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1.
Am J Clin Nutr ; 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31950134

RESUMO

BACKGROUND: Obese children are vulnerable to vitamin D deficiency and impaired cardiovascular health; vitamin D replenishment might improve their cardiovascular health. OBJECTIVES: The aims were to determine, in vitamin D-deficient overweight and obese children, whether supplementation with vitamin D3 1000 or 2000 IU/d is more effective than 600 IU/d in improving arterial endothelial function, arterial stiffness, central and systemic blood pressure (BP), insulin sensitivity (1/fasting insulin concentration), fasting glucose concentration, and lipid profile and to explore whether downregulation of adipocytokines and markers of systemic inflammation underlies vitamin D effects. METHODS: We conducted a randomized, double-masked, controlled clinical trial in 225 10- to 18-y-old eligible children. Change in endothelial function at 6 mo was the primary outcome. RESULTS: Dose-response increases in serum 25-hydroxyvitamin D concentrations were significant and tolerated without developing hypercalcemia. Changes at 3 and 6 mo in endothelial function, arterial stiffness, systemic-systolic BP, lipids, and inflammatory markers did not differ between children receiving 1000 or 2000 IU vitamin D and children receiving 600 IU. Some secondary outcomes differed between groups. Compared with the 600-IU group, central-systolic, central-diastolic, and systemic-diastolic BP was lower at 6 mo in the 1000-IU group [-2.66 (95% CI: -5.27, -0.046), -3.57 (-5.97, -1.17), and -3.28 (-5.55, -1.00) mm Hg, respectively]; insulin sensitivity increased at 3 and 6 mo and fasting glucose concentration declined at 6 mo (-2.67; 95% CI: -4.88, -0.46 mg/dL) in the 2000-IU group. CONCLUSIONS: Correction of vitamin D deficiency in overweight and obese children by vitamin D3 supplementation with 1000 or 2000 IU/d versus 600 IU/d did not affect measures of arterial endothelial function or stiffness, systemic inflammation, or lipid profile, but resulted in reductions in BP and fasting glucose concentration and in improvements in insulin sensitivity. Optimization of children's vitamin D status may improve their cardiovascular health. This trial was registered at clinicaltrials.gov as NCT01797302.

2.
Nutrients ; 11(9)2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31466225

RESUMO

Associations between whole blood transcriptome and clinical phenotypes in vitamin D-deficient overweight and obese children can provide insight into the biological effects of vitamin D and obesity. We determined differentially expressed genes (DEGs) in relation to body mass index (BMI) in vitamin D-deficient black children with a BMI ≥ 85th percentile and ascertained the cardiometabolic phenotypes associated with the DEGs. We examined whole-blood transcriptome gene expression by RNA sequencing and cardiometabolic profiling in 41, 10- to 18-year-old children. We found 296 DEGs in association with BMI after adjusting for age, race, sex, and pubertal status. Cardiometabolic phenotypes associated with the BMI-related DEGs, after adjusting for age, sex, pubertal status, and %total body fat, were (i) flow-mediated dilation (marker of endothelial function), (ii) c-reactive protein (marker of inflammation), and (iii) leptin (adipocytokine). Canonical pathways of relevance for childhood obesity and its phenotypes that were significantly associated with the BMI-related DEGs affected immune cell function/inflammation, vascular health, metabolic function, and cell survival/death; several immune and inflammatory pathways overlapped across the three phenotypes. We have identified transcriptome-based biomarkers associated with BMI in vitamin D-deficient, overweight and obese black children. Modulating effects of vitamin D supplementation on these biomarkers and their related phenotypes need further exploration.


Assuntos
Afro-Americanos/genética , Metabolismo Energético/genética , Obesidade Pediátrica/genética , Transcriptoma , Deficiência de Vitamina D/genética , Adiposidade/genética , Adolescente , Biomarcadores/sangue , Índice de Massa Corporal , Criança , Estudos Transversais , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Obesidade Pediátrica/sangue , Obesidade Pediátrica/diagnóstico , Obesidade Pediátrica/etnologia , Pennsylvania/epidemiologia , Fenótipo , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/diagnóstico , Deficiência de Vitamina D/etnologia
3.
Med Sci Sports Exerc ; 51(8): 1684-1691, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30817709

