante/diagnóstico por imagem , Espondilite Anquilosante/imunologia , Subpopulações de Linfócitos T/imunologia , Adulto , Biomarcadores/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Antígeno CD56/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Progressão da Doença , Feminino , Citometria de Fluxo , Seguimentos , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Radiografia , Subpopulações de Linfócitos T/metabolismo , Adulto Jovem
16.
J Immunol ; 185(12): 7460-6, 2010 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-21068407

RESUMO

Pim kinases are emerging as important mediators of cytokine signaling pathways in hematopoietic cells. In this study, we demonstrate that Pim-1 positively regulates RANKL-induced osteoclastogenesis and that Pim-1 expression can be upregulated by RANKL signaling during osteoclast differentiation. The silencing of Pim-1 by RNA interference or overexpression of a dominant negative form of Pim-1 (Pim-1 DN) in bone marrow-derived macrophage cells attenuates RANKL-induced osteoclast formation. Overexpression of Pim-1 DN blocks RANKL-induced activation of TGF-ß-activated kinase 1 (TAK1) and NF-κB as well as expression of NFATc1 during osteoclastogenesis. However, we found that overexpression of TAK1 in the presence of Pim-1 DN rescues NF-κB activation. Additionally, Pim-1 interacts with RANK as well as TAK1, indicating that Pim-1 is involved in RANKL-induced NF-κB activation via TAK1. Furthermore, we demonstrate that Pim-1 also regulates NFATc1 transcription activity and subsequently induces osteoclast-associated receptor expression, an osteoclast-specific gene. Taken together, our results reveal that Pim-1 positively regulates RANKL-induced osteoclastogenesis.


Assuntos
Diferenciação Celular/imunologia , NF-kappa B/imunologia , Fatores de Transcrição NFATC/imunologia , Osteoclastos/imunologia , Proteínas Proto-Oncogênicas c-pim-1/imunologia , Ligante RANK/imunologia , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Diferenciação Celular/genética , Células Cultivadas , MAP Quinase Quinase Quinases/genética , MAP Quinase Quinase Quinases/imunologia , MAP Quinase Quinase Quinases/metabolismo , Macrófagos/citologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos ICR , NF-kappa B/genética , NF-kappa B/metabolismo , Fatores de Transcrição NFATC/genética , Fatores de Transcrição NFATC/metabolismo , Osteoclastos/citologia , Osteoclastos/metabolismo , Proteínas Proto-Oncogênicas c-pim-1/genética , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Ligante RANK/genética , Ligante RANK/metabolismo , Interferência de RNA/imunologia , Transcrição Gênica/imunologia , Regulação para Cima/genética , Regulação para Cima/imunologia
17.
Biochem J ; 436(2): 253-62, 2011 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-21413932

RESUMO

NFATc1 (nuclear factor of activated T-cells c1), a key transcription factor, plays a role in regulating expression of osteoclast-specific downstream target genes such as TRAP (tartrate-resistant acid phosphatase) and OSCAR (osteoclast-associated receptor). It has been shown that RANKL [receptor activator of NF-κB (nuclear factor κB) ligand] induces NFATc1 expression during osteoclastogenesis at a transcriptional level. In the present study, we demonstrate that RANKL increases NFATc1 protein levels by post-translational modification. RANKL stimulates NFATc1 acetylation via HATs (histone acetyltransferases), such as p300 and PCAF [p300/CREB (cAMP-response-element-binding protein)-binding protein-associated factor], thereby stabilizing NFATc1 proteins. PCAF physically interacts with NFATc1 and directly induces NFATc1 acetylation and stability, subsequently increasing the transcriptional activity of NFATc1. In addition, RANKL-mediated NFATc1 acetylation is increased by the HDAC (histone deacetylase) inhibitors sodium butyrate and scriptaid. Overexpression of HDAC5 reduces RANKL- or PCAF-mediated NFATc1 acetylation, stability and transactivation activity, suggesting that the balance between HAT and HDAC activities might play a role in the regulation of NFATc1 levels. Furthermore, RANKL and p300 induce PCAF acetylation and stability, thereby enhancing the transcriptional activity of NFATc1. Down-regulation of PCAF by siRNA (small interfering RNA) decreases NFATc1 acetylation and stability, as well as RANKL-induced osteoclastogenesis. Taken together, the results of the present study demonstrate that RANKL induces HAT-mediated NFATc1 acetylation and stability, and subsequently increases the transcriptional activity of NFATc1 during osteoclast differentiation.


Assuntos
Diferenciação Celular/fisiologia , Histona Acetiltransferases/metabolismo , Fatores de Transcrição NFATC/metabolismo , Osteoclastos/citologia , Osteoclastos/metabolismo , Ligante RANK/fisiologia , Acetilação , Células Cultivadas , Células HEK293 , Humanos , Osteoclastos/enzimologia , Estabilidade Proteica
18.
J Biol Chem ; 285(8): 5224-31, 2010 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-20037154

RESUMO

The regulation of NFATc1 expression is important for osteoclast differentiation and function. Herein, we demonstrate that macrophage-colony-stimulating factor induces NFATc1 degradation via Cbl proteins in a Src kinase-dependent manner. NFATc1 proteins are ubiquitinated and rapidly degraded during late stage osteoclastogenesis, and this degradation is mediated by Cbl-b and c-Cbl ubiquitin ligases in a Src-dependent manner. In addition, NFATc1 interacts endogenously with c-Src, c-Cbl, and Cbl-b in osteoclasts. Overexpression of c-Src induces down-regulation of NFATc1, and depletion of Cbl proteins blocks NFATc1 degradation during late stage osteoclastogenesis. Taken together, our data provide a negative regulatory mechanism by which macrophage-colony-stimulating factor activates Src family kinases and Cbl proteins, and subsequently, induces NFATc1 degradation during osteoclast differentiation.


