Down Syndrome Subjects Research Articles

Alterations of ectonucleotidases and acetylcholinesterase activities in lymphocytes of Down syndrome subjects: Relation with inflammatory parameters

BackgroundSubjects with Down syndrome (DS) have an increased susceptibility to infections and autoimmune disorders. ATP, adenosine, and acetylcholine contribute to the immune response regulation, and NTPDase, adenosine deaminase (ADA) and acetylcholinesterase (AChE) are important enzymes in the control of the extracellular levels of these molecules. We evaluated the activities of these enzymes and the cytokine levels in samples of DS individuals. MethodsThe population consisted of 23 subjects with DS and 23 healthy subjects. Twelve milliliters of blood was obtained from each subject and used for lymphocyte and serum preparation. Lymphocytes were separated on Ficoll density gradients. After isolation, NTPDase and AChE activities were determined. ResultsThe NTPDase activity using ADP as substrate was increased in lymphocytes of DS patients compared to control (P<0.05); however, no alterations were observed in the ATP hydrolysis. An increase was observed in the AChE activity in lymphocytes and in ADA activity in serum of DS patients when compared to healthy subjects (P<0.05). In DS subjects, an increase in the levels of IL-1β, IL-6, TNF-α and IFN-γ and a decrease in the IL-10 levels were also observed (P<0.05). ConclusionsAlterations in the NTPDase, ADA and AChE activities as well changes in the cytokine levels may contribute to immunological alterations observed in DS.

Bone Mineral Density in Adults With Down Syndrome, Intellectual Disability, and Nondisabled Adults

Individuals with intellectual disability (ID) or Down syndrome (DS) may be at greater risk of osteoporosis. The purpose of this study was to compare bone mineral density (BMD) of DS, ID, and non-intellectually disabled (NID) populations. In each group, 33 participants between the ages of 28 and 60 years were compared. BMD was measured with dual-energy x-ray absorptiometry (DXA) scans. BMD (p < .0001) between all groups was significantly different. Participants with DS had significantly lower BMD compared to NID participants. Individuals with ID had significantly lower BMD compared to NID subjects. Participants with DS had the lowest BMD of all groups. DS subjects display a greater risk for osteoporosis than ID subjects or control populations.

Effect of Body Position and Sleep State on Obstructive Sleep Apnea Severity in Children with Down Syndrome

To investigate the influence of sleep position and sleep state on obstructive sleep apnea (OSA) severity in in children with Down syndrome (DS). Retrospective review. Sleep disorders laboratory of a tertiary medical center. Children with Down syndrome and typically developing children matched for age, gender, apneahypopnea index (AHI), and year of polysomnogram. Sleep variables from baseline polysomnography. Sensor-recorded position (supine, prone, lateral) was expressed as the percentage of total sleep time. The AHI was calculated in each sleep state (NREM, REM), position, and position-sleep state combination. Of 76 DS subjects (55% male) the median age and AHI were 4.6 years (range 0.2-17.8 years) and 7.4 events/h (range 0-133). In all subjects, AHI was higher in REM than NREM (p < 0.05); however, the NREM AHI was higher in DS subjects than controls (p < 0.05). Compared to controls, the percentage of prone sleep was greater in DS subjects (p < 0.05), but the percentage of supine or non-supine (prone plus lateral) sleep was no different. For DS subjects alone, NREM AHI was higher in supine than non-supine sleep (p < 0.05). In DS and non-DS children alike, respiratory events are predominantly REM related. However, when matched for OSA severity, children with DS have a higher NREM AHI, which is worse in the supine position, perhaps indicating a positional effect compounded by underlying hypotonia inherent to DS. These findings illustrate the clinical importance of NREM respiratory events in the DS population and implications for treatment options.

