Inserm Newsroom - Press room of the French national institute of health and medical research

Menu
close
Search

Month: April 2021

ComPaRe Covid long: development of the first scientific measure of the severity of the disease and its impact on the lives of patients

Posted on by Tatiana Marotta

SARS COV 2

@ NIAID

Researchers from the ComPaRe cohort (Community of Patients for Research, compare.aphp.fr ), led by Prof. Philippe Ravaud, AP-HP / University of Paris / Inserm, used an original method to develop and validate the first measurement science of the severity of the disease and its impact on the lives of patients. This study involving 1,022 patients suffering from long Covid was published in the journal Clinical Infectious Diseases on April 29, 2021.

“Long covid” is the term used by patients to describe the set of late manifestations occurring after infection with the SARS-CoV-2 virus. According to the National Statistics Office in the UK, around one in 10 infected people continue to have symptoms 12 weeks after the onset of infection. There are many causes for the persistence of symptoms. For example, there are organ sequelae following the acute phase of the disease (pulmonary scars, complications of resuscitation, etc.), post-traumatic stress linked to the disease or its management, viral persistence or post-viral fatigue syndrome. In a given individual, several causes are often intertwined and responsible for complex clinical pictures.

Until now, scientific studies estimating the number of patients with persistent symptoms of Covid have each used a different definition of the disease. The heterogeneity of the measures used may therefore have contributed to the discrepancies between the results of the studies.

To respond to this problem, the clinical epidemiology center of the Hôtel-Dieu AP-HP hospital, headed by Prof. Philippe Ravaud, AP-HP / University of Paris / Inserm, launched a study at the end of 2020 on the long Covid within the ComPaRe cohort, the Community of Patients for Research supported by Public Assistance – Hospitals of Paris and University of Paris. This study aimed to develop a scientific measure of the severity of the disease and its impact on the lives of patients using a two-phase method.

During the first phase (October – November 2020), the researchers interviewed 492 patients [median age 45 years, 84% female, 43% with infection confirmed by PCR] with a long covid (defined as the presence of persistent symptoms at least 3 weeks after infection with SARS CoV2). Patients were able to report, in free text, all of their symptoms and the triggers and calming factors thereof. Patients were also asked about the impact of the disease on their lives. The participants’ responses were analyzed by researchers and expert patients. They allowed the definition of a list of 53 manifestations of the disease (fatigue, chest pain, headaches, balance disorders, etc.) and six areas of patients’ lives that could be impacted by it. ci (family life,

In the second phase (November 2020 – February 2021), the researchers used these results to develop a questionnaire, completed directly by the patients, in order to measure the severity of the disease and its impact on the patients’ lives. They assessed the validity, reliability and relevance of this questionnaire in a second sample of 1022 patients with a long Covid [median age 45 years, 79% of women, 55% of patients with an infection confirmed by PCR, 12% with been hospitalized]. This second phase showed the major impact of long covid on the quality of life of patients, estimated to be around 40% lower than that of the general population. So,

In conclusion, this research has enabled the development of a quality scientific basis for measuring long covid. Standardization of measurements in scientific studies will make it possible to compare and combine the results thereof.

The measure developed is currently used to assess the evolution over time of the symptoms of patients in the ComPaRe Covid long study. This will make it possible to understand the variations in the manifestations of the disease over time and to answer the question “how long does the disease last?” “.

In order to answer these research questions, ComPaRe renews its call for participation in long-term Covid research projects carried out within the cohort. To participate, simply register on https://compare.aphp.fr .

Created in 2017 by the AP-HP, ComPaRe, the Community of Patients for Research today brings together more than 45,000 patient volunteers across France. They help advance research on their chronic disease (s) by regularly responding to researchers’ online questionnaires, on the secure platform https://compare.aphp.fr .

Today, 36 specific projects have been launched in ComPaRe. In addition to the long covid, several specific studies have been launched to follow patients suffering from diabetes, Verneuil’s disease, vitiligo, chronic low back pain, kidney disease, vasculitis, high blood pressure, endometriosis, neurofibromatosis and of Marfan syndrome. New studies and specific cohorts are being set up.