Assuntos
Diferenciação Celular/fisiologia , Regulação para Baixo/fisiologia , Fator Estimulador de Colônias de Macrófagos/metabolismo , Fatores de Transcrição NFATC/metabolismo , Osteoclastos/metabolismo , Ubiquitina/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Regulação para Baixo/efeitos dos fármacos , Humanos , Fator Estimulador de Colônias de Macrófagos/farmacologia , Camundongos , Camundongos Mutantes , Proteínas Proto-Oncogênicas c-cbl/metabolismo , Proteínas Proto-Oncogênicas pp60(c-src)/metabolismo
19.
J Immunol ; 183(3): 1862-70, 2009 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-19587010

RESUMO

IL-1 is a potent cytokine that can induce bone erosion in inflammatory sites such as rheumatoid joint regions via activation of osteoclasts. Not only is IL-1 capable of activating osteoclasts, but it is also a key cytokine involved in the differentiation, multinucleation, and survival of osteoclasts. Herein, we show that IL-1 has the potential to drive osteoclast differentiation via a receptor activator of NF-kappaB ligand (RANKL)/RANK-independent mechanism. Although IL-1 has a synergistic effect on RANKL-induced osteoclast formation, IL-1 alone cannot induce osteoclast differentiation from osteoclast precursors (bone marrow-derived macrophages (BMMs)) due to a lack of IL-1 signaling potential in these cells. However, we demonstrate that overexpression of the IL-1RI receptor in BMMs or induction of IL-1RI by c-Fos overexpression enables IL-1 alone to induce the formation of authentic osteoclasts by a RANKL/RANK-independent mechanism. The expression of IL-1RI is up-regulated by RANKL via c-Fos and NFATc1. Furthermore, the addition of IL-1 to IL-1RI overexpressing BMMs (IL-1/IL-1RI) strongly activates NF-kappaB, JNK, p38, and ERK which is a hallmark gene activation profile of osteoclastogenesis. Interestingly, IL-1/IL-1RI does not induce expression of c-Fos or NFATc1 during osteoclast differentiation, although basal levels of c-Fos and NFATc1 seem to be required. Rather, IL-1/IL-1RI strongly activates MITF, which subsequently induces osteoclast-specific genes such as osteoclast-associated receptor and tartrate-resistant acid phosphatase. Together, these results reveal that IL-1 has the potential to induce osteoclast differentiation via activation of microphthalmia transcription factor under specific microenvironmental conditions.


Assuntos
Diferenciação Celular , Interleucina-1/fisiologia , Fator de Transcrição Associado à Microftalmia/metabolismo , Osteoclastos/citologia , Animais , Células da Medula Óssea/citologia , Humanos , Camundongos , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/fisiologia , Ligante RANK , Receptor Ativador de Fator Nuclear kappa-B , Receptores Tipo I de Interleucina-1/genética , Receptores Tipo I de Interleucina-1/metabolismo
20.
Front Immunol ; 12: 700755, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34276693

RESUMO

Background: Dendritic cells (DCs) are specialized antigen-presenting cells known to bridge innate and adaptive immune reactions. However, the relationship between circulating DCs and Orientia tsutsugamushi infection is unclear. Therefore, this study aimed to examine the level and function of plasmacytoid DCs (pDCs) and conventional DCs (cDCs), two subsets of circulating DCs, in scrub typhus patients. Methods: The study included 35 scrub typhus patients and 35 healthy controls (HCs). pDC and cDC levels, CD86 and CD274 expression, and cytokine levels were measured using flow cytometry. Results: Circulating pDC and cDC levels were found to be significantly reduced in scrub typhus patients, which were correlated with disease severity. The patients displayed increased percentages of CD86+ pDCs, CD274+ pDCs, and CD274+ cDCs in the peripheral blood. The alterations in the levels and surface phenotypes of pDCs and cDCs were recovered in the remission state. In addition, the production of interferon (IFN)-α and tumor necrosis factor (TNF)-α by circulating pDCs, and interleukin (IL)-12 and TNF-α by circulating cDCs was reduced in scrub typhus patients. Interestingly, our in vitro experiments showed that the percentages of CD86+ pDCs, CD274+ pDCs, and CD274+ cDCs were increased in cultures treated with cytokines including IFN-γ, IL-12, and TNF-α. Conclusions: This study demonstrates that circulating pDCs and cDCs are numerically deficient and functionally impaired in scrub typhus patients. In addition, alterations in the expression levels of surface phenotypes of pDCs and cDCs could be affected by pro-inflammatory cytokines.


Assuntos
Células Dendríticas/imunologia , Tifo por Ácaros/imunologia , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
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