Direct analysis of thymic function in children with Down's syndrome

Prada, Nicole; Nasi, Milena; Troiano, Leonarda; Roat, Erika; Nemes, Elisa; Lugli, Enrico; Ferraresi, Roberta; Ciacci, Luigi; Bertoni, D.; Biagioni, Ornella; Gibertoni, Milena; Cornia, Cristina; Meschiari, Liviana; Gramazio, Elisabetta; Mariotti, Mauro; Consolo, Ugo; Balli, Fiorella; Cossarizza, Andrea

doi:10.1186/1742-4933-2-4

Cited by 30 publications

(12 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similarly to DGS patients, DS patients are characterized by high susceptibility to develop autoimmune phenomena and recurrent infections (39) and our data provide evidence that also in DS the reduced thymic function is a causative factor supporting both the decreased response to infections and the increased susceptibility to develop organ specific autoimmune disorders. DS thymi show abnormal architecture with an increase of the medullary compartment indicating an accelerated maturation kinetics or premature involution.…”

Section: Discussionsupporting

confidence: 57%

Thymic Epithelium Abnormalities in DiGeorge and Down Syndrome Patients Contribute to Dysregulation in T Cell Development

et al. 2019

View full text Add to dashboard Cite

The thymus plays a fundamental role in establishing and maintaining central and peripheral tolerance and defects in thymic architecture or AIRE expression result in the development of autoreactive lymphocytes. Patients with partial DiGeorge Syndrome (pDGS) and Down Syndrome (DS) present alterations in size and architecture of the thymus and higher risk to develop autoimmunity. We sought to evaluate thymic architecture and thymocyte development in DGS and DS patients and to determine the extent to which thymic defects result in immune dysregulation and T cell homeostasis perturbation in these patients. Thymi from pediatric patients and age-matched controls were obtained to evaluate cortex and medullary compartments, AIRE expression and thymocyte development. In the same patients we also characterized immunophenotype of peripheral T cells. Phenotypic and functional characterization of thymic and peripheral regulatory T (Treg) cells was finally assessed. Histologic analysis revealed peculiar alterations in thymic medulla size and maturation in DGS and DS patients. Perturbed distribution of thymocytes and altered thymic output was also observed. DGS patients showed lower mature CD4+ and CD8+ T cell frequency, associated with reduced proportion and function of Tregs both in thymus and peripheral blood. DS patients showed increased frequency of single positive (SP) thymocytes and thymic Treg cells. However, Tregs isolated both from thymus and peripheral blood of DS patients showed reduced suppressive ability. Our results provide novel insights on thymic defects associated with DGS and DS and their impact on peripheral immune dysregulation. Indeed, thymic abnormalities and defect in thymocyte development, in particular in Treg cell number and function could contribute in the pathogenesis of the immunodysregulation present in pDGS and in DS patients.

show abstract

Section: Discussionsupporting

confidence: 57%

Thymic Epithelium Abnormalities in DiGeorge and Down Syndrome Patients Contribute to Dysregulation in T Cell Development

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Precocious aging is a feature of Down syndrome, involving many organ systems, including the thymus [31, 32]. Two studies in children with Down syndrome noted that TRECs were decreased compared to a control population, and there was a strong negative correlation with age.…”

Section: Discussionmentioning

confidence: 99%

Newborn Screening for SCID in New York State: Experience from the First Two Years

