Expression of <i>N</i>-Methyl-D-Aspartate Receptor Subunits in the Bovine Ovum: Ova as a Potential Source of Autoantigens Causing Anti-NMDAR Encephalitis

Abstract

Autoimmune synaptic encephalitis is characterized by the presence of autoantibodies against synaptic constituent receptors and manifests as neurological and psychiatric disorders. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is such an autoimmune disorder that predominantly affects young women. It is associated with antibodies against the extracellular region of the NR1 subunit of postsynaptic NMDAR. Each NMDAR functions as a heterotetrameric complex that is composed of four subunits, including NR1 and NR2A, NR2B, or NR2C. Importantly, ovarian teratoma is a typical complication of anti-NMDAR encephalitis in female patients and may contain antigenic neural tissue; however, antigenic sites remain unknown in female patients without ovarian teratoma. The purpose of this study was to investigate the expression of NMDARs in the ovum. We detected NR1 and NR2B immunoreactivity in protein fractions extracted from the bovine ovary and ova by SDS-polyacrylamide gel electrophoresis and immunoblotting analysis. Immunoprecipitates digested with trypsin were analyzed by reverse phase liquid chromatography coupled to tandem mass spectrometry. We obtained the following five peptides: SPFGRFK and KNLQDR, which are consistent with partial sequences of human NR1, and GVEDALVSLK, QPTVAGAPK, and NEVMSSK, which correspond to those of NR2A, NR2B and NR2C, respectively. Immunocytochemical analysis revealed that the bovine ovum was stained with the immunoglobulin G purified from the serum of a patient with anti-NMDAR encephalitis. Taken together, we propose that the normal ovum expresses NMDARs that have strong affinity for the disease-specific IgG. The presence of NMDARs in ova may help explain why young females without ovarian teratomas are also affected by anti-NMDAR encephalitis.

Lactate promotes specific differentiation in bovine granulosa cells depending on lactate uptake thus mimicking an early post-LH stage

“…But in human ovaries functional ATP-sensitive potassium channels could be identified and moreover it was shown that blocking of these ion channels negatively influences progesterone production [ 49 ]. In ovarian tissue and granulosa cells expression of specific subunits of the NMDA receptor, the subunits 1 and 2B, had been identified [ 50 ] thus supporting the view that this receptor might be involved in these cells as well. Expression of NMDAR subunits, especially of GRIN2D and GRINA has been found in vivo in GC (see database GranulosaIMAGE [ 51 ]) as well as in vitro (own GC culture microarray dataset [ 14 ]).…”

Anti-NMDA Receptor Encephalitis: Retrospective Analysis of 15 Cases, Literature Review, and Implications for Gynecologists

“…These results indicated that normal ovaries might also play a critical role in the initiation and progression of anti-NMDA receptor encephalitis. Tachibana et al study found NMDA receptors were expressed in the bovine ovum [ 22 ]. This study further confirmed that normal ovaries might play a role in this disease.…”