RESUMO

Identifying promoters of cerebral small vein integrity is important to counter vascular contributions to cognitive impairment and dementia. PURPOSE: In this preliminary investigation, the effects of a randomized 24-month physical activity (PA) intervention on changes in cerebral small vein integrity were compared to those of a health education (HE) control. METHODS: Cerebral small vein integrity was measured in 24 older adults (n = 8, PA; n = 16, HE) using ultra-high field MRI before and at the end of the 24-month intervention. Deep medullary veins were defined as straight or tortuous; percent change in straight length, tortuous length, and tortuosity ratio were computed. Microbleed count and white matter hyperintensities were also rated. RESULTS: Accelerometry-based values of PA increased by 17.2% in the PA group but declined by 28.0% in the HE group. The PA group, but not the HE group, had a significant increase in straight vein length from baseline to 24-month follow-up (P = 0.02 and P = 0.21, respectively); the between-group difference in percent change in straight length was significant (increase: median, 93.6%; interquartile range, 112.9 for PA; median, 28.4%; interquartile range, 90.6 for HE; P = 0.07). Between group differences in other markers were nonsignificant. CONCLUSIONS: Increasing PA in late-life may promote cerebral small vein integrity. This should be confirmed in larger studies.


Assuntos
Veias Cerebrais/fisiologia , Exercício/fisiologia , Idoso , Idoso de 80 Anos ou mais , Hemorragia Cerebral/diagnóstico por imagem , Hemorragia Cerebral/fisiopatologia , Veias Cerebrais/diagnóstico por imagem , Veias Cerebrais/patologia , Circulação Cerebrovascular , Disfunção Cognitiva/patologia , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/prevenção & controle , Demência/patologia , Demência/fisiopatologia , Demência/prevenção & controle , Feminino , Educação em Saúde , Humanos , Angiografia por Ressonância Magnética , Masculino , Substância Branca/irrigação sanguínea , Substância Branca/diagnóstico por imagem
4.
Front Immunol ; 9: 1802, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30127787

RESUMO

T cells are considered autoimmune effectors in juvenile idiopathic arthritis (JIA), but the antigenic cause of arthritis remains elusive. Since T cells comprise a significant proportion of joint-infiltrating cells, we examined whether the environment in the joint could be shaped through the inflammatory activation by T cells that is independent of conventional TCR signaling. We focused on the analysis of synovial fluid (SF) collected from children with oligoarticular and rheumatoid factor-negative polyarticular JIA. Cytokine profiling of SF showed dominance of five molecules including IL-17A. Cytometric analysis of the same SF samples showed enrichment of αßT cells that lacked both CD4 and CD8 co-receptors [herein called double negative (DN) T cells] and also lacked the CD28 costimulatory receptor. However, these synovial αßT cells expressed high levels of CD31, an adhesion molecule that is normally employed by granulocytes when they transit to sites of injury. In receptor crosslinking assays, ligation of CD31 alone on synovial CD28nullCD31+ DN αßT cells effectively and sufficiently induced phosphorylation of signaling substrates and increased intracytoplasmic stores of cytokines including IL-17A. CD31 ligation was also sufficient to induce RORγT expression and trans-activation of the IL-17A promoter. In addition to T cells, SF contained fibrocyte-like cells (FLC) expressing IL-17 receptor A (IL-17RA) and CD38, a known ligand for CD31. Stimulation of FLC with IL-17A led to CD38 upregulation, and to production of cytokines and tissue-destructive molecules. Addition of an oxidoreductase analog to the bioassays suppressed the CD31-driven IL-17A production by T cells. It also suppressed the downstream IL-17A-mediated production of effectors by FLC. The levels of suppression of FLC effector activities by the oxidoreductase analog were comparable to those seen with corticosteroid and/or biologic inhibitors to IL-6 and TNFα. Collectively, our data suggest that activation of a CD31-driven, αßTCR-independent, IL-17A-mediated T cell-FLC inflammatory circuit drives and/or perpetuates synovitis. With the notable finding that the oxidoreductase mimic suppresses the effector activities of synovial CD31+CD28null αßT cells and IL-17RA+CD38+ FLC, this small molecule could be used to probe further the intricacies of this inflammatory circuit. Such bioactivities of this small molecule also provide rationale for new translational avenue(s) to potentially modulate JIA synovitis.


