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The Inflammasome: Possible Clue to a Host of Diseases

An obscure component of the immune system may play a role in several autoimmune diseases

October 2011--Ask most people what they know about the immune system and you might hear the terms T cell, B cell or antibody. Indeed, these elements of immunity are essential to our ability to protect ourselves from infection, and they make vaccination possible.

Chances are few, however, that inflammasomes would be included in that list.

Although Jungsan Sohn specializes in the study of the inflammasome, he takes no offense to the molecule’s little-known status. While researchers have studied T cells and B cells for decades, inflammasomes were discovered only about a decade ago. And only a handful of research labs, Sohn’s among them, focus on these protein complexes.

A growing body of research indicates that inflammasomes play a fundamental role in the immune process. Studies also suggest that defects in their structure or activity contribute to a variety of diseases, including Crohn’s disease, rheumatoid arthritis and systematic lupus erythematosus.

But according to Sohn, “no one knows the details of how these proteins function. It’s a big black box.”
 
So Sohn, who joined the Department of Biophysics this past February, is focusing on discovering the minute details of the inflammasome, studies he hopes will lead toward the development of therapies for inflammasome-related diseases.

Humans have two levels of immunity. The first category is called the adaptive immune system, and its members include those famous B cells and T cells. When a bacteria, virus or other microbe invades the body, the adaptive immune system “learns” to recognize the invader’s protein antigens and then targets those specific proteins. If the microbe reinvades, the adaptive immune system can mobilize against the invader even faster.

But because it’s impossible to devise a defense against every conceivable invader, the immune system also includes a second, less discriminating type of defense called the innate immune system. Inflammasomes belong to this second category of immunity. While the adaptive immune system targets specific foreign entities, the innate immune system responds immediately to any form of invasion—be it a microbe, an asbestos fiber or a sliver of wood—sending immune cells to the site of infection or cell damage and triggering inflammation. Without the innate immune system, any small scratch would leave you vulnerable to life-threatening infection. “It’s like the frontline soldiers,” says Sohn. It copes with the first sign of infection and sends a message to headquarters [that there has been an invasion.]”

“A good example of first response can be found in vaccination,” says Sohn. “Once a person gets vaccinated—say for the H1N1 virus, which causes flu—swelling will occur at the vaccination site within minutes. This is a local inflammatory response mediated by innate immunity. After a week or so, that person will have developed immunity against the virus, which is accomplished by the adaptive system.”

Scientists have a big-picture view of how the inflammasome contributes to innate immunity, says Sohn. They’ve found that inflammasomes are constructed from special, danger-sensing proteins. If a microbe invades or a cell is damaged, these proteins recognize molecular patterns associated with the invader. They then assemble to form the inflammasome.

Once assembled, the inflammasome triggers a cascade of biochemical activity that can lead to voracious white blood cells called macrophages flocking to the site of invasion and scarfing up the infected or damaged cells.

 What’s missing from this picture, says Sohn are the close-up details.

Sohn’s research strategy involves taking apart the inflammasome, examining each piece, and then observing how the pieces reassemble, using techniques such as X-ray crystallography, to gain an atom-by-atom view of the molecule. “It’s like you’d disassemble a car to learn the job of each piece,” he says. He’ll then use biochemical methods to discern which part of the molecule performs which roles, examining, for example, how each piece receives the incoming signal warning of danger, and how that information is transmitted to other immune system components.

“Humans have about 20 different types of inflammasomes, each sensing different types of pathogenic assault,” says Sohn. He is focusing on two in particular. One is called NLRP3. Malfunctions in this molecule have been found in patients with arthritis and type 2 diabetes. Yet little is known about how the NLRP3 protein assembles into the inflammasome complex, and how that structure enables the molecule to mobilize other members of the innate immune system.

The second is a molecule called AIM2. Patients with the autoimmune disease systematic lupus erythematosus produce unusually high levels of this inflammasome. Understanding the normal structure and function of AIM2 could, says Sohn, offer insights into the root cause the disease.
 
Basic research on inflammasomes might also help scientists design new drugs for diseases associated with the molecules. Most of those diseases involve “hyper-activation” of the inflammasome. The inflammasome works too hard, says Sohn, with the consequence being chronic inflammation of certain tissues. “Thus, developing a way to shut off certain inflammasomes could lead to potent anti-inflammatory therapies.”
 
“I want my research to lead to therapeutic products,” says Sohn, although he admits that his goal will take a while to achieve. “Inflammasomes are hard to study.” The large protein complexes are difficult to reconstitute in the lab, “but that is what attracts me. I like challenges.”

—Melissa Hendricks

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