Objective:

To investigate how molecular mimicry shapes B-cell development and the evolution of antigen-specific B cell responses.

Approach:

• Model Development: Generated A5H mice, a knock-in model expressing a B-cell receptor binding to the AQP5 'E' epitope.
• B-cell Analysis: Examined B-cell development, anergy, and activation in response to microbial mimic peptides.
• Immunization Studies: Immunized A5H mice with PmE-L and assessed autoantibody production and germinal center responses.

Key Findings:

• A5H mice showed normal B-cell development with reduced anergy-associated B cells and an expanded pool of mimic-reactive B cells.
• At steady state, A5H mice produced anti-PmE-L antibodies, but not anti-AQP5E autoantibodies.
• Immunization with PmE-L led to robust production of anti-AQP5E autoantibodies that cross-reacted with AQP4 and AQP1.
• Heterozygous A5H mice exhibited stronger autoantibody responses compared to homozygous A5H mice.

Interpretation:

Limitations:

• Evidence of intramolecular epitope spreading to native AQP5 was not observed.
• Minimal tissue deposition of autoantibodies and salivary gland pathology.

Conclusion: