April 14, 2021

Dr. Boris Reizis and his team, working with a group of clinical rheumatologists led by Dr. Jill Buyon, have made a connection between an enzyme that prevents people’s immune systems from reacting to their own DNA and lupus activity. In a paper just published in the Journal of Experimental Medicine they report that this enzyme has less activity in many lupus patients, likely contributing to autoimmunity.

Dr. Reizis’ work is supported by a Distinguished Innovator Award grant from the Lupus Research Alliance. The Distinguished Innovator Award is one of LRA’s largest and most prestigious grants, giving exceptional scientists up to $1 million to conduct research that addresses the fundamental causes of systemic lupus erythematosus and provides new directions towards a cure.

Most people with lupus—especially those with lupus nephritis—produce antibodies against their own DNA. But what causes these antibodies to form has not been well understood. Normally, DNA stays within cells. But when cells die, they can release some of their DNA. Our bodies have special enzymes (proteins with a specific function) that destroy this extracellular (outside of cells) DNA. One of these special enzymes is called DNASE1L3.

Dr. Reizis’ team just found that in more than half of lupus patients with nephritis, their DNASE1L3 enzyme was not working as well as it should. This is partly because these patients are making autoantibodies to DNASE1L3 itself! So now autoantibodies are attacking their own DNASE1L3 enzyme, preventing the enzyme from destroying the extracellular DNA. This DNA thus accumulates, and their immune systems then make autoantibodies against the DNA too. People with high levels of both types of antibodies—against DNASE1L3 and against the DNA that accumulates —have more severe disease and don’t respond as well to treatments for lupus nephritis as people who lack them. Dr. Reizis notes that looking for autoantibodies that target DNASE1L3 is relatively simple to do, and it correlates well with active lupus nephritis so perhaps could be used as a diagnostic test for severe lupus nephritis.

“Normally, DNASE1L3 helps our immune system avoid recognizing and reacting to our own DNA. But in many people with lupus nephritis this enzyme doesn’t work so well, and their immune system makes antibodies against their own DNA and other proteins. Maybe one day increasing the activity of this enzyme might be a good treatment for lupus. I am so grateful to the Distinguished Innovator Award for granting me the funding to research how this happens,” said Dr. Reizis.