Tracing Self-Reactive B Cells in Normal Mice.

Area of Science:

• Immunology
• B cell biology
• Autoimmunity

Background:

• Studies on B cell tolerance predominantly use BCR transgenic mice, leaving tolerance in normal mice with diverse autoreactive B cells undercharacterized.
• Understanding B cell tolerance checkpoints and the fate of autoreactive B cells in normal mice is crucial for autoimmune disease research.

Purpose of the Study:

• To investigate B cell tolerance checkpoints and characterize autoreactive B cell compartments in normal mice.
• To identify affinity setpoints governing B cell tolerance and the longevity of autoreactive B cells.

Main Methods:

• Utilized single B cell cultures to trace B cell receptor (BCR) self-reactivity across tolerance checkpoints in normal mice.
• Analyzed B cell populations in the spleen, including transitional and anergic subsets, and assessed their lifespan.
• Investigated the role of apoptosis by examining B cell-specific deletion of proapoptotic genes (Bak and Bax).

Main Results:

• Identified distinct affinity setpoints at the first (pre-B to transitional-1) and second (transitional-1 to mature follicular) B cell tolerance checkpoints.
• Observed a significant reduction in avidly DNA-specific B cells at the first checkpoint, but not the second.
• Discovered a long-lived subset of tolerized, autoreactive CD93-IgM-/loIgDhi B cells in the spleen, distinct from short-lived T3 and CD93+ anergic B cells.
• Demonstrated that apoptosis regulates persistent and ephemeral autoreactive B cells differently, with Bak/Bax deletion increasing CD93- B cell numbers.

Conclusions:

• The second B cell tolerance checkpoint does not effectively eliminate DNA-reactive B cells.
• A persistent, long-lived population of autoreactive CD93- B cells exists and may originate systemic autoimmunity.
• This autoreactive B cell subset represents a potential target for developing vaccines that elicit protective antibodies cross-reactive with self-antigens.