Mount Sinai researchers discover drug target for immune diseases

Researchers from Mount Sinai School of Medicine have found that some cells that contribute to immune system health may show signs of lupus and rheumatoid arthritis

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NEW YORK—Researchers from Mount Sinai School of Medicine have found a new mechanism that explains how certain immune cells are activated to create protective antibodies against infections or pathological antibodies such as those present in autoimmune diseases like lupus and rheumatoid arthritis.

The research is published online in the September issue of Nature Immunology.
A team led by Dr. Andrea Cerutti, professor of Medicine at Mount Sinai School of Medicine, studied human tissue and immune cells from people with mutations of TACI and MyD88, two proteins required to activate the immune system.

MyD88 is a signaling protein that alerts the so-called innate immune system—the immune system encoded at birth that remains unchanged—to the presence of pathogens. TACI is a receptor protein used to activate immune cells in the so-called adaptive immune system, a more sophisticated immune system than the innate, which is dynamic and combats pathogens. These new studies have provided unexpected and potentially important new insights in our understanding of immune diseases such as immunodeficiencies and autoimmune disorders.

Cerutti tells ddn that the team's discovery revolves around the identification of the mechanism by which B cells become activated after engagement of TACI.

"This receptor binds to BAFF and APRIL, two B cell-activating factors heavily involved in the pathogenesis of autoimmune diseases such as lupus and rheumatoid arthritis," she explains. "We found that TACI signals to B cells by interacting with the adaptor protein MyD88. Our expectation is that drugs capable of inhibiting TACI interaction with MyD88 may attenuate the abnormal activation of autoreactive B cells in patients affected with lupus and rheumatoid arthritis."

These B cells are known to cause inflammatory tissue damage through different mechanisms, including production of pathogenic autoantibodies.

"In this regard, it must be noted that many of the already existing therapies (e.g., Rituximab) for autoimmune diseases actually target B cells," adds Cerutti. "Our research provides a new target for this type of therapies."

The research team's efforts also indicate that TACI and MyD88 are part of an immune circuit that bridges the innate and adaptive immune systems.

"This circuit makes our immune response more flexible, allowing a more effective generation of protective antibodies during infections," Cerutti notes. "Genetic defects of TACI and MyD88 cause immunodeficiencies characterized by recurrent, life-threatening infections. On the other hand, an abnormally strong TACI-MyD88 interaction may exacerbate autoimmune diseases like lupus or rheumatoid arthritis."

The research wasn't without its challenges, including the fact that TACI and MyD88 proteins are not very abundant in B cells.

"In addition, TACI has the tendency of undergoing self-assembly," notes Cerutti. "These two circumstances made the execution of some experiments more difficult."

There also are other therapeutic options. Cerutti explains that inhibitors of TACI-MD88 interaction may also be useful in neoplastic disorders of B cells such as multiple myeloma and perhaps even lymphoma. A subsets of multiple myeloma cases with plasmablastic morphology and more aggressive behavior express high levels of TACI. This receptor delivers survival and growth signals to malignant B cells. Thus, inhibitors of TACI-MyD88 interaction could represent a viable strategy to attenuate tumor growth in these disorders.

"Previous studies had suggested an involvement of TACI and MyD88 in lupus. Now that we have identified this interaction, we can figure out a way to inhibit it and prevent these diseases from getting worse," she says.
Autoimmune diseases like lupus and rheumatoid arthritis are characterized by exaggerated production of molecules that activate the adaptive immune system and abnormal antibodies, which attack normal cells and cause inflammation and tissue damage. This exaggerated production may occur partly as a result of abnormally strong signaling from TACI via MyD88.

By analyzing cells and tissues from immunodeficient patients and genetically engineered mice, Cerutti's team found a previously unknown interaction between TACI and MyD88 that is important for the production of antibodies against infectious agents. Yet, the same interaction may cause the exaggerated immune response in people with autoimmune diseases.
"Our discovery provides a novel specific target, the signaling pathway between TACI and MyD88, to block the overreaction of the immune system and tissue damage in individuals with autoimmune disorders," says Cerutti. "We look forward to studying this discovery further and developing therapeutic targets that will inhibit the interaction between TACI and MyD88, preventing autoimmune diseases from progressing with fewer side effects than currently prescribed treatments."
Cerutti's team collaborated with other researchers at Mount Sinai School of Medicine, including Dr. Charlotte Cunningham-Rundles, professor of medicine and pediatrics, and Dr. Huabao Xiong, assistant professor of medicine.
Going forward, Cerutti says the team now plans to establish collaborations inside and outside Mount Sinai School of Medicine to identify TACI-MyD8 inhibitors and test their efficacy in blocking autoreactive B cells both in vivo and in vitro using suitable animal models.

"The next step is to better characterize the functional interaction of MyD88 with other important components of the TACI signaling complex, including TRAF2," she says. "In addition, we plan to screen small molecule and peptide libraries to identify specific inhibitors of TACI-MyD88 interaction."

Cerutti points out that as the team seeks continued success, it is of paramount importance to better characterize the mechanisms by which autoreactive B cells become overly activated in response to external signals provided by molecules such as BAFF and APRIL.

"Thus, an important measure of success in this research will consist in our ability to gain new insights into the ways how TACI activates B cells via MyD88," she says. "In this regard, it is important to note that MyD88 can interact with a number of different molecules, including Toll-like receptors, which are well known for their ability to trigger several steps in the cascade of events leading to lupus and rheumatoid arthritis. Another measure of success will consist in the identification of pharmacological inhibitors of TACI-MyD88 interaction."

According to the National Women's Health Information Center, autoimmune diseases impact 23.5 million Americans. Common examples include lupus, in which the immune system attacks the skin and/or several organs within the body; rheumatoid arthritis, in which the immune system attacks joints; multiple sclerosis, in which the immune system attacks the nervous system; and type 1 diabetes, in which the immune system attacks insulin-producing cells in the pancreas.

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