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1.
Front Immunol ; 10: 2606, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781109

RESUMO

In systemic lupus erythematosus (SLE), perturbed immunoregulation underpins a pathogenic imbalance between regulatory and effector CD4+ T-cell activity. However, to date, the characterization of the CD4+ regulatory T cell (Treg) compartment in SLE has yielded conflicting results. Here we show that patients have an increased frequency of CD4+FOXP3+ cells in circulation owing to a specific expansion of thymically-derived FOXP3+HELIOS+ Tregs with a demethylated FOXP3 Treg-specific demethylated region. We found that the Treg expansion was strongly associated with markers of recent immune activation, including PD-1, plasma concentrations of IL-2 and the type I interferon biomarker soluble SIGLEC-1. Since the expression of the negative T-cell signaling molecule PTPN22 is increased and a marker of poor prognosis in SLE, we tested the influence of its missense risk allele Trp620 (rs2476601C>T) on Treg frequency. Trp620 was reproducibly associated with increased frequencies of thymically-derived Tregs in blood, and increased PD-1 expression on both Tregs and effector T cells (Teffs). Our results support the hypothesis that FOXP3+ Tregs are increased in SLE patients as a consequence of a compensatory mechanism in an attempt to regulate pathogenic autoreactive Teff activity. We suggest that restoration of IL-2-mediated homeostatic regulation of FOXP3+ Tregs by IL-2 administration could prevent disease flares rather than treating at the height of a disease flare. Moreover, stimulation of PD-1 with specific agonists, perhaps in combination with low-dose IL-2, could be an effective therapeutic strategy in autoimmune disease and in other immune disorders.

2.
J Immunol ; 2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31740485

RESUMO

In mice, the ability of naive T (TN) cells to mount an effector response correlates with TCR sensitivity for self-derived Ags, which can be quantified indirectly by measuring surface expression levels of CD5. Equivalent findings have not been reported previously in humans. We identified two discrete subsets of human CD8+ TN cells, defined by the absence or presence of the chemokine receptor CXCR3. The more abundant CXCR3+ TN cell subset displayed an effector-like transcriptional profile and expressed TCRs with physicochemical characteristics indicative of enhanced interactions with peptide-HLA class I Ags. Moreover, CXCR3+ TN cells frequently produced IL-2 and TNF in response to nonspecific activation directly ex vivo and differentiated readily into Ag-specific effector cells in vitro. Comparative analyses further revealed that human CXCR3+ TN cells were transcriptionally equivalent to murine CXCR3+ TN cells, which expressed high levels of CD5. These findings provide support for the notion that effector differentiation is shaped by heterogeneity in the preimmune repertoire of human CD8+ T cells.

3.
Genome Biol ; 20(1): 230, 2019 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-31684996

RESUMO

BACKGROUND: Molecular and cellular changes are intrinsic to aging and age-related diseases. Prior cross-sectional studies have investigated the combined effects of age and genetics on gene expression and alternative splicing; however, there has been no long-term, longitudinal characterization of these molecular changes, especially in older age. RESULTS: We perform RNA sequencing in whole blood from the same individuals at ages 70 and 80 to quantify how gene expression, alternative splicing, and their genetic regulation are altered during this 10-year period of advanced aging at a population and individual level. We observe that individuals are more similar to their own expression profiles later in life than profiles of other individuals their own age. We identify 1291 and 294 genes differentially expressed and alternatively spliced with age, as well as 529 genes with outlying individual trajectories. Further, we observe a strong correlation of genetic effects on expression and splicing between the two ages, with a small subset of tested genes showing a reduction in genetic associations with expression and splicing in older age. CONCLUSIONS: These findings demonstrate that, although the transcriptome and its genetic regulation is mostly stable late in life, a small subset of genes is dynamic and is characterized by a reduction in genetic regulation, most likely due to increasing environmental variance with age.

