Interferon-γ- and interleukin-4-producing T cells in Down's syndrome

doi:10.1016/j.neulet.2005.10.048

Neuroscience Letters

Volume 395, Issue 1, 27 February 2006, Pages 67-70

https://doi.org/10.1016/j.neulet.2005.10.048 Get rights and content

Abstract

Down's syndrome (DS) associates with genetic-dependent dysregulation of the interferon (IFN) system. We used intracellular cytokine staining to analyse the percentages of IFN-γ- and interleukin (IL)-4-producing T cells in the peripheral blood of patients with DS, individuals with mental retardation (MR), and healthy controls (HCs). The percentages of IFN-γ-producing CD4⁺ and CD8⁺ T cells (IFGCs), namely Th1 (mean, 21.4 ± S.D. 1.3) and Tc1 (12.6 ± 1.1), and the Th1/Th2 ratio (6.1 ± 0.2) in DS were significantly higher than in MR (15.9 ± 1.3, 7.9 ± 0.6, 4.8 ± 0.3) and in HCs (15.6 ± 1.9, 7.2 ± 1.1, 4.6 ± 0.6). Most of the DS patients with high IFGC percentages were seropositive for anti-transglutaminase IgA. We found no correlation between sex, age, APOE genotypes, coexisting autoimmune diseases, susceptibility to infections, or degree of cognitive impairment and high IFGC percentages. This abnormality might thus contribute to immune dysfunction in DS without manifest clinical correlates.

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Acknowledgements

This work was supported by grants from the “Ministero della Salute” (IRCCS Mondino, RC 2003–4) and FAR-Insubria 2003.

