Novel regulators of plasma cell differentiation

• Applicant: Professor Dr. Thomas Dörner
• Subject Area: Immunology ; Rheumatology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 432256412

Plasma cells (PCs) play a central role in humoral immunity by producing antibodies that confer protection against pathogens and sustain the long-term efficacy of vaccination. However, autoreactive PCs can also produce pathogenic autoantibodies, contributing to the development and progression of various autoimmune diseases. Therefore, selectively targeting pathogenic PCs has emerged as a promising therapeutic strategy for the treatment of antibody-mediated autoimmunity. In our previous funding period, we performed a largescale CRISPR/Cas9 screen targeting 226 genes upregulated in human PCs and identified 38 genes that are critical for the differentiation of human B cells into PCs. These included 14 transcription factors, nine components of the unfolded protein response, 13 RNA-binding proteins, and two members of the Ras superfamily. A detailed understanding of the cellular and molecular mechanisms by which these regulators govern PC differentiation is essential for developing novel selective strategies to enhance protective antibody responses in infectious diseases while restricting autoantibody production in autoimmunity. In this proposal, we aim to: (1) elucidate the molecular and cellular mechanisms by which these newly identified regulators influence PC differentiation and immunoglobulin secretion, and (2) evaluate their role in the context of autoimmune disease (i.e. SLE). Successful completion of the proposed studies—comprising three integrated subprojects—will provide critical insights into the molecular pathways that regulate PC differentiation, longevity, and function. Ultimately, this research has the potential to inform the development of highly selective therapeutic interventions for diseases where certain plasma cells are of critical importance while holding promise to avoid periods of harsh immunodepletion that may not be required.

• DFG Programme: Research Grants
• Co-Investigator: Dr. Van Duc Dang