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In both disease and health, high (~0.5%) frequencies of unmutated CASPR2-reactive na\u00efve B cells were identified. By contrast, CASPR2-reactive memory B cells were exclusive to patients, and their B cell receptors demonstrated affinity-enhancing somatic mutations with pathogenic effects in neuronal cultures and mice. The unmutated, precursor memory B cell receptors showed a distinctive balance between strong CASPR2 reactivity and very limited binding across the remaining human proteome. Our results identify permissive central tolerance, defective peripheral tolerance, and autoantigen-specific tolerance thresholds in humans as sequential steps that license CASPR2-directed pathology. By leveraging the basic immunobiology, we rationally direct tolerance-restoring approaches, with an experimental paradigm applicable across autoimmunity.<\/jats:p>","DOI":"10.1126\/sciadv.adr9986","type":"journal-article","created":{"date-parts":[[2025,4,16]],"date-time":"2025-04-16T17:58:56Z","timestamp":1744826336000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":7,"title":["Permissive central tolerance plus defective peripheral checkpoints license pathogenic memory B cells in CASPR2-antibody encephalitis"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5507-6657","authenticated-orcid":true,"given":"Bo","family":"Sun","sequence":"first","affiliation":[{"name":"Nuffield Department of Clinical Neurosciences, University of Oxford, OX3 9DU, Oxford, UK."},{"name":"Department of Neurology, John Radcliffe Hospital, Oxford University Hospitals, OX3 9DU, Oxford, 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