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Contexte : La réforme de la première année des études de santé définie dans le décret du 4 novembre 2019 a mis fin à la première année commune aux études de santé (PACES) pour introduire un nouveau système ayant pour objectif de diversifier l’accès aux formations de médecine, maïeutique, odontologie, pharmacie et kinésithérapie (MMOP-K) par différents parcours de formation antérieurs. À l’Université de Bordeaux a été mis en place un double système avec un parcours accès spécifique santé (PASS) et des licences accès santé (L.AS). La voie L.AS étant minoritaire en cette première année de mise en place de la réforme, nous avons centré notre analyse sur les étudiant·es en PASS en 2020–2021 et l’accès à la filière médecine. Méthodes : Cette première année de PASS a été évaluée au regard des résultats académiques aux épreuves écrites des deux semestres (nombre d’UE validées, validation/échec du PASS, admissibilité dans la filière médecine) et aux épreuves orales (réussite aux mini entretiens multiples, admission dans la filière médecine). Résultats et conclusion : Nous avons identifié le niveau scolaire à l’entrée à l’Université, mesuré par la mention au bac, comme étant le principal facteur de réussite pour la validation du PASS et la réussite à l’admission dans la filière médecine. Le déterminant social est également associé à la validation du PASS, indépendamment du niveau scolaire. Les résultats montrent également que l’hétérogénéité des résultats en fonction de l’option disciplinaire et du site géographique est essentiellement liée à des disparités de niveaux scolaires à l’entrée en PASS.

During Plasmodium falciparum infections, erythrocyte-stage parasites inhibit dendritic cell maturation and function; compromising development of effective anti-malarial adaptive immunity. Human Vγ9Vδ2 T-cells can act in vitro as APCs and induce αβ T-cell activation. However, the relevance of this activity in pathophysiological contexts in vivo has remained elusive. Since Vγ9Vδ2 T-cells are activated during the early immune response against P.falciparum infection, we investigated whether they could contribute to the instruction of adaptive immune responses toward malaria parasites. In P.falciparum-infected patients,Vγ9Vδ2 T-cells presented an increased surface expression of APC-associated markers HLA-DR and CD86. In response to infected red blood cells in vitro, Vγ9Vδ2 T-cells readily up-regulated surface expression of HLA-DR, HLA-ABC, CD40, CD80, CD83 and CD86, induced naive αβ T-cell responses, and cross-presented soluble prototypical protein to antigen-specific CD8+ T-cells. Our findings indicate that P. falciparum parasites induce genuine APC properties in Vγ9Vδ2 T-cells and qualify this subset as an alternative professional APC in malaria patients, which could be harnessed for therapeutic interventions and vaccine design.

The unwarranted persistence of the immunoinflammatory process turns this critical component of the body’s natural defenses into a destructive mechanism, which is involved in a wide range of diseases, including chronic rejection. Performing a comprehensive analysis of human kidney grafts explanted because of terminal chronic rejection, we observed that the inflammatory infiltrate becomes organized into an ectopic lymphoid tissue, which harbors the maturation of a local humoral immune response. Interestingly, intragraft humoral immune response appeared uncoupled from the systemic response because the repertoires of locally produced and circulating alloantibodies only minimally overlapped. The organization of the immune effectors within adult human inflamed tissues recapitulates the biological program recently identified in murine embryos during the ontogeny of secondary lymphoid organs. When this recapitulation was incomplete, intragraft B cell maturation was impeded, limiting the aggressiveness of the local humoral response. Identification of the molecular checkpoints critical for completion of the lymphoid neogenesis program should help develop innovative therapeutic strategies to fight chronic inflammation.

International audience; This paper reports the detection of okadaic acid (OA) as a Diarrheic Shellfish Poisoning (DSP) toxin with an acoustic wave platform in real-time. According to the FDA, the threshold for safe consumption of shellfish is 20 μg of OA for 100 g of shellfish tissue. The high gravimetric sensitivity of Love wave acoustic devices allow, in liquid media, immuno-detection thanks to immobilized specific antibodies. The biosensor is composed of two lines, one for the test and one used as a reference. Sensitive films were deposited through a PolyDiMethylSiloxane (PDMS) microfluidic chip. On both lines, anti-okadaic acid antibodies (OA-Ab) and saturating agents were successively injected under continuous flow with controlled flow rate. On the test line, okadaic acid (OA) was injected while an unspecific peptide (6×Histidine, 6×His) was used on the control line. On both lines, polyclonal OA-Ab were re-injected a second time to reveal previously fixed OA on the test line. Measured frequency shifts were three times higher on test lines than on control lines. In these conditions, for only 2 μg of OA used for detection, the acoustic wave platform could detect DSP toxins with only 10 g of shellfish tissue.

