Présentation des speakers du congrès 2022
Relational autonomy and the capabilities approach: a new vision of patient emporwerment and patient centered care
Vendredi 24 Juin, 8H30-9H30
Individual autonomy is often promoted as a desirable trait to cultivate in the healthcare provider-patient relationship to enable patients to become “empowered.” However, this focus has both put considerable pressure on the patient, but also encouraged a blind spot in the entire support network necessary to help patients become empowered. We advocate for a relational autonomy approach, one that recognizes the right to choice of patients, but also the important role for a facilitating environment, whether it be the healthcare provider, the family, friends, or other patients. In order to move toward this goal, we will introduce the capabilities approach, an approach developed in philosophy and economics that helps navigate the complex environment between individual choice and the importance of others to help patients become empowered. We will also discuss why we need to move from a patient-centred care approach to a person-centred care approach and what this implies for the healthcare provider-patient relationship.
Postdoctoral researcher on the IMCOCA project (Impact Covid Cancer), Centre Léon Bérard, Lyon
Postdoctoral researcher | Research Chair on the Values of Patient Centered Care in Philosophy and Economics, University Jean Moulin, Lyon 3, Lyon
The human genetic and immunological determinants of life-threating COVID-19
Vendredi 24 Juin, 10H-11H
Jean Laurent Casanova
Professor | Senior attending physician | Head of the St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, NY
Visiting professor at the Necker Hospital for Sick Children | Head of the Laboratory of Human Genetics of Infectious Disease, Imagine Institute, University of Paris
Autosomal inborn errors of type I IFN immunity and autoantibodies against these cytokines underlie at least 10% of critical COVID-19 pneumonia cases. We report very rare, biochemically deleterious X-linked TLR7 variants in 16 unrelated male individuals aged 7 to 71 years (mean: 36.7 years) from a cohort of 1,202 male patients aged 0.5 to 99 years (mean: 52.9 years) with unexplained critical COVID-19 pneumonia. None of the 331 asymptomatically or mildly infected male individuals aged 1.3 to 102 years (mean: 38.7 years) tested carry such TLR7 variants (p = 3.5 × 10-5). The phenotypes of five hemizygous relatives of index cases infected with SARS-CoV-2 include asymptomatic or mild infection (n=2, 5 and 38 years), or moderate (n=1, 5 years), severe (n=1, 27 years), or critical (n=1, 29 years) pneumonia. Two boys (aged 7 and 12 years) from a cohort of 262 male patients with severe COVID-19 pneumonia (mean: 51.0 years) are hemizygous for a deleterious TLR7 variant.
The cumulative allele frequency for deleterious TLR7 variants in the male general population is < 6.5×10-4 We also show that blood B cell lines and myeloid cell subsets from the patients do not respond to TLR7 stimulation, a phenotype rescued by wild-type TLR7 The patients’ blood plasmacytoid dendritic cells (pDCs) produce low levels of type I IFNs in response to SARS-CoV-2. Overall, X-linked recessive TLR7 deficiency is a highly penetrant genetic etiology of critical COVID-19 pneumonia, in about 1.8% of male patients below the age of 60 years. Human TLR7 and pDCs are essential for protective type I IFN immunity against SARS-CoV-2 in the respiratory tract. Furthermore, circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/mL, in plasma diluted 1 to 10) of IFN-α and/or -ω are found in about 10% of patients with critical COVID-19 pneumonia, but not in subjects with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-α and/or -ω (100 pg/mL, in 1/10 dilutions of plasma) in 13.6% of 3,595 patients with critical COVID-19, including 21% of 374 patients > 80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1,124 deceased patients (aged 20 days-99 years; mean: 70 years).
Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-β. We also show, in a sample of 34,159 uninfected subjects from the general population, that auto-Abs neutralizing high concentrations of IFN-α and/or -ω are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% >80 years. Moreover, the proportion of subjects carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals <70 years, 2.3% between 70 and 80 years, and 6.3% >80 years. By contrast, auto-Abs neutralizing IFN-β do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over-80s, and total fatal COVID-19 cases.
Focus on the muscle weakness in skeletal muscle sodium channelopathoes
Vendredi 24 Juin, 11H-12H
Lecturer | Principal Investigator, Institut de Génomique Fonctionnelle, Montpellier
The voltage-gated sodium channel Nav1.4 is a major actor in the excitability of skeletal myofibers and muscle force developed in response to nerve impulse. For years, only dominantly-inherited diseases resulting from Nav1.4 gain of function (GoF) were known. These last years, Nav1.4 loss of function (LoF) has been demonstrated as the cause of clinically distinct forms of muscle weakness. The properties of SCN4A LoF mutations are pretty well elucidated at the channel level. Regarding the therapeutic issues for muscle sodium channelopathies, former efforts were aimed at developing subtype-selective Nav channels antagonists to block myofiber hyperexcitability. Developing therapeutic tools able to counteract Nav1.4 LoF and improve muscle weakness is then the new challenge.
Enhancing cancer treatment efficacy – example of DNA repair inhibitors
Vendredi 24 Juin, 16H-17H
Lars Petter Jorheim
Researcher at the Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Université Claude Bernard Lyon 1, Lyon
Cancer treatment efficacy is limited by interindividual and intratumoral heterogeneity and by resistance mechanisms acquired during treatment. A better knowledge of these phenomenon allows adaptation of treatments to each patient based on individual characteristics. Our research team (Oncopharmacology in Cancer Research Center of Lyon) focuses on the interaction between cancer drugs and tumor cells (cancer cells, immune cells, adipocytes…). Using original and relevant cell models, animal models and patient samples, we describe resistance mechanisms to various cancer drugs. Based on such results, we propose and develop new strategies aiming to increase the activity of the initial drugs or to preferentially kill resistant cells. Our projects are developed within multidisciplinary consortia. As an example, I will present results from our project about small molecules targeting protein-protein interactions in DNA repair and their ability to enhance the cytotoxic effect of alkylating agents such as cisplatin. In addition to the pharmacological axis, we also perform cell biology research in order to better understand the role of given proteins in cancer cell biology.
Myeloid cell complexity in health and disease
Samedi 25 Juin, 8H-9H
Within the last years, our group contributed to unravel myeloid cell complexity in tissue such as the skin and showed their phenotypic and functional heterogeneity. Using state-of-the-art flow-cytometry, transcriptomic signature and innovative mouse-models, we characterized several conventional DC subsets in tissues and their migratory counterparts in the draining lymph nodes, we also identified several monocyte and macrophage subsets and showed DC subsets functional specialization in the skin. In particular, we described and characterised the dermal XCR1+ cDC1 subset, showed its potent cross-presentation function and targetted it with vaccine strategies to induce protective anti-tumor immunity. To pursue the study of XCR1+ cDC1 subset immunobiology in vivo, we developped a new mouse model allowing conditional gene depletion in XCR1+ cDC1 subset and showed that impaired cross-talk between cDC1 and CD4+ T cells could break peripheral tolerance and induce auto-immunity. Moreover, using another mouse model (CD64-hDTR) we recently described the melanin-loaded macrophages, also called melanophages, in mouse dermis and melanocytic melanoma and revisited tattoo persistence dogma. We are currently capitalizing on our expertise to disentangle mononuclear phagocytes associated to tumors such as melanoma.
Researcher, Centre d’Immunologie Marseille-Luminy, Team Leader Bernard & Marie Malissen, Marseille