Periodic Reporting for period 4 - PREG-LAB (Distinctive characterization of regulatory plasma cells and pro-inflammatory B cells in immunity: their origins, molecular properties, and cellular fates.)
Okres sprawozdawczy: 2020-07-01 do 2021-12-31
Chronic inflammatory diseases such as autoimmune and allergic diseases affect an increasing proportion of the population in developed societies. Although some treatments exist that alleviate some symptoms caused by these pathologies, they are usually not curative so that patients require life-long treatments. In many cases, the treatments only reduce the speed of disease progression, and they can be associated with severe side effects. There is therefore an urgent need to better understand the cellular and molecular processes underlying these diseases, in order to better stratify patients, better predict disease evolution, and develop novel therapeutic strategies. During the last 20 years, B cells, a type of immune cells that has the unique capacity to produce antibodies, have emerged as major players in the pathogenesis of these diseases, as most clearly demonstrated by the beneficial effects of B cell-depletion therapy in a fraction of patients suffering for instance from rheumatoid arthritis or multiple sclerosis. However, we still do not understand precisely how B cells contribute to the pathogenesis in these diseases, and why B cell depletion therapy succeeds or fails. Answering these questions shall help to better select patients prone to respond to B cell depletion therapy, and to develop novel B cell-targeted therapies. Noteworthy, it has meanwhile emerged that B cells do not only have pathogenic functions, but can also mediate protective activities in these diseases. The objectives of the project is to characterize pathogenic pro-inflammatory B cells and protective anti-inflammatory B cells in chronic inflammatory diseases in order to be in a position to track these cells in individual patients, and to define how B cell depletion therapy affects their respective abundance.
We have identified a novel population of B cells programmed to produce the anti-inflammatory cytokine IL-10 after activation. These cells display features of activated B cells and constitutively secrete IgM antibodies, which defines them as plasma cells. They differentiate independently of any immune challenge at steady state, including when the microbiota is absent. They express antigen receptors that can recognize epitopes displayed by damaged cells including damaged red blood cells, suggesting that they are generated in response to damaged self-components, which they might help to clear. Promoting the generation of these immune suppressive cells might facilitate dampening unwanted immune responses. The depletion of such cells should be avoided when applying B cell depletion therapy. In contrast, the elimination of such cells might be beneficial in clinical situations in which an augmentation of the immune response is desirable such as during chronic malignant or infectious diseases. Noteworthy, this unique natural regulatory plasma cell subset distinguishably express immune inhibitory receptors such as LAG-3, PD-L1, PD-L2, and CD200 that are currently being targeted to improve anti-tutor immunity in human. We have furthermore discovered a novel natural regulatory plasma cells that is distinct from LAG-3-expressing regulatory plasma cells. These cells control the resolution of chronic autoimmune diseases, and are currently under characterization. We are now assessing the capacity of human B cells to give rise to such regulatory plasma cell subsets.
We are hoping to have novel insights on the B cell subsets producing pro- and anti-inflammatory cytokines, as well as on the signals and mechanisms controlling the production of these cytokines by B cells by the end of the project. This new knowledge is fundamental to identify the relevant B cell subsets in human diseases, and to understand the mechanisms driving their differentiation. We have now identified several novel plasma cell subsets, and new molecular mechanisms controlling the production of pro-inflammatory cytokines by B cells.