Evidence map›Paper›PMID 35680425›Full record

ArticleBrain : a journal of neurology2022

Cervical lymph nodes and ovarian teratomas as germinal centres in NMDA receptor-antibody encephalitis.

Adam Al-Diwani, Jakob Theorell, Valentina Damato, Joshua Bull, Nicholas McGlashan, Edward Green, Anne Kathrin Kienzler, Ruby Harrison, Tasneem Hassanali, Leticia Campo and 20 more

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Brain : a journal of neurology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
46citing papers in PubMed, 2 pooled it
10.6field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

46 citing papers in PubMed, 2 syntheses or guidelines pooled it, 89 citations in OpenAlex.

  1. Pooled it
  2. Pooled it
  3. Review
  4. Review
  5. Single-Cell Profiling Reveals Clonally Expanded CX3CR1Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026
    Article
  6. Review
  7. Article
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  11. Article
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  13. Article
  14. Autoimmune encephalitis.Nature reviews. Disease primers · 2025
    Review
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  17. Article
  18. Review
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

30 authors at 11 institutions in 7 countries.

Adam Al-DiwaniOxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.ORCID 0000-0001-6596-7579
Jakob TheorellOxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.ORCID 0000-0001-8752-3151
Valentina DamatoOxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.ORCID 0000-0003-1740-4522
Joshua BullWolfson Centre for Mathematical Biology, Mathematical Institute, University of Oxford, Oxford, UK.ORCID 0000-0003-1475-2898
Nicholas McGlashanDepartment of Radiology, John Radcliffe Hospital, Oxford University Hospitals, Oxford, UK.
Edward GreenDepartment of Radiology, John Radcliffe Hospital, Oxford University Hospitals, Oxford, UK.
Anne Kathrin KienzlerOxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.ORCID 0000-0002-3082-9210
Ruby HarrisonOxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.ORCID 0000-0003-2985-8652
Tasneem HassanaliTranslational Histopathology Laboratory, Department of Oncology, University of Oxford, Oxford, UK.ORCID 0000-0002-8680-6456
Leticia CampoTranslational Histopathology Laboratory, Department of Oncology, University of Oxford, Oxford, UK.
Molly BrowneTranslational Histopathology Laboratory, Department of Oncology, University of Oxford, Oxford, UK.
Alistair EastonTranslational Histopathology Laboratory, Department of Oncology, University of Oxford, Oxford, UK.
Hooman Soleymani MajdDepartment of Gynaecologic Oncology, Oxford University Hospitals, Oxford, UK.ORCID 0000-0003-3293-5321
Keiko TenakaDepartment of Animal Model Development, Brain Research Institute, Niigata University, Niigata, Japan.
Raffaele IorioUOC Neurologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
Russell C DaleKids Neuroscience Centre, Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, Sydney, Australia.
Paul HarrisonUniversity Department of Psychiatry, University of Oxford, Oxford, UK.ORCID 0000-0002-6719-1126
John GeddesUniversity Department of Psychiatry, University of Oxford, Oxford, UK.ORCID 0000-0002-5281-5960
Digby QuestedUniversity Department of Psychiatry, University of Oxford, Oxford, UK.ORCID 0000-0001-6155-3336
David SharpComputational, Cognitive and Clinical Neuroimaging Laboratory, Division of Brain Sciences, Imperial College London, London, UK.
Soon Tae LeeDepartment of Neurology, Seoul National University Hospital, Seoul, South Korea.ORCID 0000-0003-4767-7564
David W NauenDepartment of Pathology, Johns Hopkins Hospital, Baltimore, MD, USA.ORCID 0000-0002-2652-9944
Mateusz MakuchOxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
Belinda LennoxUniversity Department of Psychiatry, University of Oxford, Oxford, UK.ORCID 0000-0002-4972-8786
Darren FowlerDepartment of Pathology, John Radcliffe Hospital, Oxford University Hospitals, Oxford, UK.ORCID 0000-0002-3731-0948
Fintan SheerinDepartment of Radiology, John Radcliffe Hospital, Oxford University Hospitals, Oxford, UK.
Patrick WatersOxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.ORCID 0000-0003-4142-2667
M Isabel LeiteOxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.ORCID 0000-0002-4277-9855
Adam E HandelOxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.ORCID 0000-0001-8385-6346
Sarosh R IraniOxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.ORCID 0000-0002-7667-9748
University of Oxford · GBJohn Radcliffe Hospital · GBAgostino Gemelli University Polyclinic · ITJohns Hopkins Hospital · USKarolinska Institutet · SENiigata University · JPOxford University Hospitals NHS Trust · GBSeoul National University Hospital · KRThe University of Sydney · AUUniversità Cattolica del Sacro Cuore · ITWellcome Centre for Human Neuroimaging · GB

