Permissive central tolerance plus defective peripheral checkpoints license pathogenic memory B cells in CASPR2-antibody encephalitis.
Sun B., Fernandes D., Soltys J., Kienzler A-K., Paneva S., Harrison R., Ramanathan S., Harrison AL., Makuch M., Fichtner ML., Donat RF., Akdeniz D., Bayuangga H., Im MG., Williams R., Vasconcelos A., Thomsen S., Fower A., Sun R., Fox H., Mgbachi V., Davies A., Tseng M., Handel A., Kelly M., Zhao M., Bancroft J., Bashford-Rogers R., Pluvinage JV., Dandekar R., Alvarenga BD., Dustin LB., Rinaldi S., Owens R., Anthony D., Bennett DL., Waters P., Davis SJ., Wilson MR., O'Connor KC., Carvalho AL., Irani SR.
Autoantibody-mediated diseases targeting one autoantigen provide a unique opportunity to comprehensively understand the development of disease-causing B cells and autoantibodies. Convention suggests that such autoreactivities are generated during germinal center reactions. Here, we explore earlier immune checkpoints, focusing on patients with contactin-associated protein-like 2 (CASPR2)-autoantibody encephalitis. In both disease and health, high (~0.5%) frequencies of unmutated CASPR2-reactive naïve 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.