Analysis of complement and plasma cells in the brain of patients with anti-NMDAR encephalitis

Martínez‐Hernández, Eugenia; Horváth, Judit; Shiloh-Malawsky, Y.; Sangha, Namrata; Martinez‐Lage, Maria; Dalmau, Josep

doi:10.1212/wnl.0b013e318228c136

Cited by 314 publications

(278 citation 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%

“…Once internalized, antibody‐bound NMDARs traffic through both recycling endosomes and lysosomes, but do not induce compensatory changes in glutamate receptor gene expression 8, 12. Although anti‐NMDAR antibodies are mainly of the complement‐activating IgG1 and IgG3 subtypes, complement deposition was not detected in brain biopsy specimens from treatment‐naïve patients with anti‐NMDAR encephalitis, probably due to the low levels of complement present in CSF and relative preservation of the blood–brain barrier (BBB) 7, 13. Consistently, anti‐NMDAR IgG antibodies did not reduce the number of synapses, dendritic spines, dendritic complexity, or cell survival in cultured rat hippocampal neurons,9 and neuronal damage was sparse in brain biopsy specimens 13, 14.…”

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

112

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%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Malviya

Barman

Golombeck

et al. 2017

Ann Clin Transl Neurol

112

106

View full text Add to dashboard Cite

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“…First, known intrathecal synthesis of anti‐NMDAR antibody, pathologically confirmed by observing infiltration of antibody‐secreting cells in the CNS,28 indicate that plasma cells that translocate into the CNS space can evade attack from bortezomib, which had poor blood–brain barrier penetrance 29. Most specifically, long‐lived plasma cells that can survive several months to years7 may continuously secrete autoantibodies in the CNS.…”

Section: Discussionmentioning

confidence: 94%

Bortezomib treatment for severe refractory anti‐NMDA receptor encephalitis

Shin

Lee

Kim

et al. 2018

Ann Clin Transl Neurol

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ObjectiveTo evaluate the therapeutic potential of bortezomib, a proteasome inhibitor that target plasma cells, in order to revive stalled recovery in patients with anti‐N‐methyl‐d‐aspartate (NMDA) receptor encephalitis who remain bedridden even after aggressive immunotherapy.MethodsWe consecutively enrolled patients with anti‐NMDA receptor encephalitis who remained bedridden after first‐line immunotherapy (steroids and intravenous immunoglobulin), second‐line immunotherapy (rituximab), and tocilizumab treatment, and treated them with subcutaneous bortezomib. Clinical response, functional recovery, and changes in antibody titer in the serum and cerebrospinal fluid were measured.ResultsBefore the bortezomib treatment, the five patients with severe refractory anti‐NMDA receptor encephalitis were in a vegetative state. During the 8 months of follow‐up period, three patients improved to minimally conscious states within 2 months of bortezomib treatment, one failed to improve from a vegetative state. However, no patient achieved functional recovery as measured by the modified Rankin Scale score (mRS). Three patients advanced to a cyclophosphamide with bortezomib and dexamethasone regimen, which only resulted in additional adverse events, without mRS improvement. Among the four patients whose antibody titer was followed, two demonstrated a twofold decrease in the antibody titer in serum and/or cerebrospinal fluid after 2 cycles of bortezomib.InterpretationAlthough there were some improvements in severe refractory patients, clinical response to bortezomib was limited and not clearly distinguishable from the natural course of the disease. The clinical benefit of bortezomib in recent studies requires further validation in different clinical settings.

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