While lupus affects more than 200,000 US cases per year and researchers tirelessly work to improve its diagnostics and treatments, there is still a major unmet medical need in this field with only one new drug approved by the FDA in the last 50 years. Such autoimmune diseases are especially challenging to treat because they involve as many as 30-40 genetic variants that conspire to make the person’s immune system respond abnormally. Dr. Keith Elkon, Professor of Medicine and Adjunct Professor of Immunology at the University of Washington, looks at the most proximal, basic mechanisms responsible for initiating the autoimmune diseases like lupus, to impact new and more effective forms of therapy. With 30 years of experience in complex immunology that includes multiple steps in pathogenesis, Dr. Elkon inspired many original discoveries, one of which resulted in a UW startup company dedicated to removing the harmful immune complexes in lupus. Dr. Elkon and his colleagues were instrumental in developing a biological drug, which is now in Phase 2 clinical trials for lupus. Currently, his team is working on a new small molecule drug that they hope to test in the near future.

Normally, a virus infecting cells will release nucleic acids and prompt the body to produce inflammatory proteins called cytokines, one of which is interferon, which then stimulates the immune system to get ready for battle. Most studies now agree that the overexpression of type 1 interferon is a major abnormality observed in three quarters of lupus patients as well as in patients with related autoimmune diseases such as scleroderma, polymyositis, and primary Sjogren’s syndrome. Collaborating with computer scientists, medicinal chemists, molecular biologists, and immunologists, Dr. Elkon hopes to elucidate why this prominent inflammation signature turns on in the first place. He believes that when billions of cells that die on our body everyday do not get removed efficiently as in lupus, the cells will then pop open and release their contents like DNAs and RNAs, confounding the body to mistake them for a virus. He is probing these mechanisms further to design new forms of therapy that could work at the earliest stages of disease thereby preventing severe inflammation. It is possible that these approaches may also help to improve organ specific autoimmune conditions such as Type 1 Diabetes and some cases of rheumatoid arthritis that share similar mechanisms.

The specific questions that his laboratory addresses are:

• What are the cell death abnormalities that provoke an immune response? The last 15 years of research has proven that our body must rid itself of the billion cells that die everyday in an efficient and an unharmful way. However, when cells die abnormally or the body makes an inappropriate response to cell deaths, our immune system can mistake them as viruses or bacteria and stimulate responses against our own tissues. Dr. Elkon thus explores cell deaths that may cause an abnormal immune response.
• How does the cell debris released from dying cells stimulate inflammation - especially the type 1 interferon response?
• Which interferon pathways are specifically abnormal in lupus and related autoimmune disorders? Our body has multiple different interferon pathways that can be excited by many sensors in the cells. By determining which interferon pathways are active in lupus, Dr. Elkon hopes to develop drugs that selectively block appropriate pathways that are most involved in lupus.
• Lupus patients are very sensitive to sunlight. Can we use this environmental trigger (sunlight) to uncover differences in the interferon response in lupus versus controls? Sunlight causes a huge amount of cell death, and Dr. Elkon is working to define abnormal pathways triggered by sunlight. Ultimately, he hopes to determine whether the same pathways contribute to internal organ disease such as kidney and brain, and develop therapies to block these pathways.