Antibodies to metabotropic glutamate receptor 5 in the Ophelia syndrome.
OBJECTIVE
To report the metabotropic glutamate receptor 5 (mGluR5) as the autoantigen of antibodies from 2 patients with Hodgkin lymphoma (HL) and limbic encephalopathy (Ophelia syndrome).


METHODS
Immunohistochemistry with brain tissue and cultures of rat hippocampal neurons were used to demonstrate antibodies. Immunoprecipitation, mass spectrometry, and mGluR5-null mice served to identify the antigen. HEK293 cells transfected with mGluR5 or mGluR1 were used to determine immunologic crossreactivity.


RESULTS
Both patients developed symptoms consistent with limbic encephalopathy; one had MRI findings typical of this disorder and the other had more extensive radiologic involvement, including parietal and occipital cortex. Patients' sera had antibodies that predominantly reacted with the neuropil of hippocampus and cell surface of live hippocampal neurons. Immunoprecipitation from cultured neurons and mass spectrometry demonstrated that the antigen was mGluR5, a receptor involved in processes of learning and memory. The reactivity of patients' sera was abrogated in brain of mGluR5-null mice, further confirming the antibody specificity. Studies with a large number of controls including 2 patients with cerebellar ataxia and mGluR1 antibodies showed that mGluR5 was only identified by sera of the 2 patients with the Ophelia syndrome, and that despite the homology of this receptor with mGluR1 each autoantigen was specific for a distinct syndrome.


CONCLUSIONS
Antibodies to mGluR5 should be considered in patients with symptoms of limbic encephalitis and HL (Ophelia syndrome). Recognition of this disorder is important because it can affect young individuals and is reversible.
Department of Neurology, University of Pennsylvania, Philadelphia, PA 19104, USA.
E
E
Lancaster
E
E
Martinez-Hernandez
M J
MJ
Titulaer
M
M
Boulos
S
S
Weaver
J-C
JC
Antoine
E
E
Liebers
C
C
Kornblum
C G
CG
Bien
J
J
Honnorat
S
S
Wong
J
J
Xu
A
A
Contractor
R
R
Balice-Gordon
J
J
Dalmau
D000293:Adolescent; D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology*; D002478:Cells, Cultured; D005260:Female; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology; D006689:Hodgkin Disease / Q000276:immunology / Q000473:pathology; D006801:Humans; D020363:Limbic Encephalitis / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000276:immunology*; D013577:Syndrome
D001323:Autoantibodies; D001324:Autoantigens; C578935:GRM5 protein, human; C578936:Grm5 protein, mouse; C578937:Grm5 protein, rat; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1