4.
Genet Epidemiol ; 43(7): 800-814, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31433078

RESUMO

The power of genetic association analyses can be increased by jointly meta-analyzing multiple correlated phenotypes. Here, we develop a meta-analysis framework, Meta-MultiSKAT, that uses summary statistics to test for association between multiple continuous phenotypes and variants in a region of interest. Our approach models the heterogeneity of effects between studies through a kernel matrix and performs a variance component test for association. Using a genotype kernel, our approach can test for rare-variants and the combined effects of both common and rare-variants. To achieve robust power, within Meta-MultiSKAT, we developed fast and accurate omnibus tests combining different models of genetic effects, functional genomic annotations, multiple correlated phenotypes, and heterogeneity across studies. In addition, Meta-MultiSKAT accommodates situations where studies do not share exactly the same set of phenotypes or have differing correlation patterns among the phenotypes. Simulation studies confirm that Meta-MultiSKAT can maintain the type-I error rate at the exome-wide level of 2.5 × 10-6 . Further simulations under different models of association show that Meta-MultiSKAT can improve the power of detection from 23% to 38% on average over single phenotype-based meta-analysis approaches. We demonstrate the utility and improved power of Meta-MultiSKAT in the meta-analyses of four white blood cell subtype traits from the Michigan Genomics Initiative (MGI) and SardiNIA studies.


Assuntos
Estudos de Associação Genética , Metanálise como Assunto , Frequência do Gene/genética , Genótipo , Humanos , Itália , Leucócitos/metabolismo , Modelos Genéticos , Mutação/genética , Fenótipo
5.
Aging Clin Exp Res ; 2019 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-31302897

RESUMO

AIMS: Previous cross-sectional observation identified arterial aging, indexed as pulse-wave velocity (PWV), as a key determinant of the simultaneous multiple organ damage (heart, carotid artery, and kidney). The aim of the present cohort study is to investigate trajectories of repeated measures of PWV and traditional CV risk factors in subjects who eventually presented clinical evidence of multiple organ damage in the SardiNIA study. METHODS AND RESULTS: Organ damage was measured in the heart (left ventricular hypertrophy, LVH), the common carotid artery (intima-media thickness > 0.9 mm and/or plaque), and the kidney (eGFR < 60 ml/min/1.73 m2) of 2130 men and women of a broad age range participating the SardiNIA study. SHATS was defined as the simultaneous occurrence of all the three-organ damages. Trajectory in traditional CV risk factors and PWV was analyzed retrospectively (four observations over 9 years) according to the number of organ damage (from 0 to 3). Compared to subjects with no organ damage, after controlling for traditional CV risk factors, each 1 m/s increase in baseline PWV was accompanied by a 93% higher odds of developing SHATS; and each 1 cm/s (0.01 m/s) annual increase in PWV by a 31% greater odds of developing SHATS. CONCLUSIONS: Arterial stiffness, a proxy of arterial aging that can be measured clinically as PWV, is an integrated predictive marker of multiple age-associated organ damage recognized as clinical diseases.

6.
Clin Genet ; 95(5): 607-614, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30859550

RESUMO

Crisponi/cold-induced sweating syndrome (CS/CISS) is a rare autosomal recessive disorder characterized by a complex phenotype (hyperthermia and feeding difficulties in the neonatal period, followed by scoliosis and paradoxical sweating induced by cold since early childhood) and a high neonatal lethality. CS/CISS is a genetically heterogeneous disorder caused by mutations in CRLF1 (CS/CISS1), CLCF1 (CS/CISS2) and KLHL7 (CS/CISS-like). Here, a whole exome sequencing approach in individuals with CS/CISS-like phenotype with unknown molecular defect revealed unpredicted alternative diagnoses. This approach identified putative pathogenic variations in NALCN, MAGEL2 and SCN2A. They were already found implicated in the pathogenesis of other syndromes, respectively the congenital contractures of the limbs and face, hypotonia, and developmental delay syndrome, the Schaaf-Yang syndrome, and the early infantile epileptic encephalopathy-11 syndrome. These results suggest a high neonatal phenotypic overlap among these disorders and will be very helpful for clinicians. Genetic analysis of these genes should be considered for those cases with a suspected CS/CISS during neonatal period who were tested as mutation negative in the known CS/CISS genes, because an expedited and corrected diagnosis can improve patient management and can provide a specific clinical follow-up.

7.
Am J Med Genet A ; 179(4): 634-638, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30737887

RESUMO

We report here a novel de novo missense variant affecting the last amino acid of exon 30 of CREBBP [NM_004380, c.5170G>A; p.(Glu1724Lys)] in a 17-year-old boy presenting mild intellectual disability and dysmorphisms but not resembling the phenotype of classical Rubinstein-Taybi syndrome. The patient showed a marked overweight from early infancy on and had cortical heterotopias. Recently, 22 individuals have been reported with missense mutations in the last part of exon 30 and the beginning of exon 31 of CREBBP, showing this new phenotype. This additional case further delineates the genotype-phenotype correlations within the molecular and phenotypic spectrum of variants in CREBBP and EP300.