Funding

Department of HealthMedical Research Council MR/S036407/1Medical Research Council MR/V007173/1Wellcome Trust
6 · The paper itself

Abstract

Autoantibodies against the extracellular domain of the N-methyl-d-aspartate receptor (NMDAR) NR1 subunit cause a severe and common form of encephalitis. To better understand their generation, we aimed to characterize and identify human germinal centres actively participating in NMDAR-specific autoimmunization by sampling patient blood, CSF, ovarian teratoma tissue and, directly from the putative site of human CNS lymphatic drainage, cervical lymph nodes. From serum, both NR1-IgA and NR1-IgM were detected more frequently in NMDAR-antibody encephalitis patients versus controls (both P < 0.0001). Within patients, ovarian teratoma status was associated with a higher frequency of NR1-IgA positivity in serum (OR = 3.1; P < 0.0001) and CSF (OR = 3.8, P = 0.047), particularly early in disease and before ovarian teratoma resection. Consistent with this immunoglobulin class bias, ovarian teratoma samples showed intratumoral production of both NR1-IgG and NR1-IgA and, by single cell RNA sequencing, contained expanded highly-mutated IgA clones with an ovarian teratoma-restricted B cell population. Multiplex histology suggested tertiary lymphoid architectures in ovarian teratomas with dense B cell foci expressing the germinal centre marker BCL6, CD21+ follicular dendritic cells, and the NR1 subunit, alongside lymphatic vessels and high endothelial vasculature. Cultured teratoma explants and dissociated intratumoral B cells secreted NR1-IgGs in culture. Hence, ovarian teratomas showed structural and functional evidence of NR1-specific germinal centres. On exploring classical secondary lymphoid organs, B cells cultured from cervical lymph nodes of patients with NMDAR-antibody encephalitis produced NR1-IgG in 3/7 cultures, from patients with the highest serum NR1-IgG levels (P < 0.05). By contrast, NR1-IgG secretion was observed neither from cervical lymph nodes in disease controls nor in patients with adequately resected ovarian teratomas. Our multimodal evaluations provide convergent anatomical and functional evidence of NMDAR-autoantibody production from active germinal centres within both intratumoral tertiary lymphoid structures and traditional secondary lymphoid organs, the cervical lymph nodes. Furthermore, we develop a cervical lymph node sampling protocol that can be used to directly explore immune activity in health and disease at this emerging neuroimmune interface.

Indexed as

Anti-N-Methyl-D-Aspartate Receptor EncephalitisLymphatic VesselsTeratomaAutoantibodiesFemaleGerminal CenterHumansImmunoglobulin AImmunoglobulin GOvarian NeoplasmsReceptors, N-Methyl-D-AspartateAutoantibodiesImmunoglobulin AImmunoglobulin GReceptors, N-Methyl-D-Aspartatebrain autoimmunitycervical lymph nodegerminal centreNMDAR-antibody encephalitisteratoma

Identifiers

PMID35680425
PMCPMC9486890
OpenAlexW4214821204

What OpenQuestion holds

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LicenceCC BY
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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.