Inserm and AstraZeneca join forces to test the efficacy of monoclonal antibody combination AZD7442 on Covid-19 in the European DisCoVeRy trial

Posted on by Graziella Cara

SARS-CoV-2

AZD7442 is a combination of two long-acting monoclonal antibodies (LAAB) derived from the plasma of two convalescent patients who have recovered from Sars-CoV-2 infection. © Electron microscopy of a cell infected with SARS-CoV-2 (Philippe Roingeard, Anne Bull-Maurer, Sonia Georgeault, unité Inserm U1259 MAVIVH & Université de Tours, France)

A long-acting antibody (LAAB) combination developed by AstraZeneca is to be evaluated in DisCoVeRy, the Inserm-coordinated European trial aimed at finding a treatment for COVID-19. It is planned to enroll 1240 patients across Europe in this Phase III clinical trial.

With its wealth of experience in the domain of targeted therapies (oncology, respiratory diseases), AstraZeneca has developed a combination of two monoclonal antibodies targeting the spike protein of SARS-CoV-2: AZD7442. This combination is now being clinically tested in various settings, both as a preventive and curative treatment for COVID-19.

International scientific commitments against Covid-19 

DisCoVeRy, the clinical trial coordinated by Inserm, was set up in the very first months of the COVID-19 pandemic as a “daughter” trial of Solidarity – the international WHO trial with which it shares its data.

Jointly coordinated by Prof. Florence Ader, infectious disease specialist at Croix-Rousse Hospital of the Hospices Civils de Lyon (France) and Prof. Maya Hites, infectious disease specialist at Erasmus University Hospital in Brussels (Belgium), DisCoVeRy evaluates the clinical and virological efficacy and safety of a candidate treatment versus standard of care in adult patients hospitalized for Covid-19. The primary endpoint is patient clinical status at day 15[1]. An initial series of four treatments was tested. These were successively deemed ineffective on the basis of interim analyses, leading to the suspension of enrolments. The results of these analyses are currently being published in international peer-reviewed journals and those concerning the first three treatments are also available on the medRXive website.

Funded by Europe (European Union Horizon 2020 program for research and innovation), Discovery is now Work Package 1 of the European Research and Preparedness Network for Pandemics and Emerging Infectious Diseases (EU-RESPONSE) funded by the EU Horizon 2020 research and innovation program, bringing together 21 partners (clinics, hospitals, universities…) from 13 European Union countries, plus Norway, Switzerland, and Turkey). Created in response to the COVID-19 epidemic emergency, EU-RESPONSE, coordinated by Prof. Yazdan Yazdanpanah, also makes it possible to expand DisCoVeRy to involve other European countries and build a sustainable clinical trial platform to fight COVID-19 followed by any other emerging epidemics.

It was within this academic framework that the partnership between Inserm, through its private subsidiary Inserm Transfert, and AstraZeneca to evaluate a promising new treatment for SARS-CoV-2 was born. 

 

AZD7442

Developed by AstraZeneca for Covid-19 patients, AZD7442 is a combination of two monoclonal long-acting antibodies (LAABs) derived from the plasma of two convalescent patients following SARS-CoV-2 infection. These antibodies directed against the S protein of the virus were selected for their ability to neutralize it in a synergistic manner. In addition, these antibodies that recognize two distinct parts of the S protein are less likely to be affected by mutations concerning that protein.

This combination of antibodies is administered as a single dose by parenteral route with the objective of limiting severity of infection in patients at risk of developing a severe form.

AstraZeneca is already evaluating AZD7442 in other clinical trials: as a preventive treatment in PROVENT and STORM CHASER and as a curative treatment in TACKLE, ACTIV-2, and ACTIV-3.

The randomized, multicenter, double-blind, placebo-controlled DisCoVeRy trial will therefore make it possible to test the efficacy of AZD7442 in hospitalized patients with Covid-19.

The first inclusion is taking place in France at the beginning of this week, followed by those in the partner countries.

The efficacy of the treatment will be assessed on the basis of the following criteria:

  • Primary endpoint: patient clinical status at day 15 after treatment administration
  • Secondary endpoint: lasting recovery between 14 and 90 days without re-hospitalization following discharge

The 1240 patients enrolled in the study in Europe will be followed up over a 15-month period until November 2022. An initial analysis of the results is expected to take place at the end of 2021.

“We hope that this treatment will help reduce disease severity and will improve the clinical condition of hospitalized patients” conclude Prof. Florence Ader and Prof. Maya Hites, co-lead investigators of the study.