Assuntos
Artrite Juvenil/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Sinovite/imunologia , Linfócitos T/imunologia , Antígenos CD28 , Criança , Estudos de Coortes , Citocinas/metabolismo , Feminino , Humanos , Interleucina-17/genética , Masculino , Metaloporfirinas/farmacologia , Oxirredutases/metabolismo , Fosforilação , Molécula-1 de Adesão Celular Endotelial a Plaquetas , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-abl/antagonistas & inibidores , Subpopulações de Linfócitos T/imunologia
5.
Am J Geriatr Psychiatry ; 26(6): 690-699, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29628321

RESUMO

OBJECTIVES: Hippocampal hyperactivation marks preclinical dementia pathophysiology, potentially due to differences in the connectivity of specific medial temporal lobe structures. Our aims were to characterize the resting-state functional connectivity of medial temporal lobe sub-structures in older adults, and evaluate whether specific substructural (rather than global) functional connectivity relates to memory function. METHODS: In 15 adults (mean age: 69 years), we evaluated the resting state functional connectivity of medial temporal lobe substructures: dentate/Cornu Ammonis (CA) 4, CA1, CA2/3, subiculum, the molecular layer, entorhinal cortex, and parahippocampus. We used 7-Tesla susceptibility weighted imaging and magnetization-prepared rapid gradient echo sequences to segment substructures of the hippocampus, which were used as structural seeds for examining functional connectivity in a resting BOLD sequence. We then assessed correlations between functional connectivity with memory performance (short and long delay free recall on the California Verbal Learning Test [CVLT]). RESULTS: All the seed regions had significant connectivity within the temporal lobe (including the fusiform, temporal, and lingual gyri). The left CA1 was the only seed with significant functional connectivity to the amygdala. The left entorhinal cortex was the only seed to have significant functional connectivity with frontal cortex (anterior cingulate and superior frontal gyrus). Only higher left dentate-left lingual connectivity was associated with poorer CVLT performance (Spearman r = -0.81, p = 0.0003, Benjamini-Hochberg false discovery rate: 0.01) after multiple comparison correction. CONCLUSIONS: Rather than global hyper-connectivity of the medial temporal lobe, left dentate-lingual connectivity may provide a specific assay of medial temporal lobe hyper-connectivity relevant to memory in aging.


Assuntos
Mapeamento Encefálico , Hipocampo/fisiopatologia , Memória/fisiologia , Idoso , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Rememoração Mental/fisiologia , Vias Neurais/fisiopatologia
6.
Front Immunol ; 7: 530, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27933066

RESUMO

The fundamental challenge of aging and long-term survivorship is maintenance of functional independence and compression of morbidity despite a life history of disease. Inasmuch as immunity is a determinant of individual health and fitness, unraveling novel mechanisms of immune homeostasis in late life is of paramount interest. Comparative studies of young and old persons have documented age-related atrophy of the thymus, the contraction of diversity of the T cell receptor (TCR) repertoire, and the intrinsic inefficiency of classical TCR signaling in aged T cells. However, the elderly have highly heterogeneous health phenotypes. Studies of defined populations of persons aged 75 and older have led to the recognition of successful aging, a distinct physiologic construct characterized by high physical and cognitive functioning without measurable disability. Significantly, successful agers have a unique T cell repertoire; namely, the dominance of highly oligoclonal αßT cells expressing a diverse array of receptors normally expressed by NK cells. Despite their properties of cell senescence, these unusual NK-like T cells are functionally active effectors that do not require engagement of their clonotypic TCR. Thus, NK-like T cells represent a beneficial remodeling of the immune repertoire with advancing age, consistent with the concept of immune plasticity. Significantly, certain subsets are predictors of physical/cognitive performance among older adults. Further understanding of the roles of these NK-like T cells to host defense, and how they integrate with other physiologic domains of function are new frontiers for investigation in Aging Biology. Such pursuits will require a research paradigm shift from the usual young-versus-old comparison to the analysis of defined elderly populations. These endeavors may also pave way to age-appropriate, group-targeted immune interventions for the growing elderly population.

7.
Neurobiol Aging ; 36(11): 3038-3044, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26279115

RESUMO

We aimed to investigate if trajectory components (baseline level, slope, and variability) of peripheral interleukin-6 (IL-6) over time were related to cognitive impairment and smaller hippocampal volume and if hippocampal volume explained the associations between IL-6 and cognitive impairment. Multivariable regression models were used to test the association between IL-6 trajectory components with change in neuroimaging measures of the hippocampus and with cognitive impairment among 135 older adults (70-79 years at baseline) from the Healthy Brain Project over 14 years. IL-6 variability was positively associated with cognitive impairment (odds ratio [OR] = 5.86, 95% confidence interval [CI]: 1.24, 27.61) and with greater decrease per year of gray matter volume of the hippocampus (ß = -0.008, standard error = 0.004, p = 0.03). After adjustment for hippocampal volume, the OR of cognitive impairment decreased for each unit of IL-6 variability and CIs widened (OR = 4.36, 95% CI: 0.67, 28.29). Neither baseline levels nor slopes of IL-6 were related to cognitive impairment or hippocampal volume. We believe this has potential clinical and public health implications by suggesting adults with stable levels of peripheral IL-6 may be better targets for intervention studies for slowing or preventing cognitive decline.


