Down Syndrome B-Lymphocyte Subpopulations, Intrinsic Defect or Decreased T-Lymphocyte Help

Verstegen, Ruud H J; Kusters, Maaike A.; Gemen, Eugenie F.A.; Vries, Esther de

doi:10.1203/pdr.0b013e3181d4ecc1

Cited by 82 publications

(72 citation statements)

References 25 publications

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“…Finally, the impact of T21 on HSC/progenitors is likely to vary with age given the different patterns of hematopoietic abnormalities during fetal and postnatal life (11,13,15). Because we found that by 14-wk gestation, FL hematopoiesis is already perturbed, this raises the question of whether T21 also affects HSC/progenitor behavior during early embryonic development and in primitive hematopoietic cells, which is clearly extremely shown relative to GAPDH.…”

Section: Discussionmentioning

confidence: 81%

“…These data show extensive dysregulation of B-cell development from HSC to mature B cells. Whether similar dysregulation of B-progenitor development persists beyond birth is unknown, but we hypothesize that "molecular resetting" of the fetal Blymphoid differentiation program contributes to B-cell immune deficiency (15) and B-ALL in children with DS (26).…”

Section: Discussionmentioning

confidence: 98%

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Perturbation of fetal liver hematopoietic stem and progenitor cell development by trisomy 21

Roy¹,

Cowan²,

Mead

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

146

168

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The 40-fold increase in childhood megakaryocyte-erythroid and B-cell leukemia in Down syndrome implicates trisomy 21 (T21) in perturbing fetal hematopoiesis. Here, we show that compared with primary disomic controls, primary T21 fetal liver (FL) hematopoietic stem cells (HSC) and megakaryocyte-erythroid progenitors are markedly increased, whereas granulocyte-macrophage progenitors are reduced. Commensurately, HSC and megakaryocyte-erythroid progenitors show higher clonogenicity, with increased megakaryocyte, megakaryocyte-erythroid, and replatable blast colonies. Biased megakaryocyte-erythroid-primed gene expression was detected as early as the HSC compartment. In lymphopoiesis, T21 FL lymphoid-primed multipotential progenitors and early lymphoid progenitor numbers are maintained, but there was a 10-fold reduction in committed PreproB-lymphoid progenitors and the functional B-cell potential of HSC and early lymphoid progenitor is severely impaired, in tandem with reduced early lymphoid gene expression. The same pattern was seen in all T21 FL samples and no samples had GATA1 mutations. Therefore, T21 itself causes multiple distinct defects in FL myelo-and lymphopoiesis.transient myeloproliferative disorder | aneuploidy | human fetus C onstitutional trisomy 21 (T21) causes Down syndrome (DS), the most common syndrome-associated chromosomal anomaly in humans (1). As well as with neurodevelopmental, cardiac, and gut anomalies (2), there is a striking increase in childhood acute leukemia in DS, even though the risk of solid tumors is much lower than with the general population (3). Intriguingly, this susceptibility to hematopoietic tumors manifests as an increased risk both of acute megakaryocyte (MK)-erythroid leukemia (known as ML-DS) by 150-fold and of acute B-lymphoblastic leukemia (B-ALL) by 33-fold (3, 4).DS leukemias display distinct characteristics that support a crucial role for T21 in their pathogenesis. Hallmarks of ML-DS are the megakaryoblastic phenotype, clinical presentation confined to the first 5 y of childhood (5, 6), an antecedent clonally linked preleukemic condition (termed transient myeloproliferative disorder, TMD) in most cases, and acquired N-terminal truncating mutations in the erythroid-MK transcription factor GATA1 (7-9). Such mutations in GATA1 are present in both ML-DS and TMD (9) but are not found in patients without DS who develop megakaryoblastic leukemia (7) and are not leukemogenic in the absence of T21 (10).Molecular, biologic, and clinical data indicate that TMD is initiated before birth (9,(11)(12)(13)(14). We previously reported that by the second trimester, the T21 fetal liver (FL) myeloid progenitor compartment is abnormal and that this occurs in the absence of GATA1 mutation (11, 12). Specifically, the MK-erythroid progenitor (MEP) population is expanded with increased cell-intrinsic MK and erythroid lineage proliferation from CD34 + cells. These data suggest that T21-mediated developmental alterations to FL myeloid progenitor development provide a cell-specific substrate for...

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 98%

Perturbation of fetal liver hematopoietic stem and progenitor cell development by trisomy 21

Roy¹,

Cowan²,

Mead

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

146

168

View full text Add to dashboard Cite

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“…Studies on the adaptive immune system of DS have shown that total lymphocyte numbers are decreased in this population (8)(9)(10)(11)(12)(13)(14). This holds true for the CD4 + and CD8 + T cell subsets, especially in the first 2 y of life, but becomes less pronounced with increasing age and eventually normalizes around the age of 16 y. Subdivision of T cells into naive and memory cells showed that in fact only the naive subsets are smaller compared with healthy controls (8,9,(11)(12)(13).…”

mentioning

confidence: 87%

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

Bloemers

Bont

Weger

et al. 2011

The Journal of Immunology

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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.

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“…For persons with Down syndrome aged <3 years, respiratory illnesses are the most common cause of hospital admissions [165], and respiratory disease is by far the most common cause of death in persons with Down syndrome [38]. Both intrinsic immune defects and extrinsic (anatomical) factors contribute to disturbed immune function and respiratory infection in individuals with Down syndrome [166][167][168]. Reduced numbers of T-and B-lymphocytes and abnormalities of their function both undoubtedly contribute to altered immunoglobulin levels, poor responses to vaccinations and increased respiratory infections [36,166,169,170].…”

Section: Immune System Disturbances Impacting Cardiopulmonary Functiomentioning

confidence: 99%

What people with Down Syndrome can teach us about cardiopulmonary disease

Colvin

Yeager

2017

Eur Respir Rev

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Down syndrome is the most common chromosomal abnormality among live-born infants. Through full or partial trisomy of chromosome 21, Down syndrome is associated with cognitive impairment, congenital malformations ( particularly cardiovascular) and dysmorphic features. Immune disturbances in Down syndrome account for an enormous disease burden ranging from quality-of-life issues (autoimmune alopecia) to more serious health issues (autoimmune thyroiditis) and life-threatening issues (leukaemia, respiratory tract infections and pulmonary hypertension). Cardiovascular and pulmonary diseases account for ∼75% of the mortality seen in persons with Down syndrome. This review summarises the cardiovascular, respiratory and immune challenges faced by individuals with Down syndrome, and the genetic underpinnings of their pathobiology. We strongly advocate increased comparative studies of cardiopulmonary disease in persons with and without Down syndrome, as we believe these will lead to new strategies to prevent and treat diseases affecting millions of people worldwide.

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Down Syndrome B-Lymphocyte Subpopulations, Intrinsic Defect or Decreased T-Lymphocyte Help

Cited by 82 publications

References 25 publications

Perturbation of fetal liver hematopoietic stem and progenitor cell development by trisomy 21

Perturbation of fetal liver hematopoietic stem and progenitor cell development by trisomy 21

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

What people with Down Syndrome can teach us about cardiopulmonary disease

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