Irani, Sarosh R.

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.

Abstract Background The recognition of autoimmune causes of encephalitis has led to epidemiological shifts in the worldwide characteristics of encephalitis. N-methyl-D-aspartate receptor (NMDAR) antibody encephalitis leads to well-established complex neuropsychiatric manifestations. In low- and middle-income countries, including Vietnam, its relative incidence, especially in children, is unknown and most neurologists currently consider infectious encephalitis prior to autoimmune etiologies. Methods The study was prospectively conducted at Children's Hospital 1 in Ho Chi Minh City between March 2020 and December 2022. Any child admitted to the Department of Infectious Diseases and Neurology fulfilling the case definition of encephalitis was eligible to participate. Cerebrospinal fluid samples were collected alongside meta-clinical data for analysis. Results We recruited 164 children with a clinical diagnosis of encephalitis. Etiologies were determined as NMDAR antibody encephalitis in 23 of 164 cases (14.0%), Japanese encephalitis virus in 14 of 164 (8.5%), and herpes simplex virus in 4 of 164 (2.4%). Clinical categorizations suggested idiopathic viral encephalitis in another 71 (43.3%), and autoimmune encephalitis of unknown origin in the remaining 52. Factors including demographics, specific clinical features, cerebrospinal fluid and electroencephalogram findings, and length of hospital stay were significantly different between NMDAR antibody encephalitis and Japanese encephalitis. Conclusions At a tertiary children's hospital in Vietnam, the prevalence of NMDAR antibody encephalitis exceeds that of Japanese encephalitis, the most common infectious encephalitis cause in Southeast Asia. NMDAR antibody encephalitis is associated with long hospital stay and poor outcomes. These findings should change pediatric diagnostics, to earlier consider autoimmune treatments in this clinical setting.

AbstractLymph nodes (LNs) are specialized secondary lymphoid tissues essential to the priming and maintenance of adaptive immune responses, including the B cell germinal center response; thus, they are central to immunity. However, the anatomically restricted and time‐resolved nature of immune priming means that sampling disease‐relevant human LNs requires specialized techniques. This article describes the application of ultrasound‐guided fine‐needle aspiration (FNA) to sample LNs, using cervical LNs of the head and neck as an exemplar. This minimally invasive technique allows collection of both immune cells and cell‐free material that are relevant to both neuroimmune diseases and basic lymphatic functions. Downstream use of cellular material can include multiplexed flow cytometry, single‐cell transcriptome sequencing (RNA‐seq), and B cell cultures. The cell‐free supernatant can be used for proteomics or other similar ‘omics approaches. This unit describes collection of samples by FNA as well as processing and storage of samples for downstream assays. © 2024 The Author(s). Current Protocols published by Wiley Periodicals LLC.Basic Protocol 1: Sampling of human cervical lymph nodes by ultrasound‐guided fine‐needle aspirationAlternate Protocol: Sampling of human lymph nodes by ultrasound‐guided fine‐needle aspiration with negative pressureBasic Protocol 2: Processing and storage of human lymph node samples

ABSTRACT. Encephalitis is a significant global health problem, especially in children. Knowledge of its economic burden is essential for policymakers in prioritizing the development and implementation of interventions but remains limited. An observational study was prospectively conducted at a major children’s hospital in Ho Chi Minh City, Vietnam from 2020 to 2022. Data on direct medical costs, direct nonmedical costs, and productivity costs were collected alongside demographic information, clinical features, diagnosis, severity, and outcomes of study participants. This was used to undertake a cost of illness analysis from a societal perspective. Data were collected from a total of 164 pediatric patients. The median cost of illness was estimated at US $1,859 (interquartile range [IQR]: US $1,273–$3,128). The direct costs were the main cost driver, accounting for 83.9% of the total cost of illness (US $1,560; IQR: US $975–$2,460). The productivity costs accounted for a median of US $275 (IQR: US $154–$474). The cost of illness was higher in more severe patients, patients with sequelae, patients with morbidities, and ventilated patients. Most direct medical costs were attributed to hospitalization and resulted in out-of-pocket payments from the patient’s family (30.2%; US $316). The results showed that the cost of illness of encephalitis in children is considerable and will be useful for policymakers in prioritizing resources for the development and implementation of intervention strategies to reduce the burden of pediatric encephalitis.

