Autoantibodies to neuronal glutamate receptors in patients with paraneoplastic neurodegenerative syndrome enhance receptor activation.
BACKGROUND
Paraneoplastic syndromes are "remote" complications of cancer characterized clinically by neurological disease. The sera and cerebrospinal fluid (CSF) from patients with paraneoplastic neurological syndromes (PNS) frequently contain autoantibodies to ill-defined neuronal antigens. We report here that neuronal glutamate receptors are targets for autoantibodies found in the serum from some patients with well-characterized PNS.


METHODS
We have analyzed the serum from seven patients with well-characterized PNS for the presence of autoreactive antibodies to non-NMDA glutamate receptor subunits. Autoantibodies were assessed using Western blot, immunohistochemistry, and immunocytochemistry. Whole-cell electrophysiological recordings were used to examine the effect of antibodies on glutamate receptors expressed by cortical neurons in culture.


RESULTS
Six of seven patients' serum contained autoantibodies to the non-NMDA glutamate receptor (GluR) subunits GluR1, GluR4, and/or GluR5/6. No patient had autoantibodies to GluR2, and only one patient exhibited weak immunoreactivity to GluR3. Electrophysiological analysis demonstrated that the serum from four of the six GluR-antibody-positive patients enhanced glutamate-elicited currents on cultured cortical neurons but had no effect on receptor function alone. Enhancement of glutamate-elicited currents was also produced by affinity-purified antibody to GluR5.


CONCLUSIONS
The occurrence of autoantibodies to specific neuronal neurotransmitter subunits in the sera of patients with PNS and the ability of these autoantibodies to modulate glutaminergic receptor function suggest that some paraneoplastic neurological injury could result from glutamate-mediated excitotoxicity.
Gahring
L C
LC
Geriatric Research, Education, and Clinical Center, Veterans Affairs Medical Center, Salt Lake City, Utah, USA.
Twyman
R E
RE
Greenlee
J E
JE
Rogers
S W
SW
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D001323:Autoantibodies / Q000097:blood* / Q000276:immunology; D015153:Blotting, Western; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004594:Electrophysiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D009474:Neurons / Q000378:metabolism; D010257:Paraneoplastic Syndromes / Q000276:immunology* / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D017470:Receptors, Glutamate / Q000276:immunology* / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000276:immunology; D014162:Transfection
D001323:Autoantibodies; D018691:Excitatory Amino Acid Antagonists; D017470:Receptors, Glutamate; D011993:Recombinant Fusion Proteins; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione