Gregory Barton, PhD

University of California, Berkeley, CA

2007 Why the Lupus Immune System Reacts to Its Own DNA

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.

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.

Select publications:

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.

Ongoing funding:

In 2008, Dr. Barton won a $1.65 million NIH/NIAID grant to expand on this research.

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