Immune Defect in Adults With Down Syndrome: Insights Into a Complex Issue.

Children with Down syndrome (DS) suffer from recurrent respiratory infections, which represent the leading cause of mortality during childhood. This susceptibility to infections is usually considered multifactorial and related to both impaired immune function and non-immunological factors. Infections are also one of the top causes of death in DS at adulthood. DS is considered an immunodeficiency with syndromic features by some researchers because of this high rate of infection and the immunological characteristics observed in children with DS. Little is known about the immune status of adult patients. Herein, we report the clinical and immune phenotype of 44 adults with DS, correlated with their infectious history. We observed that these adults had an aberrant lymphocyte phenotype with decreased naïve/memory T cell ratios and reduced numbers of switched memory B cells. The lower incidence of infectious events at adulthood distinguish DS from other inborn errors of immunity. Primary immunodeficiency-related features in DS could explain the increased risk of developing autoimmunity, malignancies, and infections. During adulthood, this immune dysfunction may be compensated for in mid-life, and infection-related mortality observed in older patients might be favored by multiple factors such as neurological impairment or nosocomial antigen exposure. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT01663675 (August 13, 2012).

Protocol for TRAUMADORNASE: a prospective, randomized, multicentre, double-blinded, placebo-controlled clinical trial of aerosolized dornase alfa to reduce the incidence of moderate-to-severe hypoxaemia in ventilated trauma patients.

BACKGROUND: Acute respiratory distress syndrome continues to drive significant morbidity and mortality after severe trauma. The incidence of trauma-induced, moderate-to-severe hypoxaemia, according to the Berlin definition, could be as high as 45%. Its pathophysiology includes the release of damage-associated molecular patterns (DAMPs), which propagate tissue injuries by triggering neutrophil extracellular traps (NETs). NETs include a DNA backbone coated with cytoplasmic proteins, which drive pulmonary cytotoxic effects. The structure of NETs and many DAMPs includes double-stranded DNA, which prevents their neutralization by plasma. Dornase alfa is a US Food and Drug Administration-approved recombinant DNase, which cleaves extracellular DNA and may therefore break up the backbone of NETs and DAMPs. Aerosolized dornase alfa was shown to reduce trauma-induced lung injury in experimental models and to improve arterial oxygenation in ventilated patients. METHODS: TRAUMADORNASE will be an institution-led, multicentre, double-blinded, placebo-controlled randomized trial in ventilated trauma patients. The primary trial objective is to demonstrate a reduction in the incidence of moderate-to-severe hypoxaemia in severe trauma patients during the first 7 days from 45% to 30% by providing aerosolized dornase alfa as compared to placebo. The secondary objectives are to demonstrate an improvement in lung function and a reduction in morbidity and mortality. Randomization of 250 patients per treatment arm will be carried out through a secure, web-based system. Statistical analyses will include a descriptive step and an inferential step using fully Bayesian techniques. The study was approved by both the Agence Nationale de la Sécurité du Médicament et des Produits de Santé (ANSM, on 5 October 2018) and a National Institutional Review Board (CPP, on 6 November 2018). Participant recruitment began in March 2019. Results will be published in international peer-reviewed medical journals. DISCUSSION: If early administration of inhaled dornase alfa actually reduces the incidence of moderate-to-severe hypoxaemia in patients with severe trauma, this new therapeutic strategy may be easily implemented in many clinical trauma care settings. This treatment may facilitate ventilator weaning, reduce the burden of trauma-induced lung inflammation and facilitate recovery and rehabilitation in severe trauma patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03368092. Registered on 11 December 2017.

[Performance criteria for the verification of IgE and tryptase assay methods: recommendations from the AllergoBioNet network]. / Critères de performance pour la vérification des méthodes de dosages des IgE et de la tryptase : recommandations du réseau AllergoBioNet.

Accreditation of an in vitro diagnostic assay according to the NF/EN/ISO 15189 standard requires to analyze its technical performance before implementation for routine use, and annually when reviewing effectiveness of quality controls. Performance is evaluated through repeatability, intermediate fidelity, accuracy and uncertainty of measurement. The coefficients of variation (CV) of the intra-assay and inter-assay precision tests must be compared with those of "peers" (results from laboratories employing the same method) and also with those obtained with "all methods", i.e., results from all laboratories performing the same assay, irrespective of the method. To our best knowledge, there is currently no French or international recommendation on what the acceptable limits of performance for specific IgE and tryptase assays should be. Therefore, the AllergoBioNet network of hospital allergy laboratories set out to characterize the performance of their current methods as a basis for the development of recommendations. The results provided by 24 centers were analyzed and led to consensus recommendations for specific IgE, total IgE and tryptase assays.