Evaluation of oral hygiene status and periodontal health in Down′s syndrome subjects in comparison with normal healthy individuals

Aim of the study was to assess the oral hygiene status and periodontal status of Down's syndrome (DS) and normal subjects. The study was undertaken at Opportunity School at Vepery, Chennai, India. Two hundred subjects were selected. Among them100 were DS subjects and100 healthy normal subjects were selected (students from Madha School, Chennai, India) for comparison. All were screened for oral hygiene and periodontal status by OHI-Sand Community Periodontal Index of Treatment Needs (CPITN). Statistical analysis was done by Pearson's correlation coefficient. The results showed that the DS subjects had decreased prevalence rate of periodontitis.

Assessment of Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans in Down's syndrome subjects and systemically healthy subjects: A comparative clinical trial.

Objectives:To compare and quantify the presence of periodontal pathogens Aggregatibacter actinomycetemcomitans (Aac) and Porphyromonas gingivalis (Pg) in Down's syndrome (DS) and systemically healthy subjects with periodontitis and gingivitis.Materials and Methods:Fifty-nine age-matched subjects were categorized into four groups; Group I: DS subjects with gingivitis, Group II: DS subjects with periodontitis, Group III: Systemically healthy subjects with gingivitis and Group IV: Systemically healthy subjects with periodontitis. Plaque samples from all the four groups were collected and analyzed to evaluate the presence of Aac and Pg using real time polymerase chain reaction. The indices used were oral hygiene index simplified, community periodontal index for treatment needs and plaque index.Results:This study showed a statistically significant detection in the levels of both Aac (<0.001) and Pg (<0.001) in DS subjects with periodontitis when compared with the healthy controls with periodontitis; moreover, there was a statistically significant increase in Pg levels compared to Aac in DS gingivitis group.Conclusion:There was a statistically significant presence of Pg and Aac in both DS gingivitis and DS periodontitis over control groups with increased levels of Pg compared with Aac in DS gingivitis group.

Microarray based global transcriptome profiling reveals involvement of non-Hsa21 genes and microRNAs in molecular mechanism of Down syndrome pathogenesis

Down syndrome (DS), the most frequent genetic disorder leading to mental retardation is caused by partial/complete triplication of human chromosome 21 (Hsa21). The differential expression of genes located on extra chromosome 21 is assumed responsible for phenotypic abnormalities but this gene dosage hypothesis has not been assessed on genome-wide basis. The gene expression patterns related to phenotypic abnormalities may provide insights into their roles in DS pathogenesis. To analyze the differential gene expression and understand the molecular mechanism underlying pathogenesis of DS, we performed global gene expression profiling in blood samples of 14 DS and 4 normal subjects using human whole transcriptome microarray. The microarray analysis revealed total of 624 genes (195 upregulated and 429 down regulated) were differentially expressed in DS patients as compared to control. Out of the genes present on chromosome-21, a total of 210 genes were differentially expressed ranging from 1.5 to 5 fold compared to normal individuals. Genes involved in physiological pathways such as apoptosis and cell cycle regulation, signal transduction, cell maturation, and immunity showed dysregulation. Several genes localized on Hsa21 such as APP, SOD1, DYRK1A, COL6A1 showed differential expression and the levels were conserved across all DS subjects. Interestingly, several non-Hsa21 genes such as RCAN3 (Hsa1), ANK3 (Hsa10), CDK17 (Hsa12) etc., having roles in cardiogenesis, signal transduction and differentiation of neurons showed conserved levels of expression across the DS subjects. Further to investigate the role of microRNAs (miRNAs) in regulation of gene expression, global miRNA profiling was performed in 4 DS patients and 1 control using Affymetrix miRNA 3.0 array. Several Hsa21 miRNAs like miR-99a, let-7c, miR-125b-2, miR155, miR-802 showed overexpression effecting the regulation of genes involved in DS pathogenesis. Our results substantiate that involvement of non-Hsa21 genes and miRNAs provide etiological basis for abnormal phenotypes during DS pathogenesis. Our data lead to more systematic understanding of molecular mechanism underlying DS pathogenesis and identification of miRNA based therapeutic targets for better management of the disease.

