Horizon, Host: Ted Simons

August 1, 2013


Host: Ted Simons

Putting the Brakes on Inflammation


  • A team led by a University of Arizona researcher has discovered a previously unknown mechanism that prevents the immune system from going into overdrive. That could shed light not only on how our body controls its response to pathogens but on conditions such as autoimmune diseases, allergies and chronic inflammation. The group found a protein previously believed to only play a role in blood clotting acts to tell defense cells to slow down, thereby preventing an immune reaction from spiraling out of control. Sourav Ghosh, assistant professor in the department of cellular and molecular medicine at the UA College of Medicine, and Dr. Jonathan Leighton of the Mayo Clinic will discuss the new findings.
Guests:
  • Sourav Ghosh - Assistant Professor of Cellular and Molecular Medicine, UA College of Medicine
  • Dr. Jonathan Leighton - Mayo Clinic
Category: Medical/Health   |   Keywords: UA, immune system, update, mechanism, health, inflammation,

View Transcript
Steve Goldstein: Inflammation is something we all deal with as we age. It can strike in many places and cause a variety of ailments. But there is hope. A team led by a University of Arizona researcher has discovered a previously unknown mechanism that prevents the immune system from going into overdrive. That could shed light not only on how our body controls its response to pathogens but on conditions such as autoimmune diseases, allergies, and chronic inflammation. The group found a protein thought to play a role only in blood clotting can tell defense cells to slow down, thereby preventing an immune reaction from spiraling out of control. Sourav Ghosh, assistant professor in the department of cellular and molecular medicine at the U of A college of medicine, and Dr. Jonathan Leighton of the Mayo clinic join us to discuss the new findings. How will this new discovery affect them?

Jonathan Leighton: I think that it is very important. If you start from the concept of inflammation, inflammation is actually very important as a way that the body defends itself against bacteria and so if someone gets a cut or if you get an upper respiratory infection, it's the inflammatory process that actually defends the body and clears the infection. The differences in those conditions, the body knows to turn the inflammation off. Now, if we shift gears to chronic inflammatory conditions, like inflammatory bowel disease, the body does start that inflammatory process, but for some unknown reason, the body doesn't know to turn that inflammation off and that leads to chronic inflammatory diseases, and then other squeale from that. It has always been something that we have wanted to understand better is what does that? So, if we take inflammatory bowel disease, for example, there are three main etiologies that we think contribute. One is genetics. Two is the environment. And then the third is the immune system, and that inflammation. And, again, what a lot of research is focused on is trying to understand why the body doesn't turn off that inflammation. And that's where Sourav and his coworkers have done some incredible work in that area and have identified a possible mechanism.

Steve Goldstein: Sourav, it's been a long process. This is not something that happened overnight. People when they hear research and hear conclusions, they want to believe there was some sort of revelation that happened, but this took a while.

Sourav Ghosh: Right. So, let me first start by acknowledging the people who did the work. I co-lead with-- Carla, Yale University, a professor, and her team, and it was a pleasure working with clinicians like Jonathan Leighton, Anthony Perry in Gilbert. And Carla and I, we were post-doctoral research fellows at the institute in La Jolla. An institute founded by who discovered polio vaccine. It has been about 10 years, 10 years back that we started to trying to understand the function of a molecular circuit. Imagine this is a molecular signal that functions within an immune cell. These are the first of the defense cells in the body that immediately respond to an infection. Pathogen, bacteria, or a virus. This breaking mechanism is something that operates in a cell disengaging them. This is something that we discovered before. But at the time we didn't know, in the body, in the context of an actual immune response, what's the signal that pushes this break sort of. How is this engaged? That is what we discovered recently in terms of the function --

Steve Goldstein: Without getting too much into scientific speak that most of us won't understand. What does it look like when researchers first see the difference and feel like okay, now I realize why the immune system is reacting that way? What looks different?

Sourav Ghosh: As you said, it's a long process. Mainly expected results or lots of failures, and there are those wow moments that we live for. In this case, what we did was we took advantage of genetic techniques, such as generating an animal, a mouse model. A mammal, closest approximation that we have in terms of understanding diseases in humans, we could actually genetically take out the gene that makes -- protein -- only specifically in the T-cells. This animal then suffered from increased, overzealous inflammatory response, chronic inflammation, and that was sort of the proof that, absolute proof that we're looking for. But this has been a process of deductive reasoning. Sherlock Holmes, one of my favorite characters, and thinking where the signal might come from. To explain that, I will have to tell you a little bit about the process of immune response in very general terms. When you have an infection, you have a first line of response. These are the innate immune cells. And their job is to respond very quickly. But rather nonspecifically. So it doesn't matter which bacteria you are getting. It's a general response making a lot of chemicals to try to contain the infection. Now, if this persists, however, there is collateral damage. There is a lot of toxic chemicals that the body is making trying to fight off the infection. In the process of a normal physiological immune response, a gradual progression, where the innate immune cells -- specialized specific cells that attack the particular bacteria. And that doesn't have associated collateral response. So, we were thinking where would the signal to turn off the innate immune response come from? We deduced it could be once you engaged specific response, fine-tuned without the collateral damage, that might give the signal itself to disengage --

Steve Goldstein: Tell us a little bit more.

Jonathan Leighton: I think what is very exciting about this, they studied this in the lab. Studied it in animals. Found a possible mechanism, and then what we call translational research then took it into humans, and so of course they identified this protein-S, which again is normally involved in blood clotting, and they identified reasons to think that this protein-S might provide that negative feedback to those initial inflammatory cells, and so what we did was we took patients with inflammatory bowel disease and tested them for their protein-S levels and we found pretty consistently that the protein-S levels are low. If you -- in fact, protein-S -- just to remember what we're saying is that remember I said that the problem in chronic inflammatory conditions is that the body doesn't know to turn itself off. And, Sourav and Carla's work suggests that protein-S may be that negative feedback mechanism to turn the inflammation off. You can imagine if protein S levels are low and there is not enough available, the protein S can't give the feedback to turn that inflammation off. If, in fact, that turns out to be the case, then that -- then that leads to possible ways of treating these chronic conditions, and reducing the inflammation. So, there is huge implications if this is the mechanism.

Steve Goldstein: Just a few seconds. Give us the overview.

Sourav Ghosh: Protein-S -- it is the signal that is picked up by receptors on the immune cells. This would be analogous to antennas, small antennas that pick up the signal telling the cells to calm down. You've done your job. As Jonathan alluded, it was really a very interesting finding, that the patients who are suffering from chronic inflammatory diseases that do not have the key signaling molecule. Immune cells to learn that the job is done.

Steve Goldstein: Fascinating. Thank you for the discussion.

Jonathan Leighton: Thank you.


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