2007 Why the Lupus Immune System Reacts to Its Own DNA
2012 Defining Factors that Control the Initial Break in Tolerance in Lupus
The Study and What It Means to Patients
"In the last few years, we have started to learn how the immune system regulates TLRs,” said Dr. Barton. “The next challenge, and the focus of our work, is to determine whether differences in these processes can explain why certain people develop lupus while others do not.”
Focusing on TLRs as prime suspects, Dr. Barton seeks to solve why TLRs cause a problem in people with lupus but not in healthy people. His work will determine if the reason the lupus immune system begins to attack its own DNA might lie with proteins inside immune cells whose job is to control TLR activity. Dr. Barton anticipates proving that lupus patients have defects in these control proteins that allow TLRs to mistakenly switch into action.
Dr. Barton’s study seeks to pinpoint the earliest errors made by the lupus immune system and suggest new treatments to correct them. His investigations also have broad implications for autoimmune disease, infectious disease and beyond. The new knowledge generated by his work could even inform vaccine design against infectious diseases or cancer.
Title: Defining factors that control the initial break in tolerance in lupus
A clear link has been established between the activation of Toll-like receptors (TLRs) 7 and 9 by self nucleic acids and systemic lupus erythematosus (SLE). The localization of TLR7 and TLR9 is thought to
limit activation by self-RNA and DNA, respectively. Anti-nuclear antibodies (ANA), a hallmark of SLE, can bypass this compartmentalization, but this mechanism cannot be the only factor that predicates disease because ANA are typically only produced after an initial break in tolerance.
Therefore, two key questions for our understanding of SLE are how and why the initial break in tolerance occurs. In this proposal, I describe experiments that will examine these fundamental issues in light of recent TLR9 activation are regulated. We have determined how the trafficking chaperone Unc93b1 regulates the localization of these, and the mechanisms may explain how the activation thresholds for TLR7 and TLR9 are set. Moreover, we have discovered that the trafficking and localization of TLR7 and TLR9 are distinct, and we propose that these differences may account for the differing roles these receptors play in SLE. Our ultimate goal is to understand how alterations in TLR
regulation lead to the development of SLE.
See more here.
Subsequent Publication 2013
The blueprint for what makes us each unique—DNA and RNA—is carried inside the nucleus of our cells. And normally, our immune systems deftly distinguish our DNA and RNA from that of foreign invaders such as viruses and bacteria.
But in people with lupus, the immune system reacts to its own DNA and RNA as if these blueprint “chips” were the enemy that required extermination. What prompts these cases of misidentification?
Tantalizing research indicates that proteins called Toll-Like Receptors (TLRs), which normally recognize DNA and RNA only from infectious pathogens such as viruses, may be to blame.
Dr. Barton has found that the level of TLR7 and TLR9 in cells–the TLRs implicated in lupus so far—is tightly controlled by a specialized protein disposal system.
He suspects that if this specialized disposal system breaks down, cells will have too much TLR7 and TLR9 and will, as a result, be more likely to erroneously respond to the immune system’s own DNA and RNA.
To test this, he will tinker with the disposal system and watch to see if lupus ensues.
With his LRI grant, Dr. Barton discovered a new checkpoint that prevents the immune system from making a basic error and attacking its own tissues.
"Our findings are exciting because they reveal an entirely new pathway that controls the balance between immunity and autoimmunity," Dr. Barton said. "Of course it's early, but we can't help but be excited about the therapeutic potential of this discovery for treating diseases like lupus."
Normal immune systems are smart about distinguishing those blueprints inside each of our cells-our DNA and RNA-from that of foreign invaders such as viruses and bacteria.
But in lupus, the immune system makes a basic error and attacks its own DNA and RNA.
Tantalizing research over the past few years has indicated that proteins called Toll-Like Receptors (TLRs-specifically, TLR7 and TLR9-may be to blame for these cases of misidentification and attack.
In the December 2008 Nature article Dr. Barton shows that specialized proteins called "proteases" are needed to control the activity of TLR7s and TLR9s.
The ectodomain of Toll-like receptor 9 is cleaved to generate a functional receptor. Ewald SE, Lee BL, Lau L, Wickliffe KE, Shi GP, Chapman HA, Barton GM. Nature. 2008 Dec 4;456(7222):658-62.
In 2008, Dr. Barton won a $1.65 million NIH/NIAID grant to expand on the research funded by the LRI Novel Research Grant.