8.
Cell Cycle ; 18(6-7): 708-722, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30784348

RESUMO

Nuclear factor 90 (NF90) is a dual DNA- and RNA-binding protein expressed ubiquitously in mammalian cells, including monocytes. Here, to elucidate the function of NF90 in the immune response, we analyzed systematically its influence on gene expression programs in the human monocytic cell line THP-1 expressing normal or reduced NF90 levels. RNA sequencing analysis revealed many mRNAs showing differential abundance in NF90-silenced cells, many of them encoding proteins implicated in the response to immune stimuli and malaria infection. The transcription of some of them (e.g. TNF, LILRB1, and CCL2 mRNAs) was modulated by silencing NF90. Ribonucleoprotein immunoprecipitation (RIP) analysis further revealed that a subset of these mRNAs associated directly with NF90. To understand how NF90 influenced globally the immune response to malaria infection, lysates of red blood cells infected with Plasmodium falciparum (iRBC lysates) or uninfected/mock-infected (uRBC lysates) were used to treat THP-1 cells as a surrogate of malaria infection. NF90 affected the stability of a few target mRNAs, but influenced more generally the translation and secretion of the encoded cytokines after treatment with either uRBC or iRBC lysates. Taken together, these results indicate that NF90 contributes to repressing the immune response in cells responding to P. falciparum infection and suggest that NF90 can be a therapeutic target in malaria.

9.
Commun Biol ; 2: 28, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30675526

RESUMO

The impact of the parental origin of associated alleles in GWAS has been largely ignored. Yet sequence variants could affect traits differently depending on whether they are inherited from the mother or the father, as in imprinted regions, where identical inherited DNA sequences can have different effects based on the parental origin. To explore parent-of-origin effects (POEs), we studied 21 quantitative phenotypes in a large Hutterite pedigree to identify variants with single parent (maternal-only or paternal-only) effects, and then variants with opposite parental effects. Here we show that POEs, which can be opposite in direction, are relatively common in humans, have potentially important clinical effects, and will be missed in traditional GWAS. We identified POEs with 11 phenotypes, most of which are risk factors for cardiovascular disease. Many of the loci identified are characteristic of imprinted regions and are associated with the expression of nearby genes.

10.
BMC Med Genet ; 20(1): 16, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-30642272

RESUMO

BACKGROUND: KBG syndrome is a very rare autosomal dominant disorder, characterized by macrodontia, distinctive craniofacial findings, skeletal findings, post-natal short stature, and developmental delays, sometimes associated with seizures and EEG abnormalities. So far, there have been over 100 cases of KBG syndrome reported. CASE PRESENTATION: Here, we describe two sisters of a non-consanguineous family, both presenting generalized epilepsy with febrile seizures (GEFS+), and one with a more complex phenotype associated with mild intellectual disability, skeletal and dental anomalies. Whole exome sequencing (WES) analysis in all the family members revealed a heterozygous SCN9A mutation, p.(Lys655Arg), shared among the father and the two probands, and a novel de novo loss of function mutation in the ANKRD11 gene, p.(Tyr1715*), in the proband with the more complex phenotype. The reassessment of the phenotypic features confirmed that the patient fulfilled the proposed diagnostic criteria for KBG syndrome, although complicated by early-onset isolated febrile seizures. EEG abnormalities with or without seizures have been reported previously in some KBG cases. The shared variant, occurring in SCN9A, has been previously found in several individuals with GEFS+ and Dravet syndrome. CONCLUSIONS: This report describe a novel de novo variant in ANKRD11 causing a mild phenotype of KGB syndrome and further supports the association of monogenic pattern of SCN9A mutations with GEFS+. Our data expand the allelic spectrum of ANKRD11 mutations, providing the first Brazilian case of KBG syndrome. Furthermore, this study offers an example of how WES has been instrumental allowing us to better dissect the clinical phenotype under study, which is a multilocus variation aggregating in one proband, rather than a phenotypic expansion associated with a single genomic locus, underscoring the role of multiple rare variants at different loci in the etiology of clinical phenotypes making problematic the diagnostic path. The successful identification of the causal variant in a gene may not be sufficient, making it necessary to identify other variants that fully explain the clinical picture. The prevalence of blended phenotypes from multiple monogenic disorders is currently unknown and will require a systematic re-analysis of large WES datasets for proper diagnosis in daily practice.