Engagement of surface receptors contributes to the antimicrobial activity of human immune cells. We show here that infection of human monocyte-derived macrophages (MDM) with liveMycobacterium aviuminduced the expression of CD23 on their membrane. Subsequent cross-linking of surface CD23 by appropriate ligands induced a dose-dependent antibacterial activity of MDM and the elimination of most infected cells. The stimulation of inducible nitric oxide synthase-dependent generation of NO from MDM after CD23 activation played a major role during their anti-M. aviumactivity. CD23 activation also induced tumor necrosis factor alpha (TNF-α) production from MDM. Mycobacteria reduction was partially inhibited by the addition of neutralizing anti-TNF-α antibody to cell cultures without affecting NO levels, which suggested the role of this cytokine for optimal antimicrobial activity. Finally, interleukin-10, a Th2 cytokine known to downregulate CD23 pathway, is shown to decrease NO generation and mycobacteria elimination by macrophages. Therefore, (i) infection withM. aviumpromotes functional surface CD23 expression on human macrophages and (ii) subsequent signaling of this molecule contributes to the antimicrobial activity of these cells through an NO- and TNF-α-dependent pathway. This study reveals a new human immune response mechanism to counter mycobacterial infection involving CD23 and its related ligands.

The fact that you can vaccinate a child at 5 years of age and find lymphoid B cells and antibodies specific for this vaccination 70 years later remains an immunologic enigma. It has never been determined how these long-lived memory B cells are maintained and whether they are protected by storage in a special niche. We report that, whereas blood and spleen compartments present similar frequencies of IgG+ cells, antismallpox memory B cells are specifically enriched in the spleen where they account for 0.24% of all IgG+ cells (ie, 10-20 million cells) more than 30 years after vaccination. They represent, in contrast, only 0.07% of circulating IgG+ B cells in blood (ie, 50-100 000 cells). An analysis of patients either splenectomized or rituximab-treated confirmed that the spleen is a major reservoir for long-lived memory B cells. No significant correlation was observed between the abundance of these cells in blood and serum titers of antivaccinia virus antibodies in this study, including in the contrasted cases of B cell– depleting treatments. Altogether, these data provide evidence that in humans, the two arms of B-cell memory—long-lived memory B cells and plasma cells—have specific anatomic distributions—spleen and bone marrow—and homeostatic regulation.

We investigated an otherwise healthy patient presenting two episodes of staphylococcal cellulitis and abscesses, accompanied by high fever and biological signs of inflammation but, paradoxically, with no detectable increase in serum levels of C-reactive protein (CRP), an IL-6-responsive protein synthesized in the liver. Following in vitro activation of whole blood cells from the patient with multiple cytokines, TLR agonists, heat-killed bacteria, and mitogens, we observed a profound and specific impairment of IL-6 secretion. However, the patient’s PBMCs, activated in the same conditions but in the absence of the patient’s plasma, secreted IL-6 normally. The patient’s serum contained high titers of IgG1 autoantibodies against IL-6, which specifically neutralized IL-6 production by control PBMCs as well as IL-6 responses in the human hepatocellular carcinoma cell line Hep3B. These anti-IL-6 autoantibodies were detected over a period of 4 years, in the absence of any other autoantibodies. Our results indicate that these Abs probably prevented an increase in CRP concentration during infection and that impaired IL-6-mediated immunity may have contributed to staphylococcal disease. Patients with severe bacterial infections and low serum CRP concentrations should be tested for anti-IL-6 autoantibodies, especially in the presence of other clinical and biological signs of inflammation.

