Human lupus autoantibodies against NMDA receptors mediate cognitive impairment

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Human lupus autoantibodies against NMDA
receptorsmediate cognitive impairment

• Czeslawa Kowal, Lorraine A. DeGiorgio, Ji Y. Lee,
  Mark A. Edgar, Patricio T. Huerta, Bruce T. Volpe
  and Betty Diamond

Kowal et al. Proceedings of the National Academy
of Science PNAS vol. 103 (52) no. 53,
pp.19854-19859 Mentor Bruce T.
Volpe Affiliation Burke Cornell Medical
Research Institute White
Plains, NY
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What does the title mean?

• Lupus a disease in which some antibodies of a
  person damage the kidney, skin and brain.
• Autoantibodies (autoself) they work against the
  organs of the same person that produced them.
• NMDA receptors proteins in the membrane of some
  some neurons that bind with the neurotransmitter
  glutamate.
• cognitive impairment (cognition to know) when
  a person has severe difficulties knowing and
  remembering events

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INTRODUCTION

• Lupus
• first discovered in the middle ages, Latin for
  wolf.
• The name refers to the skin of the sufferer which
  turns red in the final stages of the disease.
• In adults, out of 10 patients 9 are women
• Children with lupus die very quickly because it
  destroys the cells of the heart.

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NMDA receptors in the brain

• Stimulated NMDA receptors allow for Calcium
  to enter the neuron
• Over-stimulated receptors lead to cell death

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• Autoantibodies
• They are produced by B cells of the immune system
  just like normal antibodies .
• They go rogue and attack the organs of the
  person who made them as if the organs were
  foreign pathogens.
• Several hundreds of autoantibodies have been
  described, each defining its own disease.

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In Lupus, the autoantibodies target the NMDA
receptors in the brain.
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In Lupus the autoantibodies target the NMDA
receptors in the brain.
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• Blood-brain barrier (BBB)
• A selectively permeable layer around each blood
  vessel in the brain.
• It only allows oxygen, glucose and very small
  molecules like amino acids to enter the brain.
• Antibodies never naturally cross the blood brain
  barrier because they are large.

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• Conditions that rupture the BBB
• High levels of stress
• Bacterial infections
• Recreational drugs
• Smoking
• Methamphetamines (crystal meth)

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PROBLEM

• The hypothesis of the study is
• the lupus autoantibodies are in the blood
• They only cross through the blood brain barrier
  when it is ruptured.
• Once in the brain they bind to areas rich in NMDA
  receptors
• Once bound the NMDA receptors they cause severe
  neuronal damage.

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METHODS

• A dying lupus patient donated her brain to
  scientific research.
• The authors extracted the autoantibodies from the
  blood and the brain of the patient.
• They injected the antibodies into a group of mice
  (experimental group)
• An inactive antibody was injected into a second
  group (control group)

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• An infectious agent was given to all the mice to
  break the BBB
• The mice underwent a learning test to check their
  memory
• The brains of the mice were analyzed for stress
  and dead cells

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LUPUS BRAIN LUPUS BLOOD
AUTO-ANTIBODIES
CONTROL ANTIBODIES (from brain of Parkinsons
patient)
CONTROL GROUP
EXPERIMENTAL GROUP
BLOOD-BRAIN BARRIER IS BREACHED WITH INFECTIOUS
AGENT
LEARNING TASK IN CYLINDER WITH COLD WATER AT THE
BOTTOM
MOUSE BRAINS ARE EXTRACTED AND EXAMINED FOR DAMAGE
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RESULTS

• The lupus autoantibodies extracted from the blood
  (Anti-NMDAR Serum) bind to the NMDA receptor

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• 2. The lupus autoantibody (Anti-NMDAR Serum)
  produces cognitive impairment, measured as slower
  learning in the circular water chamber

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• 3. The lupus autoantibody (Anti-NMDAR Serum)
  damages neurons that are rich in NMDA receptor

EXPERIMENTAL Without BBB breach
CONTROL
EXPERIMENTAL With BBB breach
White cells are damaged cells
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DISCUSSION

• When the BBB is broken the autoantibodies cause
  severe neuronal damage to the brain.
• The important part of the brain that is primarily
  attacked it the Hipocampus
• Damage to the Hippocampus causes cognitive
  impairment and memory loss.

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CONCLUSIONS

• The authors found that Lupus autoantibodies only
  cause damage when the BBB is broken and that
  once they enter the brain they target the
  hippocampus and other important sectors of the
  brain.

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FUTURE RESEARCH

• Further research on the cure to Lupus (inhibiting
  the rogue antibodies or making the NMDA receptors
  resistant to the autoantibodies)
• Applying the cognitive impairment test used on
  mice to other diseases that effect the brain.
• Finding a way to repair or enhance the BBB.

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CITATIONS

• Kowal et al. Proceedings of the National Academy
  of Science PNAS vol. 103 (52) no. 53,
  pp.19854-19859
• dad