Novel regulators of plasma cell differentiation

• Applicants: Dr. Van Trung Chu; Professor Dr. Thomas Dörner
• Subject Area: Immunology ; Cell Biology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 432256412

Plasma cells are the antibody secreting cells of the immune system. The production of antibodies by plasma cells is of tremendous importance to human health, providing immunity during initial exposure to pathogens and mediating the long-lasting protective effect of vaccination. The elicitation of memory B cells and long-lived plasma cells is the basis for almost all effective vaccines currently in use. On the other hand, the production of autoantibodies by plasmablasts and plasma cells contributes to the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE). Targeting plasmablasts and plasma cells has become a promising therapeutic strategy for the treatment SLE and other autoimmune diseases. Therefore, elucidating the cellular and molecular mechanisms underlying plasma cell differentiation is of critical importance for the design of better vaccines and therapies aimed to boost antibody production in infectious settings and mute antibody production in autoimmunity. The opportunity now exists to take advantage of an in vitro plasma cell differentiation system and the recently developed CRISPR/Cas9-mediated mutagenesis to perform functional screening to identify novel regulators controlling plasma cell differentiation and antibody secretion. In this proposal, we will (1) perform CRISPR/Cas9-mediated high throughput screening of genes controlling UPR signaling, Ras superfamily (WP1), RNA-binding proteins, and microRNAs (WP2) to identify novel regulators of plasma cell differentiation and antibody secretion. (2) Perform in vivo functional analysis of candidate genes identified in (1) through CRISPR/Cas9-mediated mutagenesis in hematopoietic stem/progenitor cells (HSPCs) and subsequent in vivo reconstitution experiments, as already established in our consortium. We will also generate conditional knockout mice for select candidate genes for further functional and mechanistic investigations. (3) Perform functional validation of human homologs of candidate genes in a human in vitro plasma cell differentiation system, and identify dysregulation or mutation of these genes in SLE patients, with the aim of establishing causative relationship between alterations in these candidate genes and SLE pathogenesis. Upon completion of the proposed research, we expect to identify novel genes and pathways that play important roles in plasma cell differentiation and antibody secretion. In the long run, the specific functions and molecular mechanisms of these genes and pathways will be investigated. Some of them may become valuable diagnostic markers or novel targets for therapeutic interventions of autoimmune diseases.

• DFG Programme: Research Grants
• International Connection: China
• Partner Organisation: National Natural Science Foundation of China
• Cooperation Partner: Professor Dr. Changchun Xiao
• Co-Investigator: Professor Dr. Klaus Rajewsky