Better Understanding How to Control Inflammation in Autoimmune Diseases

March 25, 2019

Scientists may better understand how to control the immune system more precisely.

LL37scaffolding mid

LL37 molecules self-assemble into scaffolds (green and teal) to organize DNA (red) into periodic lattices, which amplify inflammation. Credit: UT Austin and UCLA.

In autoimmune diseases such as psoriasis, the immune system goes into overdrive in response to people’s own DNA being released from damaged cells—a reaction that causes inflammation in the body.

Until recently, the molecular processes behind that immune response have not been fully understood, but a new study could help change that.

A collaborative team including researchers from UT Austin’s Department of Biomedical Engineering has discovered that anti-microbial peptides (AMP) such as LL37 molecules, which are found in the immune system, play an unexpected role in revving up the body’s self-defense response. The finding, published in Nature Communications, may help scientists better understand how to control the immune system more precisely.

Pengyu Ren, a professor of biomedical engineering, and Changsheng Zhang a postdoctoral researcher working in Ren’s lab (now working at Peking University), contributed advanced modeling techniques to help researchers better understand how LL37 molecules control toll-like-receptors in autoimmune response. LL37 molecules kill bacteria and strengthen immune response by working together with toll-like protein receptors that act as early warning sensors that detect foreign entities.

Using high performance graphics processing unit-based computing clusters, UT Austin researchers generated three-dimensional structural models of three different AMPs, including LL37, superhelices and their complexes with DNAs. Ren and Zhang created the models using small-angle X-ray scattering data gathered by UCLA collaborators.

The atomic structures generated from X-ray data combined with powerful computational models helped researchers learn how LL37 molecules assemble and organize DNA that binds to toll-like receptors. Researchers found that the large number of repeating DNA units binding to multiple toll-like receptors increases inflammation and the body’s immune response. Researchers also found that two other AMPs found in amphibians and insects behave the same way as the LL37 molecules found in humans.

The study reveals insights into the role of LL37 molecules that could give researchers a more specific target to use in studies aimed at controlling immune system response.

The experimental study was led by Gerard Wong, UCLA professor of bioengineering, chemistry and biochemistry. Other authors included Will Connell, Mandy Hung, Nicolas Malkoff and Veronika Veksler of UCLA; Jeremy Di Domizio and Michel Gilliet of Lausanne University Hospital; and Fan Jin of the University of Science and Technology of China.

The study was supported by the National Psoriasis Foundation, the National Institutes of Health, and the Robert A. Welch Foundation. X-ray research was supported by the U.S. Department of Education Office of Basic Energy and Sciences. This news release was written with collaboration from UCLA.