Permissive central tolerance plus defective peripheral checkpoints license pathogenic memory B cells in
Bo Sun1,2, Dominique Fernandes3,4, John Soltys1,5
1Nuffield Department of Clinical Neurosciences, University of Oxford, OX3 9DU, Oxford, UK.
Researchers identified unmutated B cells reactive to contactin-associated protein-like 2 (CASPR2) in healthy individuals and patients. Pathogenic, mutated memory B cells targeting CASPR2 were exclusive to patients, revealing immune tolerance defects in CASPR2-autoantibody encephalitis.
Area of Science:
- Immunology
- Neuroscience
- Autoimmunity
Background:
- Autoantibody-mediated diseases offer insights into B cell and autoantibody development.
- Conventional understanding attributes autoreactivity to germinal center reactions.
Purpose of the Study:
- To investigate early immune checkpoints in contactin-associated protein-like 2 (CASPR2)-autoantibody encephalitis.
- To understand the B cell repertoire and autoantibody generation in CASPR2-autoantibody encephalitis.
Main Methods:
- Analysis of unmutated and mutated B cells in patients and healthy individuals.
- Assessment of B cell receptor reactivity and pathogenic effects in neuronal cultures and mouse models.
Main Results:
- High frequencies of unmutated CASPR2-reactive naïve B cells were found in both health and disease.
- CASPR2-reactive memory B cells, exclusive to patients, displayed affinity-enhancing somatic mutations with pathogenic effects.
- Precursor memory B cell receptors showed specific CASPR2 reactivity with limited cross-reactivity.
Conclusions:
- Sequential steps including permissive central tolerance, defective peripheral tolerance, and autoantigen-specific tolerance thresholds license CASPR2-directed pathology.
- Findings provide a framework for developing tolerance-restoring therapies applicable to various autoimmune conditions.
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