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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.
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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