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Cervical lymph nodes and ovarian teratomas as germinal centres in NMDA receptor-antibody encephalitis. 2022

Adam Al-Diwani, and Jakob Theorell, and Valentina Damato, and Joshua Bull, and Nicholas McGlashan, and Edward Green, and Anne Kathrin Kienzler, and Ruby Harrison, and Tasneem Hassanali, and Leticia Campo, and Molly Browne, and Alistair Easton, and Hooman Soleymani Majd, and Keiko Tenaka, and Raffaele Iorio, and Russell C Dale, and Paul Harrison, and John Geddes, and Digby Quested, and David Sharp, and Soon Tae Lee, and David W Nauen, and Mateusz Makuch, and Belinda Lennox, and Darren Fowler, and Fintan Sheerin, and Patrick Waters, and M Isabel Leite, and Adam E Handel, and Sarosh R Irani
Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.

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.

UI MeSH Term Description Entries
D007070 Immunoglobulin A Represents 15-20% of the human serum immunoglobulins, mostly as the 4-chain polymer in humans or dimer in other mammals. Secretory IgA (IMMUNOGLOBULIN A, SECRETORY) is the main immunoglobulin in secretions. IgA,IgA Antibody,IgA1,IgA2,Antibody, IgA
D007074 Immunoglobulin G The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of IgG, for example, IgG1, IgG2A, and IgG2B. Gamma Globulin, 7S,IgG,IgG Antibody,Allerglobuline,IgG(T),IgG1,IgG2,IgG2A,IgG2B,IgG3,IgG4,Immunoglobulin GT,Polyglobin,7S Gamma Globulin,Antibody, IgG,GT, Immunoglobulin
D010051 Ovarian Neoplasms Tumors or cancer of the OVARY. These neoplasms can be benign or malignant. They are classified according to the tissue of origin, such as the surface EPITHELIUM, the stromal endocrine cells, and the totipotent GERM CELLS. Cancer of Ovary,Ovarian Cancer,Cancer of the Ovary,Neoplasms, Ovarian,Ovary Cancer,Ovary Neoplasms,Cancer, Ovarian,Cancer, Ovary,Cancers, Ovarian,Cancers, Ovary,Neoplasm, Ovarian,Neoplasm, Ovary,Neoplasms, Ovary,Ovarian Cancers,Ovarian Neoplasm,Ovary Cancers,Ovary Neoplasm
D005260 Female Females
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D001323 Autoantibodies Antibodies that react with self-antigens (AUTOANTIGENS) of the organism that produced them. Autoantibody
D013724 Teratoma A true neoplasm composed of a number of different types of tissue, none of which is native to the area in which it occurs. It is composed of tissues that are derived from three germinal layers, the endoderm, mesoderm, and ectoderm. They are classified histologically as mature (benign) or immature (malignant). (From DeVita Jr et al., Cancer: Principles & Practice of Oncology, 3d ed, p1642) Dysembryoma,Teratoid Tumor,Teratoma, Cystic,Teratoma, Mature,Teratoma, Benign,Teratoma, Immature,Teratoma, Malignant,Benign Teratoma,Benign Teratomas,Dysembryomas,Immature Teratoma,Immature Teratomas,Malignant Teratoma,Malignant Teratomas,Teratoid Tumors,Teratomas,Teratomas, Benign,Teratomas, Immature,Teratomas, Malignant,Tumor, Teratoid,Tumors, Teratoid