“This collaboration is a very good example of a public/private partnership in which the relevance of a therapeutic developed by an industrial player can be validated by academic teams with internationally recognized expertise in the field. AstraZeneca is very proud to participate in this trial, that will bring a curative treatment of Covid-19 to hospitalized patients, if positive,” concludes Professor Gabriel Thabut, Medical Director Respiratory and Immunology at AstraZeneca.

 

[1]Measured on the WHO 7-point ordinal scale

EPIPAGE-2 Study: Outcomes for Preterm Children After 5.5 Years

Posted on by Graziella Cara

© Gabe Pierce – Unsplash

At 5.5 years of age, near-normal developmental outcomes can be expected for 35% of children born extremely preterm, for around 45% of those born very preterm, and for 55% of those born moderately preterm. Difficulties that are encountered range from severe but rare disabilities to more subtle disorders that require the mobilization of considerable medical, paramedical, and familial resources. At 5.5 years of age, a time when it becomes easier to explore the major neurodevelopmental domains, over one third of children born prematurely have so-called minor difficulties in the motor, sensory, cognitive, or behavioral domains. Their frequency of occurrence requires close monitoring of the children in structured networks in order to catch them early and take action at a time when brain plasticity is at its peak.

These are the findings of EPIPAGE-2, a study performed by researchers from the Inserm-Université de Paris Obstetrical Perinatal and Pediatric Epidemiology Research Team (EPOPé) from the Center of Research in Epidemiology and Statistics (CRESS, Unit 1153), and with the participation of teams from the Paris Hospital Group (AP-HP) and from the CHU of Lille. This study looked at the outcomes of 3083 children who had been born prematurely: school integration, healthcare use, and the concerns felt by their parents. It has been published in The British Medical Journal.

In France, prematurity is the leading cause of neonatal mortality and is responsible for half of all disabilities of perinatal origin. It affects around 55,000 births each year. Among these many thousands of infants, 8 to 10,000 are born at 22 to 31 weeks of gestation and are described as extremely preterm or very preterm.

Extremely preterm: infants born between 24 and 26 completed weeks of gestation

Very preterm: infants born between 27 and 31 completed weeks of gestation

Moderately preterm: infants born between 32 and 34 completed weeks of gestation

EPIPAGE-2 is a French study led by Inserm whose initial population was 5170 children, born prematurely at between 5 and 7.5 months’ gestation, between April and December 2011. One objective of the researchers coordinating it is to improve knowledge of how prematurity impacts children, more specifically their neuromotor, sensory, cognitive, and behavioral development as well as their learning. A total of 3083 children were assessed within the framework of specialist consultations dedicated to the study at 5.5 years of age.

“The age of five and a half is a key time in a child’s development, making it possible to diagnose learning difficulties and study cognitive skills, which are much more difficult in younger children,” emphasizes Pierre-Yves Ancel, EPOPé team leader from the Public Health and Social Medicine Department of Cochin Hospital AP-HP (Mother-Child Clinical Investigation Unit).

Prematurity determines neurodevelopment

A preterm child with a neurodevelopmental difficulty is a child who, as he or she grows up, deviates from the developmental characteristics observed in most children born at term.

“The objective of the study is to paint a precise picture of the difficulties faced by these children during their development in order to enable appropriate care,” explains Véronique Pierrat, EPOPé team researcher and neonatologist at Lille University Hospital.

The study reveals that the more premature the birth, the more the child will present neurodevelopmental difficulties. While 27% of children born extremely preterm were found to have severe or moderate developmental difficulties, 19% of those born very preterm presented similar difficulties, compared to 12% of children born moderately preterm.

These difficulties include motor, vision or hearing difficulties, or intellectual disabilities. Regardless of how preterm the children were, more than one third of them were found to have so-called minor difficulties. However, the majority of those minor difficulties were still found to require support and the right care to prevent them from affecting the child’s daily life or learning.

School integration and complex developmental interventions

The results of the study show that the more premature the birth, the more the child’s schooling needs to be adapted. While 93% of moderately preterm children were enrolled in regular classes (with no specific support), this proportion was only 73% for children born extremely preterm.

It can also be noted that over half of the children born extremely preterm, one third of those born very preterm and one quarter of those born moderately preterm benefited from complex developmental interventions (speech therapy, physiotherapy, psychological support, etc.). However, 20 to 40% of children with severe difficulties received no support.