Assuntos
Envelhecimento/metabolismo , Envelhecimento/patologia , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/patologia , Hipocampo/patologia , Interleucina-6/metabolismo , Idoso , Estudos de Coortes , Feminino , Substância Cinzenta/patologia , Humanos , Masculino , Neuroimagem , Estudos Prospectivos , Análise de Regressão , Fatores de Tempo
8.
Semin Arthritis Rheum ; 45(3): 284-93, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26254121

RESUMO

OBJECTIVE: To evaluate peripheral blood T-helper (TH) cell-associated cytokine and chemokine profiles in localized scleroderma (LS), and correlate them with clinical disease features, including disease activity parameters. METHODS: A 29-plex Luminex platform was used to analyze the humoral profile of plasma samples from 69 pediatric LS patients and 71 healthy pediatric controls. Cytokine/chemokine levels were compared between these two groups and within LS patients, focusing on validated clinical outcome measures of disease activity and damage in LS. RESULTS: Plasma levels of IP-10, MCP-1, IL-17a, IL-12p70, GM-CSF, PDGF-bb, IFN-α2, and IFN-γ were significantly higher in LS subjects compared to healthy controls. Analysis within the LS group demonstrated IP-10, TNF-α, and GM-CSF correlated with clinical measures of disease activity. Several cytokines/chemokines correlated with anti-histone antibody, while only a few correlated with positive ANA and single-stranded DNA antibody. CONCLUSION: This is the first time that multiple cytokines and chemokines have been examined simultaneously in LS. In general, a TH1 (IFN-γ) and TH17 (IL-17a) predominance was demonstrated in LS compared to healthy controls. There is also an IFN-γ signature with elevated IP-10, MCP-1, and IFN-γ, which has been previously demonstrated in systemic sclerosis, suggesting a shared pathophysiology. Within the LS patients, those with active disease demonstrated IP-10, TNF-α, and GM-CSF, which may potentially serve as biomarkers of disease activity in the clinical setting.


Assuntos
Quimiocinas/sangue , Citocinas/sangue , Esclerodermia Localizada/sangue , Linfócitos T Auxiliares-Indutores , Adolescente , Becaplermina , Quimiocina CCL2/sangue , Criança , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/sangue , Humanos , Interferon-alfa/sangue , Interferon gama/sangue , Interleucina-12/sangue , Interleucina-17/sangue , Masculino , Proteínas Proto-Oncogênicas c-sis/sangue , Receptores de Citocinas/sangue
9.
Infect Immun ; 83(10): 4056-67, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26216426

RESUMO

Rhesus macaques were studied to directly address the potential for plasmid-deficient Chlamydia trachomatis to serve as a live attenuated vaccine in the genital tract. Five repeated cervical inoculations of rhesus macaques with wild-type serovar D strain D/UW-3/Cx or a plasmid-deficient derivative of this strain, CTD153, resulted in infections with similar kinetics and induced comparable levels of protective immunity. After all animals received five challenges with D/UW-3/Cx, levels of inflammation observed grossly and histologically were similar between the groups. Animals in both groups developed evidence of oviduct dilatation; however, reduced oviduct dilatation was observed for "controllers," i.e., animals without detectable chlamydial DNA in the fimbriae at weeks 5 and 12. Grouping animals into "ascenders" and "controllers" revealed that elevated early T cell responses were associated with protection, whereas higher antibody responses were associated with ascension. Protected animals shared common major histocompatibility complex (MHC) alleles. Overall, genetic differences of individual animals, rather than the presence or absence of the chlamydial plasmid in the primary infecting strain, appeared to play a role in determining the outcome of infection.


