Deconvolution of plasma cell/plasmablast: heterogeneity and origin in systemic lupus

• Applicant: Professor Dr. Thomas Dörner
• Subject Area: Rheumatology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 550129671

Recent data support that plasma cells (PC) represent a heterogeneous population in the human healthy bone marrow (BM) beyond our original identification of CD19low and CD19high BMPC subsets. Here not only the Ig isotype has been shown to differentiate PC further but also carry cytokine imprints by IFN type I and II, IL-21, IL-6, TGF-ß among other factors characterizing at least 10 distinct BMPC clans. Both CD19low and CD19high PC appear to result from primary immune responses while secondary responses induce preferentially CD19high PC which indicates different instruction by T cells and cytokines. Based on these findings obtained from healthy volunteers, the current grant will undertake comparative studies of peripheral plasmablasts occurring during lupus flares and PC from BM and spleens from SLE patients to delineate signatures of their potentially distinct induction principles (WP1). Such study becomes relevant as more treatment options that target PC in autoimmune diseases, such as anti-CD38, CD19- CART, BCMA-CART become available while requiring risk assessment of protective immunity. Another topic of the grant (WP2) is the identification of autoreactive PC and PB (anti-Ro/SS-A 52 kD and anti-phosphatidylcholine/PtC) and their distribution among the BMPC clans and compared to known protective PC (tetanus, RBD, pentraxin 3) across PC clans following the hypothesis of their different residence within defined BMPC clans and related to potentially dictinct induction principles. To further validate our concept that T cell/cytokine engagement define distinct PC clans residing in the BM including their instruction during primary and secondary responses, we will adapt an established in vitro PC differentiation assay by modifying cytokine exposure and different BCR, TLR9 or CD40 dependent instruction of distinct PC (WP3). Here, an established gene editing (CRISPR/Cas9) system of naïve and memory B cells modulating cytokine receptors of type I and II IFN, IL-21, IL-6R, gp130 will validate to which extent these cytokines are critical for certain PC subsets. The proposal will provide deeper insight into potential mechanisms of PC subset induction as basis of selective targeting of pathogenic PC in SLE.

• DFG Programme: Research Grants