Origin, regulation and therapeutic targeting of extracellular DNA

Dr. Reizis and his team are pursuing a novel idea that could explain what causes lupus, why flares develop, and how a treatment might be developed to prevent the attack. It has been shown that billions of cells die every day in our blood and release their DNA packaged into small containers called microparticles. they believe that the abnormal buildup of DNA in these microparticles can cause the immune attack to begin and that the microparticles may provide vehicles for the DNA to travel throughout the body, causing the immune system to attack specific organs in their wake.

What this study means for people with lupus:

Dr. Reizis will study how the DNA-carrying microparticles form and how the body normally gets rid of this DNA. they also plan to develop techniques that eliminate this DNA to provide a basis for future lupus treatments.

The hallmark of systemic lupus erythematosus (SLE) is the production of antibodies to nuclear antigens including chromatin and DNA. It has been shown previously that microparticles released from apoptotic cells contain genomic DNA and expose it at their surface. Our recent work demonstrated that secreted nuclease DNASE1L3 digests DNA in microparticles, and SLE in DNASE1L3-deficient animals and human patients is associated with its accumulation. These data suggest that extracellular DNA in circulating microparticles represents the relevant antigenic form of self-DNA and a potential therapeutic target in SLE. Our overall goal is to understand its origin, regulation and role in SLE, and develop tools for its targeting. First, we will use genetic tracers to identify chromatin-containing microparticles in vivo, define their tissue origin and characterize them in the steady state and in SLE. Second, we will analyze the role of the classical complement pathway in the disposal of DNA-containing microparticles. Finally, we will characterize the process of DNA incorporation into apoptotic microparticles, and develop a screening platform for its genetic and chemical regulators. Collectively, these studies would elucidate the properties and regulation of a key self-antigen in SLE, and pave the way for more specific immunotherapies for the disease.