et al. 2014

View full text Add to dashboard Cite

Purpose To describe the process and assess outcomes for the first 2 years of newborn screening for severe combined immunodeficiency (SCID NBS) in New York State (NYS). Methods The NYS algorithm utilizes a first-tier molecular screen for TRECs (T-cell receptor excision circles), the absence of which is indicative of increased risk of immunodeficiency. Results During the first 2 years, 485,912 infants were screened for SCID. Repeat specimens were requested from 561 premature and 746 non-premature infants with low or borderline TRECs. A total of 531 infants were referred for diagnostic evaluation leading to identification of 10 infants with SCID and 87 with a clinically significant non-SCID abnormality based on flow cytometry or CBC results (positive predictive value 20.3 %). Nine infants were diagnosed with typical SCID and one with leaky SCID. SCID diagnoses included two patients with adenosine deaminase deficiency, three patients with typical and one with leaky IL2RG-related SCID, one patient with IL7Rα-related SCID, and three cases of typical SCID, etiology unknown. TRECs were undetectable in eight of the nine babies with typical SCID. Infants with other non-SCID conditions included 27 patients with a syndrome that included T-cell impairment, 18 of which had DiGeorge syndrome. Seventeen infants had T-cell impairment secondary to another clinically significant condition, and 13 were classified as ‘other’. Among 30 infants classified as idiopathic T-cell lymphopenia, 11 have since resolved, and the remainder continues to be followed. One infant with undetectable TRECs had normal follow-up studies. Molecular studies revealed the presence of two changes in the infant’s DNA. Conclusions Overall, ten infants with SCID were identified during the first 2 years of screening in NYS, yielding an incidence of approximately 1 in 48,500 live births, which is consistent with the incidence observed by other states screening for SCID. The incidence of any clinically significant laboratory abnormality was approximately 1 in 5,000; both estimates are higher than estimates prior to the onset of newborn screening for SCID. Improvements to the NYS algorithm included the addition of a borderline category that reduced the proportion of infants referred for flow cytometric analysis, without decreasing sensitivity. We identified a large number of infants with abnormal TRECs and subsequent idiopathic T-cell lymphopenia. Long-term follow-up studies are needed to determine the prognosis and optimal treatment for this group of patients, some of whom may present with previously unrecognized, transient lymphopenia of infancy.

show abstract

“…Increased frequency of peripheral γδ-T cells and lower frequency of naïve T cells have also been reported ( 13 ). Decreased numbers of recent thymic emigrant (RTE) cells ( 13 ) and significantly lower TREC levels have been observed, suggesting decreased thymopoiesis ( 11 – 14 ). Expression of thymic-specific proteasome subunit β5t, but not of cathepsin, has also been reported as markedly reduced in DS thymi ( 15 ).…”

Section: Introductionmentioning

confidence: 99%

Premature Senescence and Increased Oxidative Stress in the Thymus of Down Syndrome Patients

et al. 2021

View full text Add to dashboard Cite

Down syndrome (DS) patients prematurely show clinical manifestations usually associated with aging. Their immune system declines earlier than healthy individuals, leading to increased susceptibility to infections and higher incidence of autoimmune phenomena. Clinical features of accelerated aging indicate that trisomy 21 increases the biological age of tissues. Based on previous studies suggesting immune senescence in DS, we hypothesized that induction of cellular senescence may contribute to early thymic involution and immune dysregulation. Immunohistochemical analysis of thymic tissue showed signs of accelerated thymic aging in DS patients, normally seen in older healthy subjects. Moreover, our whole transcriptomic analysis on human Epcam-enriched thymic epithelial cells (hTEC), isolated from three DS children, which revealed disease-specific transcriptomic alterations. Gene set enrichment analysis (GSEA) of DS TEC revealed an enrichment in genes involved in cellular response to stress, epigenetic histone DNA modifications and senescence. Analysis of senescent markers and oxidative stress in hTEC and thymocytes confirmed these findings. We detected senescence features in DS TEC, thymocytes and peripheral T cells, such as increased β-galactosidase activity, increased levels of the cell cycle inhibitor p16, telomere length and integrity markers and increased levels of reactive oxygen species (ROS), all factors contributing to cellular damage. In conclusion, our findings support the key role of cellular senescence in the pathogenesis of immune defect in DS while adding new players, such as epigenetic regulation and increased oxidative stress, to the pathogenesis of immune dysregulation.

show abstract

Direct analysis of thymic function in children with Down's syndrome

Cited by 30 publications

References 23 publications

Thymic Epithelium Abnormalities in DiGeorge and Down Syndrome Patients Contribute to Dysregulation in T Cell Development

Thymic Epithelium Abnormalities in DiGeorge and Down Syndrome Patients Contribute to Dysregulation in T Cell Development

Newborn Screening for SCID in New York State: Experience from the First Two Years

Premature Senescence and Increased Oxidative Stress in the Thymus of Down Syndrome Patients

Contact Info

Product

Resources

About