Human lupus autoantibodies against NMDA receptors

mediate 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 SciencePNAS: vol. 103 (52) no. 53, pp.19854-19859

Mentor: Bruce T. VolpeAffiliation: Burke Cornell Medical Research Institute White Plains, NY

What does the title mean?

• Lupus: a disease in which some antibodies of a person damage the kidney, skin and brain.

• Autoantibodies: (auto=self) 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

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.

NMDA receptors in the brain

presynaptic axon

NMDA receptor

AMPA receptor

postsynaptic dendrite

GLUTAMATE

spine

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

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.

In Lupus, the autoantibodies target the NMDA receptors in the brain.

In Lupus the autoantibodies target the NMDA receptors in the brain.

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.

Conditions that rupture the BBB:

1. High levels of stress

1. Bacterial infections

2. Recreational drugs – Smoking– Methamphetamines (crystal meth)

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.

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)

• 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

CONTROL GROUP

CONTROL ANTIBODIES(from brain of Parkinson’s patient)

LUPUS BRAIN& LUPUS BLOOD

LEARNING TASK IN CYLINDER WITH COLD WATER AT THE BOTTOM

EXPERIMENTAL GROUP

AUTO-ANTIBODIES

MOUSE BRAINS ARE EXTRACTED AND EXAMINED FOR DAMAGE

BLOOD-BRAIN BARRIER IS BREACHED WITH INFECTIOUS AGENT

RESULTS:1. The lupus autoantibodies extracted from the blood (Anti-NMDAR Serum) bind

to the NMDA receptor

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

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

EXPERIMENTALWithout BBB breach

White cells are damaged cells

CONTROL EXPERIMENTALWith BBB breach

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.

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.

FUTURE RESEARCH:

1. Further research on the cure to Lupus (inhibiting the rogue antibodies or making the NMDA receptors resistant to the autoantibodies)

2. Applying the cognitive impairment test used on mice to other diseases that effect the brain.

3. Finding a way to repair or enhance the BBB.

CITATIONS:

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

• dad