CASP3 protein expression by flow cytometry in Down’s syndrome subjects

Down's syndrome (DS), the most common chromosomal disorder, is caused by 21 trisomy and is featured by intellectual disability. Subjects with DS can develop some traits of Alzheimer disease (AD) at an earlier age than subjects without trisomy 21. Apoptosis is a programmed cell death process under both normal physiological and pathological conditions. Caspase-3 (CASP3) plays an important role in neuronal death during nervous system development and under certain pathological conditions. Furthermore, in vitro and in vivo studies report elevated expression and activation of CASP3 in models of AD. On this account, the expression of CASP3 gene was evaluated in cultures of fibroblasts of DS and normal subjects by flow cytometry. CASP3 protein was up-regulated in fibroblasts of DS. The data obtained from this study strengthen the hypothesis that the over-expression of CASP3 gene could have a role in the activation of the apoptotic pathways acting in the neurodegenerative processes in DS.

Functionality of the pneumococcal antibody response in down syndrome subjects

We investigated the anti-polysaccharide antibody responses in subjects with Down syndrome (DS) because DS subjects show decreased peripheral B-lymphocyte numbers in all age groups, and a clinical picture of recurrent respiratory tract infections and increased incidence of autoimmune diseases which is reminiscent of common variable immunodeficiency disorders (CVID)-like disease. We determined titers and opsonophagocytosis in response to conjugated and unconjugated pneumococcal serotypes in 18 DS subjects aged 6–24 years. The results show adequate serotype-specific antibody titers in response to all conjugated and almost all unconjugated serotypes used. Opsonophagocytosis activity as measured against pneumococcal serotypes 9N, 19F and 23F was also found to be intact. We conclude that DS subjects do not have a clear defect in their anti-polysaccharide antibody response.

Pericentrin expression in Down’s syndrome

Down's syndrome (DS) is the most frequent genetic cause of intellectual disability and is a chromosomal abnormality of chromosome 21 trisomy. The pericentrin gene (PCNT) has sequenced in 21q22.3 inside of the minimal critical region for Down's syndrome. Alterations of PCNT gene are associated with dwarfism, cardiomyopathy and other pathologies. In this study, we have evaluated the possible differential expression of PCNT mRNA, by qRT-PCR, in peripheral blood leukocytes of DS subjects compared with the normal population. In the present case-control study, PCNT gene expression was increased by 72.72% in 16 out 22 DS samples compared with normal subjects. Our data suggest that changes in the expression levels of PCNT in DS subjects may be involved into the molecular mechanism of Down's syndrome.

Significant Modifications of the Salivary Proteome Potentially Associated with Complications of Down Syndrome Revealed by Top-down Proteomics

People with Down syndrome, a frequent genetic disorder in humans, have increased risk of health problems associated with this condition. One clinical feature of Down syndrome is the increased prevalence and severity of periodontal disease in comparison with the general population. Because saliva plays an important role in maintaining oral health, in the present study the salivary proteome of Down syndrome subjects was investigated to explore modifications with respect to healthy subjects. Whole saliva of 36 Down syndrome subjects, divided in the age groups 10-17 yr and 18-50 yr, was analyzed by a top-down proteomic approach, based on the high performance liquid chromatography-electrospray ionization-MS analysis of the intact proteins and peptides, and the qualitative and quantitative profiles were compared with sex- and age-matched control groups. The results showed the following interesting features: 1) as opposed to controls, in Down syndrome subjects the concentration of the major salivary proteins of gland origin did not increase with age; as a consequence concentration of acidic proline rich proteins and S cystatins were found significantly reduced in older Down syndrome subjects with respect to matched controls; 2) levels of the antimicrobial α-defensins 1 and 2 and histatins 3 and 5 were significantly increased in whole saliva of older Down syndrome subjects with respect to controls; 3) S100A7, S100A8, and S100A12 levels were significantly increased in whole saliva of Down syndrome subjects in comparison with controls. The increased level of S100A7 and S100A12 may be of particular interest as a biomarker of early onset Alzheimer's disease, which is frequently associated with Down syndrome.