Infection risk among adults with down syndrome: a two group series of 101 patients in a tertiary center.

BACKGROUND: Down syndrome (DS) is the most common form of viable chromosomal abnormality. DS is associated with recurrent infections, auto-immunity and malignancies in children. Little is known about immunity and infections in DS at adulthood. METHODS: We studied two separate group of adults (> 18 years old) with DS in a single referral tertiary center (Strasbourg University Hospital). The first group included 37 ambulatory DS patients between November 2014 and May 2017. We analyzed exhaustive serological and immunobiological parameters, at one point, together with the prevalence of infections, autoimmune manifestations and malignancies. The second group included 64 hospitalized patients (138 stays) in the same center, between January 2005 and December 2016. RESULTS: One hundred and one adult patients with DS were included. Unlike children and despite a global lymphopenia, adults with DS underwent few infections in our ambulatory group. They did not experience any malignancy and, apart from hypothyroidism, they presented only occasional autoimmune manifestations. Hospitalized DS patients were older than ambulatory ones (median age 47 years (18-73) vs. 27 (18-52), p < 0.0001) and admitted mostly for infections (76.8%). Infections were associated with epilepsy and dementia (OR 6.5 (2.2-19), p = 0.001; p = 0.0006 in multivariate analysis) and higher mortality (OR 7.4 (1.4-37), p = 0.01). CONCLUSION: Despite persistent immunobiological abnormalities at adulthood, young ambulatory adults with DS remain healthy with a low rate of infections. Infections are associated with neurological degeneration and increase the mortality arguing for a dedicated support of older DS patients. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01663675 (August 13, 2012). Hospital Clinical Research Program (PHRC): number 2012-A00466-37 (Dr Y. Alembik).

Zika virus enhances monocyte adhesion and transmigration favoring viral dissemination to neural cells.

Zika virus (ZIKV) invades and persists in the central nervous system (CNS), causing severe neurological diseases. However the virus journey, from the bloodstream to tissues through a mature endothelium, remains unclear. Here, we show that ZIKV-infected monocytes represent suitable carriers for viral dissemination to the CNS using human primary monocytes, cerebral organoids derived from embryonic stem cells, organotypic mouse cerebellar slices, a xenotypic human-zebrafish model, and human fetus brain samples. We find that ZIKV-exposed monocytes exhibit higher expression of adhesion molecules, and higher abilities to attach onto the vessel wall and transmigrate across endothelia. This phenotype is associated to enhanced monocyte-mediated ZIKV dissemination to neural cells. Together, our data show that ZIKV manipulates the monocyte adhesive properties and enhances monocyte transmigration and viral dissemination to neural cells. Monocyte transmigration may represent an important mechanism required for viral tissue invasion and persistence that could be specifically targeted for therapeutic intervention.

Effects of long-term dietary intake of magnesium on oxidative stress, apoptosis and ageing in rat liver.

In the present study, we investigated the effect of long-term dietary Mg intake on the rate of oxidative stress, apoptosis and ageing in rat livers. To address this issue, rats were fed diets containing either a moderately deficient (0.15 g Mg/kg diet), a standard (0.8 g Mg/kg diet) or a high (3.2 g Mg/kg diet) Mg dose for two years. It is noteworthy that a higher percentage of animal mortality was observed in the lowest Mg diet, as compared to the other groups. Oxidative stress and antioxidant status were evaluated by measuring different enzyme activities, among which glutathione peroxidase activity was significantly reduced when Mg content was decreased in the diet. Moreover, we obtained an activation of caspase-3 and a higher lipid peroxidation in the Mg-deficient group, as compared to the Mg standard group, while no changes in Mg-supplemented group were observed, in accordance with our previously published data in primary cultures of rat hepatocytes (Martin et al., J Nutr 2003). Telomere shortening was measured in rat livers, as a marker of ageing. We found that telomere length was decreased in old animals, as compared to young animals confirming that telomere shortening correlated well with ageing events. Moreover, in old animals, we obtained a decrease of telomere length in the Mg-deficient group, as compared to the other groups. Taken together, our results show that a long-term chronic Mg deficiency led to oxidative stress, apoptosis and an acceleration of ageing in rat livers.

FACS - based isolation of human eosinophils allows purification of high quality RNA.