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Down syndrome (DS) is the most common genetic cause of intellectual disability and increases the risk of other brain-related dysfunctions, like seizures, early-onset Alzheimer’s disease, and autism. To reveal the molecular profiles of DS-associated brain phenotypes, we performed a meta-data analysis of the developmental DS brain transcriptome at cell type and co-expression module levels. In the DS brain, astrocyte-, microglia-, and endothelial cell-associated genes show upregulated patterns, whereas neuron- and oligodendrocyte-associated genes show downregulated patterns. Weighted gene co-expression network analysis identified cell type-enriched co-expressed gene modules. We present eight representative cell-type modules for neurons, astrocytes, oligodendrocytes, and microglia. We classified the neuron modules into glutamatergic and GABAergic neurons and associated them with detailed subtypes. Cell type modules were interpreted by analyzing spatiotemporal expression patterns, functional annotations, and co-expression networks of the modules. This study provides insight into the mechanisms underlying brain abnormalities in DS and related disorders.
Altered immune parameters correlate with infection-related hospitalizations in children with Down syndrome
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Citation Excerpt :
While overexpression/altered function of some genes (ITGB2 [5] and IFNGR2 [7], key in leukocyte migration and Th1 cell development, respectively) may predispose to infections, others (ICOSLG involved in Treg cell function [8] and IFNAR1 implicated in autoantibody production [9]) may be more related to the autoimmunity developed by DS children. As a consequence of these and/or other defects, the multifunctional T cell responses (studied only in adults [10]) of DS children may be altered. In this study, we tested the hypothesis that the relative protein expressions of IFNGR2, IFNAR1, CD18, and CD275 (all encoded by genes in chromosome 21 and related to the function of the immune system) are altered in circulating leucocytes of DS children, and that these children have altered multifunctional T cells (evaluated by an intracellular cytokine/proliferation assay).
In addition to previously studied immunological variables, the relative expression of IFNGR2, IFNAR1, CD18, and CD275 (all encoded in chromosome 21) on circulating leucocytes and multifunctional T cells (evaluated by an intracellular cytokine/proliferation assay) were compared between children with Down syndrome (DS) and healthy controls (HC). As previously reported, numbers of lymphocytes, CD4⁺ T cells, Treg cells, B cells, and levels of serum IgM were decreased, and levels of IgG and IgA were increased in children with DS. Moreover, the relative expression of CD18 on T and B cells (previously and not previously reported, respectively) were elevated in DS children (p ⩽ 0.01). Age and numbers of B and Treg cells moderately correlated with retrospectively identified infection related hospitalizations (rho: 0.300–0.460, p ⩽ 0.003). Age and the numbers of Treg cells also correlated with prospectively identified infection related hospitalizations. Future studies are necessary to clarify the role of these parameters in the immunity of DS patients.
Epidemiology of childhood leukemia in the presence and absence of Down syndrome
2014, Cancer Epidemiology
Citation Excerpt :
Resistance to growth inhibitory cytokines (e.g., TGF beta or Interferon) is suggested to give a growth advantage to existing pre-leukemic clones predisposing to progression to frank leukemia [112,113]. This hypothesis may be particularly relevant to the evolvement of DS-ALL since the immunodeficiency in DS was reported to be associated with increased sensitivity to interferon [114–116]. Several studies have suggested that infections in childhood could play a protective role against the development of childhood leukemia [88,117–120], whereas others reported the opposite [121–123] or produced a wide range of results that have tended to be imprecise and uninformative on their own [87,124–128].
Down syndrome (DS) is a common congenital anomaly, and children with DS have a substantially higher risk of leukemia. Although understanding of genetic and epigenetic changes of childhood leukemia has improved, the causes of childhood leukemia and the potential role of environmental exposures in leukemogenesis remain largely unknown. Although many epidemiologic studies have examined a variety of environmental exposures, ionizing radiation remains the only generally accepted environmental risk factor for childhood leukemia. Among suspected risk factors, infections, exposure to pesticides, and extremely low frequency magnetic fields are notable. While there are well-defined differences between leukemia in children with and without DS, studies of risk factors for leukemia among DS children are generally consistent with trends seen among non-DS (NDS) children.
We provide background on DS epidemiology and review the similarities and differences in biological and epidemiologic features of leukemia in children with and without DS. We propose that both acute lymphoblastic and acute myeloblastic leukemia among DS children can serve as an informative model for development of childhood leukemia. Further, the high rates of leukemia among DS children make it possible to study this disease using a cohort approach, a powerful method that is unfeasible in the general population due to the rarity of childhood leukemia.
Alterations of ectonucleotidases and acetylcholinesterase activities in lymphocytes of Down syndrome subjects: Relation with inflammatory parameters
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Subjects 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.
The 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.
The 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).
Alterations in the NTPDase, ADA and AChE activities as well changes in the cytokine levels may contribute to immunological alterations observed in DS.
Metabolic, immune, epigenetic, endocrine and phenotypic abnormalities found in individuals with autism spectrum disorders, Down syndrome and Alzheimer disease may be caused by congenital and/or acquired chronic cerebral toxoplasmosis
2011, Research in Autism Spectrum Disorders
Toxoplasma gondii is a protozoan parasite that infects about a third of human population. It is generally believed that in immunocompetent hosts, the parasite infection takes usually asymptomatic course and induces self-limiting disease, but in immunocompromised individuals may cause significant morbidity and mortality. T. gondii uses sulfated proteoglycans for host cell invasion and sulfated sugars on the surface of host cells may functions as key parasite receptors. Patients with autism spectrum disorders (ASD) have many inborn or acquired abnormalities of metabolism, including impaired sulfation and sulfoxidation. The impaired sulfation of dehydroepiandrosterone (DHEA) to DHEA-S affected normal development of various brain functions because DHEA-S inhibited vascular neuroinflammation in ASD individuals probably caused by cerebral toxoplasmosis (CT). Treatment of endothelial cells with DHEA-S dramatically inhibited the TNF-α-induced activation of NF-κB, an inflammatory transcription factor, and increased protein levels of the NF-κB inhibitor, IκB-α. A significant decrease in sulfation capacity found during pregnancy compared with post partum probably reflect a defense reaction of the host due to increased production of proinflammatory cytokines associated with frequent and widespread infection with this parasite. This suggestion may be supported by the finding that TNF and IL-1 mediated inhibitory effect of lipopolysaccharide on DHEA sulfotransferase mRNA level in Hep3B human hepatoma cells. It seems however that the impaired sulfation and sulfonation may be also beneficial for the host because lack or a markedly diminished anionic charge of the host cells associated with this event did not promote binding to the negatively charged outer leaflet of T. gondii plasma membranes. Phosphorylation of the parasite and/or host proteins is also of great importance in the process of T. gondii–host cell interaction. Furthermore, the increased male to female ratio characteristic for autistic participants most likely resulted from significantly increased testosterone levels associated with congenital T. gondii infection. It was demonstrated that the parasite, aging and dietary restriction have been able to induce DNA breakage, therefore one may suggest that such an epigenetic mechanism play an important role in development of Down syndrome (DS). Several data may support this notion: (a) autism occurs 10 times more often in children with trisomy 21 than in the general population, (b) the parasite can be transmitted by semen and ovum, (c) autistic children exhibit impaired DNA methylation capacity, and (d) T. gondii affect chromatin structure and may cause dysregulation of the host cell cycle. Alzheimer disease (AD) also may be caused by CT because this abnormality is more prevalent in women, characterizes with a skewed capacity for xenobiotic metabolism especially of compounds containing sulfur that manifest as a decreased plasma levels of DHEA-S, and has marked immune irregularies in part due to aging. Moreover, chronic neuroinflammation characteristic for AD and DS individuals is associated with vascular lesions, patients with AD have increased levels of DNA breaks in the cerebral cortex, markedly enhanced production of proinflammatory cytokines, reactive oxygen species, and lipid peroxidation, disturbances in glucose metabolism, and irregularities in hypothalamic–pituitary axis. It must be noted that similar metabolic and endocrine disturbances have been reported also in humans and mice with chronic toxoplasmosis. Overproduction of IFN-γ and other proinflammatory cytokines associated with persistent neuroinflammation resulted in neurodegeneration and induced amyloid-β production also in DS, as well as accounted for cognitive impairment. Because bradyzoites and sporozoites throughout their life cycle accumulate large amounts of crystalline storage polysaccharide granules analogous to amylopectin within the cytoplasm and are able to build more complex macromolecules, they may be at least in part responsible for the production of amyloid-β senile plaques. Moreover, it seems that the accumulation of iron in senile plaques reflect a defense of the host against T. gondii because this transition metallic ion is necessary for proliferation of tachyzoites. Finally, the beneficial effects of ibuprofen in the patients with AD that restored cellular immunity, decreased production of proinflammatory cytokines, NO, amyloid-β, reduced lipid peroxidation and free radical generation, were consistent with the suggestion that congenital and/or acquired chronic latent CT play an important role in development of these types of neurodegeneration.
The relationship between premature ageing and immune responses in the oral cavity of Down syndrome
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Citation Excerpt :
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Interferon-γ- and interleukin-4-producing T cells in Down's syndrome

Abstract

Section snippets

Acknowledgements

J. Neuroimmunol.

Blood

J. Neurol. Sci.

J. Allergy Clin. Immun.

Immunol. Today

Clin. Immunol.

Immunity

Derangements of immunoglobulin levels, phytohemagglutinin responsiveness and T and B cell markers in Down's syndrome at different ages

Eur. J. Immunol.