Assuntos
Infecções por Chlamydia/microbiologia , Chlamydia trachomatis/fisiologia , Infecções do Sistema Genital/microbiologia , Animais , Linfócitos T CD8-Positivos/imunologia , Infecções por Chlamydia/imunologia , Infecções por Chlamydia/patologia , Chlamydia trachomatis/classificação , Chlamydia trachomatis/genética , Chlamydia trachomatis/isolamento & purificação , Feminino , Humanos , Macaca mulatta , Plasmídeos/genética , Plasmídeos/metabolismo , Infecções do Sistema Genital/imunologia , Infecções do Sistema Genital/patologia , Sorogrupo
10.
AIDS ; 28(17): 2505-15, 2014 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-25574956

RESUMO

OBJECTIVE: To determine associations between circulating markers of immune activation, immune cell senescence, and inflammation with HIV-associated abnormalities of pulmonary function. DESIGN: HIV infection is an independent risk factor for abnormal pulmonary function. Immune activation, immune senescence, and chronic inflammation are characteristics of chronic HIV infection that have been associated with other HIV-associated comorbidities and may be related to pulmonary disease in this population. METHODS: Participants from an HIV-infected cohort (n = 147) completed pulmonary function testing (PFT). Markers of T-cell activation and senescence were determined by flow cytometry, and plasma levels of interleukin-6, interleukin-8, and C-reactive protein (CRP) were measured, as was telomere length of peripheral blood mononuclear cells (PBMC). Regression models adjusting for clinical risk factors were constructed to examine relationships between biomarkers and PFT outcomes. RESULTS: Activated CD25(+) T cells and activated/senescent CD69(+)/CD57(+)/CD28(null) CD4(+) T cells, interleukin-6, and CRP were associated with PFT abnormalities. Shortening of PBMC telomere length correlated with airflow obstruction and diffusing impairment. Paradoxically, circulating senescent CD57(+)/CD28(null) CD8(+) T cells were associated with better PFT outcomes. CONCLUSION: Circulating T cells expressing markers of activation and inflammatory cytokine levels are independently correlated with PFT abnormalities in HIV-infected persons. Overall telomere shortening was also associated with pulmonary dysfunction. The paradoxical association of senescent CD8(+) T cells and better PFT outcomes could suggest an unrecognized beneficial compensatory function of such cells or a redistribution of these cells from the circulation to local compartments. Further studies are needed to differentiate and characterize functional subsets of local pulmonary and circulating T-cell populations in HIV-associated pulmonary dysfunction.


Assuntos
Infecções por HIV/complicações , Infecções por HIV/imunologia , Pneumopatias/epidemiologia , Ativação Linfocitária , Linfócitos T/imunologia , Adulto , Envelhecimento , Estudos de Coortes , Estudos Transversais , Citocinas/sangue , Feminino , Humanos , Pneumopatias/patologia , Masculino , Pessoa de Meia-Idade , Testes de Função Respiratória
11.
Sci Signal ; 6(278): ra44, 2013 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-23737552

RESUMO

The proinflammatory cytokine interleukin-17 (IL-17) is the signature cytokine of the T helper 17 (TH17) subset of CD4(+) T cells, and antibodies targeting IL-17 or the IL-17 receptor (IL-17R) show clinical efficacy in several autoimmune diseases. Although important for protective immunity against microorganisms, IL-17 causes collateral damage in inflammatory settings. TNFAIP3 encodes the deubiquitinase A20 and is genetically linked to numerous autoimmune syndromes. A20, a potent inhibitor of tumor necrosis factor-α signaling, removes ubiquitin from signaling intermediates upstream of nuclear factor κB (NF-κB), thereby dampening NF-κB-mediated inflammation. We demonstrated that IL-17 stimulates TNFAIP3 expression. Enhanced IL-17-mediated induction of genes encoding proinflammatory factors, including IL-6 and various chemokines, occurred upon knockdown of A20 with short inhibitory RNA or in A20(-/-) cells. A20 associated with the E3 ubiquitin ligase TRAF6 (tumor necrosis factor receptor-associated factor 6) in an IL-17-dependent manner and restricted the IL-17-dependent activation of NF-κB and mitogen-activated protein kinases. A20 interacted directly with the distal domain of IL-17RA, a previously defined inhibitory domain. Together, these data describe a mechanism of restraining IL-17 signaling and reveal an aspect of A20 activity that may help to explain its role in autoimmunity in humans.


