NMDA receptor Autoantibodies

Encephalitis is the inflammation of the brain usually brought on by a viral infection. The N-methyl-D-aspartate receptor is an ion channel for Na+ and Ca2+ that is gated by the synthetic ligand NMDA. Its natural ligands are glycine/D-serine and glutamate. Influx of Na+ and Ca2+ into the cell causes the neuron to depolarize sending an action potential down its axon that results in the release neurotransmitter into the synapse in the vicinity of the dendrites of the post synaptic neuron. Opening and closing of the pore that allows the passage of Na+ and Ca2+ into the cell is gated by the binding of glutamate (Glu) and glycine.

Figure 1 The NMDA receptor A. The NMDA receptor consists of two subunits: NR1 and NR2. Auto antibodies are against NR1 The 5 potential glycosylations were not in the original reference. B. Domains of the NR1 receptor form UniProt.org. C. The typical IgG auto antibody is anticipated to be 50% larger than the NR1 subunit of the NMDA receptor

The authors of a recent review on NMDA receptor encephalitis discuss the correlation of the symptoms with the Ab titers in the CSF rather than the serum. [1]. Teratomas contain multiple cell types and may arise from the ovary or testicle.

  • A tumor may express the neuronal ion channel. Ovarian teratomas were given as an example. [1]
  • Herpes simplex virus infections were given as another example. [1] The authors did not speculate as to whether or not a virus must infect neurons in order to trigger production of auto antibodies against neuronal surface proteins.
  • Unlike the example of the streptococcal M protein resembling cardiac myosin components in rheumatic heart disease, we don’t have an example of compoents of any viral protein resembling the NR1 subunit of the NMDA receptor.
  • Genetic susceptibility was mentioned as a cause. [1]
  • Auto antibody binding to the NMDA receptor was mentioned as resembling pharmacology. [1] Which pharmaceuticals? Let’s look at NMDA receptor antagonists. We have the competitive inhibitor Aspartame, the artificial sweetener with neurological side effects. Gabapentin, the anti-convulsant, is a noncompetitive inhibitor. Among NMDA receptor agonists we have the allosteric modulator cholesterol and the partial agonist NMDA.
A journey of the imagination

Just looking at the cartoon in Figure 1A we see that extracellular domain S2 has six potenital glycosylation sites that may offer steric protection from auto antibody binding. Antibodies against the N-terminal domain (NTD) could conceivably block access of glycine. .. or mimic the binding of glycine. Receptor cross linking with a single IgG, what would be the consequences? Some might say receptor endocytosis. The physician treating a patient with unexplained symptoms might order an auto antibody panel to test the CSF. Many of these amateurish questions have been asked in a more sophisticated manner by Dr. Yue-Qiao Huang of Philadelphia College of Osteopathic Medicine Georgia School of Pharmacy and coauthors and coauthors. [2] This review is truly comprehensive and covers many animal models. [2] How do these auto antibodies get past the blood brain barrier in the first place?

Getting auto antibodies past the blood brain barrier

The Wandinger review briefly mentioned a small study that partially answered this question. [1] This study looked for antibody producing plasma cells in the brains of deceased patients who had auto immune encephalitis [3] Some physicians will learn that the blood brain barrier is far more complicated than they may have been taught in medical school. The two main findings of this study were

  1. Syndecan / CD138+ cells were found in the brains of diseased patients with anti-NMDAR encephalitis. Syndecan is an extracellular membrane attached protein that was used as a marker for antibody producing plasma cells.[3]. While syndecan may be expressed in multiple organs and cell types, its immuno reactivity was was not found in control brains in this study. [3] These authors reported syndecan staining cells in Virchow-Robin spaces. [3]
  2. These authors also reported complement staining in the brains of of diseased patients with anti-NMDAR encephalitis. [3].
Figure 2, Interpretation of reference [2]. The perivascular space image is from Wikipedia. Antibody secreting plasma cells were shown to hang out in this space, presumably attached to walls using syndecan/CD138. Secreted antibodies can presumably diffuse past the astrocyte barrier to bind to the NR1 subunits of NMDA receptors on neurons. Complement binding was detected in this region.C1 is fllowed by C2-4 and eventually the membrane attack complex C5-9.

