B cell tolerance checkpoints that restrict pathways of antigen-driven differentiation

Area of Science:

• Immunology
• Autoimmunity
• B cell biology

Background:

• Autoreactive B cells are typically regulated by deletion, receptor editing, or anergy.
• Rheumatoid factor (RF)-expressing B cells in normal mice do not secrete autoantibodies and were thought to be quiescent.
• These autoreactive B cells are constitutively activated by self-antigens.

Purpose of the Study:

• To investigate the regulation of RF-expressing B cells in normal and autoimmune settings.
• To identify novel checkpoints controlling autoreactive B cell activation and autoantibody production.

Main Methods:

• Comparative analysis of B cell populations in normal (BALB/c) and autoimmune mice.
• Assessment of germinal center (GC) formation, B cell expansion, selection, and antibody-forming cell (AFC) generation.

Main Results:

• RF B cells in normal mice form GCs but few AFCs, indicating a regulatory checkpoint.
• Autoimmune mice readily generate RF AFCs, suggesting a failure of this checkpoint.
• Autoantigen-specific RF GCs in normal mice exhibit impaired B cell expansion and selection compared to autoimmune mice.
• Two novel checkpoints are identified: one preventing AFC formation post-GC entry, and another impairing GC selection.

Conclusions:

• Normal mice possess regulatory checkpoints that prevent autoantibody production from activated autoreactive B cells.
• These checkpoints involve limitations on germinal center B cell selection and differentiation into antibody-forming cells.
• Failure of these regulatory checkpoints contributes to autoimmunity.