Permissive central tolerance plus defective peripheral checkpoints licence pathogenic memory B cells in...

Area of Science:

• Immunology
• Neuroscience
• Autoimmunity

Background:

• Autoimmune diseases affect 10% of the population, with autoantibody-mediated conditions offering insights into B cell development.
• Understanding immune checkpoints in autoantigen-specific B cell tolerance is crucial but poorly understood.
• CASPR2-autoantibody encephalitis serves as a model for studying these mechanisms.

Purpose of the Study:

• To investigate the roles of immune checkpoints in autoantigen-specific B cell tolerance.
• To elucidate the developmental pathway of pathogenic B cells and autoantibodies in CASPR2-autoantibody encephalitis.
• To identify mechanisms underlying autoantigen-specific tolerance in humans.

Main Methods:

• Comparative analysis of B cell populations in patients with CASPR2-autoantibody encephalitis and healthy controls.
• Assessment of B cell receptor somatic mutations and binding kinetics.
• In vitro and in vivo functional studies of autoantibodies.

Main Results:

• Comparable frequencies of unmutated CASPR2-reactive naive B cells were found in both patients and controls.
• CASPR2-reactive memory B cells, exclusive to patients, showed affinity-enhancing somatic mutations and heterogeneous binding.
• These autoantibodies exhibited epitope-dependent pathogenic effects on neuronal cells.
• Precursor B cells displayed a balance between CASPR2 reactivity and limited cross-reactivity.

Conclusions:

• Permissive central tolerance, defective peripheral tolerance, and heterogeneous autoantibody binding are sequential steps in CASPR2-directed pathology.
• These findings propose novel mechanisms for autoantigen-specific tolerance in humans.
• The study provides a framework for developing tolerance-restoring therapies for CASPR2-antibody diseases and potentially other autoimmune conditions.