Distinct autoreactive CD19^- plasma cell subsets accumulate in lupus-prone mice.

Area of Science:

• Immunology
• Autoimmunity
• Molecular Biology

Background:

• Plasma cells (PCs) drive systemic lupus erythematosus (SLE) pathogenesis through autoantibody and cytokine secretion.
• Current therapies targeting all PCs risk depleting protective long-lived PCs.
• Identifying pathogenic PC subsets is crucial for selective therapeutic targeting in SLE.

Purpose of the Study:

• To identify and characterize disease- and organ-specific pathogenic plasma cell subsets in lupus.
• To investigate the origin and potential role of CD19-negative PCs in lupus pathogenesis.
• To explore the translational relevance of these findings in human SLE.

Main Methods:

• Single-cell RNA sequencing
• B cell receptor repertoire analysis
• Genetic mouse models of lupus
• Analysis of peripheral blood from SLE patients

Main Results:

• A significant expansion of autoreactive CD19-negative PCs was observed in lupus-prone mice.
• Specific subsets, including class-switched CXCR3+ and phosphatidylcholine-specific B-1 derived PCs, showed unique gene expression profiles.
• CD19-negative PCs were found to originate unidirectionally from CD19-positive PCs.
• Elevated frequencies of CD19-negative PCs were detected in the peripheral blood of SLE patients.

Conclusions:

• Autoreactive CD19-negative PCs emerge as a critical pathogenic feature in mouse models of lupus.
• These cells are implicated in sustaining pathogenic activity in SLE.
• Therapeutic strategies for SLE should consider targeting CD19-negative PCs, extending beyond current CD19-targeting approaches.