Characteristics of Down syndrome subjects in a Saudi sample

To compare the cephalometric characteristics of Down syndrome (DS) subjects with those of normal subjects. Cephalometric radiographs of 60 Saudi DS subjects and 60 controls with specific inclusion criteria were used. Descriptive statistics were used to describe the quantitative and categorical variables, and the Student's t-test for two independent samples was used to compare the mean values of quantitative variables. SBa and SN were higher in controls than in DS subjects, whereas the NSBa was significantly higher in DS subjects than in controls. SNA, Co-A, ANB, and A-Na perp of controls were higher than the DS subjects. However, SN-MP, PP-MP, ANS-Me/N-Me, Y-axis, and Ar-Go-Me of the DS subjects were higher than those of the controls. In addition, U1-NA, U1-NA mm, L1-NB, and L1-NB mm of the DS subjects were also higher than the controls with a more acute U1-L1 angle in DS. NLA was larger in controls than in DS, whereas LL-E and UL-E of the DS subjects were higher than the controls. Differences between DS subjects and controls can be found when examining cephalometric radiographs. Anterior and posterior cranial base lengths are shorter with a backward inclination of the posterior cranial base in DS subjects. DS subjects present with a retrognathic maxilla and shorter effective length, with an increased LFH and a hyperdivergent mandible. Bimaxillary dental protrusion can also be expected in DS subjects with prominent lips and a reduced nasolabial angle.

Feedback reliance during an arm-tapping task with obstacle avoidance in adults with Down syndrome

Optimal movement control reflects a combination of both feedback and feedforward processes. However, as motor control evolves, feedforward mechanisms become prevailing respect to feedback-based movements, and less reliance on sensory information leads to a decreased number of corrections in the trajectory. In subjects with Down syndrome (DS), the study of the wrist's trajectory during an arm-tapping task revealed feedback-based corrections designed to reduce the degree of discrepancy between the position of the limb and the target, leading to the assumption that performers with DS have problems with movement planning and feedforward control. The present study was aimed at expanding the evidence about motor control in DS by evaluating the influence of a perturbing factor (an obstacle) on motor control strategies during an arm-tapping task and to clarify if the presence of an obstacle elicited a higher reliance on feedback control in controls and in DS. Sixteen right-handed adults with DS and 21 right-handed, age-matched control subjects (N) were evaluated by means of quantitative motion analysis. The results suggest that the presence of an obstacle elicited changes in the motor strategies of both DS and N, with a destabilizing effect that led subjects to rely more on feedback control. DS showed some aspects of movement efficiency that were in accordance with N strategies, but the prevailing factor of optimization in these subjects remained safety. A focused rehabilitation could help DS subjects to develop more efficient motor strategies in the presence of motor uncertainty and perturbations.

Oxidative burst intensity of peripheral phagocytic cells and periodontitis in Down syndrome

This study investigated the oxidative burst function of peripheral phagocytic cells (granulocytes and monocytes) and assessed the relation between oxidative burst and periodontal status in adult individuals with Down syndrome (DS) vs. other groups. Of 55 DS individuals (18-56years old), 74 individuals with mental retardation (MR) and 88 medically healthy controls (HC) participated in the study. The MR and HC groups were age, race and gender matched with the DS group. Gingival index, plaque index, probing depth, attachment level and bleeding on probing were recorded for each subject. Whole blood was collected for granulocyte/monocyte oxidative burst tests. Oxidative burst was determined by flow cytometry in terms of percentage of cells actively involved in oxidative burst, and oxidative intensity (magnitude of ROIs per cell). The basal oxidative burst intensity of DS granulocytes was higher than that of HC and MR granulocytes (p=0.05). The Escherichia coli stimulated oxidative burst intensity of DS monocytes was higher than that of HC and MR monocytes (p=0.05). Regression analysis controlling for age, sex, race and plaque levels showed a significant association between monocyte oxidative burst intensity and loss of periodontal attachment in DS subjects (p<0.01). Regression analysis also showed a significant association between granulocyte oxidative burst intensity and bleeding on probing in all subjects (p<0.05). Oxidative burst activity of peripheral monocytes and granulocytes is elevated in DS affected individuals and may contribute to periodontal tissue inflammation and loss of periodontal attachment in this susceptible group.

