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Despite causes of lupus proving complex, critical ’checkpoint’ suggesting new therapy is revealed


Mouse studies yield cause and potential cure, with human studies in progress

Scientists at The Rockefeller University have determined that the autoimmune disease lupus results from a combination of genetics that likely varies from person to person, and that a common "gatekeeper" gene called FCRgIIB is critical to the prevention of this devastating disease.

What’s more, the same scientists have determined that reversing the defect of that gatekeeper gene can restore health in animal models of lupus by preventing the unfortunate accumulation of auto-antibodies (molecular "arrows" that trigger immune system assault on the body’s own tissues) that lead to the vexing symptoms -- fatigue, fever, joint pain, anemia, and in some cases, kidney failure, seizures and neurological damage, blood clotting and respiratory inflammation -- associated with the disease.

The findings are reported in two new publications, one in the January 28 edition of Science and another in January’s Nature Immunology. "Our Science publication makes an important new point in responding to lupus as an autoimmune disease," says Jeffrey Ravetch, M.D., Ph.D., 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 a specific Fc receptor functions to prevent the accumulation of the auto-antibodies that are responsible for the disease progression in lupus. They also have discovered that the Fc receptor is defective in lupus-prone strains of mice. Restoring its strength is sufficient to avert disease in those susceptible animals.

"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.

In the Science publication, 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 immune and autoimmune 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, M.D., 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 between too much and too little," says Ravetch. "We’re seeing 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 strongholds, like the Fc receptor, may be enough to restore health in multiple diseases.

Lynn Love | EurekAlert!
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