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July 27, 2011

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

August 9, 2011 issue
77 (6) 589-593

Abstract

Objectives:

Most patients with anti-NMDA receptor (NMDAR) encephalitis have intrathecal synthesis of antibodies, which cause a decrease of cell surface and synaptic NMDAR. Antibodies are immunoglobulin G (IgG)1 and IgG3 subtypes and can potentially activate complement. We examined whether complement immunoreactivity and antibody-secreting cells (plasma cells/plasmablasts) are present in the brain of these patients.

Methods:

Cultured rat hippocampal neurons were used in an immunocytochemical assay to test whether patients' antibodies can fix complement. Using the same reagents (antibodies to C9neo, C5b-9, C3), complement immunoreactivity was determined in the brain of 5 patients, the teratoma of 21 patients, and appropriate control tissues. A set of markers for B (CD20), T (CD3, CD4, CD8) and antibody-secreting cells (plasma cells/plasmablasts, CD138) were used to examine the brain inflammatory infiltrates.

Results:

Patients' antibodies were able to bind complement in vitro, but deposits of complement were not detected in patients' brain. Parallel experiments with teratomas showed that in contrast to the brain, the neural tissue of the tumors contained complement. Analysis of the inflammatory infiltrates in brain samples from autopsy or biopsy performed 3–4 weeks after symptom presentation demonstrated numerous antibody-secreting cells (CD138+) in perivascular, interstitial, and Virchow-Robin spaces, and B and T cells predominantly located in perivascular regions.

Conclusions:

Complement-mediated mechanisms do not appear to play a substantial pathogenic role in anti-NMDAR encephalitis. In contrast, there are copious infiltrates of antibody-secreting cells (plasma cells/plasmablasts) in the CNS of these patients. The demonstration of these cells provides an explanation for the intrathecal synthesis of antibodies and has implications for treatment.

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Supplementary Material

File (appendix_e-1.pdf)
File (e-references.pdf)
File (figure_e-1.pdf)
File (figure_e-2.pdf)

ACKNOWLEDGMENT

The authors thank the physicians who provided clinical information and tissue samples.

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Information & Authors

Information

Published In

Neurology®
Volume 77Number 6August 9, 2011
Pages: 589-593
PubMed: 21795662

Publication History

Received: February 24, 2011
Accepted: April 20, 2011
Published online: July 27, 2011
Published in print: August 9, 2011

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Disclosure

Dr. Martinez-Hernandez receives research support from the Fondo de Investigaciones Sanitarias, FIS, Spain. Dr. Horvath has received funding for travel from UCB and research support from the Parkinson Swiss Foundation. Dr. Shiloh-Malawsky and Dr. Sangha report no disclosures. Dr. Martinez-Lage holds a patent re: Compositions and methods for the treatment of frontotemporal lobar degeneration with TDP-43 inclusions. Dr. Dalmau serves on the editorial board of Neurology®; receives royalties from the editorial board of Up-To-Date; has filed a patent application for the use of LGI1 as a diagnostic test; has received royalties from Athena Diagnostics, Inc. for a patent re: Ma2 autoantibody test and has patents pending re: NMDA and GABAB receptor autoantibody tests (license fee payments received from EUROIMMUN AG); and receives research support from EUROIMMUN AG, the NIH/NCI, and a McKnight Neuroscience of Brain Disorders award. Dr. Dalmau is ICREA (Institució Catalana de Recerca i Estudis Avançats) Research Professor at IDIBAPS, Hospital Clínic, Barcelona, Spain.

