Characterization of a novel antibody secreting cell population and exploration of its relation with autoimmune pathology

• Applicant: Privatdozentin Dr. Nina Chevalier
• Subject Area: Rheumatology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 566949448

Autoimmune diseases like systemic lupus erythematosus (SLE) are characterized by chronic inflammation and immune dysregulation due to a failure in self-tolerance, driven by complex interactions between genetic and environmental factors. Autoantibodies secreted by plasma cells (PCs) are central to disease progression. However, many aspects of PC biology in antibody-mediated autoimmune diseases remain poorly understood. Current B cell-targeted therapies indiscriminately deplete both protective and pathogenic PCs, underscoring the need to identify pathogenic PCs and understand their biology to develop more effective, targeted treatments for diseases like SLE. In lupus-prone mice, we identified a novel population of antibody-secreting cells (ASCs) marked by distinct surface markers, plasma cell-associated molecules, unique metabolic features, exclusive IgG production, and autoantibody enrichment. This population, which also emerges following viral infections but not after protein immunization, likely represents an autoimmune-associated subset driven by environmental factors and immune senescence. We found that these autoimmune-related, potentially pathogenic ASCs form a highly proliferative plasmablast (PB) subset, lacking long-lived plasma cells (LL-PCs) but retaining the ability to generate memory PCs. To further investigate these pathogenic ASCs, we will employ phenotypic, transcriptomic, and metabolic profiling to characterize their heterogeneity and hierarchy, identifying targetable pathways that could selectively eliminate autoreactive ASCs while preserving protective counterparts. By understanding humoral memory development, we aim to identify and deplete precursors that could prevent the formation of long-lived pathogenic PCs, thus improving therapeutic strategies. Additionally, we will explore whether these pathogenic ASCs originate from germinal center (GC) or extrafollicular (EF) responses and how inflammation and B cell dysregulation may drive their expansion at the expense of protective immunity. Targeting these pathways could shift the immune balance from autoimmunity to durable immune memory, reducing auto-reactivity while enhancing protective humoral responses. Having identified a corresponding ASC population in humans, we will assess whether these cells correlate with disease activity, autoreactive Ig secretion, and treatment responses. Using multi-modal sequencing, we will identify expanded autoimmune clones, assess their functional status, and analyze their developmental trajectories, precursors, and clonotype expansion across various autoimmune diseases, disease stages, and therapies. Our goal is to use these clonotypes as biomarkers for disease activity, prognosis, and treatment response. Ultimately, our findings hold direct clinical relevance by identifying biomarkers and potential targets for more precise, targeted therapeutic interventions in antibody-driven autoimmune diseases like SLE.

• DFG Programme: Research Grants