Abstract Encephalitis with antibodies to leucine-rich glioma-inactivated 1 (LGI1-Ab-E) is a common form of autoimmune encephalitis, presenting with seizures and neuropsychiatric changes, predominantly in older males. More than 90% of patients carry the human leukocyte antigen (HLA) class II allele, HLA-DRB1*07:01. However, this is also present in 25% of healthy controls. Therefore, we hypothesized the presence of additional genetic predispositions. In this genome-wide association study and meta-analysis, we studied a discovery cohort of 131 French LGI1-Ab-E and a validation cohort of 126 American, British and Irish LGI1-Ab-E patients, ancestry-matched to 2613 and 2538 European controls, respectively. Outside the known major HLA signal, we found two single nucleotide polymorphisms at genome-wide significance (P < 5 × 10−8), implicating PTPRD, a protein tyrosine phosphatase, and LINC00670, a non-protein coding RNA gene. Meta-analysis defined four additional non-HLA loci, including the protein coding COBL gene. Polygenic risk scores with and without HLA variants proposed a contribution of non-HLA loci. In silico network analyses suggested LGI1 and PTPRD-mediated interactions via the established receptors of LGI1, ADAM22 and ADAM23. Our results identify new genetic loci in LGI1-Ab-E. These findings present opportunities for mechanistic studies and offer potential markers of susceptibility, prognostics and therapeutic responses.

Abstract In animal models, brain neurodegeneration biomarkers drain into cervical lymph nodes (CLNs), and this drainage function is reduced with ageing. If this occurred in humans, CLNs may provide a readily accessible measure of this aspect of protein clearance. We tested this hypothesis in people using ultrasound-guided fine needle aspiration. We measured amyloid-beta 40 and 42, phosphorylated tau 181 (pTau181), glial fibrillary acidic protein and neurofilament light using single molecule array in CLN aspirates and plasma from: (i) a discovery cohort of 25 autoimmune patients; and (ii) plasma, CLNs and capillary blood in four healthy volunteers, an optimization cohort. Ultrasound-guided fine needle aspiration was well-tolerated by all participants. In both cohorts, all biomarkers were detected in all plasma and CLN samples, other than neurofilament light (8/17 of discovery cohort). CLN biomarker concentrations were significantly greater than plasma concentrations for all except neurofilament light, most markedly for pTau181 (266-fold; P < 0.02), whose CLN concentrations decreased with age (Spearman r = −0.66, P = 0.001). This study presents the first evidence that neurodegenerative biomarkers are detectable in human CLNs. Raised CLN:plasma biomarker ratios suggest their concentration in CLNs may offer a distinct compartment for minimally-invasive measurement of brain clearance and lymphatic drainage, with potential applicability to study of ageing and future clinical trials.

Abstract This post hoc analysis of the randomized, placebo‐controlled N‐MOmentum study (NCT02200770) of inebilizumab in neuromyelitis optica spectrum disorder (NMOSD) evaluated relationships between circulating B‐cell subsets and aquaporin‐4 immunoglobulin G (AQP4‐lgG) titers and attacks. Among participants receiving placebo, CD20 + and CD27 + B‐cell counts were modestly increased from the pre‐attack visit to attack; plasmablast/plasma cell gene signature was increased from baseline to the pre‐attack visit ( p = 0.016) and from baseline to attack ( p = 0.009). With inebilizumab treatment, B‐cell subset counts decreased and did not increase with attacks. No difference in change of AQP4‐IgG titers from baseline to time of attack was observed.

This scientific commentary refers to ‘NMDA receptor autoantibodies primarily impair the extrasynaptic compartment’ by Jamet et al. (https://doi.org/10.1093/brain/awae163).