Authors

Affiliations & Disclosures

E. Martinez-Hernandez, MD
From the Departments of Neurology (E.M.-H., J.D.) and Pathology and Laboratory Medicine (M.M.-L.), University of Pennsylvania, Philadelphia; Department of Neurosciences (J.H.), Clinic of Neurology, University of Geneva, Switzerland; Department of Neurology (Y.S.-M.), University of North Carolina, Chapel Hill; and Department of Neurology (N.S.), Kaiser Permanente, Los Angeles, CA. E.M.-H. is currently with the Department of Neurology, Hospital de Sant Pau, University Autònoma of Barcelona, Spain. J.D. is currently at Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Hospital Clinic, University of Barcelona, Spain.
J. Horvath, MD
From the Departments of Neurology (E.M.-H., J.D.) and Pathology and Laboratory Medicine (M.M.-L.), University of Pennsylvania, Philadelphia; Department of Neurosciences (J.H.), Clinic of Neurology, University of Geneva, Switzerland; Department of Neurology (Y.S.-M.), University of North Carolina, Chapel Hill; and Department of Neurology (N.S.), Kaiser Permanente, Los Angeles, CA. E.M.-H. is currently with the Department of Neurology, Hospital de Sant Pau, University Autònoma of Barcelona, Spain. J.D. is currently at Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Hospital Clinic, University of Barcelona, Spain.
Y. Shiloh-Malawsky, MD
From the Departments of Neurology (E.M.-H., J.D.) and Pathology and Laboratory Medicine (M.M.-L.), University of Pennsylvania, Philadelphia; Department of Neurosciences (J.H.), Clinic of Neurology, University of Geneva, Switzerland; Department of Neurology (Y.S.-M.), University of North Carolina, Chapel Hill; and Department of Neurology (N.S.), Kaiser Permanente, Los Angeles, CA. E.M.-H. is currently with the Department of Neurology, Hospital de Sant Pau, University Autònoma of Barcelona, Spain. J.D. is currently at Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Hospital Clinic, University of Barcelona, Spain.
N. Sangha, MD
From the Departments of Neurology (E.M.-H., J.D.) and Pathology and Laboratory Medicine (M.M.-L.), University of Pennsylvania, Philadelphia; Department of Neurosciences (J.H.), Clinic of Neurology, University of Geneva, Switzerland; Department of Neurology (Y.S.-M.), University of North Carolina, Chapel Hill; and Department of Neurology (N.S.), Kaiser Permanente, Los Angeles, CA. E.M.-H. is currently with the Department of Neurology, Hospital de Sant Pau, University Autònoma of Barcelona, Spain. J.D. is currently at Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Hospital Clinic, University of Barcelona, Spain.
M. Martinez-Lage, MD
From the Departments of Neurology (E.M.-H., J.D.) and Pathology and Laboratory Medicine (M.M.-L.), University of Pennsylvania, Philadelphia; Department of Neurosciences (J.H.), Clinic of Neurology, University of Geneva, Switzerland; Department of Neurology (Y.S.-M.), University of North Carolina, Chapel Hill; and Department of Neurology (N.S.), Kaiser Permanente, Los Angeles, CA. E.M.-H. is currently with the Department of Neurology, Hospital de Sant Pau, University Autònoma of Barcelona, Spain. J.D. is currently at Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Hospital Clinic, University of Barcelona, Spain.
J. Dalmau, MD, PhD
From the Departments of Neurology (E.M.-H., J.D.) and Pathology and Laboratory Medicine (M.M.-L.), University of Pennsylvania, Philadelphia; Department of Neurosciences (J.H.), Clinic of Neurology, University of Geneva, Switzerland; Department of Neurology (Y.S.-M.), University of North Carolina, Chapel Hill; and Department of Neurology (N.S.), Kaiser Permanente, Los Angeles, CA. E.M.-H. is currently with the Department of Neurology, Hospital de Sant Pau, University Autònoma of Barcelona, Spain. J.D. is currently at Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Hospital Clinic, University of Barcelona, Spain.

Notes

References e1–e9 are available on the Neurology® Web site at www.neurology.org.
Study funding: Supported in part by RO1CA89054 and RO1CA107192 (J.D.) and Fondo de Investigaciones Sanitarias FI08/00285 (E.M.-H.).
Address correspondence and reprint requests to Dr. Josep Dalmau, Department of Neurology, 3 W. Gates, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104 [email protected]

Author Contributions

Dr. Martinez-Hernandez: drafting/revising the manuscript, analysis or interpretation of data, acquisition of data, study supervision. Dr. Horvath: drafting/revising the manuscript, acquisition of data. Dr. Shiloh-Malawsky: drafting/revising the manuscript, contribution of vital reagents/tools/patients. Dr. Sangha: drafting/revising the manuscript. Dr. Martinez-Lage: drafting/revising the manuscript, analysis or interpretation of data, acquisition of data. Dr. Dalmau: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, contribution of vital reagents/tools/patients, statistical analysis, study supervision, obtaining funding.

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