Immune to Fear
When antibodies fail to distinguish between your own body and an
invading microbe, they make you sick. This happens in chronic
autoimmune diseases such as rheumatoid arthritis, multiple sclerosis
and systemic lupus erythematosus, which have complex constellations
of variable, often debilitating symptoms because of
autoantibodies—antibodies that target the body's own tissues.
Although it might make intuitive sense that autoantibodies to
connective tissue afflict the joints and those against motor neurons
impair movement, autoimmune diseases are seldom so tidy in their
causes and effects. Impaired memory and altered mood are common to
many autoimmune diseases, and even some "classic"
neurologic and psychiatric conditions—movement disorders,
schizophrenia, autism and others—are linked to antibodies
against the brain. However, unlike joints and peripheral nerves, the
brain is sequestered behind a barrier that excludes large molecules
such as antibodies. Exactly how antibodies get into the brain and
effect changes in behavior and function is poorly understood.
Recent reports help to fill that void. Using mice that were
immunized to carry one of the principal antibodies found in lupus
patients, investigators led by Betty Diamond at Columbia University
Medical Center report that infection or stress can allow the
antibodies to penetrate specific parts of the brain, killing neurons
and changing behavior.
The authors had previously shown that most of the 1.4 million people
with lupus in the United States carry antibodies against
double-stranded DNA. Some of these antibodies cross-react with
proteins, particularly a string of five amino acids:
aspartate-tryptophan-glutamate-tyrosine-serine, or DWEYS, to use
their one-letter abbreviations. The team searched the database to
find proteins with that sequence and found two parts of a receptor
for the neurotransmitter glutamate: the NR2A and NR2B subunits of
the so-called NMDA variety of glutamate receptor.
Injecting the DWEYS peptide into mice caused them to develop
antibodies similar to those found in lupus patients, but the
antibodies had no immediate effect on cells or behavior, presumably
because they were excluded from the central nervous system by the
blood-brain barrier. But this defense can be compromised, by head
trauma, bacterial toxins, osmotic changes or stress in the form of a
spike in adrenaline. In a recent paper (Immunity, August
2004), Diamond and her colleagues used an injection of
lipopolysaccharide, a bacterial endotoxin, to breach the barrier and
allow antibodies to cross into the mice's brains. The antibodies
bound to neurons in the hippocampus, a structure rich with NMDA
receptors, and killed a significant number of cells within a week.
Not surprisingly, those mice scored worse than controls on memory
tests that require the hippocampus; performance on non-hippocampal
tasks was normal. The lipopolysaccharide had no effect on mice that
had not been immunized with the DWEYS peptide.
The scientists determined just how the cells died by giving the mice
memantine (which blocks the NMDA receptor) prior to opening the
blood-brain barrier: The neurons were spared, and behavior was
normal. This result shows that the cause of cell death was
overstimulation of the NMDA receptors. The neurons didn't die
because the antibodies incurred the wrath of the immune system; they
died because their uninterrupted firing was toxic.
The follow-up paper was published online January 4 in
Proceedings of the National Academy of Sciences. The
study design was similar, except that the authors used an injection
of epinephrine (adrenaline) rather than a mock bacterial infection
to penetrate the blood-brain barrier. Surprisingly, cells in the
hippocampus were spared. The mice did fine on memory tests and
behaved normally. But neurons in the amygdala were half dead. This
part of the brain regulates emotion—particularly
fear—and is essential for a Pavlovian behavioral task called
fear conditioning. In this test, mice are placed in a special cage
and conditioned to associate a mild electrical shock with
distinctive sensory cues such as novel smells, textures or sounds.
Later, when confronted with the same cues, the animals anticipate
the shock, get scared and freeze. But the mice with lupus antibodies
that received the adrenaline could not muster the same response of
fear. As before, memantine prevented the anatomical and behavioral
changes. Furthermore, treatment with a version of the DWEYS peptide
had a similar protective effect, presumably because it bound the
antibodies before they reached the NMDA receptor.
This story would be interesting enough by itself—preclinical
studies of a lupus drug based on the peptide are under way—but
the implications for other diseases are even bigger. Viruses,
bacteria, parasites and vaccines have all been implicated in
neuropsychiatric conditions, including schizophrenia and autism. But
scientists seldom know how or why an infection leads to behavioral
consequences. Clearly it is more than infection alone: Not every
person with toxoplasmosis develops schizophrenia, and not every
schizophrenic has antibodies to Toxoplasma gondii.
Diamond's results offer one example of how to connect these dots.