Homeostatic Cytokines and Expansion of Regulatory T Cells Accompany Thymic Impairment in Children with Down Syndrome

Down syndrome (DS), or trisomy of chromosome 21, is the most common genetic disorder associated with autoimmune diseases. Autoimmune regulator protein (AIRE), a transcription factor located on chromosome 21, plays a crucial role in autoimmunity by regulating promiscuous gene expression (pGE). To investigate if autoimmunity in DS is promoted by the reduction of pGE owing to dysregulation of AIRE, we assessed the expression of AIRE and of several peripheral tissue-restricted Ag genes by quantitative PCR in thymus samples from 19 DS subjects and 21 euploid controls. Strikingly, despite the 21 trisomy, AIRE expression was significantly reduced by 2-fold in DS thymuses compared with controls, which was also confirmed by fluorescent microscopy. Allele-specific quantification of intrathymic AIRE showed that despite its lower expression, the three copies are expressed. More importantly, decreased expression of AIRE was accompanied by a reduction of pGE because expression of tissue-restricted Ags, CHRNA1, GAD1, PLP1, KLK3, SAG, TG, and TSHR, was reduced. Of interest, thyroid dysfunction (10 cases of hypothyroidism and 1 of Graves disease) developed in 11 of 19 (57.9%) of the DS individuals and in none of the 21 controls. The thymuses of these DS individuals contained significantly lower levels of AIRE and thyroglobulin, to which tolerance is typically lost in autoimmune thyroiditis leading to hypothyroidism. Our findings provide strong evidence for the fundamental role of AIRE and pGE, namely, central tolerance, in the predisposition to autoimmunity of DS individuals.

Section: Discussionsupporting

confidence: 90%

Autoimmune Predisposition in Down Syndrome May Result from a Partial Central Tolerance Failure due to Insufficient Intrathymic Expression of AIRE and Peripheral Antigens

Giménez‐Barcons

Casteràs

Armengol

et al. 2014

“…Thus, our results are in general agreement with the recent proposal by Kusters et al (6) that "the immune system in DS is intrinsically deficient from the very beginning, and not simply another victim of a generalized process of precocious aging," as hypothesized by others (7,8,54,55). Altogether, our data indicate that DS is indeed a primary, rather than a secondary, immunodeficiency, contrary to what is largely accepted (47).…”

Section: Ds: a Primary Immunodeficiency?supporting

confidence: 92%

“…Thus, the thymus in DS individuals had been reported to be smaller and hypocellular, even in infants, containing a decreased proportion of phenotypically mature TCR-ab + thymocytes (6). The number of TRECs and the size of T cell subpopulations (CD4 + , CD8 + , CD4 + CD45 + RA cells) in the peripheral blood of DS individuals have been described as reduced at various age groups (4,6,7). It was also demonstrated that DS patients present low naive T cell numbers (44).…”

Section: Impaired Thymic Function and Development In Dsmentioning

confidence: 99%

“…DS is associated with several complex clinical features including immunological abnormalities (4)(5)(6)(7)(8), and it has long been noticed that patients present abnormal thymuses, characterized by lymphocyte depletion, cortical atrophy, and loss of corticomedullary demarcation (9,10). In addition to higher susceptibility to infections-as evidenced during the H1N1 2009 pandemic where the likelihood of death was 300 times greater for DS patients (11)-DS is characterized by increased frequency of organ-specific autoimmune disorders and of lymphoid and myeloid leukemias, contrasting with a decreased risk for allergic diseases, particularly asthma (12,13).…”

mentioning

confidence: 99%

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Decreased AIRE Expression and Global Thymic Hypofunction in Down Syndrome

Lima

Moreira-Filho

Ramos

et al. 2011

The Down syndrome (DS) immune phenotype is characterized by thymus hypotrophy, higher propensity to organ-specific autoimmune disorders, and higher susceptibility to infections, among other features. Considering that AIRE (autoimmune regulator) is located on 21q22.3, we analyzed protein and gene expression in surgically removed thymuses from 14 DS patients with congenital heart defects, who were compared with 42 age-matched controls with heart anomaly as an isolated malformation. Immunohistochemistry revealed 70.48 ± 49.59 AIRE-positive cells/mm2 in DS versus 154.70 ± 61.16 AIRE-positive cells/mm2 in controls (p < 0.0001), and quantitative PCR as well as DNA microarray data confirmed those results. The number of FOXP3-positive cells/mm2 was equivalent in both groups. Thymus transcriptome analysis showed 407 genes significantly hypoexpressed in DS, most of which were related, according to network transcriptional analysis (FunNet), to cell division and to immunity. Immune response-related genes included those involved in 1) Ag processing and presentation (HLA-DQB1, HLA-DRB3, CD1A, CD1B, CD1C, ERAP) and 2) thymic T cell differentiation (IL2RG, RAG2, CD3D, CD3E, PRDX2, CDK6) and selection (SH2D1A, CD74). It is noteworthy that relevant AIRE-partner genes, such as TOP2A, LAMNB1, and NUP93, were found hypoexpressed in DNA microarrays and quantitative real-time PCR analyses. These findings on global thymic hypofunction in DS revealed molecular mechanisms underlying DS immune phenotype and strongly suggest that DS immune abnormalities are present since early development, rather than being a consequence of precocious aging, as widely hypothesized. Thus, DS should be considered as a non-monogenic primary immunodeficiency.

“…In contrast, the fraction of CD8 + T cells within the T cell compartment is increased, and the fraction of CD4 + T cells decreased (9). Percentages of naive cells have been described to be decreased and memory and effector subsets to be increased in both CD4 + and CD8 + T cells (15)(16)(17). Several studies have ascribed the immunologic impairment of T cells in DS to abnormal thymus development and function (16,(18)(19)(20)(21).…”

mentioning

confidence: 99%

Decreased Thymic Output Accounts for Decreased Naive T Cell Numbers in Children with Down Syndrome

Bloemers

Bont

Weger

et al. 2011

Children with Down syndrome (DS) have low numbers of naive T cells and abnormal thymus development and function. Because next to thymic production, peripheral proliferation greatly contributes to naive T cell generation in healthy children, we examined the cause of reduced naive T cell numbers in children with DS. Compared with aged matched controls, the total number of signal joint TCR excision circles (sjTREC) per ml blood was reduced in DS. Reduced frequencies and absolute numbers of protein tyrosine kinase 7-positive recent thymic emigrants, but similar levels of naive T cell apoptosis and Ag-driven activation in DS, suggested that reduced thymic output and not increased peripheral loss of naive T cells caused the reduced sjTREC numbers. We found no support for defective peripheral generation of naive T cells in DS. In DS the naive T cells responded to IL-7 and, based on Ki-67 expression, had similar proliferation rates as in healthy controls. sjTREC content per naive CD8+ T cells was not increased, but even decreased, pointing to increased survival or peripheral generation of naive T cells in DS. In conclusion, we show in this study that reduced thymic output, but not reduced peripheral generation nor increased loss of naive T cells, results in the low naive T cell numbers found in DS.