International audience; T cell-dependent immune responses develop soon after birth, whereas it takes 2 yr for humans to develop T cell-independent responses. We used this dissociation to analyze the repertoire diversification of IgM(+)IgD(+)CD27(+) B cells (also known as "IgM memory" B cells), comparing these cells with switched B cells in children

Malaria induces potent activation and expansion of the Vγ9Vδ2 subpopulation of γδT cells, which inhibit the Plasmodium falciparum blood cycle through soluble cytotoxic mediators, abrogating merozoite invasion capacity. Intraerythrocytic stages efficiently trigger Vγ9Vδ2 T-cell activation and degranulation through poorly understood mechanisms. P. falciparum blood-stage extracts are known to contain phosphoantigens able to stimulate Vγ9Vδ2 T cells, but how these are presented by intact infected red blood cells (iRBCs) remains elusive. Here we show that, unlike activation by phosphoantigen-expressing cells, Vγ9Vδ2 T-cell activation by intact iRBCs is independent of butyrophilin expression by the iRBC, and contact with an intact iRBC is not required. Moreover, blood-stage culture supernatants proved to be as potent activators of Vγ9Vδ2 T cells as iRBCs. Bioactivity in the microenvironment is attributable to phosphoantigens, as it is dependent on the parasite DOXP pathway, on Vγ9Vδ2 TCR signaling, and on butyrophilin expression by Vγ9Vδ2 T cells. Kinetic studies showed that the phosphoantigens were released at the end of the intraerythrocytic cycle at the time of parasite egress. We document exquisite sensitivity of Vγ9Vδ2 T cells, which respond to a few thousand parasites. These data unravel a novel framework, whereby release of phosphoantigens into the extracellular milieu by sequestered parasites likely promotes activation of distant Vγ9Vδ2 T cells that in turn exert remote antiparasitic functions.

Pentahydroxyflavone dihydrate, quercetin (QU) is one of common flavonols biosynthesized by plants and has been suggested to modulate inflammatory responses in various models. In the present study, we investigated in vivo effects of oral or intra-cutaneous QU in chronic rat adjuvant-induced arthritis (AA). Growth delay and arthritic scores were evaluated daily after AA induction in Lewis rats. Oral administration of QU (5 x 160 mg/kg) to arthritic rats resulted in a clear decrease of clinical signs compared to untreated controls. Intra-cutaneous injections of lower doses (5 x 60 mg/kg) of QU gave similar anti-arthritic effects, while 5 x 30 mg/kg concentrations were inefficient in this respect. Finally, injection of relatively low QU doses (5 x 30 mg/kg) prior to AA induction significantly reduced arthritis signs. As QU was suggested to inhibit macrophage-derived cytokines and nitric oxide (NO), we then analyzed macrophage response ex vivo. Anti-arthritic effects of QU correlated with significant decrease of inflammatory mediators produced by peritoneal macrophages, ex vivo and in vitro. These data indicate that QU is a potential anti-inflammatory therapeutic and preventive agent targeting the inflammatory response of macrophages.

In addition to parasite spread, the severity of disease observed in cases of human African trypanosomiasis (HAT), or sleeping sickness, is associated with increased levels of inflammatory mediators, including tumor necrosis factor (TNF)-α and nitric oxide derivatives. In the present study, quercetin (3,3′,4′,5,7-pentahydroxyflavone), a potent immunomodulating flavonoid, was shown to directly induce the death of Trypanosoma brucei gambiense , the causative agent of HAT, without affecting normal human cell viability. Quercetin directly promoted T. b. gambiense death by apoptosis as shown by Annexin V binding. In addition to microbicidal activity, quercetin induced dose-dependent decreases in the levels of TNF-α and nitric oxide produced by activated human macrophages. These results highlight the potential use of quercetin as an antimicrobial and anti-inflammatory agent for the treatment of African trypanomiasis.

B-cell chronic lymphocytic leukaemia (B-CLL) is a neoplastic disorder characterized by defective apoptosis, cell accumulation in G0/G1, and high expression of BCL2 oncogene. Intracellular cyclic adenosine monophosphate (cAMP) accumulation increases the chemosensitivity of B-CLL cells in vitro and in vivo. In the present study, we investigated the effects of beta2-adrenergic compounds, well known cAMP-inducing drugs, on the in vitro survival of leukaemia cells. In contrast to the short-acting beta2-mimetic (beta2Mim) salbutamol, a consistent pro-apoptotic effect was observed with the long-acting beta2Mim salmeterol and formoterol. Normal B cells isolated from control donors were totally resistant to the above molecules. These compounds also increased chlorambucil- and fludarabine-induced death of B-CLL cells. Blockade of beta-adrenergic receptor signalling or cAMP did not alter B-CLL apoptosis with beta2 Mimagents. Leukaemia cell apoptosis by beta2Mim correlated with an increase in calcium influx, decreased bcl-2 protein and mRNA levels, increase in BAX gene expression and a marked rise in BCL2/BAX mRNA ratios. Interleukin-4, a cytokine that increases bcl-2 expression in B-CLL cells, rescued leukaemia cell from apoptosis with beta2Mim. These data show that long-acting beta2-adrenergic agents promote apoptotic leukaemia cell death through an adrenoreceptor- and cAMP-independent, Ca2+-dependent mechanism.

