Bennett, David L
Mayo Clinic
Nuffield Department of Clinical Neurosciences, University of Oxford, OX3 9DU, Oxford, UK.
Citations 2
Permissive central tolerance plus defective peripheral checkpoints license pathogenic memory B cells in CASPR2-antibody encephalitis
Sun, Bo , Fernandes, Dominique , Soltys, John , Paneva, Sofija , Harrison, Ruby , Harrison, Anna, Makuch, Mateusz , Fichtner, Miriam L. , Donat, Robert F. , Akdeniz, Deniz, Bayuangga, Halwan Fuad , Im, Min Gyu , Williams, Robyn , VASCONCELOS, ANA RAQUEL GOUVEIA , Thomsen, Selina, Fower, Andrew , Sun, Ruyue, Fox, Hannah , Mgbachi, Victor , Davies, Alexander J. , Tseng, Mandy , Handel, Adam E. , Kelly, Mark , Zhao, Meng , Bancroft, James , Bashford-Rogers, Rachael , Pluvinage, John V. , Dandekar, Ravi , Alvarenga, Bonny D. , Dustin, Lynn B. , Rinaldi, Simon , Owens, Raymond J. , Anthony, Daniel C. , Bennett, David , Davis, Simon J. , Wilson, Michael R. , O’Connor, Kevin C. , Carvalho, Ana Luı́sa , Irani, Sarosh R. , Kienzler, Anne-Kathrin , Paneva, Sofija , Harrison, Ruby , Harrison, Anna L , Fichtner, Miriam L , Bayuangga, Halwan , Im, Min Gyu , Vasconcelos, Ana , Fower, Andrew , Fox, Hannah , Davies, Alexander , Tseng, Mandy , Handel, Adam , Kelly, Mark , Zhao, Meng , Bancroft, James , Pluvinage, John V , Dandekar, Ravi , Alvarenga, Bonny D , Dustin, Lynn B , Rinaldi, Simon , Owens, Ray , Anthony, Daniel , Bennett, David L , Davis, Simon J , Wilson, Michael R , O'Connor, Kevin C , Carvalho, Ana Luisa , Irani, Sarosh R , Sun, Bo , Williams, Robyn L , Ramanathan, Sudarshini , Sun, Ruyue, Waters, Patrick
Science Advances | April 16, 2025 | Volume: 11 | Issue: 16 | Pages: No page available
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.
Immunotherapy‐Resistant Neuropathic Pain and Fatigue Predict Quality‐of‐Life in Contactin‐Associated Protein‐Like 2 Antibody Disease
Ceronie, Bryan , Strippel, Christine , Uy, Christopher , Paneva, Sofija , Makuch, Mateusz , Soleimani, Babak , Turaga, Sanchit, Ramanathan, Sudarshini , Michael, Sophia , Varley, James , Easton, Ava , Bennett, David , Irani, Anushka , Irani, Sarosh R. , Ramanathan, Sudarshini , Themistocleous, Andreas , Bennett, David L , Irani, Anushka , Irani, Sarosh R , Paneva, Sofija , Binks, Sophie , Dawes, John M. , Handel, Adam E.
Annals of Neurology | January 18, 2025 | Volume: 97 | Issue: 3 | Pages: 521-528
The long‐term clinical outcomes and associated prognostic factors in contactin‐associated protein‐like 2 (CASPR2)‐antibody diseases are unknown. A total of 75 participants with CASPR2 antibodies were longitudinally assessed for disability, quality‐of‐life, and chronic pain. Although most symptoms improved within 6 months of treatment, neuropathic pain and fatigue were the most immunotherapy refractory, and persisted for up to 6 years. Furthermore, these two factors—but not CASPR2 antibody levels or subclasses—independently predicted worse disability and quality‐of‐life at 24 months. Quality‐of‐life varied widely for any given modified Rankin Scale score, indicating a divergence between patient and clinician assessed outcomes. Further work should study the relative importance of these measures, and the immunopathogenesis underlying intractable symptoms. ANN NEUROL 2025;97:521–528