Assuntos
Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/genética , Epilepsia Generalizada/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Deficiência Intelectual/genética , Mutação , Fenótipo , Proteínas Repressoras/genética , Convulsões Febris/genética , Anormalidades Dentárias/genética , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/etiologia , Anormalidades Múltiplas/fisiopatologia , Adolescente , Alelos , Doenças do Desenvolvimento Ósseo/diagnóstico por imagem , Doenças do Desenvolvimento Ósseo/etiologia , Doenças do Desenvolvimento Ósseo/fisiopatologia , Brasil , Eletroencefalografia , Epilepsia Generalizada/fisiopatologia , Facies , Feminino , Loci Gênicos , Heterozigoto , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/etiologia , Deficiência Intelectual/fisiopatologia , Canal de Sódio Disparado por Voltagem NAV1.7/genética , Linhagem , Convulsões Febris/fisiopatologia , Anormalidades Dentárias/diagnóstico por imagem , Anormalidades Dentárias/etiologia , Anormalidades Dentárias/fisiopatologia , Sequenciamento Completo do Exoma
11.
Nat Genet ; 51(2): 237-244, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30643251

RESUMO

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders1. They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6-11. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures.


Assuntos
Consumo de Bebidas Alcoólicas/genética , Fumar/genética , Tabagismo/genética , Feminino , Variação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Risco , Tabaco/efeitos adversos
12.
Genet Epidemiol ; 43(1): 112-117, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30565766

RESUMO

It is unclear whether insertions and deletions (indels) are more likely to influence complex traits than abundant single-nucleotide polymorphisms (SNPs). We sought to understand which category of variation is more likely to impact health. Using the SardiNIA study as an exemplar, we characterized 478,876 common indels and 8,246,244 common SNPs in up to 5,949 well-phenotyped individuals from an isolated valley in Sardinia. We assessed association between 120 traits, resulting in 89 nonoverlapping-associated loci.We evaluated whether indels were enriched among credible sets of potential causal variants. These credible sets included 1,319 SNPs and 88 indels. We did not find indels to be significantly enriched. Indels were the most likely causal variant in seven loci, including one locus associated with monocyte count where an indel with causality and mechanism previously demonstrated (rs200748895:TGCTG/T) had a 0.999 posterior probability. Overall, our results show a very modest and nonsignificant enrichment for common indels in associated loci.


Assuntos
Mutação INDEL/genética , Polimorfismo de Nucleotídeo Único/genética , Loci Gênicos , Humanos , Itália , Anotação de Sequência Molecular
13.
Nat Commun ; 9(1): 4455, 2018 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-30367059

RESUMO

Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves' disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.

14.
Nucleic Acids Res ; 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30272251

RESUMO

Polymorphisms in untranslated regions (UTRs) of disease-associated mRNAs can alter protein production. We recently identified a genetic variant in the 3'UTR of the TNFSF13B gene, encoding the cytokine BAFF (B-cell-activating factor), that generates an alternative polyadenylation site yielding a shorter, more actively translated variant, BAFF-var mRNA. Accordingly, individuals bearing the TNFSF13B variant had higher circulating BAFF and elevated risk of developing autoimmune diseases. Here, we investigated the molecular mechanisms controlling the enhanced translation of BAFF-var mRNA. We identified nuclear factor 90 (NF90, also known as ILF3) as an RNA-binding protein that bound preferentially the wild-type (BAFF-WT mRNA) but not BAFF-var mRNA in human monocytic leukemia THP-1 cells. NF90 selectively suppressed BAFF translation by recruiting miR-15a to the 3'UTR of BAFF-WT mRNA. Our results uncover a paradigm whereby an autoimmunity-causing BAFF polymorphism prevents NF90-mediated recruitment of microRNAs to suppress BAFF translation, raising the levels of disease-associated BAFF.

