Yorgo Modis, PhD

Yale University, New Haven, CT

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 each of our cells. Normally, our immune systems deftly distinguish our own 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. Modis is among the LRI researchers who have a novel idea for uncovering more about the role of TLRs in lupus.

By creating highly detailed three-dimensional models of TLR proteins bound to DNA and RNA, he will be able to observe how the receptors transmit their “on” signals to the immune system. These intricate models also offer possible ways to design drugs that interfere with, and stop, the alert signals that trigger such devastation in lupus.

In 2012, the NIH approved a $1.13 million grant to Dr. Modis  – a direct evolution of his LRI Novel Research Project. His work on intricate three-dimensional structures of the TLR (toll-like receptor) -- proteins that recognize genetic material important in lupus -- has now won a total of $1,630,000 in extended funding to advance new insights into these key players. “I want to thank LRI for funding our research early on, at a time when it was too risky and preliminary for NIH funding,” said Dr. Modis. “This major NIH grant is a testament to the value of the LRI grants in promoting research in lupus. It would not have been possible without the LRI!” 

Select publications:

A ligand-binding pocket in the dengue virus envelope glycoprotein. Modis Y, Ogata S, Clements D, Harrison SC. (2003) Proc Natl Acad Sci USA 100:6986-91.

X-ray structure of a protein-conducting channel. Van den Berg B, Clemons Jr WM, Collinson I, Modis Y, Hartmann E, Harrison SC, Rapoport TA. (2004) Nature 427:36-44.

Structure of the dengue virus envelope protein after membrane fusion. Modis Y, Ogata S, Clements D, Harrison SC. (2004) Nature 427:313-9.

Crystal structure of West Nile virus envelope glycoprotein reveals viral surface epitopes. Kanai R, Kar K, Anthony K, Gould LH, Ledizet M, Fikrig E, Marasco, WA, Koski RA, Modis Y. (2006) J Virol 80:11000-8.

Ongoing funding:

In 2007, Dr. Modis won a 7-year, $500,000 grant from the Burroughs Wellcome Fund (Investigators in the Pathogenesis of Infectious Disease Award) to continue the work that he began with his LRI funding.