Descrizione del progetto
Comprendere le funzioni pro- e anti-infiammatorie delle cellule B nel contesto dell’immunità
Le malattie infiammatorie croniche autoimmuni e allergiche colpiscono un numero crescente di persone in tutto il mondo. Tuttavia, i trattamenti attualmente a disposizione riducono esclusivamente la velocità di progressione della malattia e sono spesso associati a gravi effetti collaterali. Le cellule B svolgono un ruolo fondamentale nella patogenesi di tali malattie, e la terapia di deplezione delle cellule B migliora le condizioni dei pazienti con artrite reumatoide e sclerosi multipla. Ciononostante, i meccanismi precisi alla base del contributo delle cellule B alla patogenesi di queste malattie sono tuttora poco noti. Recenti scoperte dimostrano che le cellule B possono mediare le attività protettive contro queste patologie. Il progetto PREG-LAB, finanziato dal CER, intende definire le caratteristiche delle cellule B con funzioni pro- e anti-infiammatorie in modelli murini, sfruttando la genetica avanzata per identificare e tracciare le cellule che esprimono citochine. Questa ricerca contribuirà, in ultima analisi, a identificare marcatori simili negli esseri umani.
Obiettivo
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.
Campo scientifico
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-COG - Consolidator GrantIstituzione ospitante
75654 Paris
Francia