Targeting inflammation-associated plasma cells in rheumatoid arthritis

• Applicant: Elodie Mohr, Ph.D.
• Subject Area: Rheumatology ; Immunology
• Term: from 2016 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 284187180

Rheumatoid arthritis (RA) is a chronic inflammatory disease largely mediated by autoantibody-secreting plasma cells (PC) resistant to current treatments. Recently we identified a new subtype of PC associated with disease activity and presenting an inflammatory profile characterized by high expression of the chemokine receptor CXCR3. I found that the expression of CXCR3 is a hallmark of inflammation-associated PC acquired in IFN-gamma-rich environments such as those in joints of RA patients, under the control of the transcription factor T-bet. This proposal aims at characterizing the transcriptome, homeostasis and trafficking of CXCR3 PC in mouse models, in order to develop new strategies to eliminate pathogenic PC in RA. My preliminary work and data from the literature indicate that CXCR3 itself could be involved in the development and activity of inflammation-associated PC, and may represent a mean to target these cells specifically. To test this possibility, we will clarify the function of CXCR3 during B cell responses in vaccines and in mouse arthritis. To this aim we will improve existing pre-clinical mouse models for RA to study self-reactive PC recognizing proteins in the joints. This model will enable for the first time to monitor specifically self-reactive PC, to correlate directly their activity with disease progression and to evaluate the therapeutic potential of CXCR3 abrogation. It will also provide a breakthrough platform to test new therapeutic strategies targeting gene candidates identified through the characterisation of CXCR3 PC.We expect to discover novel molecule candidates that will generate collaborations with industrial partners to test chemical or biological drugs for future design of combined therapy in RA. Finally, the knowledge gathered along this research programme will spread broadly to the fields of other autoimmune diseases, vaccine design aiming at eliciting B cell memory against infectious pathogens or cancer cells, and in the context of multiple myeloma involving CXCR3 PC.

• DFG Programme: Research Grants