Citations

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.

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

Abstract Autoimmunity affects 10% of the population. Within this umbrella, autoantibody-mediated diseases targeting one autoantigen provide a unique opportunity to comprehensively understand the developmental pathway of disease-causing B cells and autoantibodies. While such autoreactivities are believed to be generated during germinal centre reactions, the roles of earlier immune checkpoints in autoantigen-specific B cell tolerance are poorly understood. We address this concept in patients with CASPR2-autoantibody encephalitis and healthy controls. In both groups, comparable and 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 heterogenous binding kinetics. These effector molecules possessed epitope-dependent pathogenic effects in vitro neuronal cultures and in vivo. The unmutated common ancestors of these memory B cells showed a distinctive balance between strong CASPR2 reactivity and very limited binding across the remaining human proteome. Our results are the first to propose mechanisms underlying autoantigen-specific tolerance in humans. We identify permissive central tolerance, defective peripheral tolerance and heterogenous autoantibody binding properties as sequential pathogenic steps which licence CASPR2-directed pathology. By leveraging the basic immunobiology, we rationally direct tolerance-restoring approaches in CASPR2-antibody diseases. This paradigm is applicable across autoimmune conditions.

AbstractObjectiveThe first international consensus criteria for optic neuritis (ICON) were published in 2022. We applied these criteria to a prospective, global observational study of acute optic neuritis (ON).MethodsWe included 160 patients with a first‐ever acute ON suggestive of a demyelinating CNS disease from the Acute Optic Neuritis Network (ACON). We applied the 2022 ICON to all participants and subsequently adjusted the ICON by replacing a missing relative afferent pupillary defect (RAPD) or dyschromatopsia if magnetic resonance imaging pathology of the optical nerve plus optical coherence tomography abnormalities or certain biomarkers are present.ResultsAccording to the 2022 ICON, 80 (50%) patients were classified as definite ON, 12 (7%) patients were classified as possible ON, and 68 (43%) as not ON (NON). The main reasons for classification as NON were absent RAPD (52 patients, 76%) or dyschromatopsia (49 patients, 72%). Distribution of underlying ON etiologies was as follows: 78 (49%) patients had a single isolated ON, 41 (26%) patients were diagnosed with multiple sclerosis, 25 (16%) patients with myelin oligodendrocyte glycoprotein antibody‐associated disease, and 15 (9%) with neuromyelitis optica spectrum disorder. The application of the adjusted ON criteria yielded a higher proportion of patients classified as ON (126 patients, 79%).InterpretationAccording to the 2022 ICON, almost half of the included patients in ACON did not fulfill the requirements for classification of definite or possible ON, particularly due to missing RAPD and dyschromatopsia. Thorough RAPD examination and formal color vision testing are critical to the application of the 2022 ICON.

ImportanceRapid and accurate diagnosis of autoimmune encephalitis encourages prompt initiation of immunotherapy toward improved patient outcomes. However, clinical features alone may not sufficiently narrow the differential diagnosis, and awaiting autoantibody results can delay immunotherapy.ObjectiveTo identify simple magnetic resonance imaging (MRI) characteristics that accurately distinguish 2 common forms of autoimmune encephalitis, LGI1- and CASPR2-antibody encephalitis (LGI1/CASPR2-Ab-E), from 2 major differential diagnoses, viral encephalitis (VE) and Creutzfeldt-Jakob disease (CJD).Design, Setting, and ParticipantsThis cross-sectional study involved a retrospective, blinded analysis of the first available brain MRIs (taken 2000-2022) from 192 patients at Oxford University Hospitals in the UK and Mayo Clinic in the US. These patients had LGI1/CASPR2-Ab-E, VE, or CJD as evaluated by 2 neuroradiologists (discovery cohort; n = 87); findings were validated in an independent cohort by 3 neurologists (n = 105). Groups were statistically compared with contingency tables. Data were analyzed in 2023.Main Outcomes and MeasuresMRI findings including T2 or fluid-attenuated inversion recovery (FLAIR) hyperintensities, swelling or volume loss, presence of gadolinium contrast enhancement, and diffusion-weighted imaging changes. Correlations with clinical features.ResultsAmong 192 participants with MRIs reviewed, 71 were female (37%) and 121 were male (63%); the median age was 66 years (range, 19-92 years). By comparison with VE and CJD, in LGI1/CASPR2-Ab-E, T2 and/or FLAIR hyperintensities were less likely to extend outside the temporal lobe (3/42 patients [7%] vs 17/18 patients [94%] with VE; P < .001, and 3/4 patients [75%] with CJD; P = .005), less frequently exhibited swelling (12/55 [22%] with LGI1/CASPR2-Ab-E vs 13/22 [59%] with VE; P = .003), and showed no diffusion restriction (0 patients vs 16/22 [73%] with VE and 8/10 [80%] with CJD; both P < .001) and rare contrast enhancement (1/20 [5%] vs 7/17 [41%] with VE; P = .01). These findings were validated in an independent cohort and generated an area under the curve of 0.97, sensitivity of 90%, and specificity of 95% among cases with T2/FLAIR hyperintensity in the hippocampus and/or amygdala.Conclusions and RelevanceIn this study, T2 and/or FLAIR hyperintensities confined to the temporal lobes, without diffusion restriction or contrast enhancement, robustly distinguished LGI1/CASPR2-Ab-E from key differential diagnoses. These observations should assist clinical decision-making toward expediting immunotherapy. Their generalizability to other forms of autoimmune encephalitis and VE should be examined in future studies.

Abstract Patient‐reported quality‐of‐life (QoL) and carer impacts are not reported after leucine‐rich glioma‐inactivated 1‐antibody encephalitis (LGI1‐Ab‐E). From 60 patients, 85% (51 out of 60) showed one abnormal score across QoL assessments and 11 multimodal validated questionnaires. Compared to the premorbid state, QoL significantly deteriorated ( p < 0.001) and, at a median of 41 months, fatigue was its most important predictor ( p = 0.025). In total, 51% (26 out of 51) of carers reported significant burden. An abbreviated five‐item battery explained most variance in QoL. Wide‐ranging impacts post‐LGI1‐Ab‐E include decreased QoL and high caregiver strain. We identify a rapid method to capture QoL in routine clinic or clinical trial settings.