Scientists find new “gatekeeper” gene that may help avert lupus

New mouse studies have uncovered a gatekeeper gene that may be critical in the prevention of lupus. While the disease results from a combination of genetics that likely vary from person to person, this newly identified gene, known as FCRgIIB, may be a common link and could have an important role in averting disease progression. The findings were reported in the January 28, 2005 issue of Science and January 2005 issue of Nature Immunology.

“Our Science publication makes an important new point in responding to lupus as an autoimmune disease,” Dr Jeffrey Ravetch (Rockefeller University, New York, NY) said in a news release. “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, known for his work in identifying an important family of antibody-binding molecules known as Fc receptors, worked with his team to reveal that a specific Fc receptor prevents the accumulation of the autoantibodies responsible for disease progression in lupus. “Once we determined that this receptor inhibits the culprit immune-system cells from becoming activated and limits the production of autoantibodies, we wondered whether restoring it as the body’s last bastion of defense would be enough to prevent autoimmunity,” Ravetch said.Receptor prevents accumulation of autoantibodies responsible for disease progressionIn the current study, led by Dr Tracy McGaha (Rockefeller University), Ravetch and colleagues found that, in mice genetically predisposed to lupuslike autoimmunity and with a reduced Fc-receptor capacity, they could artificially coax the Fc receptors back into working order. Their modest increase in Fc-receptor activity was enough to push the mice back to health.”The difference between immune and autoimmune for each individual is quite small,” Ravetch said. “We were able to reestablish the Fc receptor’s activity by increasing its expression by only about 40% and in only about half the B cells.”The researchers point out that while the precise mechanism by which FCRgIIB expression on B cells contributes to the maintenance of tolerance is still under investigation, “we have recently demonstrated that RIIB expression on B cells regulates the accumulation of autoreactive plasma cells.” They continue, “Relatively small changes in surface expression of this receptor appear to be critical for determining disease progression; this provides a rational basis for a novel therapeutic approach based on manipulating expression of this receptor to restore tolerance in autoimmune diseases.”In the study published in Nature Immunology, lead author Dr Hidehero Fukuyama (Rockefeller University) and colleagues explain that the ability of the immune system to distinguish self from nonself is central to its ability to provide protection from pathogens while maintaining the integrity of the organism. “The mechanisms that provide for this property operate at discrete checkpoints in the immune system,” they write. The researchers note that tolerance checkpoints have been identified from the analysis of mouse transgenic models in which lymphocytes are created with antiself specificity and from the analysis of human autoimmune disease such as lupus. “Our data are consistent with previous studies that have suggested editing is the primary central mechanism for converting anti-DNA reactivity to harmless specificities at the price of limiting the diversity of the B-cell receptor repertoire,” they comment. Ravetch and his team conclude that B cells may be a new target for the prevention of autoimmune diseases by preventing the accumulation of pathogenic immunoglobulin G autoantibodies.”The immune system is a balance between too much and too little,” Ravetch said. “We’re seeing 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 strongholds, like the Fc receptor, may be enough to restore health in multiple diseases.”Dr Betty Diamond (Columbia University’s College of Physicians and Surgeons, New York, NY) is collaborating with Ravetch to determine whether the same progression to lupus, including Fc-receptor failure, occurs in patients. “Jeff has laid the groundwork well for understanding this pathway to disease,” Diamond said in a news release. “We have hopes of confirming this pathway in humans with lupus.” (Source: Rockefeller University New York, JointandBone, February 2005)