Assuntos
Receptores de Interleucina-17/metabolismo , Transdução de Sinais , Proteases Específicas de Ubiquitina/metabolismo , Humanos , NF-kappa B/metabolismo , Regiões Promotoras Genéticas , Receptores de Interleucina-17/genética , Fator 6 Associado a Receptor de TNF/metabolismo
12.
Arthritis Rheum ; 65(8): 2201-10, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23686519

RESUMO

OBJECTIVE: CD8+ T cells lacking CD28 were originally reported to be a characteristic feature of juvenile idiopathic arthritis (JIA), but the relevance of these unusual cells to this disease remains to be elucidated. Because of recent evidence that loss of CD28 cells is typical of terminally differentiated lymphocytes, the aim of this study was to examine functional subsets of CD8+ T cells in patients with JIA. METHODS: Blood and/or waste synovial fluid samples were collected from children with a definite diagnosis of JIA (n = 98). Deidentified peripheral blood (n = 33) and cord blood (n = 13) samples from healthy donors were also collected. CD8+ and CD4+ T cells were screened for novel receptors, and where indicated, bioassays were performed to determine the functional relevance of the identified receptor. RESULTS: JIA patients had a naive T cell compartment with shortened telomeres, and their entire T cell pool had reduced proliferative capacity. They had an overabundance of CD31+CD28(null) CD8+ T cells, which was a significant feature of oligoarticular JIA (n = 62) as compared to polyarticular JIA (n = 36). CD31+ CD28(null) CD8+ T cells had limited mitotic capacity and expressed high levels of the senescence antigens histone γH2AX and/or p16. Ligation of CD31, which was independent of the T cell receptor (TCR), sufficiently induced tyrosine phosphorylation, vesicle exocytosis, and production of interferon-γ and interleukin-10. CONCLUSION: These data provide the first evidence of cell senescence, as represented by CD31+CD28(null) CD8+ T cells, in the pathophysiology of JIA. Activation of these unusual cells in a TCR-independent manner suggests that they are maladaptive and could be potential targets for immunotherapy.


Assuntos
Artrite Juvenil/imunologia , Linfócitos T CD8-Positivos/imunologia , Senescência Celular/fisiologia , Ativação Linfocitária/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Adolescente , Artrite Juvenil/patologia , Antígenos CD28 , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Proliferação de Células , Criança , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Feminino , Sangue Fetal/citologia , Sangue Fetal/imunologia , Histonas/metabolismo , Humanos , Masculino , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Líquido Sinovial/citologia , Líquido Sinovial/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/patologia , Telômero/patologia , Fatores de Tempo
13.
PLoS One ; 8(5): e64619, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23705001

RESUMO

PURPOSE: To investigate the effects of inflammatory factors and oxidative stress on cell survival of the human retinal pigment epithelial (RPE) cell line, ARPE-19. METHODS: Confluent RPE cells were treated with peripheral blood mononuclear cells-conditioned medium (PCM), H2O2, NaIO3, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, or combinations of these. Cell viability was determined by viability assays and by light microscopy. Effector molecules of cell death were investigated by immunofluorescence microscopy and flow cytometry. Microarrays were performed to screen for differential expression of anti-oxidative enzymes, and protein expression was validated by immunoblotting. RESULTS: Viability of RPE cells was reduced by exposure to inflammatory agents (PCM, IFNγ+/-TNFα) or to oxidative agents (H2O2 or NaIO3). Unexpectedly, cells treated with either H2O2 or NaIO3 were partially protected from cell death by the addition of PCM. This protection was conferred, at least in part, by IFNγ and TNFα. Cell death induced by H2O2 or NaIO3 was preceded by mitochondrial dysfunction and by p62 upregulation, both of which were attenuated by PCM and/or by IFNγ+TNFα. RPE cells co-cultured with activated T cells, or treated with cytokines showed increased expression of anti-oxidative genes, with upregulation of superoxide dismutase 2 protein following PCM treatment. CONCLUSION: Oxidative stress-induced cell death was reduced by concomitant inflammatory stress. This is likely due to the cytokine-mediated induction of the anti-oxidative stress response, upregulating protective anti-oxidant pathway(s). These findings suggest caution for the clinical use of anti-inflammatory agents in the management of immune-associated eye diseases such as age-related macular degeneration.


