Migration-dependent extrafollicular programming of pre-plasmablast age-associated B cells drives lupus pathogenesis

Area of Science:

• Immunology
• Autoimmune Diseases
• Cell Biology

Background:

• Systemic lupus erythematosus (SLE) involves autoantibody production.
• Extrafollicular (EF) B cell responses, particularly from age-associated B cells (ABCs), are key to SLE pathogenesis.
• The migratory cues directing ABC differentiation into autoantibody-secreting plasmablasts (PBs) in SLE are not fully understood.

Purpose of the Study:

• To identify a distinct ABC state with plasmablast precursor characteristics (pre-PB ABCs).
• To elucidate the migration-dependent program governing pre-PB ABC generation and function in SLE.
• To investigate the role of EBI2 and the COMMD3/8 complex in ABC migration and differentiation in SLE.

Main Methods:

• Single-cell analysis in SLE patients and mouse models.
• Characterization of B cell populations and their migratory behavior.
• Investigation of molecular pathways involving EBI2 and the COMMD3/8 complex.

Main Results:

• A novel pre-PB ABC state was identified, enriched in autoreactive clones and correlated with SLE disease activity.
• EBI2 directs ABCs to EF niches, promoting pre-PB ABC formation and autoreactive PB output.
• The COMMD3/8 complex regulates chemoattractant receptor signaling, influencing B cell trafficking to various tissues and ameliorating SLE in mouse models.

Conclusions:

• A migration-dependent program drives the differentiation of ABCs into autoreactive PBs in SLE.
• EBI2-mediated migration and the COMMD3/8 complex are critical for pathogenic B cell distribution in SLE.
• Targeting this migratory program presents a potential therapeutic strategy for SLE.