Caractérisation immunogénétique des cellules dendritiques non-conventionelles dans un contexte auto-immun

Les cellules dendritiques (DC) agissent en tant que joueur clé dans l’interaction entre l’immunité innée et adaptative via leur fonction de cellule présentatrice d’antigène professionnelle. Ces dernières, qui se divisent en plusieurs sous-populations aux fonctions distinctes, sont impliquées dans des contextes inflammatoires ou tolérogènes. On observe d’ailleurs des corrélations entre le nombre de certaines de ces populations in vivo et la susceptibilité génétique à certaines maladies, comme le diabète auto-immun. Cependant, il reste difficile d’établir si ces corrélations sont en fait causales, puisque l’on ignore l’identité des facteurs responsables de la régulation spécifique du nombre des sous-types de DC, limitant notre capacité à moduler ces phénotypes indépendamment. Nous avons donc voulu identifier les déterminants génétiques impliqués dans la régulation spécifique du nombre de sous-populations de DC via des analyses de liaison génétique, pour ensuite vérifier si la susceptibilité au diabète auto-immun varie suite à des modulations du nombre de sous-types de DC. Nous avons démontré qu’une augmentation de pDC chez la souris NOD, prédisposée au diabète auto-immun, est régulée par un locus dominant sur le chromosome 7 proximal, mais n’influence pas l’incidence du diabète dans des études de souris congéniques. En contraste, une augmentation d’un nouveau sous-type de DC, dénommé mcDC, est régulée par un intervalle distal du chromosome 2. Cet intervalle, nommé Idd13, est d’ailleurs également associé à la susceptibilité génétique au diabète auto-immun, suggérant un rôle central du nombre de mcDC dans la maladie, possiblement via leur capacité à renverser l’anergie de lymphocytes T. Ces résultats démontrent que les sous-types de DC sont régulés par des déterminants distincts. Malgré les corrélations entre le nombre de pDC/mcDC et la susceptibilité au diabète auto-immun, nos résultats démontrent également une contribution divergente des sous-types de DC à la maladie. Nous investiguerons davantage les intervalles génétiques, afin d’identifier les gènes candidats impliqués dans la régulation du pDC et du mcDC.Dendritic cells (DC) play a key role in the immune system by bridging the innate and adaptive immune system using their Antigen Presenting Cell (APC) function. They can be subdivided into several subsets with distinct features, which are involved in either tolerogenic or inflammatory processes. Variations in the in vivo number of those DC subsets have been associated with genetic susceptibility to certain diseases, such as autoimmune diabetes. However, proving a causal connection from these correlations remains a challenge, as we have not identified the factors involved in the specific regulation of the DC subsets number, limiting our ability to modulate theses phenotypes independently. Thus, we aimed to identify genetic determinants responsible for the specific regulation of DC subset numbers using linkage analysis in mice, to then determine if autoimmune diabetes susceptibility varies following DC subset modulations. We have shown an increase in pDC number in NOD mice, which is genetically susceptible to autoimmune diabetes. This phenotype is regulated by a dominant locus on proximal chromosome 7, but it not associated with diabetes incidence in congenic mice. In contrast, we also observe an increase in the number of a novel DC subset, termed mcDC, which is regulated by a distal chromosome 2 interval. This locus, termed Idd13, is also associated with diabetes genetic susceptibility, suggesting a vital role of mcDC in disease, possibly through their T cell anergy reversal function. These results show that DC subsets are regulated by distinct determinants.. Despite the correlation between pDC/mcDC number and autoimmune diabetes susceptibility, our results demonstrate a divergent contribution of DC subsets to pathogenesis. We shall investigate further to refine genetic intervals and identify the candidates genes involved in the regulation of both pDC and mcDC in vivo number

The Dichotomous Pattern of IL-12R and IL-23R Expression Elucidates the Role of IL-12 and IL-23 in Inflammation

IL-12 and IL-23 cytokines respectively drive Th1 and Th17 type responses. Yet, little is known regarding the biology of these receptors. As the IL-12 and IL-23 receptors share a common subunit, it has been assumed that these receptors are co-expressed. Surprisingly, we find that the expression of each of these receptors is restricted to specific cell types, in both mouse and human. Indeed, although IL-12Rβ2 is expressed by NK cells and a subset of γδ T cells, the expression of IL-23R is restricted to specific T cell subsets, a small number of B cells and innate lymphoid cells. By exploiting an IL-12- and IL-23-dependent mouse model of innate inflammation, we demonstrate an intricate interplay between IL-12Rβ2 NK cells and IL-23R innate lymphoid cells with respectively dominant roles in the regulation of systemic versus local inflammatory responses. Together, these findings support an unforeseen lineage-specific dichotomy in the in vivo role of both the IL-12 and IL-23 pathways in pathological inflammatory states, which may allow more accurate dissection of the roles of these receptors in chronic inflammatory diseases in humans

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

A pre-vaccination immune metabolic interplay determines the protective antibody response to a dengue virus vaccine

Summary: Protective immunity to dengue virus (DENV) requires antibody response to all four serotypes. Systems vaccinology identifies a multi-OMICs pre-vaccination signature and mechanisms predictive of broad antibody responses after immunization with a tetravalent live attenuated DENV vaccine candidate (Butantan-DV/TV003). Anti-inflammatory pathways, including TGF-β signaling expressed by CD68low monocytes, and the metabolites phosphatidylcholine (PC) and phosphatidylethanolamine (PE) positively correlate with broadly neutralizing antibody responses against DENV. In contrast, expression of pro-inflammatory pathways and cytokines (IFN and IL-1) in CD68hi monocytes and primary and secondary bile acids negatively correlates with broad DENV-specific antibody responses. Induction of TGF-β and IFNs is done respectively by PC/PE and bile acids in CD68low and CD68hi monocytes. The inhibition of viral sensing by PC/PE-induced TGF-β is confirmed in vitro. Our studies show that the balance between metabolites and the pro- or anti-inflammatory state of innate immune cells drives broad and protective B cell response to a live attenuated dengue vaccine