Assuntos
Citocinas/farmacologia , Citoproteção/efeitos dos fármacos , Células Epiteliais/patologia , Mediadores da Inflamação/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Epitélio Pigmentado da Retina/patologia , Adulto , Autofagia/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Cocultura , Meios de Cultivo Condicionados/farmacologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Peróxido de Hidrogênio/farmacologia , Interferon gama/farmacologia , Iodatos/farmacologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Oxidantes/farmacologia , Superóxido Dismutase/metabolismo , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
14.
15.
Aging Dis ; 3(1): 5-15, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22500268

RESUMO

Successful aging is a multidimensional construct that could be viewed as a continuum of achievement. Based on the disability model proposed by the WHO International Classification of Functioning, Disability and Health, successful aging includes not only the presence or absence of disease, but also aspects of mobility and social participation. Here we review definitions of successful aging and discuss relevance of the disability model in the evaluation of successful aging and frailty. In particular, we summarize evidences that highlight the importance of measures of mobility (ability to walk and perform activities of daily living), and social participation in identifying and locating older adults across the range of the successful aging continuum. Lastly, we discuss the role of inflammation in age-related decline and in frailty. Future research directions are proposed, including identifying causal pathways among inflammatory markers, disability, and frailty. A better understanding of immunological functioning in late life may help unlock novel ways to promote successful aging.

16.
Aging Dis ; 3(1): 34-50, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22500270

RESUMO

Studies comparing chronologically "young" versus "old" humans document age-related decline of classical immunological functions. However, older adults aged ≥65 years have very heterogeneous health phenotypes. A significant number of them are functionally independent and are surviving well into their 8(th)-11(th) decade life, observations indicating that aging or old age is not synonymous with immune incompetence. While there are dramatic age-related changes in the immune system, not all of these changes may be considered detrimental. Here, we review evidences for novel immunologic processes that become elaborated with advancing age that complement preserved classical immune functions and promote immune homeostasis later in life. We propose that elaboration such of late life immunologic properties is indicative of beneficial immune remodeling that is an integral component of successful aging, an emerging physiologic construct associated with similar age-related physiologic adaptations underlying maintenance of physical and cognitive function. We suggest that a systems approach integrating immune, physical, and cognitive functions, rather than a strict immunodeficiency-minded approach, will be key towards innovations in clinical interventions to better promote protective immunity and functional independence among the elderly.

17.
PLoS One ; 6(10): e26558, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22028907

RESUMO

Exceptional aging has been defined as maintenance of physical and cognitive function beyond the median lifespan despite a history of diseases and/or concurrent subclinical conditions. Since immunity is vital to individual fitness, we examined immunologic fingerprint(s) of highly functional elders. Therefore, survivors of the Cardiovascular Health Study in Pittsburgh, Pennsylvania, USA were recruited (n = 140; mean age = 86 years) and underwent performance testing. Blood samples were collected and examined blindly for humoral factors and T cell phenotypes. Based on results of physical and cognitive performance testing, elders were classified as "impaired" or "unimpaired", accuracy of group assignment was verified by discriminant function analysis. The two groups showed distinct immune profiles as determined by factor analysis. The dominant immune signature of impaired elders consisted of interferon (IFN)-γ, interleukin (IL)-6, tumor necrosis factor-α, and T cells expressing inhibitory natural killer-related receptors (NKR) CD158a, CD158e, and NKG2A. In contrast, the dominant signature of unimpaired elders consisted of IL-5, IL-12p70, and IL-13 with co-expression of IFN-γ, IL-4, and IL-17, and T cells expressing stimulatory NKRs CD56, CD16, and NKG2D. In logistic regression models, unimpaired phenotype was predicted independently by IL-5 and by CD4(+)CD28(null)CD56(+)CD57(+) T cells. All elders had high antibody titers to common viruses including cytomegalovirus. In cellular bioassays, T cell receptor (TCR)-independent ligation of either CD56 or NKG2D elicited activation of T cells. Collectively, these data demonstrate the importance of immunological parameters in distinguishing between health phenotypes of older adults. NKR(+) T cells and cytokine upregulation indicate a unique physiologic environment in old age. Correlation of particular NKR(+) T cell subsets and IL-5 with unimpaired performance, and NKR-driven TCR-independent activation of T cells suggest novel immunopathway(s) that could be exploited to improve immunity in old age.


Assuntos
Envelhecimento/sangue , Envelhecimento/imunologia , Transtornos Cognitivos/fisiopatologia , Citocinas/sangue , Células Matadoras Naturais/imunologia , Subpopulações de Linfócitos T/imunologia , Adolescente , Adulto , Idoso de 80 Anos ou mais , Envelhecimento/fisiologia , Antígeno CD56/metabolismo , Fenômenos Fisiológicos Cardiovasculares , Transtornos Cognitivos/sangue , Transtornos Cognitivos/imunologia , Regulação da Expressão Gênica/imunologia , Humanos , Imunidade Humoral , Longevidade/imunologia , Longevidade/fisiologia , Masculino , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Fenótipo , Aptidão Física/fisiologia , Subpopulações de Linfócitos T/metabolismo , Adulto Jovem
18.
Int Immunol ; 23(6): 375-84, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21551245

