Expression of retroelements in lupus patients

In recent years, the role of intrinsic (endogenous) retroviruses and other retroelements in triggering autoimmunity has become clear. Forty percent of our genome consists of retroelement sequences, many of which are expressed in cells and potentially contribute to disease. For example, patients lacking an enzyme that degrades nucleic acids of retroelements suffer from various inflammatory diseases, including systemic lupus erythematosus (lupus) and Aicardi-Goutières syndrome. We will probe the role and identity of these retroelements in lupus. Our working hypothesis postulates that inflammation is triggered by expression of a retroelement variant that is generated in the patient.

But which retroelements are active? We have a two-pronged approach to finding out. In the first approach, we will study a byproduct of the life cycle of these elements. When the life cycle is not completed, circular DNA is produced, and this is a great surrogate marker for a retroelement that is active. Our plan is to exploit this fact and to identify the retroelements that are active in patients with lupus. We will isolate and analyze this circular DNA and compare it to circular DNA from healthy individuals. In the second approach, we will identify by deep sequencing all retroelement transcripts in lymphocytes that are specifically expressed in patients with lupus.

In collaboration with Dr. Lindsey Criswell, Chief of Rheumatology, University of California, San Francisco.