Greg Barton, PhD

Greg Barton

Greg Barton, PhD

University of California, Berkeley
San Francisco, CA


Title: 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.

Scientific Abstract

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.