Brain immunohistopathological study in a patient with anti-NMDAR encephalitis

Camdessanché, Jean‐Philippe; Streichenberger, Nathalie; Cavillon, Gaëlle; Rogemond, Véronique; Jousserand, Guillemette; Honnorat, Jérôme; Convers, Philippe; Antoine, Jean‐Christophe

doi:10.1111/j.1468-1331.2010.03180.x

Cited by 97 publications

(76 citation statements)

References 11 publications

(17 reference statements)

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“…Consistently, prominent CD138 + plasma cells could be detected in perivascular, and interstitial spaces of a biopsy specimen from another patient with anti‐NMDAR encephalitis (Fig. 1D) 6, 7…”

Section: Resultssupporting

confidence: 59%

“…Irrespective of the trigger of anti‐NMDAR encephalitis, data from previous studies suggested an enhancement of the immune response within the CNS, with potential antigen‐driven affinity maturation and clonal expansion of plasma cells 16. This hypothesis was suggested by three findings, (1) a frequent intrathecal synthesis of NMDAR antibodies even early in the disease course,1 (2) biopsy and autopsy material from patients showing brain inflammatory infiltrates containing plasma cells,6, 7 and (3) the better correlation of the course of the disease with CSF antibody titers than with serum antibody titers 5. All four treatment‐naive patients with recent onset anti‐NMDAR encephalitis in the current study showed intrathecal B‐cell and plasma cell accumulation and intrathecal production of NMDAR‐specific IgG.…”

Section: Discussionmentioning

confidence: 99%

“…The intrathecal source of pathogenic antibodies in anti‐NMDAR encephalitis has been suggested to originate from CD138 + plasma cells identified in perivascular and interstitial spaces in biopsy and autopsy studies 6, 7…”

Section: Introductionmentioning

confidence: 99%

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NMDAR encephalitis: passive transfer from man to mouse by a recombinant antibody

Malviya

Barman

Golombeck

et al. 2017

Ann Clin Transl Neurol

110

106

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ObjectiveAutoimmune encephalitis is most frequently associated with anti‐NMDAR autoantibodies. Their pathogenic relevance has been suggested by passive transfer of patients' cerebrospinal fluid (CSF) in mice in vivo. We aimed to analyze the intrathecal plasma cell repertoire, identify autoantibody‐producing clones, and characterize their antibody signatures in recombinant form.MethodsPatients with recent onset typical anti‐NMDAR encephalitis were subjected to flow cytometry analysis of the peripheral and intrathecal immune response before, during, and after immunotherapy. Recombinant human monoclonal antibodies (rhuMab) were cloned and expressed from matching immunoglobulin heavy‐ (IgH) and light‐chain (IgL) amplicons of clonally expanded intrathecal plasma cells (cePc) and tested for their pathogenic relevance.ResultsIntrathecal accumulation of B and plasma cells corresponded to the clinical course. The presence of cePc with hypermutated antigen receptors indicated an antigen‐driven intrathecal immune response. Consistently, a single recombinant human GluN1‐specific monoclonal antibody, rebuilt from intrathecal cePc, was sufficient to reproduce NMDAR epitope specificity in vitro. After intraventricular infusion in mice, it accumulated in the hippocampus, decreased synaptic NMDAR density, and caused severe reversible memory impairment, a key pathogenic feature of the human disease, in vivo.InterpretationA CNS‐specific humoral immune response is present in anti‐NMDAR encephalitis specifically targeting the GluN1 subunit of the NMDAR. Using reverse genetics, we recovered the typical intrathecal antibody signature in recombinant form, and proved its pathogenic relevance by passive transfer of disease symptoms from man to mouse, providing the critical link between intrathecal immune response and the pathogenesis of anti‐NMDAR encephalitis as a humorally mediated autoimmune disease.

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Section: Resultssupporting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

NMDAR encephalitis: passive transfer from man to mouse by a recombinant antibody

Malviya

Barman

Golombeck

et al. 2017

Ann Clin Transl Neurol

110

106

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“…Further studies focusing particularly on the cognitive deficits have shown that there is a long-term morbidity in this disorder, with a good outcome for the patient dependent on early and aggressive treatment (Finke et al 2012). The brains of these patients show few inflammatory cells (mostly T cells) (Tuzun et al 2009;Camdessanche et al 2011;Martinez-Hernandez et al 2011;Bien et al 2012) and magnetic resonance imaging (MRI), and pathological studies show that the neuronal loss in most cases is remarkably mild (Dalmau et al 2007;Iizuka et al 2010;Bien et al 2012). The antibodies have been shown to be pathogenic, at least in vitro.…”

Section: Nmda Receptor (Nmdar) Antibodies Encephalitismentioning

confidence: 99%

Immunity and Inflammation in Epilepsy

Vezzani

Lang

Aronica

2015

Cold Spring Harb Perspect Med

185

145

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This review reports the available evidence on the activation of the innate and adaptive branches of the immune system and the related inflammatory processes in epileptic disorders and the putative pathogenic role of inflammatory processes developing in the brain, as indicated by evidence from experimental and clinical research. Indeed, there is increasing knowledge supporting a role of specific inflammatory mediators and immune cells in the generation and recurrence of epileptic seizures, as well as in the associated neuropathology and comorbidities. Major challenges in this field remain: a better understanding of the key inflammatory pathogenic pathways activated in chronic epilepsy and during epileptogenesis, and how to counteract them efficiently without altering the homeostatic tissue repair function of inflammation. The relevance of this information for developing novel therapies will be highlighted.

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“…The immunopathogenesis of this encephalitis is possibly related to antibody immune-responses of B cell and antibody-secreting cells (e.g., plasma cells), which are derived from activated B cells (10)(11)(12). In the present case, normal mouse brain showed immunoreactions to serum samples from this patient, which had been collected after administration of first-line immunotherapy, and before the administration of rituximab.…”

Section: Discussionmentioning

confidence: 55%

Rituximab Used Successfully in the Treatment of Anti-NMDA Receptor Encephalitis

et al. 2012

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We report the case of a young woman with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, without tumor, who was successfully treated with rituximab. Because conventional immunotherapy, including corticosteroids, immunoglobulin (IVIg), and plasma exchange showed little improvement in our patient, we introduced another treatment using rituximab. A week after the first administration of rituximab, her symptoms improved gradually and significantly. This case provides in vivo evidence that rituximab is an effective agent for treating anti-NMDAR encephalitis, even in those cases where conventional immunotherapies have been ineffective. Rituximab should be regarded as a beneficial therapeutic agent for this disease.

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Brain immunohistopathological study in a patient with anti-NMDAR encephalitis

Abstract: These findings suggest that the B cells interact with the T cells and are involved in antibody secretion by the plasma cells.

Cited by 97 publications

References 11 publications

NMDAR encephalitis: passive transfer from man to mouse by a recombinant antibody

NMDAR encephalitis: passive transfer from man to mouse by a recombinant antibody

Immunity and Inflammation in Epilepsy

Rituximab Used Successfully in the Treatment of Anti-NMDA Receptor Encephalitis

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