A major breakthrough in lupus research - one that may fundamentally change thinking on how the disease affects behavior and cognition - was reported in the January 17, 2006 Proceedings of the National Academy of Sciences (PNAS). Entitled Immunity and behavior: Antibodies alter emotion, the research builds upon a framework of findings supported by Lupus Research Institute (LRI) funds from 2001 to 2004.
A number of people with systemic lupus erythematosus (S.L.E.) experience subtle but insidious changes in behavior (affect), such as unusual feelings of fear (or lack of fear) and loss of interest or curiosity. And an estimated 8 in 10 at some point experience progressive cognitive impairment characterized by headache, confusion, fatigue, memory loss, difficulty expressing thoughts, and (occasionally) seizures or strokes.
Aside from actual inflammation in the brain, a grave but relatively uncommon lupus complication, the causes of these behavioral and cognition issues in people with lupus have been elusive. Now answers to the mystery are starting to surface, thanks to the bold and novel research of Betty Diamond, M.D., Chief of the Division of Rheumatology and Professor of Medicine at Columbia University College of Physicians and Surgeons, and lead author of the PNAS study.
The LRI - the leading nonprofit sponsor of research into lupus - awarded Dr. Diamond the Novel Research Grant that enabled her to first explore the channels responsible for brain damage in lupus.
"Our initial grant from LRI allowed us to test our hypothesis," said Dr. Diamond, "linking lupus antibodies and stress to cognitive impairment. I am convinced that, without Lupus Research Institute funding, our research would not have gotten off the ground."
With the LRI grant, Dr. Diamond and colleagues made three, core discoveries. Using mice, they concluded that lupus antibodies can destroy nerve cells in the brain, causing serious cognitive impairment. They also found that infection can pave the way for these damaging antibodies to penetrate into the brain, which is normally protected from various antibodies by a "wall" called the blood-brain barrier. Finally, they identified the Alzheimer's medicine, memantine, as a potential drug model for inhibiting lupus brain damage.
With the PNAS study, Dr. Diamond and colleagues report that the penetration of toxic antibodies into the brain likely leads not just to thinking (cognition) problems, but also to changes in behavior. Specifically, the disease's anti-DNA antibodies leak not only into the brain and damage neurons in an area called the hippocampus, which houses memories and the ability to navigate (among other things). They can also make their way into the amygdala, a brain region that governs fear and emotional responses, and cause damage there.
The researchers identify the stress hormone, epinephrine, as the agent responsible for letting the lupus antibodies gain access to the amygdale. These antibodies cause damage by binding to neurons and activating a receptor on the surface of the cell. Overstimulation of the receptor can lead to cell death. Epinephrine, which is also known as adrenaline, is produced by the adrenal glands in reaction to stress. Increased levels of the hormone can raise blood flow to the brain and cause leaks in the normally well-sealed barriers to this precious organ.
The PNAS authors identified two potential therapies for protecting the brain. The Alzheimer's drug (memantine) blocks glutamate, and may prevent the death of cells in parts of the brain such as the amygdala. Given this drug's various undesirable side effects, the authors also propose investigating the therapeutic potential of a small molecule (a peptide) that they identified. The peptide may be able to protect brain cells from the anti-DNA antibodies as well.
"The LRI's decision to fund Dr. Diamond's brilliant research clearly demonstrates its acumen in selecting novel ideas of real merit that ultimately pay off in a very big way," said William Paul, M.D., Chairman of the LRI Scientific Advisory Board, upon hearing of the new research. Dr. Paul is Chief of the Laboratory of Immunology at the NIH's National Institute of Allergy and Infectious Diseases.
"The LRI is a catalyst. It brings innovative work to the fore, allowing investigators to make important discoveries that are essential to command greater funding from the NIH and the pharmaceutical industry."
Adds Margaret G. Dowd, LRI President: "By supporting scientists who are willing to defy conventional thinking, we are helping to change the face of lupus research. The strategy behind the Lupus Research Institute is clearly working, and the more than 1.5 million Americans with the disease will directly benefit."
Lupus is a chronic autoimmune disease in which the body's immune system, which normally functions to protect against foreign invaders, becomes hyperactive, forming antibodies that attack normally healthy tissues, including the heart, kidneys, lungs, liver, blood and skin. Complications from lupus can lead to heart attack, stroke and kidney failure.