Targeting Plasma Cells in Autoimmune Diseases

Plasma cells (PCs) possess the unique capacity to produce antibodies (Abs), effectors of the humoral response against virtually all microbes and toxins, but also against self-antigens, participating in the development of autoimmune diseases (ADs). In recent years, it has become evident that PCs contribute in more ways than just secreting Abs, as their cytokine production, such as IL-10+LAG3+ PCs or IL-35+ PCs, partial complement activation, or their interaction with other cells are critical for immune homeostasis. Thus, PCs represent a heterogeneous immune compartment composed of several subsets with different functions in immunity and immunoregulation. These findings suggest that certain characteristics, such as surface markers of disease-specific PC subsets, allow targeting pathogenic PCs with high selectivity in various ADs. Selective targeting of pathogenic PCs is a fundamental part of precision medicine in ADs such as systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA). Long-lived PCs (LLPCs) that produce high-affinity antibodies and reside in the bone marrow are essential for protection against infections but are also generated during autoimmune responses and resist current therapies. A unique subset of CD19-lacking PCs (CD19- PCs) was found enriched in human bone marrow, while almost absent from blood, tonsils, and spleen. New therapies targeting pathogenic PCs while sparing protective and regulatory ones represent an unmet medical need in ADs, replacing current depletion strategies based on antibodies against pan-PC markers.