Potential contribution of SIM2 and ETS2 functional polymorphisms in Down syndrome associated malignancies

BackgroundProper expression and functioning of transcription factors (TFs) are essential for regulation of different traits and thus could be crucial for the development of complex diseases. Subjects with Down syndrome (DS) have a higher incidence of acute lymphoblastic leukemia (ALL) while solid tumors, like breast cancer (BC) and oral cancer (OC), show rare incidences. Triplication of the human chromosome 21 in DS is associated with altered genetic dosage of different TFs. V-ets erythroblastosis virus E26 oncogene homolog 2 (ETS2) and Single Minded 2 (SIM2) are two such TFs that regulate several downstream genes involved in developmental and neurological pathways. Here we studied functional genetic polymorphisms (fSNP) in ETS2 and SIM2 encoding genes in a group of patients and control subjects to better understand association of these variants with DS phenotypes.MethodsWe employed an in silico approach to identify potential target pathways of ETS2 and SIM2. fSNPs in genes encoding for these two TFs were identified using available databases. Selected sites were genotyped in individuals with DS, their parents, ALL, BC, OC as well as ethnically matched control individuals. We further analyzed these data by population-based statistical methods.ResultsAllelic/genotypic association analysis showed significant (P < 0.03) differences of rs2070530, rs1051476, rs11254, rs711 for DS subjects compared to control. rs711 also exhibited significantly different genotypic distribution pattern in parents of DS probands (P < 0.02) and BC patients (P < 0.02). Interaction analysis revealed independent main effect of rs711 in all the groups, while rs11254 exhibited independent main effect in DS subjects only. High entropy values were noticed for rs461155 in the solid tumor groups. Significant interactive effects of rs2070531 with rs1051475, rs1051476, rs11254 were observed in all the groups except DS.ConclusionsWe infer from the present investigation that the difference in frequencies of fSNPs and their independent as well as interactive effects may be the cause for altered expression of SIM2 and ETS2 in DS and malignant groups, which affects different downstream biological pathways. Thus, altered expression of SIM2 and ETS2 could be one of the reasons for variable occurrence of different malignant conditions in DS.

Epigallocatechin-3-gallate prevents oxidative phosphorylation deficit and promotes mitochondrial biogenesis in human cells from subjects with Down's syndrome

A critical role for mitochondrial dysfunction has been proposed in the pathogenesis of Down's syndrome (DS), a human multifactorial disorder caused by trisomy of chromosome 21, associated with mental retardation and early neurodegeneration. Previous studies from our group demonstrated in DS cells a decreased capacity of the mitochondrial ATP production system and overproduction of reactive oxygen species (ROS) in mitochondria. In this study we have tested the potential of epigallocatechin-3-gallate (EGCG) – a natural polyphenol component of green tea – to counteract the mitochondrial energy deficit found in DS cells. We found that EGCG, incubated with cultured lymphoblasts and fibroblasts from DS subjects, rescued mitochondrial complex I and ATP synthase catalytic activities, restored oxidative phosphorylation efficiency and counteracted oxidative stress. These effects were associated with EGCG-induced promotion of PKA activity, related to increased cellular levels of cAMP and PKA-dependent phosphorylation of the NDUFS4 subunit of complex I. In addition, EGCG strongly promoted mitochondrial biogenesis in DS cells, as associated with increase in Sirt1-dependent PGC-1α deacetylation, NRF-1 and T-FAM protein levels and mitochondrial DNA content.In conclusion, this study shows that EGCG is a promoting effector of oxidative phosphorylation and mitochondrial biogenesis in DS cells, acting through modulation of the cAMP/PKA- and sirtuin-dependent pathways. EGCG treatment promises thus to be a therapeutic approach to counteract mitochondrial energy deficit and oxidative stress in DS.