Here we extensively describe a FACS-based protocol for isolating intact non-stained human eosinophils from peripheral blood; a stop forward from our recently published initial study. This method of purification could be accomplished in <3 h with only small volumes of whole blood necessary, even in healthy subjects generally exhibiting low levels of circulating eosinophils. Eosinophil activation during the isolation steps appeared to be minimal and this purification procedure yielded high quality RNA. Moreover, these FACS-isolated eosinophils had prolonged viability in culture and were suitable for further activation assays.

Distribution and reduction magnitude of HIV-DNA burden in CD4+ T cell subsets depend on art initiation timing.

OBJECTIVE: The aim of our study was to analyze the dynamics of HIV-DNA levels in CD4 T-cell subsets in individuals starting successful dolutegravir-based regimens. DESIGN: Twenty-seven individuals with acute infection (AI, n = 8) or chronic infection (CI, n = 5) and patients in virological success (VS, n = 10) or virological failure (VF, n = 4) on antiretroviral therapy (ART) who initiated a dolutegravir-based regimen were enrolled (NCT02557997). METHODS: CD4 T-cells from baseline and week 48 of successful treatment were sorted into effector memory (TEM), transitional memory (TTM), central memory (TCM) and naïve (TN) cell groups for total HIV-DNA measurements by qPCR. Bayesian methods were used to estimate the posterior probability of a HIV-DNA decrease more than 0.25 log copies/10 cells at week 48. RESULTS: All patients achieved HIV-RNA suppression at 48 weeks. At baseline and week 48, the highest contributions to the HIV-DNA-infected pool from CD4 T cells were observed in TTM cells in the AI group (62.4 and 60.2%, respectively), but in TCM cells for the CI, VS and VF groups (54.6 and 59.4%, 58.2 and 62.9%, 62.4 and 67.2%), respectively. HIV-DNA burden declined in all subsets after 48 weeks of treatment in the AI (probability (Pr) > 91%), CI (Pr > 52%) and VF (Pr > 52%) groups, but only in TEM cells in the VS group (Pr = 95%). CONCLUSION: Our study showed that dolutegravir-based treatment reduced the HIV-DNA cellular burden in individuals from the AI, CI and VF groups, though the reduction levels differed between the patient subgroups. Early treated patients had the highest probability of HIV-DNA reduction. Interestingly, in the aviremic VS group, HIV-DNA reduction was limited to TEM cells.

Severe combined immunodeficiency caused by deficiency in either the delta or the epsilon subunit of CD3.

We investigated the molecular mechanism underlying a severe combined immunodeficiency characterized by the selective and complete absence of T cells. The condition was found in 5 patients and 2 fetuses from 3 consanguineous families. Linkage analysis performed on the 3 families revealed that the patients were carrying homozygous haplotypes within the 11q23 region, in which the genes encoding the gamma, delta, and epsilon subunits of CD3 are located. Patients and affected fetuses from 2 families were homozygous for a mutation in the CD3D gene, and patients from the third family were homozygous for a mutation in the CD3E gene. The thymus from a CD3delta-deficient fetus was analyzed and revealed that T cell differentiation was blocked at entry into the double positive (CD4+CD8+) stage with the accumulation of intermediate CD4-single positive cells. This indicates that CD3delta plays an essential role in promoting progression of early thymocytes toward double-positive stage. Altogether, these findings extend the known molecular mechanisms underlying severe combined immunodeficiency to a new deficiency, i.e., CD3epsilon deficiency, and emphasize the essential roles played by the CD3epsilon and CD3delta subunits in human thymocyte development, since these subunits associate with both the pre-TCR and the TCR.

1,25(OH)2D3 inhibits in vitro and in vivo intracellular growth of apicomplexan parasite Toxoplasma gondii.

The hormonal form of vitamin D, 1,25-dyhydroxyvitamin D3 (1,25(OH)2D3), is implicated in a wide range of functions other than its classical role in calcium and phosphorous homeostasis. When Toxoplasma gondii-infected BALB/c mice were treated with 1,25(OH)2D3, they succumb to death sooner than their counterparts. But they showed less parasite burden in tissues which was further supported by mild pathological lesions. As an effort to understand the physiological mechanism for the above observation an in vitro study was performed. Fewer parasites were observed when 1,25(OH)2D3 pre-treated murine intestinal epithelial cells were challenged with parasites. Moreover, the observed inhibition was dose-dependent and had a maximum effect with 10(-7)M of 1,25(OH)2D3. However, no observable difference was observed, when pre-incubated parasites were added to cells suggesting that the observed inhibition was a result of an effect from 1,25(OH)2D3 on Toxoplasma intracellular growth. Our data support the notion that 1,25(OH)2D3 may inhibit intra cellular T. gondii parasite proliferation in vivo and in vitro.