15.
Artigo em Inglês | MEDLINE | ID: mdl-30169833

RESUMO

Background: The relationship of kidney size to ageing, kidney function and kidney disease risk factors is not fully understood. Methods: Ultrasound length and parenchymal kidney volume were determined from a population-based sample of 3972 Sardinians (age range 18-100 years). We then identified the subset of 2256 'healthy' subjects to define age- and sex-specific reference ranges (2.5-97.5 percentile) of kidney volume. Logistic regression (accounting for family clustering) was used to identify the clinical characteristics associated with abnormally large kidneys or abnormally small kidneys. Results: In the healthy subset, kidney volume and length increased up to the fourth to fifth decade of life followed by a progressive decrease in men, whereas there was a gradual kidney volume decrease throughout the lifespan of women. In the whole sample, independent predictors of lower kidney volume (<2.5 percentile for age and sex) were male sex, low body mass index, short height, low waist:hip ratio and high serum creatinine (SCr); the independent predictors of larger kidney volume (>97.5 percentile for age and sex) were younger age, female sex, diabetes, obesity, high height, high waist:hip ratio and lower SCr. Estimated heritability for kidney volume was 15%, and for length 27%; kidney volume correlated strongly with birthweight. Conclusions: Overall, in a general healthy population, kidney measures declined with age differently in men and women. The determinants of kidney parenchymal volume include genetic factors and modifiable clinical factors.

16.
Nat Genet ; 50(10): 1426-1434, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30224645

RESUMO

The population of the Mediterranean island of Sardinia has made important contributions to genome-wide association studies of complex disease traits and, based on ancient DNA studies of mainland Europe, Sardinia is hypothesized to be a unique refuge for early Neolithic ancestry. To provide new insights on the genetic history of this flagship population, we analyzed 3,514 whole-genome sequenced individuals from Sardinia. Sardinian samples show elevated levels of shared ancestry with Basque individuals, especially samples from the more historically isolated regions of Sardinia. Our analysis also uniquely illuminates how levels of genetic similarity with mainland ancient DNA samples varies subtly across the island. Together, our results indicate that within-island substructure and sex-biased processes have substantially impacted the genetic history of Sardinia. These results give new insight into the demography of ancestral Sardinians and help further the understanding of sharing of disease risk alleles between Sardinia and mainland populations.

17.
Cytokine ; 111: 189-193, 2018 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-30173124

RESUMO

OBJECTIVE: Cytokines release by adipocytes could interact with TSH secretion. We evaluated the relationship between adipocytokines and TSH. We further tested for association of cytokines and thyroid autoimmunity. METHODS: We conducted a cross-sectional study in a community-based sample including 5385 individuals (2964 female) with TSH within the reference range. Subjects who reported taking thyroid medications or drugs that alter thyroid function were excluded. TSH, FT4, adiponectin, leptin, antibody against thyroperoxidase and against thyroglobulin were measured. Linear and logistic regression models were used to test for association. RESULTS: Females had higher adiponectin and leptin level and increased frequency of thyroid antibodies. In multiple regression analysis TSH was directly associated with leptin (ß = 0.003, p = 0.001) and the presence of circulating antibody against thyroperoxidase (ß = 0.315, p < 0.001), but negatively associated with age (ß = -0.012, p < 0.001) and FT4 (ß = -0.359, p < 0.001). Adiponectin, the presence of antibody against thyroglobulin and smoking habit were not associated with TSH levels (p = 0.223, p = 0.174 and p = 0.788, respectively). Logistic regression analysis revealed that higher adiponectin levels were associated with thyroid autoimmunity. CONCLUSIONS: Leptin is positively associated with TSH levels in euthyroid individuals, suggesting an effect of the adipokine on TSH secretion. Our results support the hypothesis that the leptin and pituitary-thyroid axis might interact in the context of energy homeostasis. The effect of adiponectin on thyroid autoimmunity will require more studies.