Gene Dosage-Dependent Association of DYRK1A With the Cytoskeleton in the Brain and Lymphocytes of Down Syndrome Patients

The triplication of the DYRK1A gene encoding proline-directed serine/threonine kinase and located in the critical region of Down syndrome (DS) has been implicated in cognitive deficits and intellectual disability of individuals with DS. We investigated the effect of abnormal levels of this kinase on the cytoskeleton in brain and peripheral tissues of DS subjects. In DS tissues, the predictable approximately equal to 1.5-fold enhancement of the levels of DYRK1A protein was demonstrated. An association of DYRK1A with all 3 major cytoskeleton networks was identified using immunoprecipitation. We concentrated on the actin cytoskeleton because its association with DYRK1A was the most affected by the enzyme levels. As measured by coimmunoprecipitation in DS tissues, but not in fragile X lymphocytes, actin association with DYRK1A was reduced. This reduced association was dependent on the state of phosphorylation of cytoskeletal proteins and was present only in cells overproducing DYRK1A kinase; therefore, the effect was attributable to the DYRK1A gene dosage. Alterations of DYRK1A-actin assemblies were detected in newborn and infant groups, thereby linking DYRK1A overexpression with abnormal brain development of DS children. The identification of the actin cytoskeleton as one of cellular targets of DYRK1A action provides new insights into a gene dosage-sensitive mechanism by which DYRK1A could contribute to the pathogenesis of DS. In addition, the presence of this DS-specific cytoskeleton anomaly in lymphocytes attests to the systemic nature of some features of DS. To our knowledge, this is the first study conducted in human tissue that shows DYRK1A association with the cytoskeleton.

Imaging brain amyloid in nondemented young adults with Down syndrome using Pittsburgh compound B

Down syndrome (DS) is one of the most common causes of intellectual disability. Although DS accounts for only 15% of all individuals with intellectual disabilities, adults with DS account for approximately 60% of individuals with intellectual disabilities and Alzheimer's disease. This is thought to be because of overproduction of the β-amyloid (Aβ) protein due to trisomy for the Aβ precursor protein gene on chromosome 21. Pittsburgh compound B (PiB) is a noninvasive invivo positron emission tomography tracer used to image amyloid deposition in living humans. Studies using PiB have shown an age-dependent asymptomatic amyloid deposition in more than 20% of the cognitively normal elderly population. Presymptomatic carriers of presenilin (PS-1) and Aβ precursor protein gene mutations who are destined to develop Alzheimer's disease also show preclinical amyloid deposition. This report describes a pilot study involving the use of PiB in seven adults with DS (age: 20-44 years). Compared with objective cutoffs for amyloid positivity in older non-DS cognitively normal control subjects, only two of the seven DS subjects (age: 38 and 44 years) showed increased PiB retention. The remaining five subjects aged between 20 and 35 years showed no detectable increase in PiB retention. Interestingly, the two subjects who showed elevated PiB retention showed a striatal-predominant pattern similar to that previously reported for PS-1 mutation carriers. These results demonstrate the feasibility of conducting PiB positron emission tomography scanning in this special population, and suggest a link between Aβ overproduction and early striatal deposition of fibrillar Aβ.