Does auto antibody binding to the NMDA receptor mimic pharmaceuticals and/or initiate a membrane attack complex? Most standard treatments seek to turn off all immune response or counter all antibodies, auto or against foreign antigens. Is there a diet that mitigates the migration of plasma cells into this perivascular space?

Case studies

In many of these reports there is a lack of certainty of a causal relationship between a Covid-19 infection and anti-NMDA receptor antibodies. Perhaps the Coivd-19 infection triggered the movement of plasma cells programmed to produce anti-NMDA receptor antibodies into the perivascular spaces of the brain. Did the Covid-19 infection trigger the production of these auto-antibodies?

agegenderCovid  countryfeverOther symptomtreatmentreference
17male?Indiayesdeliriousmethylprednisolone[4]
23maleYesItalyyesAutonomic dysfunctionDexamethasone, IVIG[5]
50maleyesItalyyesDelirious seizures,methylprednisolone, IVIG .[6]
23 mofemaleyesUSAyesSeizures, dyskinesia, autonomic, dysfunction fussyIVIG[7]
7maleyesTurkeynoAtaxia, dyskinesia, seizures, autonomic dysfunctionIVIG, pulse steroids[8]
53femaleyesUKyespalilalia, echolalia, motor perseverations, focal seizures and prominent dysautonomiahydroxychloroquine, IVIG, tocilizumab, antibiotics, amphotericin, levetiracetam[9]
Case reports of Covid1=9 concombinant with anti-NMDA receptor encephalitis

Management

Management of autoimmune encephalitis is pretty much as we have discussed so far. [10]. This review discusses the pharmacology of antibodies binding to various neurotransmitter receptors that goes beyond what we have discussed so far. [10], Autoimmune-enc ephalitis.org has some interesting things, both positive and negative, about the keto diet. Aside from the ketogenic diet, there really isn’t a diet for autoimmune encephalitis.

References

  1. Wandinger KP, Leypoldt F, Junker R. (2018) Autoantibody-Mediated Encephalitis.Dtsch Arztebl Int. 2018 Nov 5;115(40):666-673. PMC free article
  2. Huang, Y. Q., & Xiong, H. (2021). Anti-NMDA receptor encephalitis: a review of mechanistic studies. International journal of physiology, pathophysiology and pharmacology, 13(1), 1–11. PMC free article
  3. Martinez-Hernandez, E., Horvath, J., Shiloh-Malawsky, Y., Sangha, N., Martinez-Lage, M., & Dalmau, J. (2011). Analysis of complement and plasma cells in the brain of patients with anti-NMDAR encephalitis. Neurology, 77(6), 589–593. PMC free article
  4. Moideen, S., Thomas, R., Suresh Kumar, P. N., Uvais, N. A., & Ul Haq Katshu, M. Z. (2020). Psychosis in a patient with anti-NMDA-receptor antibodies experiencing significant stress related to COVID-19. Brain, behavior, & immunity – health, 7, 100125 PMC free article
  5. Panariello, Adelaide et al. “Anti-NMDA receptor encephalitis in a psychiatric Covid-19 patient: A case report.” Brain, behavior, and immunity vol. 87 (2020): 179-181. PMC free article
  6. Monti, G., Giovannini, G., Marudi, A., Bedin, R., Melegari, A., Simone, A. M., Santangelo, M., Pignatti, A., Bertellini, E., Trenti, T., & Meletti, S. (2020). Anti-NMDA receptor encephalitis presenting as new onset refractory status epilepticus in COVID-19. Seizure, 81, 18–20. PMC free article
  7. Burr, Tyler et al. “N-Methyl-d-Aspartate Receptor Encephalitis Associated With COVID-19 Infection in a Toddler.” Pediatric neurology vol. 114 (2021): 75-76. PMC free article
  8. Sarigecili, E., Arslan, I., Ucar, H. K., & Celik, U. (2021). Pediatric anti-NMDA receptor encephalitis associated with COVID-19. Child’s nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery, 1–4. Advance online publication. PMC free articles
  9. McHattie, A. W., Coebergh, J., Khan, F., & Morgante, F. (2021). Palilalia as a prominent feature of anti-NMDA receptor encephalitis in a woman with COVID-19. Journal of neurology, 1–3. PMC free article
  10. Macher S (2018) Management of Autoimmune Encephalitis: An Observational Monocentric Study of 38 Patients. Front. Immunol., 22 November 2018 PMC free article

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