Description du projet
Comprendre les fonctions des cellules B pro- et anti-inflammatoires dans l’immunité
Les maladies inflammatoires chroniques, auto-immunes et allergiques touchent un nombre croissant de personnes dans le monde. Les traitements actuels ne font que réduire la vitesse de progression de la maladie et sont souvent associés à des effets secondaires graves. Les cellules B jouent un rôle majeur dans la pathogenèse de ces maladies et la thérapie de déplétion des cellules B améliore la situation des patients atteints de polyarthrite rhumatoïde et de sclérose en plaques. Cependant, les mécanismes précis qui sous-tendent la contribution des cellules B à la pathogenèse de ces maladies restent mal compris. Des découvertes récentes montrent notamment que les cellules B peuvent jouer un rôle protecteur dans ces maladies. Le projet PREG-LAB, financé par le CER, entend caractériser les cellules B présentant des fonctions pro- et anti-inflammatoires dans des modèles murins en utilisant la génétique avancée pour identifier et suivre les cellules exprimant des cytokines. À terme, cela permettra d’identifier des marqueurs similaires chez l’être humain.
Objectif
B cells can act both as negative regulators and as drivers of immunity through the production of cytokines. Through secretion of interleukin (IL)-10 B cells inhibited immunity in autoimmune and infectious diseases. For instance, IL-10 from B cells drove complete recovery from disease in experimental autoimmune encephalomyelitis (EAE), the primary animal model for multiple sclerosis (MS), while a lack of IL-10 production by B cells resulted in a severe chronic EAE. B cells can also suppress immunity via IL-35. Human B cells might similarly play inhibitory roles. In few patients with immune-mediated diseases B cell depletion therapy with Rituximab was associated with exacerbation of symptoms, or onset of new pathologies. Conversely, an opposite role of B cells as drivers of immunity was highlighted by the beneficial effect of Rituximab in some patients with rheumatoid arthritis or MS. Clinical improvement often precedes reduction in autoantibody levels in Rituximab treated patients, indicating that B cell-mediated pathogenesis is largely antibody-independent. A candidate factor for the deleterious effects of B cells in MS is IL-6. IL-6 secretion is a major mechanism of B cell-mediated pathogenesis in EAE, and B cells from MS patients produced more IL-6 than cells from healthy individuals. There is now an urgent need for the characterization of the phenotypes of the B cells producing IL-6, IL-10, and IL-35 in vivo at single cell and molecular levels. Markers for these cells might allow understanding the paradoxical effects of B cell-depletion therapy, and guide the development of novel agents depleting distinctively pro-inflammatory B cells, while sparing the remaining of the B cell compartment. Using advanced genetic models to identify and track cytokine-expressing cells, our project aims at characterizing B cells with pro- and anti-inflammatory functions in mice in vivo, to subsequently guide the identification of comparable markers in human.
Champ scientifique
Programme(s)
Régime de financement
ERC-COG - Consolidator GrantInstitution d’accueil
75654 Paris
France