Project description
Understanding the pro- and anti-inflammatory B-cells functions in immunity
Chronic inflammatory autoimmune and allergic diseases affect an increasing number of people worldwide. Current treatments only reduce the speed of disease progression and are often associated with severe side effects. B-cells play a major role in the pathogenesis of these diseases and B-cell depletion therapy improves conditions in rheumatoid arthritis and multiple sclerosis patients. However, the precise mechanisms underlying B-cell contribution to the pathogenesis of these diseases remain poorly understood. Importantly, recent findings show that B-cells can mediate protective activities in these diseases. The ERC-funded PREG-LAB project aims to characterise B-cells with pro- and anti-inflammatory functions in mice models by using advanced genetics to identify and track cytokine-expressing cells. Ultimately, this will help identify similar markers in humans.
Objective
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.
Fields of science
Programme(s)
Funding Scheme
ERC-COG - Consolidator GrantHost institution
75654 Paris
France