Quantitative 3D evaluation of step ascent and descent in individuals with Down syndrome – analysis of a daily challenging task

Step ascent and descent can perturb stability increasing the incidence of falls, especially in older individuals with functional limitations and intellectual disabilities, such as those with Down syndrome (DS). The aim of this study was to investigate the biomechanics and motor coordination of step ascent and descent in adults with DS and compare them with a group of healthy individuals, considering movement kinematics and kinetics. Fourteen adults with DS and 12 similarly aged adults without DS who were free of known motor problems were quantitatively assessed during ascending and descending a step using an optoelectronic system (BTS SMART-D), force platforms and video recording. Kinematic and kinetic parameters were identified and calculated for each study participant and comparisons were made between the DS and a control group (CG). Despite similar age ranges, subjects in the DS group performed the step ascent and descent movements slower, with longer duration and with a more accentuated range of motion of the trunk and of the ankle joint than those in the CG. Additionally, the double stance phase on the step was substantially longer in the DS group when represented as a percentage of the entire stepping sequence (ascent, double stance on the step and descent). In terms of kinetics, ground force platform data revealed that the DS subjects showed higher instability in the medio-lateral direction during double support phase than similarly aged CG subjects and cannot be attributed to age-associated changes in stability. These findings help to elucidate the complex biomechanical strategy of people with DS during a step ascent and descent movement task and may have a major role in the multidimensional evaluation and tailored management for them.

KIF21A mRNA expression in patients with Down syndrome

Down syndrome (DS) is a chromosomal disorder caused by chromosome 21 trisomy and is the most frequent genetic cause of intellectual disability. The gene for the kinesin family member 21A (KIF21A), is a member of the kinesin superfamily involved in the anterograde fast axonal transport. In this study, we have evaluated the possible differential expression of KIF21A mRNA, by qRT-PCR, in peripheral blood leukocytes of DS subjects and it compared with the normal population. In the assumption that changes in KIF21A gene expression levels may affect the axonal transport and the development of the nervous system of subjects with DS. In the present case-control study, KIF21A gene expression was increased in 72.72 % of DS samples compared with normal subjects. This finding suggests that changes in the expression levels of KIF21A in DS subjects may affect the axonal transport and the development of the nervous system.

Down syndrome, autoimmunity and T regulatory cells.

Autoimmune diseases are more represented in Down syndrome (DS) individuals compared to chromosomally normal people. Natural T regulatory cells (nT(reg) ) have been considered to be primary in the role of controlling the intensity and targets of the immune response. We have investigated the phenotypical and functional alteration of nT(reg) in a group of DS people. The phenotypical characteristic of T(reg) cells of 29 DS was analysed and compared with an age-matched healthy control group. The inhibitory potential of CD4(+) CD25(high) CD127(low) T regulatory cells was evaluated on autologous CD4(+) CD25(-) T cell proliferation in response to activation with a mytogenic pan-stimulus (anti-CD2, anti-CD3 and anti-CD28 antibodies). The CD4(+) CD25(high) cells in the DS and control groups were 2·692±0·3808%, n=29 and 1·246±0·119, n=29%, respectively (P=0.0007), with a percentage of forkhead box protein 3 (FoxP3)-expressing cells of 79·21±3·376%, n=29 and 59·75±4·496%, respectively (P=0.0015). CD4(+) CD25(+) FoxP3(+) cells were increased in peripheral blood from DS subjects (DS mean 5·231±0·6065% n=29, control mean 3·076±0·3140% n=29). The majority of CD4(+) CD25(high) were CD127(low) and expressed a high percentage of FoxP3 (natural T(reg) phenotype). While the proliferative capacity of DS T cells was not altered significantly compared to normal individuals, a reduced inhibitory potential of T(reg) compared to healthy controls was clearly observed (mean healthy control inhibition in T(eff) : T(reg) 1:1 co-culture: 58·9%±4·157%, n=10 versus mean DS inhibition in T(eff) :T(reg) 1:1 co-culture: 39·8±4·788%, n=10, P=0.0075; mean healthy control inhibition in T(eff) : T(reg) 1:0·5 co-culture: 45·10±5·858%, n=10 versus DS inhibition in T(eff) : T(reg) 1:0·5 co-culture: 24·10±5·517%, n=10, P=0.0177). DS people present an over-expressed peripheral nT(reg) population with a defective inhibitory activity that may partially explain the increased frequency of autoimmune disease.