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Lupus illuminated
Thanks to a newly identified
gatekeeper gene, lupus is now
a preventable disease for mice.
Humans could be next.
BY LYNN LOVE
Despite the fact that lupus results from a combination
of genetic factors that may vary from person to person, Rockefeller
scientists have found a common “gatekeeper” gene critical to
its prevention — and say that reversing a defect in the gene leads to
restored health in animal models.
Lupus, which afflicts some 1.4 million Americans,
occurs when auto-antibodies — molecular arrows that trigger the
immune system to assault the body’s own tissues — accumulate,
leading to fatigue, fever, joint pain, anemia and, in some cases, kidney
failure, seizures and neurological damage, blood clotting and respiratory
inflammation.
But the results of two new studies from Jeffrey Ravetch’s
Rockefeller laboratory suggest that a specific molecule, which binds to
antibodies on the surface of cells, plays a key role in preventing this
accumulation.
“Our research makes an important new point in
responding to lupus as an autoimmune disease,” says Ravetch, the
Theresa and Eugene M. Lang Professor and head of the Leonard Wagner
Laboratory of Molecular Genetics and Immunology. “Although the
disease itself is a reflection of a cumulative set of factors that work in
concert to reach a threshold and then trigger symptoms that are
self-enhanced and self-sustaining, we have shown that it may be enough to
simply correct a critical ‘gatekeeper’ function and thereby
reverse the disease.”
Ravetch, a leader in basic immunology known for his
elucidation of an important family of antibody binding molecules called the
Fc receptors, and his colleagues have learned that it’s a specific Fc
receptor, FCRgIIB,
that wards off the accumulation of auto-antibodies. The team, which
includes postdocs Tracy McGaha, Hidehiro Fukuyama and Falk Nimmerjahm, also
have discovered that this receptor is defective in lupus-prone strains of
mice.
“Once we determined that this receptor inhibits
the culprit immune system cells from becoming activated and limits the
production of auto-antibodies, we wondered whether restoring it as the
body’s last bastion of defense would be enough to prevent
autoimmunity,” says Ravetch.
The researchers found that in mice genetically
predisposed to lupus-like autoimmunity and with a reduced Fc receptor
capacity, they could artificially coax the Fc receptors back into working
order. Their modest increases in Fc receptor activity — the
equivalent of effective gene therapy in humans — was enough to push
the mice back to health.
“The difference between protective immunity and
pathological autoimmunity for each individual is quite small,” he
added. “We were able to reestablish the Fc receptor’s activity
by increasing its expression by only about 40 percent, and in only about
half the B cells.”
Betty Diamond, a physician-researcher at Columbia
University’s College of Physicians and Surgeons, is collaborating
with Ravetch to take the first steps in determining whether the same
progression to lupus, including Fc receptor failure, occurs in humans.
“Jeff has laid the groundwork well for understanding this pathway to
disease,” says Diamond. “We have hopes of confirming this
pathway in humans with lupus.”
What may be even more interesting in the Rockefeller
team’s findings is that the experiment restored the health of mice
with lupus-like symptoms by increasing Fc receptor inhibition of
auto-antibody formation. Auto-antibodies that were produced before the
therapy persisted in the body, but with no further evidence of disease.
These findings suggest that if the human disease is synonymous with the
mouse model, a gene therapy approach to restoring Fc receptor activity in
lupus patients could cure the disease’s aggravating and disabling
symptoms.
“The immune system is a balance of excess and
inadequacy,” says Ravetch. “We’re seeing evidence that
the inhibitory Fc receptor on dendritic cells, another immune system cell
type, may play a similar role in other illnesses. We may reach a
convergence of understanding on immune system-related diseases, where small
adjustments to certain checkpoints, like the Fc receptor, may be enough to
restore health in multiple diseases.”
March 18, 2005
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Copyright © 2006
The Rockefeller University
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