V. Michael Holers, MD

University of Colorado Health Sciences Center, Denver, CO

2003/2004 Why the Lupus Immune System Reacts to Its Own DNA, Human Lupus Biology

Researchers still do not have a firm grasp on how people with lupus develop antibodies to their own genetic material—their own DNA.

The discovery of a receptor or binding protein that interacts with DNA on lymphocytes called Complement Receptor 2 (CR2) generated a lot of excitement and interest in this regard, as the binding protein is found on many cells that are believed to be involved in lupus, from B cells to follicular dendritic cells and a subset of T-cells.

In addition, alterations in CR2 have been found in people with lupus.

With LRI funding and using three-dimentional models of DNA and mice, Dr. Holers and his team sought to determine how the receptor binds to DNA in people with lupus, and whether dysfunction in the binding process is important in triggering the disease.

The hope: to link alteration in CR2 to the development of the autoimmunity.

“If we prove that a dysfunction in the binding process plays a role in causing lupus, it's another advance in understanding the cause of S.L.E. and this information can help us better understand how to treat it,” he says.

And could there be a lupus “treatment” role for a class of drugs known as complement regulators, with which doctors can fix the receptor and make it functional?

“We have lots of ideas on how we can fix it if CR2 is what’s broken,” he says.

Based on his LRI work, Dr. Holers quickly reported that CR2 could also bind to interferon, which is also implicated in the cause and development of lupus. He reported on this in the Journal of Immunology in 2006.

Now he is working to generate transgenic mice that express the human form of the CR2 receptor.

And significantly, Dr. Holers and his team also have developed inhibitors of CR2 based on the alternative ligands (interferon and DNA)-and have licensed fundamental technology to a company that is working to develop an inhibitor as a potential new drug for lupus.

Select publications:

Characterization of human complement receptor type 2 (CR2/CD21) as a receptor for IFN-alpha: a potential role in systemic lupus erythematosus. Asokan R, Hua J, Young KA, Gould HJ, Hannan JP, Kraus DM, Szakonyi G, Grundy GJ, Chen XS, Crow MK, Holers VM. J Immunol. 2006 Jul 1;177(1):383-94.

Rev. July 2010