RESUMO

Chronic lymphocytic leukemia (CLL) is a common malignancy characterized by the accumulation of B lymphocytes with an antigen-experienced activated CD19(+)CD5(+) clonal phenotype. Clinically, ∼50% of cases will behave more aggressively. Here, we investigate the role of the major B-cell transcription factor E2A, a known regulator of B-cell survival and proliferation, to CLL persistence. We show that E2A is elevated at the mRNA and protein levels relative to normal B-cell subsets. E2A silencing in primary CLL cells leads to a significant increase in spontaneous apoptosis in both CD38(+) (aggressive) and CD38(-) (indolent) cases. Moreover, E2A knockdown synergizes with the immunomodulatory drug lenalidomide to reduce CLL viability. E2A is known to restrain the proliferation of primary B and T lymphocytes at multiple stages of maturation and we report that targeted E2A disruption increases the frequency of Ki-67(+) CLL cells in the absence of effects on de novo proliferation. At the molecular level, E2A siRNA-treated CLL cells display reduced expression of key genes associated with survival and cell cycling including p27, p21 and mcl-1, of which the former two are known E2A target genes. Thus, E2A, a key transcription factor associated with the B-cell activation profile, regulates apoptosis in CLL and may contribute to disease pathology.


Assuntos
Apoptose/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Células Cultivadas , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Adulto Jovem
19.
Ageing Res Rev ; 10(3): 315-8, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21315185

RESUMO

Census reports of many countries indicate continuing trends for the graying of their populations. For the United States alone, persons aged ≥65 years are projected to comprise over 20% of the population by the year 2050. In view of the special medical needs of elders, scientific investigation into the biological aspects of ageing is key towards the improvement of geriatric care for the coming decades. This special issue of Ageing Research Reviews focuses on advances in research on the immunology of human ageing. Herein are nine articles about the age-related alterations in both the innate and adaptive arms of the immune system, and about continuing hurdles in vaccinology. These articles point to a common theme that the immunological milieu in old age is substantially different from that seen in the young. This suggests that new development and/or innovation of immune-based clinical interventions for the elderly may need to be customized for their age group, rather than the mere adoption of therapies that have been designed for and/or tested for younger persons.


Assuntos
Envelhecimento/imunologia , Envelhecimento/fisiologia , Pesquisa Biomédica/tendências , Imunidade Adaptativa/fisiologia , Idoso , Idoso de 80 Anos ou mais , Serviços de Saúde para Idosos , Humanos , Imunidade Inata/fisiologia , Imunoterapia Ativa
20.
J Clin Invest ; 121(3): 976-84, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21285510

RESUMO

Defects in cholesterol synthesis result in a wide variety of symptoms, from neonatal lethality to the relatively mild dysmorphic features and developmental delay found in individuals with Smith-Lemli-Opitz syndrome. We report here the identification of mutations in sterol-C4-methyl oxidase­like gene (SC4MOL) as the cause of an autosomal recessive syndrome in a human patient with psoriasiform dermatitis, arthralgias, congenital cataracts, microcephaly, and developmental delay. This gene encodes a sterol-C4-methyl oxidase (SMO), which catalyzes demethylation of C4-methylsterols in the cholesterol synthesis pathway. C4-Methylsterols are meiosis-activating sterols (MASs). They exist at high concentrations in the testis and ovary and play roles in meiosis activation. In this study, we found that an accumulation of MASs in the patient led to cell overproliferation in both skin and blood. SMO deficiency also substantially altered immunocyte phenotype and in vitro function. MASs serve as ligands for liver X receptors α and ß(LXRα and LXRß), which are important in regulating not only lipid transport in the epidermis, but also innate and adaptive immunity. Deficiency of SMO represents a biochemical defect in the cholesterol synthesis pathway, the clinical spectrum of which remains to be defined.


Assuntos
Dermatite/genética , Deficiências do Desenvolvimento/genética , Microcefalia/genética , Oxigenases de Função Mista/genética , Oxigenases de Função Mista/metabolismo , Mutação , Psoríase/genética , Adolescente , Colesterol/metabolismo , Dermatite Esfoliativa/diagnóstico , Dermatite Esfoliativa/genética , Feminino , Humanos , Ligantes , Receptores X do Fígado , Meiose , Receptores Nucleares Órfãos/metabolismo
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