Permissive central tolerance plus defective peripheral checkpoints license pathogenic memory B cells in CASPR2-antibody encephalitis

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.

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Publication Details

Journal
Science Advances
Published
2025-04-16
DOI
https://doi.org/10.1126/sciadv.adr9986
Citations
4
Primary Topic
Autoimmune Neurological Disorders and Treatments
Type
article
Field-Weighted Citation Impact
5.56
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Permissive central tolerance plus defective peripheral checkpoints license pathogenic memory B cells in CASPR2-antibody encephalitis

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Permissive central tolerance plus defective peripheral checkpoints license pathogenic memory B cells in CASPR2-antibody encephalitis

Bonny D. Alvarenga, John V. Pluvinage, Raymond J. Owens, David Bennett, Mateusz Makuch, Kevin C. O’Connor, Michael R. Wilson, Daniel C. Anthony, Ren Sun, Lynn B. Dustin, Anne‐Kathrin Kienzler, Rachael Bashford-Rogers, Selina Thomsen, Patrick Joseph Waters, Dominique Fernandes, James Bancroft, Adam E. Handel, Mark Kelly, Ana Luı́sa Carvalho, Sarosh R. Irani, Victor Mgbachi, Robyn Williams, Simon Rinaldi, Halwan Fuad Bayuangga, John Soltys, Miriam L. Fichtner, Andrew Fower, Deniz Akdeniz, Meng Zhao, Simon J. Davis, Robert F. Donat, Mandy Tseng, Bo Sun, Sudarshini Ramanathan, Ruby Harrison, Sofija Paneva, Ravi Dandekar, Alexander J. Davies, Hannah Fox, Anna Harrison, ANA RAQUEL GOUVEIA VASCONCELOS, Min Gyu Im
article en
4 citations

Abstract

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.

Science AdvancesVol. 11(16)
The University of Sydney (AU), Centre for Human Genetics (GB), University of California, San Francisco (US), Concord Repatriation General Hospital (AU), WinnMed (US), John Radcliffe Hospital (GB), Yale University (US), University of Oxford (GB), Rosalind Franklin Institute (GB), Mayo Clinic in Florida (US), University of Coimbra (PT)
Good health and well-being
Openalex Percentile: Top 4%
Autoimmune Neurological Disorders and Treatments
5.56
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