Identification d'une signature immune associée à la maladie d'Alzheimer

La maladie d’Alzheimer (MA) est un désordre neurologique progressif et irréversible caractérisé par l’accumulation de peptides β-amyloïdes, de plaques amyloïdes et de dégénérescence neurofibrillaires. L’inflammation et des altérations du système immunitaire ont été reliées à la MA, suggérant que le système immunitaire périphérique pourrait jouer un rôle pendant la phase asymptomatique de la maladie. Les lymphocytes natural killer et les neutrophiles (PMN) participent à la surveillance immune innée et leurs rôles demeurent controversés dans la MA. Nous avons étudié les changements phénotypiques et fonctionnels des cellules NK et des PMN du sang périphérique dans une cohorte de patients composée de personnes âgées en bonne santé, de patients amnestic mild cognitive impairment (aMCI) et de personnes atteintes de la MA à un stade léger (mMA). L’analyse phénotypique des lymphocytes NK a révélé des différences d’expression de CD16 (augmenté chez les patients mMA), de NKG2A (diminué chez les patients aMCI), et des TLR2 et TLR9 (tous deux diminués chez les patients mMA). Les tests fonctionnels ont révélé que l’activité cytotoxique des lymphocytes NK ainsi que leur capacité de dégranulation étaient inchangés dans les 3 groupes de patients. Au contraire, l’expression du récepteur CD95 était augmentée chez les aMCI et mMA et l’expression de granzyme B et la production de cytokines telles que TNFα et IFNγ étaient augmentées chez les aMCI mais pas chez les patients mMA. Le chimiotactisme induit par la chimiokine CCL19 et non par CC21 était diminué chez les aMCI et mMA, malgré l’augmentation de l’expression du CCR7 chez les patients aMCI. L’analyse des PMN révèle une augmentation spécifique de l’expression de CD177 chez les patients mMA. La stimulation à l’IL-8 entraine l’augmentation attendue de l’intégrine CD11b à la surface des PMN des patients âgés contrôles, mais les patients aMCI et mMA ne répondent pas. La baisse de l’expression des récepteurs CD14 et CD16 a été observée sur les PMN des patients mMA uniquement. Au contraire, seul les PMN des patients aMCI présentent une baisse de l’expression du marqueur CD88 et du TLR2. La phagocytose est différentiellement diminuée dans les PMN des patients aMCI et mMA tandis que l’ingestion de particules de Dextran est absente uniquement chez les patients mMA. Le killing contre Candida albicans est sévèrement diminué dans les groupes aMCI et mMA, alors que la production de radicaux libres est seulement diminuée au stade mMA. La production de cytokines inflammatoires (TNFα, IL-6, IL-1β, IL-12p70) et de chimiokines (MIP-1α, MIP-1β, IL-8) en réponse à une stimulation au LPS est très basse chez les patients aMCI et absente chez les mMA. Ces résultats suggèrent un état d’activation des cellules NK chez les patients aMCI qui pourrait refléter une réponse immunitaire active dirigée contre une agression encore non identifiée. L’altération différentielle des capacités de réponse à des agressions pathologiques des PMN des patients aMCI et mMA pourrait se traduire par une baisse progressive de la réponse immune associée au développement de la MA

Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel NaV1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on NaV1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings

Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility.

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel Na1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on Na1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Identification d'une signature immune associée à la maladie d'Alzheimer

