Human neurexin-3α antibodies associate with encephalitis and alter synapse development.

Nuria Gresa-Arribas, Jesús Planagumà, Mar Petit-Pedrol, Izumi Kawachi, Shinichi Katada, Carol A. Glaser, Mateus M. Simabukuro, Thaís Armangué, Eugenia Martínez-Hernández, Francesc Graus, Josep Dalmau
Neurology. 2016-05-11; 86(24): 2235-2242
DOI: 10.1212/wnl.0000000000002775

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Gresa-Arribas N(1), Planagumà J(1), Petit-Pedrol M(1), Kawachi I(1), Katada S(1), Glaser CA(1), Simabukuro MM(1), Armangué T(1), Martínez-Hernández E(1), Graus F(1), Dalmau J(2).

Author information:
(1)From the Neuroimmunology Program, Biomedical Research Institute August Pi i
Sunyer (IDIBAPS) (N.G.-A., J.P., M.P.-P., T.A., E.M.-H., F.G., J.D.), and Service
of Neurology, Hospital Clínic (F.G.), University of Barcelona, Spain; Department
of Neurology (I.K., S.K.), Brain Research Institute, Niigata University, Japan;
Division of Pediatric Infectious Diseases (C.A.G.), Kaiser Permanente, Oakland
Medical Center and University of California, San Francisco; Neurology Division
(M.M.S.), Hospital das Clínicas, São Paulo University (HC/FMUSP), Brazil;
Pediatric Neuroimmunology Unit (T.A.), Sant Joan de Déu Children’s Hospital;
Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; and
Catalan Institution for Research and Advanced Studies (ICREA) (J.D.), Barcelona,
Spain. N.G.-A. is currently affiliated with the Department of Neuroscience,
Karolinska Institute, Stockholm, Sweden.
(2)From the Neuroimmunology Program, Biomedical Research Institute August Pi i
Sunyer (IDIBAPS) (N.G.-A., J.P., M.P.-P., T.A., E.M.-H., F.G., J.D.), and Service
of Neurology, Hospital Clínic (F.G.), University of Barcelona, Spain; Department
of Neurology (I.K., S.K.), Brain Research Institute, Niigata University, Japan;
Division of Pediatric Infectious Diseases (C.A.G.), Kaiser Permanente, Oakland
Medical Center and University of California, San Francisco; Neurology Division
(M.M.S.), Hospital das Clínicas, São Paulo University (HC/FMUSP), Brazil;
Pediatric Neuroimmunology Unit (T.A.), Sant Joan de Déu Children’s Hospital;
Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; and
Catalan Institution for Research and Advanced Studies (ICREA) (J.D.), Barcelona,
Spain. N.G.-A. is currently affiliated with the Department of Neuroscience,
Karolinska Institute, Stockholm, Sweden. .

OBJECTIVE: To report a novel autoimmune encephalitis in which the antibodies
target neurexin-3α, a cell adhesion molecule involved in the development and
function of synapses.
METHODS: Five patients with encephalitis and antibodies with a similar pattern of
brain reactivity were selected. Antigen precipitation and determination of
antibody effects on cultured rat embryonic neurons were performed with reported
techniques.
RESULTS: Immunoprecipitation and cell-based assays identified neurexin-3α as the
autoantigen of patients’ antibodies. All 5 patients (median age 44 years, range
23-50; 4 female) presented with prodromal fever, headache, or gastrointestinal
symptoms, followed by confusion, seizures, and decreased level of consciousness.
Two developed mild orofacial dyskinesias, 3 needed respiratory support, and 4 had
findings suggesting propensity to autoimmunity. CSF was abnormal in all patients
(4 pleocytosis, 1 elevated immunoglobulin G [IgG] index), and brain MRI was
abnormal in 1 (increased fluid-attenuated inversion recovery/T2 in temporal
lobes). All received steroids, 1 IV immunoglobulin, and 1 cyclophosphamide; 3
partially recovered, 1 died of sepsis while recovering, and 1 had a rapid
progression to death. At autopsy, edema but no inflammatory cells were
identified. Cultures of neurons exposed during days in vitro (div) 7-17 to
patients’ IgG showed a decrease of neurexin-3α clusters as well as the total
number of synapses. No reduction of synapses occurred in mature neurons (div 18)
exposed for 48 hours to patients’ IgG. Neuronal survival, dendritic morphology,
and spine density were unaffected.
CONCLUSION: Neurexin-3α autoantibodies associate with a severe but potentially
treatable encephalitis in which the antibodies cause a decrease of neurexin-3α
and alter synapse development.

© 2016 American Academy of Neurology.

 

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