Parental concerns

The parents were asked about the general health of their children, their behavior, schooling and quality of social interactions, as well as their concerns about their development. The study highlights the importance of the environment in which the child develops and reinforces the need to offer families coordinated medical, educational, and social support. These concerns are real, even when the child’s development is considered normal. Therefore they deserve to be better understood and will continue to be monitored.

Further analysis of the links between development at 2 years of age and development at 5.5 years of age is expected to provide a better understanding of how to improve the monitoring of these children.

For their families, it is important to emphasize that development at a given age is not set in stone, that the child’s brain is still developing, and that the difficulties observed can be managed and supported, provided that they have been properly identified and the care pathways optimized.

This cohort continues to be monitored with a new collection of information planned for when the children are 10 years old.

COVIDOM – Study on the clinical characteristics and factors associated with hospitalization or death of ambulatory patients monitored remotely

Posted on by Graziella Cara

SARS-CoV-2

Microscopie électronique d’une cellule infectée par le SARS-CoV-2 © Philippe Roingeard, Anne Bull-Maurer, Sonia Georgeault, unité Inserm U1259 MAVIVH & Université de Tours, France

 

Teams from AP-HP, Sorbonne University and Inserm at the Pierre Louis Institute of Epidemiology and Public Health, coordinated by Dr Youri Yordanov and Prof. Agnès Dechartres, assessed the clinical characteristics, fate and factors associated with hospitalization or death of ambulatory patients followed using the COVIDOM device. 

This study, promoted by the AP-HP, and funded by the Fondation de France, the AP-HP Foundation, EIT-Health and a national PHRC (COVID 2020) was the subject of a publication on April 26, 2021 , in the journal Clinical Microbiology and Infection (CMI) .

COVIDOM is a home medical telemonitoring solution for patients with or suspected of Covid-19, co-built by AP-HP, Nouveal e-santé and URPS Ile-de-France, under the direction of Pr Patrick Jourdain (AP-HP, Université Paris-Saclay) medical director of COVIDOM.

Studies of COVID-19 infections have mainly focused on hospital patients or those with a severe form of the infection. To carry out the work that is currently the subject of a publication, researchers set up in March 2020 a prospective cohort of outpatients with mild or moderate COVID-19, monitored remotely using the solution of COVIDOM remote monitoring.

COVIDOM represents to date the largest telemonitoring program deployed in the world within the framework of COVID-19 (109,000 patients remotely monitored since the start of the epidemic) and a unique source of epidemiological data concerning outpatients with COVID -19.

From March to August 2020, more than 43,000 patients were included in the cohort. The average age was 43; 93% of the patients were under 65 years of age and almost 62% were women. For almost 70% of patients, data on comorbidities and symptoms were available. The main comorbidities reported by the patients were asthma (13%), hypertension (12%) and diabetes (5%).

A small proportion (4%) of patients included in the COVIDOM cohort presented clinical worsening (hospitalization or death). The hospitalization rate was 4% and the death rate 0.1%. Factors associated with clinical worsening were: male gender, age, obesity and co-morbidities such as chronic renal failure or cancer under treatment. The likelihood of worsening was reduced with anosmia / ageusia.

The work carried out shows that clinical worsening was rare in ambulatory patients with a mild or moderate form of COVID-19, monitored remotely using the COVIDOM monitoring solution. Gender, age, and comorbidities such as chronic renal failure, active cancer, or obesity were independently associated with clinical worsening. However, more research is needed to confirm this assessment as it can be considered that this cohort included younger and healthier patients than in the general population.

A personalized precision medicine approach is needed to treat Covid-19 as more than one type of “Cytokine storm” is induced by SARS-CoV-2

Posted on by Graziella Cara

SARS-CoV-2

Electron microscopy of a cell infected with SARS-CoV-2 © Philippe Roingeard, Anne Bull-Maurer, Sonia Georgeault, unité Inserm U1259 MAVIVH & Université de Tours, France.

 

The severe form of Covid-19 is known to be associated with the excessive elevation of many cytokines, a condition termed “cytokine storm”. Therapy with biological agents intended to block these cytokines, for example anti-interleukin-6 or anti-interleukin-1 antibodies, was already tried, albeit with a limited success. However, a study recently published in the Journal of Allergy and Clinical Immunology  shows that there are at least two distinct types of cytokine storms induced by SARS-CoV-2 infection that are differentially associated with Covid-19 severity and mortality. As these distinct elevated cytokine profiles show up differently in different patients, this would imply the need for a personalized precision medicine approach to treat Covid-19. 