An original series of 4-substituted pyrrolo[1,2-a]quinoxaline derivatives, new structural analogues of Galipea species quinoline alkaloids, was synthesized from various substituted 2-nitroanilines via multistep heterocyclizations and tested for in vitro antiparasitic activity upon Leishmania amazonensis and Leishmania infantum strains. Structure-activity relationships enlighten the importance of the 4-substituted alkenyl side chain on the pyrrolo[1,2-a]quinoxaline moiety to modulate the antileishmanial activity.

B-cell chronic lymphocytic leukaemia (B-CLL) is a neoplastic disorder characterized by defective apoptosis, cell accumulation in G0/G1, and high expression of BCL2 oncogene. Intracellular cyclic adenosine monophosphate (cAMP) accumulation increases the chemosensitivity of B-CLL cells in vitro and in vivo. In the present study, we investigated the effects of beta2-adrenergic compounds, well known cAMP-inducing drugs, on the in vitro survival of leukaemia cells. In contrast to the short-acting beta2-mimetic (beta2Mim) salbutamol, a consistent pro-apoptotic effect was observed with the long-acting beta2Mim salmeterol and formoterol. Normal B cells isolated from control donors were totally resistant to the above molecules. These compounds also increased chlorambucil- and fludarabine-induced death of B-CLL cells. Blockade of beta-adrenergic receptor signalling or cAMP did not alter B-CLL apoptosis with beta2 Mimagents. Leukaemia cell apoptosis by beta2Mim correlated with an increase in calcium influx, decreased bcl-2 protein and mRNA levels, increase in BAX gene expression and a marked rise in BCL2/BAX mRNA ratios. Interleukin-4, a cytokine that increases bcl-2 expression in B-CLL cells, rescued leukaemia cell from apoptosis with beta2Mim. These data show that long-acting beta2-adrenergic agents promote apoptotic leukaemia cell death through an adrenoreceptor- and cAMP-independent, Ca2+-dependent mechanism.

The synthesis of new 7-hydroxy-2-substituted-methyl-5 H -oxazolo[3,2- a] pyrimidin-5-ones derivatives, designed as structural bicyclic analogues of the iron chelator deferiprone, is described. They were tested for their ability to inhibit proliferation in human Bcr-Abl + leukemia cells.

It is often postulated that trans-3,4',5-trihydroxystilbene (resveratrol, RES) exhibits cell growth regulatory and chemopreventive activities. However, mechanisms by which this polyphenol inhibits tumor cell growth, and its therapeutic potential are poorly understood. Using various human leukemia cells, we have first defined the anti-tumoral doses of this compound. RES inhibited the proliferation and induced the apoptosis of all tested lymphoid and myeloid leukemia cells with IC(50) = 5-43 microM. Prior to apoptosis, RES-induced caspase activity in a dose-dependent manner and cell cycle arrest in G(2)/M-phase, correlating with a significant accumulation of cyclins A and B. Leukemia cell death with RES required both caspase-dependent and -independent proteases, as it was significantly inhibited by simultaneous addition of Z-VAD-FMK and leupeptin to these cultures. While RES did not affect non-activated normal lymphocytes, this agent decreased the growth and induced the apoptosis of cycling normal human peripheral blood lymphocytes at lower concentrations (IC(50)

Background Chikungunya fever is an emerging arboviral disease characterized by an algo-eruptive syndrome, inflammatory polyarthralgias, or tenosynovitis that can last for months to years. Up to now, the pathophysiology of the chronic stage is poorly understood. Case presentation We report the first case of CHIKV infection with chronic associated rheumatism in a patient who developed progressive erosive arthritis with expression of inflammatory mediators and persistence of specific IgM antibodies over 24 months following infection. Conclusions Understanding the specific features of chikungunya virus as well as how the virus interacts with its host are essential for the prevention, treatment or cure of chikungunya disease.