D016194 Receptors, N-Methyl-D-Aspartate A class of ionotropic glutamate receptors characterized by affinity for N-methyl-D-aspartate. NMDA receptors have an allosteric binding site for glycine which must be occupied for the channel to open efficiently and a site within the channel itself to which magnesium ions bind in a voltage-dependent manner. The positive voltage dependence of channel conductance and the high permeability of the conducting channel to calcium ions (as well as to monovalent cations) are important in excitotoxicity and neuronal plasticity. N-Methyl-D-Aspartate Receptor,N-Methyl-D-Aspartate Receptors,NMDA Receptor,NMDA Receptor-Ionophore Complex,NMDA Receptors,Receptors, NMDA,N-Methylaspartate Receptors,Receptors, N-Methylaspartate,N Methyl D Aspartate Receptor,N Methyl D Aspartate Receptors,N Methylaspartate Receptors,NMDA Receptor Ionophore Complex,Receptor, N-Methyl-D-Aspartate,Receptor, NMDA,Receptors, N Methyl D Aspartate,Receptors, N Methylaspartate
D042601 Lymphatic Vessels Tubular vessels that are involved in the transport of LYMPH and LYMPHOCYTES. Capillaries, Lymphatic,Lymphatic Capillaries,Lymphatic Venules,Venules, Lymphatic,Capillary, Lymphatic,Lymphatic Capillary,Lymphatic Venule,Lymphatic Vessel,Venule, Lymphatic,Vessel, Lymphatic,Vessels, Lymphatic
D060426 Anti-N-Methyl-D-Aspartate Receptor Encephalitis Disorder characterized by symptoms of CATATONIA; HYPOVENTILATION; DYSKINESIAS; ENCEPHALITIS; and SEIZURES followed by a reduced CONSCIOUSNESS. It is often followed by a viral-like prodrome. Many cases are self-limiting and respond well to IMMUNOMODULATORY THERAPIES against the NMDA RECEPTORS antibodies. Anti-NMDA Receptor Encephalitis,Anti-NMDAR Encephalitis,Non-paraneoplastic Anti-N-Methyl-D-Aspartate Receptor Encephalitis,Non-paraneoplastic Anti-NMDA Receptor Encephalitis,Non-paraneoplastic Anti-NMDAR Encephalitis,Paraneoplastic Anti-N-Methyl-D-Aspartate Receptor Encephalitis,Paraneoplastic Anti-NMDA Receptor Encephalitis,Paraneoplastic Anti-NMDAR Encephalitis,Anti N Methyl D Aspartate Receptor Encephalitis,Anti NMDA Receptor Encephalitis,Anti NMDAR Encephalitis,Anti-N-Methyl-D-Aspartate Receptor Encephalitides,Anti-NMDA Receptor Encephalitides,Anti-NMDAR Encephalitides,Anti-NMDAR Encephalitides, Non-paraneoplastic,Anti-NMDAR Encephalitides, Paraneoplastic,Anti-NMDAR Encephalitis, Non-paraneoplastic,Anti-NMDAR Encephalitis, Paraneoplastic,Encephalitides, Anti-N-Methyl-D-Aspartate Receptor,Encephalitides, Anti-NMDA Receptor,Encephalitides, Anti-NMDAR,Encephalitides, Non-paraneoplastic Anti-NMDAR,Encephalitides, Paraneoplastic Anti-NMDAR,Encephalitis, Anti-N-Methyl-D-Aspartate Receptor,Encephalitis, Anti-NMDA Receptor,Encephalitis, Anti-NMDAR,Encephalitis, Non-paraneoplastic Anti-NMDAR,Encephalitis, Paraneoplastic Anti-NMDAR,Non paraneoplastic Anti N Methyl D Aspartate Receptor Encephalitis,Non paraneoplastic Anti NMDA Receptor Encephalitis,Non paraneoplastic Anti NMDAR Encephalitis,Non-paraneoplastic Anti-NMDAR Encephalitides,Paraneoplastic Anti N Methyl D Aspartate Receptor Encephalitis,Paraneoplastic Anti NMDA Receptor Encephalitis,Paraneoplastic Anti NMDAR Encephalitis,Paraneoplastic Anti-NMDAR Encephalitides,Receptor Encephalitides, Anti-NMDA,Receptor Encephalitis, Anti-NMDA

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