Apart from corticoid therapy, various treatments that were tested to reduce the COVID-19 associated cytokine storm seem to show disappointing results. The effectiveness of reducing mortality by blocking interleukins (for example, IL-6 and IL-1) has so far not been demonstrated. It has also been proposed that early-stage administration of type-I interferon therapy would slow SARS-CoV-2 replication, yet again with only limited reduction in mortality. It is possible that this apparent low effectiveness could be explained by the lack of stratification of patients to receive different treatments adapted to their individual cytokine profile.

Orages Cytokiniques

© Guy Gorochov

To answer this question, Prof. Guy Gorochov’s team (CIMI Research Center, Sorbonne University / INSERM, Paris, France), in collaboration with Prof. Avidan Neumann’s bioinformatics group (Department of Environmental Medicine, University of Augsburg, Germany), studied the levels of a large number of cytokines in the blood of 115 COVID-19 patients at the day of hospitalization during the first wave of the pandemic. The results of this study were then confirmed by a second validation cohort comprising of 86 patients from the second wave of the SARS-CoV-2 pandemic in Paris1.

Analysis of the results demonstrated that when looking at each cytokine separately, their blood levels showed great heterogeneity for each individual patient. “By looking at all cytokines together, using a non-supervised bioinformatics method called principle component analysis (PCA), we were able to reduce the large multi-dimensional variation into a two-dimensional perspective of cytokine combinations”, says Prof. Avidan Neumann. “Thus, we identified two distinct cytokine profiles that appear in different levels according to disease severity”.

Moderately severe patients, who initially do not have a severe respiratory illness, develop a response dominated by type-I interferons, in a context of high viral load, and relatively lower levels of pro-inflammatory cytokines. Conversely, patients with critical respiratory severity show elevated levels of pro-inflammatory cytokines (various levels of IL-6, IL-8, IL-10 and TNF-). Unexpectedly, SARS-CoV-2 antigen levels were lower in the critically severe patients, while the interferon anti-viral response is also less prominent in these patients. “These results go against the notion that high COVID-19 severity is always associated with excessive viral replication”, says Prof. Gorochov.

Nevertheless, having a strong type-I interferon response is not always good. An important observation was that the risk of death one month after hospital admission was related in each group to the intensity of the particular cytokine signature typical for that group. In particular, in the moderate severity group mortality was predicted by higher type-I interferon levels, while in the critical severity group mortality was associated with higher pro-inflammatory cytokine levels. Of note, mortality in the critical severity group was best predicted by higher levels of interlukin-10, rather than interlukin-6 or interlukin-1, thus possibly explaining the low effectiveness of therapy blocking the latter cytokines. Moreover, “our results suggest new therapeutic avenues”, says Prof. Gorochov, “as a higher risk of death in the most severe patients requiring ECMO is associated with lower levels of interleukin-17 and interleukin-18, cytokines that are associated with antibacterial response, treatment to increase their levels may improve patients’ survival”.

Overall these results suggest that COVID-19 severity and mortality are associated not with one cytokine storm, but rather with at least two distinct cytokine profiles.

Particularly not only an elevated pro-inflammatory response is dangerous but also, in some patients, an exacerbated anti-viral interferon response is associated with higher risk for mortality.

On the one hand, these results indicate that it would not be necessarily beneficial to administer type-I interferons in patients with already highly elevated levels of these cytokines2. On the other hand, therapy with biological agents should be targeted to block specific pro-inflammatory cytokines that are shown to be elevated in individual patients, rather than a one-for-all therapy. Thus, Prof. Claudia Traidl-Hoffmann, head of the Department of Environmental Medicine at the University of Augsburg, suggests that “this implies a paradigm change in COVID-19 therapy, personalized precision medicine, based on cytokine profiling, should be used to optimize COVID-19 treatment”.

Furthermore, Prof. Neumann adds “generalization of these results to earlier timepoints, currently tested in our on-going Early-Opt project at the Uniklinikum Augsburg, will allow optimization of both public-health and clinical management of COVID-19”.