What if in France the dispensary pharmacist could administer the tetanus vaccines? State of play in France and abroad, interests and survey among adults In France, the Diphtheria-Tetanus-Poliomyelitis-Pertussis (Tdap) vaccination is compulsory for young children, but it remains only recommended for adults. A large part of this population does not get the boosters necessary to maintain their vaccination status, exposing them to avoidable risks. Despite the fact that the TdP vaccine is part of the routine vaccinations, the vaccination coverage of the adult population remains unsatisfactory. Since 2019, the dispensary pharmacist has been authorized to perform influenza vaccination and the population benefiting from it seems satisfied. Some countries, offering the same service, have extended vaccination to other vaccines including TdP in order to improve their vaccination coverage, however we do not have the necessary hindsight to assess the impact of such a measure. A survey was carried out among 203 French adults in order to measure the interest in offering this vaccination in pharmacies. Among them, 63% (n = 128) would be interested if the pharmacist could administer the TdP or DTaP vaccine to them, including 13 people who said they were not up to date with the vaccine.; En France, la vaccination Diphtérie-Tétanos-Poliomyélite-Coqueluche (DTPCa) est obligatoire pour les jeunes enfants, mais elle reste seulement recommandée pour les adultes. Une importante partie de cette population ne fait pas les rappels nécessaires au maintien de leur statut vaccinal, l’exposant à des risques évitables. Malgré que le vaccin DTP fasse partie des vaccinations de routine, la couverture vaccinale de la population adulte reste insatisfaisante. Depuis 2019 le pharmacien d’officine est habilité à pratiquer la vaccination antigrippale et la population qui en bénéficie semble satisfaite. Certains pays, proposant le même service officinal, ont étendu la vaccination à d’autres vaccins dont celui du DTP afin d’améliorer leur couverture vaccinale, cependant nous n’avons pas le recul nécessaire pour évaluer l’impact d’une telle mesure. Une enquête a été réalisée auprès de 203 adultes français afin de mesurer l’intérêt de proposer cette vaccination en officine. Parmi eux 63% (n=128) seraient intéressés si le pharmacien pouvait leur administrer le vaccin DTP ou DTPCa, dont 13 personnes ne se disant pas à jour du vaccin.

Vaccination is still one of the best protections that humans have designed to protect themselves from infectious diseases. The growing knowledge of the mechanisms regarding innate and adaptative immunities has enabled the development of a multitude of vaccines to address increasingly complex problems, while ensuring efficacy, safety and low cost. Despite all these advances, the ageing population characterized by immunosenescence brings new challenges to this vaccination. Indeed, this abstruse and continuous remodelling of the immune system is in addition to generalized aging, which is also characterized by genetic and functional alterations. The development of new vaccines is therefore confronted with growing and intereconnected issues. Far from being exhaustive, this thesis will focus on the relevance of our current vaccine methods with regard to immunosenescence, on the advent of systems biology as a new axis of vaccine research and development ; as well as on the advantages, defects and limitations of a vaccination that aim to be ever more personalized., La vaccination est aujourd’hui encore une des meilleures protections que l’homme ait conçu pour se protéger des maladies infectieuses. La connaissance de plus en plus fine des mécanismes des immunités innées et adaptatives a permis le développement d’une multitude de vaccins dans le but de répondre à des problèmes de plus en plus complexes, tout en garantissant l’efficacité, la sûreté et un coût peu onéreux. Malgré l’ensemble de ces avancées, le vieillissement de la population caractérisée par l’immunosénescence oppose de nouveaux défis à cette vaccination. En effet, ce remodelage abscons et continu du système immunitaire s’ajoute à un vieillissement généralisé, qui lui aussi, se caractérise par des altérations génétiques et fonctionnelles. Le développement de nouveaux vaccins est donc confronté à des problématiques grandissantes et interconnectées. Loin d’être exhaustive, cette thèse se centrera sur la pertinence de nos méthodes actuelles vaccinales au regard de l’immunosénescence, sur l’avènement de la biologie systémique comme nouvel axe de recherche et de développement vaccinal ainsi que sur les avantages, défauts et limites d’une vaccination qui se voudrait toujours plus personnalisée.