Marion Mandon PhD (Engineer); Rachel Jean (Technician); Stéphane Rodriguez PhD (Post-doc); Aleth Perdriger, MD PhD (Professor of Rheumatology); Céline Delaloy, PhD (CRCN Inserm); Laure Michel, MD PhD (Professor of Neurology); Patricia Amé, PharmD PhD (Professor of Immunology)
B cells are considered as major players in autoimmunity, not only by producing antibodies but by secretion of proinflammatory/regulatory cytokines, antigen presentation and generation of tertiary lymphoid organs. Similarly, Tfh cells have also been involved in the development of autoimmune diseases (AID) through both facilitating the aberrant generation of autoantibodies and supporting the formation of tertiary lymphoid structures (TLS) that may serve as central points to reactivate pathogenic cells.
Multiple sclerosis (MS) and rheumatoid arthritis (RA) are two inflammatory auto-immune diseases affecting the central nervous system and joints, respectively. Even if MS has long been considered as a T-cell mediated disease, Ig deposits and anti-CD20 antibody efficacy point out a crucial role for B cells in MS physiopathogenesis. Conversely, RA has always been considered as a B-cell mediated AID due to the presence of pathognomonic autoantibodies like anti-citrullinated protein antibodies. However, Th1 and Th17 cell involvement in RA is now well documented. Interestingly, RA and MS also show abnormalities in the biology of IL-2, a cytokine involved in late B cell maturation. Of note, both AID show organized TLS in their specific inflammatory localizations. Finally, experimental autoimmune encephalomyelitis (EAE) and antigen-induced arthritis (AIA) mouse models are amenable to genetically engineered mice and can be used to address pathogenic mechanisms in vivo.
Specific aims adressed in our project
Based on our expertise in the understanding of the crosstalk between B cells and their specialized microenvironment in normal and malignant setting, we want to decipher B/Tfh crosstalk in AID. Using high-dimensional analyses of normal versus pathophysiological human and mouse MS and RA samples complemented with in vitro modeling of B/Tfh interactions, we want to:
- Characterize the alterations of B/Tfh crosstalk at the transcriptomic, phenotypic and functional level in RA and MS patients
- Analyze IL-2 signaling dysregulation in B cells and Tfh homeostasis
- Unravel new druggable targets in B/Tfh crosstalk