18.
Front Immunol ; 9: 1618, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30087674

RESUMO

Human aging is associated with a profound loss of thymus productivity, yet naïve T lymphocytes still maintain their numbers by division in the periphery for many years. The extent of such proliferation may depend on the cytokine environment, including IL-7 and T-cell receptor (TCR) "tonic" signaling mediated by self pMHCs recognition. Additionally, intrinsic properties of distinct subpopulations of naïve T cells could influence the overall dynamics of aging-related changes within the naïve T cell compartment. Here, we investigated the differences in the architecture of TCR beta repertoires for naïve CD4, naïve CD8, naïve CD4+CD25-CD31+ (enriched with recent thymic emigrants, RTE), and mature naïve CD4+CD25-CD31- peripheral blood subsets between young and middle-age/old healthy individuals. In addition to observing the accumulation of clonal expansions (as was shown previously), we reveal several notable changes in the characteristics of T cell repertoire. We observed significant decrease of CDR3 length, NDN insert, and number of non-template added N nucleotides within TCR beta CDR3 with aging, together with a prominent change of physicochemical properties of the central part of CDR3 loop. These changes were similar across CD4, CD8, RTE-enriched, and mature CD4 subsets of naïve T cells, with minimal or no difference observed between the latter two subsets for individuals of the same age group. We also observed an increase in "publicity" (fraction of shared clonotypes) of CD4, but not CD8 naïve T cell repertoires. We propose several explanations for these phenomena built upon previous studies of naïve T-cell homeostasis, and call for further studies of the mechanisms causing the observed changes and of consequences of these changes in respect of the possible holes formed in the landscape of naïve T cell TCR repertoire.

19.
J Hypertens ; 36(12): 2340-2349, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30063641

RESUMO

OBJECTIVE: Arterial ageing is characterized by increasing arterial stiffness as measured by pulse wave velocity (PWV). This process is enhanced in participants with early vascular ageing (EVA), but slowed in participants with healthy vascular ageing (HVA). We aimed to describe characteristics of EVA and HVA in a transcontinental study including 11 cohorts. METHODS: In all, 18 490 participants from the global MARE Consortium, free of cardiovascular disease, participated with data on PWV and cardiometabolic risk factors. We defined HVA as the lowest 10% and EVA as the highest 10% of the standardized PWV distribution, adjusted for age intervals. HVA individuals were compared with the 90% of non-HVA individuals with ANCOVA, adjusted for age, sex and hypertension. RESULTS: The 1723 HVA participants were at the same age as the rest of the population, more likely women (59.4 vs 57.0%), and with significantly lower levels of established cardiovascular risk factors (blood pressure, lipids, glucose). Similarly, the prevalence rate of obesity, diabetes mellitus, hypertension and the metabolic syndrome was lower in the HVA participants. In the presence of similar levels of cardiovascular risk factors, HVA participants in the 50-64 years of age group presented lower PWV 5.8 (SD 0.5) vs. 7.4 (1.4) m/s (P < 0.0001) than control individuals in the 35-49 years of age group, corresponding to an estimated difference in chronological age of 14 years. CONCLUSION: Participants with healthy vascular ageing (HVA), belonging to the lowest end of the PWV distribution, are in general characterized by an up to 14 years estimated younger biological (vascular) age than those with higher PWV values, and have lower levels of risk factors.

20.
Front Immunol ; 9: 1201, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29915580

RESUMO

CD4+ regulatory T cells have been intensively studied during aging, but little is still known about age-related changes of other regulatory T cell subsets. It was, therefore, the goal of the present study to analyze CD8+human leukocyte antigen-antigen D related (HLADR)+ T cells in old age, a cell population reported to have suppressive activity and to be connected to specific genetic variants. We demonstrate a strong increase in the number of CD8+HLADR+ T cells with age in a cohort of female Sardinians as well as in elderly male and female persons from Austria. We also show that CD8+HLADR+ T cells lack classical activation molecules, such as CD69 and CD25, but contain increased numbers of checkpoint inhibitory molecules, such as cytotoxic T lymphocyte-associated antigen 4, T cell immunoglobulin and mucin protein-3, LAG-3, and PD-1, when compared with their HLADR- counterparts. They also have the capacity to inhibit the proliferation of autologous peripheral blood mononuclear cells. This suppressive activity is, however, decreased when CD8+HLADR+ T cells from elderly persons are analyzed. In accordance with this finding, CD8+HLADR+ T cells from persons of old age contain lower percentages of checkpoint inhibitory molecules than young controls. We conclude that in spite of high abundance of a CD8+ regulatory T cell subset in old age its expression of checkpoint inhibitory molecules and its suppressive function on a per cell basis are reduced. Reduction of suppressive capacity may support uncontrolled subclinical inflammatory processes referred to as "inflamm-aging."

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