SARS-CoV-2: infection induces antibodies capable of killing infected cells regardless of disease severity

Posted on by Graziella Cara

 

SARS-COV-2

©AdobeStock

 

Drawing on epidemiological field studies and the FrenchCOVID hospital cohort coordinated by Inserm, teams from the Institut Pasteur, the CNRS and the Vaccine Research Institute (VRI, Inserm/University Paris-Est Créteil) studied the antibodies induced in individuals with asymptomatic or symptomatic SARS-CoV-2 infection. The scientists demonstrated that infection induces polyfunctional antibodies. Beyond neutralization, these antibodies can activate NK (natural killer) cells or the complement system, leading to the destruction of infected cells. Antibody levels are slightly lower in asymptomatic as opposed to symptomatic individuals, but polyfunctional antibodies were found in all individuals. These findings show that infection induces antibodies capable of killing infected cells regardless of the severity of the disease. The research was published in the journal Cell Reports Medicine on April 21st, 2021.

Nearly half of those infected with SARS-CoV-2 do not develop symptoms. Yet, the immune response induced by asymptomatic forms of COVID-19 remains poorly characterized. The extent of the antiviral functions of SARS-CoV-2 antibodies is also poorly characterized. Antibodies are capable of both neutralizing the virus and activating “non-neutralizing” functions. The latter include antibody-dependent cellular cytotoxicity (ADCC) and complement activation, which are major components of the immune response and play a key role in the efficacy of some vaccines. ADCC is a two-stage process in which infected cells are first recognized by antibodies, then destroyed by NK cells. The complement system consists of a series of plasma proteins that also enable the elimination of cells targeted by antibodies. The ability of antibodies to activate these non-neutralizing functions has been little described for SARS-CoV-2 infection so far.

The teams from the Institut Pasteur, the CNRS and the VRI (Inserm/University Paris-Est Créteil) initially developed new assays to measure the various antibody functions. They produced assays to study cell death induced by NK cells or by complement in the presence of antibodies. By analyzing cultures in real time using video microscopy, the scientists showed that NK cells kill infected cells in the presence of antibodies, demonstrating new antiviral activity employed by SARS-CoV-2 antibodies.

The scientists then examined the serum of patients with symptomatic or asymptomatic forms of COVID-19 with their new assays. They also used methods previously developed at the Institut Pasteur, such as the S-Flow assay, to detect SARS-CoV-2 anti-spike antibodies, and the S-Fuse assay, to measure the neutralization capacity of these antibodies

“This study demonstrated that individuals infected with SARS-CoV-2 have antibodies that are capable of attacking the virus in different ways, by preventing it from entering cells (neutralization) or by activating NK cells to kill infected cells (via ADCC). We therefore use the term polyfunctional antibodies,” explains Timothée Bruel, co-last author of the study and a scientist in the Institut Pasteur’s Virus & Immunity Unit[1] and at the VRI.

By comparing different groups of patients, the scientists then showed that asymptomatic individuals also have polyfunctional antibodies and that their response is slightly weaker than those of patients with moderate forms of COVID-19.

“The study reveals new mechanisms of action of SARS-CoV-2 antibodies and suggests that the protection induced by an asymptomatic infection is very close to that observed after a symptomatic infection,” concludes Olivier Schwartz, co-last author of the study, head of the Virus & Immunity Unit and at the VRI.

 

[1] Department of Virology (CNRS/Institut Pasteur)

La thérapie génique, un espoir contre les maladies de Charcot-Marie-Tooth

Posted on by Graziella Cara

Démence : des nuits plus courtes associées à un risque accru de développer la maladie

Posted on by Tatiana Marotta

 

Persistence of rituximab-resistant memory B cells contributes to relapses in adult patients with immunologic thrombocytopenia

Posted on by Graziella Cara

lymphocytes B

Image of a persistent germinal center (mouse spleen, 4 months after immunization), comprising B lymphocytes or memory B cells (green), strongly interacting with follicular dendritic cells (CD35, red), and follicular T helper cells (CD4, blue). ©Inserm/Reynaud, Claude-Agnès

Teams of Prof. Matthieu Mahévas from the reference center for autoimmune cytopenias in adults and the Mondor Biomedical Research Institute (Henri-Mondor AP-HP / Inserm / Université Paris-Est Créteil), Prof. Jean- Claude Weill and Dr Claude-Agnès Reynaud at the Institut Necker-Enfants Malades (Inserm / CNRS / University of Paris) studied the presence of self-reactive memory B lymphocytes before and after treatment with rituximab in adult patients with thrombocytopenia immunologic disease (ITP), a rare autoimmune disease.