La maladie d’Alzheimer (MA) est un désordre neurologique progressif et irréversible caractérisé par l’accumulation de peptides β-amyloïdes, de plaques amyloïdes et de dégénérescence neurofibrillaires. L’inflammation et des altérations du système immunitaire ont été reliées à la MA, suggérant que le système immunitaire périphérique pourrait jouer un rôle pendant la phase asymptomatique de la maladie. Les lymphocytes natural killer et les neutrophiles (PMN) participent à la surveillance immune innée et leurs rôles demeurent controversés dans la MA. Nous avons étudié les changements phénotypiques et fonctionnels des cellules NK et des PMN du sang périphérique dans une cohorte de patients composée de personnes âgées en bonne santé, de patients amnestic mild cognitive impairment (aMCI) et de personnes atteintes de la MA à un stade léger (mMA). L’analyse phénotypique des lymphocytes NK a révélé des différences d’expression de CD16 (augmenté chez les patients mMA), de NKG2A (diminué chez les patients aMCI), et des TLR2 et TLR9 (tous deux diminués chez les patients mMA). Les tests fonctionnels ont révélé que l’activité cytotoxique des lymphocytes NK ainsi que leur capacité de dégranulation étaient inchangés dans les 3 groupes de patients. Au contraire, l’expression du récepteur CD95 était augmentée chez les aMCI et mMA et l’expression de granzyme B et la production de cytokines telles que TNFα et IFNγ étaient augmentées chez les aMCI mais pas chez les patients mMA. Le chimiotactisme induit par la chimiokine CCL19 et non par CC21 était diminué chez les aMCI et mMA, malgré l’augmentation de l’expression du CCR7 chez les patients aMCI. L’analyse des PMN révèle une augmentation spécifique de l’expression de CD177 chez les patients mMA. La stimulation à l’IL-8 entraine l’augmentation attendue de l’intégrine CD11b à la surface des PMN des patients âgés contrôles, mais les patients aMCI et mMA ne répondent pas. La baisse de l’expression des récepteurs CD14 et CD16 a été observée sur les PMN des patients mMA uniquement. Au contraire, seul les PMN des patients aMCI présentent une baisse de l’expression du marqueur CD88 et du TLR2. La phagocytose est différentiellement diminuée dans les PMN des patients aMCI et mMA tandis que l’ingestion de particules de Dextran est absente uniquement chez les patients mMA. Le killing contre Candida albicans est sévèrement diminué dans les groupes aMCI et mMA, alors que la production de radicaux libres est seulement diminuée au stade mMA. La production de cytokines inflammatoires (TNFα, IL-6, IL-1β, IL-12p70) et de chimiokines (MIP-1α, MIP-1β, IL-8) en réponse à une stimulation au LPS est très basse chez les patients aMCI et absente chez les mMA. Ces résultats suggèrent un état d’activation des cellules NK chez les patients aMCI qui pourrait refléter une réponse immunitaire active dirigée contre une agression encore non identifiée. L’altération différentielle des capacités de réponse à des agressions pathologiques des PMN des patients aMCI et mMA pourrait se traduire par une baisse progressive de la réponse immune associée au développement de la MA

Blood-based redox-signature and their association to the cognitive scores in MCI and Alzheimer’s disease patients

International audienceOxidative stress plays a pivotal and early role in the pathophysiology of Alzheimer's disease (AD). There is convincing evidence that oxidative alterations in AD and in mild cognitive impairment (MCI) patients are not limited to the brain but are extended to the blood compartment. However, the oxidative pattern in plasma is still inconclusive. Moreover, their potential association with the clinical scores MMSE (Mini-Mental State Examination) and MoCA (Montreal Cognitive Assessment) is poorly investigated. The aim of our study was to establish a pattern of blood-based redox alterations in prodromal AD and their evolution during the progression of the disease. Our results showed a reduction in the total antioxidant capacity (TAC) and an increase of the stress-response proteins apolipoprotein J (ApoJ) and Klotho in MCI subjects. For the first time, we evidenced circulating-proteasome activity. We found that the alteration of the circulating-proteasome activity is associated with the accumulation of oxidized proteins in plasma form early AD. Interestingly, the TAC, the levels of vitamin D and the activity of proteasome were positively associated to the clinical scores MMSE and MoCA. The levels of protein carbonyls and of ApoJ were negatively associated to the MMSE and MoCA scores. The levels of apolipoprotein D (ApoD) were not different between groups. Interestingly, the receiver operating characteristic (ROC) curves analysis indicated that these redox markers provide a fair classification of different groups with high accuracy. Overall, our results strengthen the notion that some specific oxidative markers could be considered as non-invasive blood-based biomarkers for an early MCI diagnosis and AD progression

Alteration of High-Density Lipoproteins functionality in Alzheimer’s disease patients

The aims of the present study were to determine whether High-Density Lipoproteins functionality (HDL)-mediated cholesterol efflux is altered in Alzheimer’s disease (AD) and to investigate the role and effect of amyloid-beta (Aβ) in the regulation of the anti-atherogenic activity of HDL. Eighty-seven elderly subjects were recruited, of whom 27 were healthy, 27 had mild cognitive impairment (MCI), and 33 had mild Alzheimer’s disease (mAD). Our results showed that total cholesterol levels are negatively correlated with the Mini Mental State Examination (MMSE) score (r = –0.2602, p = 0.0182). HDL from the mAD patients was less efficient at mediating cholesterol efflux from J774 macrophages (pThe accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author