The results of this study, which is the subject of a publication in the journal Science Translational Medicine on April 14, 2021 , show in particular that a fraction of memory B lymphocytes self-reactive towards platelet antigens resist treatment with rituximab, persist in the spleen for several months and participates in relapses. The discovery of these cells could open up new therapeutic avenues.    

Patients with B cell mediated autoimmune diseases, such as immunologic thrombocytopenia (ITP), may benefit from treatment with the anti-CD20 antibody, targeting B cells, rituximab. However, a significant proportion of patients relapse after this treatment.

The teams of Prof. Matthieu Mahévas from the internal medicine department of Henri-Mondor AP-HP hospital (Prof. Godeau and Prof. Michel), from the “Transfusion and red blood cell diseases” research unit of the Mondor Research Institute Biomedical (UPEC / Inserm), Prof. Jean-Claude Weill and Dr. Claude-Agnès Reynaud from the Necker-Enfants Malades Institute (Inserm / CNRS / University of Paris), in collaboration with numerous clinicians from the National Center for Auto Cytopenias -immunes of adults (CERECAI), sought to understand why by studying the presence of memory B lymphocytes reactive towards platelets in the spleen of patients splenectomized for a relapse of immunological thrombocytopenia after treatment with rituximab.

Several innovative experimental approaches have been carried out by Dr Crickx and Chappert in order to determine the phenotype, the transcriptional program and the specificity of these B cells capable of secreting anti-platelet antibodies in the spleen of patients during relapses. This work has made it possible to demonstrate that cells newly generated after B lymphocyte reconstitution and memory cells that have resisted treatment participate in relapses.

It thus appears that these pathogenic cells, resistant to rituximab, have lost the expression of CD20 on their surface but preserved the expression of CD19, specifically expressed by B lymphocytes, which could therefore constitute a new potential therapeutic target in this disease.

The persistence of immune memory is generally studied for the benefit it provides in terms of anti-infectious protection. This work demonstrates that memory cells can also persist during periods of remission of an autoimmune disease and contribute to subsequent relapses, suggesting new avenues to be explored to promote prolonged remissions in autoimmune diseases.

This work benefited from ANR funding (Auto-Immuni-B – ANR-18-CE15-0001).

Weightlessness: A Challenge for Both the Body and the Brain!

Posted on by Graziella Cara

Etude des mouvements

3D motion capture ©Inserm/Guénet, François

 

With one week to go before astronaut Thomas Pesquet sets out on his space mission Alpha, knowledge about how we adapt to gravity here on Earth is progressing. Researchers from Inserm and Université de Bourgogne within the Cognition, Action and Sensorimotor Plasticity (CAPS) laboratory are interested in how the movements that depend on this omnipresent force are carried out.

For the past 30 years, it was thought that the brain – responsible for motor control – worked to continuously compensate for the effects of gravity. In an initial study in 2016, the researchers had suggested that our brains use gravity to minimize the effort our muscles have to make. Those results were recently confirmed by new experiments conducted in collaboration with New York University on non-human primate models and humans, the findings of which have been published in Science Advances.

 

Our brain uses the effects of gravity to minimize the physical exertion required.

In order to perform our many activities, the movements of our limbs need to be precise. For a movement to be successful, the brain must generate muscle contractions by anticipating the environmental factors liable to affect that movement. One of the most important of these factors is gravity. The brain develops an internal representation of gravity that it can use to anticipate its effects on our body.

 

What is the purpose of this anticipation?

Initially, the researchers thought that the brain continuously compensated for the effects of gravity to achieve movements undisturbed by them. Recent studies by researchers from Université de Bourgogne and Inserm at the CAPS laboratory in collaboration with a team from New York University (Dora E. Angelaki, Professor of Neuroscience at the Tandon School of Engineering – New York) challenge this idea. The researchers hypothesized that anticipating the effects of gravity allows us to plan movements that use those effects on our bodies to minimize our muscular exertion.

To confirm this theory, the research team recorded the activations that the brain sends to the muscles. These recordings were made in non-human primates and humans performing horizontal and vertical arm movements.

The information obtained show that the brain sends electrical commands that activate and deactivate the muscles in a very precise way – phenomena that last just a few milliseconds – in order to harness the effects of gravity to accelerate our downward movements and decelerate our upward movements. These findings were observed in both the non-human primates and humans.

This observation supports the hypothesis of profound nervous system adaptation to its environment. 

In the long term, this new knowledge could be put to use in various fields such as movement assistance for people with disabilities or the programming of humanoid robot movements.

Search
fermer