NIAID Now | February 24, 2020
When the body experiences injury or infection, the immune system launches a natural, healthy inflammatory response in which immune cells and supporting proteins rush in to fight disease-causing pathogens. While that inflammation heals the body, it also makes us feel sick with fever, swelling, redness, and pain. Once the threat is neutralized, a healthy immune system pulls back, and we’ll start to feel better. In people living with a rare group of disorders called autoinflammatory diseases, however, inflammation rages on—causing chronic fevers, organ damage, and other life-threatening complications.
Medicine has recognized these genetic conditions for just over 20 years, and while early diagnosis and treatment can improve patient outcomes, similar symptoms across different autoinflammatory diseases can make them difficult to diagnose and manage. Now, NIAID scientists and their colleagues have developed an integrated approach that combines next-generation genetic sequencing with advanced diagnostic techniques to characterize inflammatory responses. In doing so, investigators discovered three new autoinflammatory diseases. Their findings were published today in The Journal of Clinical Investigation.
In the new study, researchers led by Raphaela T. Goldbach-Mansky, M.D., M.H.S., chief of NIAID’s Translational Autoinflammatory Diseases Section, evaluated 66 children and young adults with symptoms of autoinflammatory diseases that had not yet received a specific diagnosis. In addition to sequencing participants’ entire genomes to detect genetic abnormalities, researchers employed advanced techniques to identify the types of cytokines involved in a participant’s inflammatory response, including a measure of a participant’s “interferon signature.” Inflammatory cytokines, including interferons, are proteins released by the immune system in response to viral, bacterial and fungal infections.
“While interferons and other cytokines are critical to surviving infections, uncontrolled levels of these proteins cause disease in people living with autoinflammatory disease,” said Dr. Goldbach-Mansky. “Screening for the interferon signature and selected cytokines allowed us to distinguish between diseases with different inflammatory signatures, much like taking a fingerprint. Along with a patient’s genetic information, these data allow us to identify and characterize new autoinflammatory diseases.”
Investigators found an interferon “fingerprint” in 55% of study participants. In contrast to participants without an interferon signature, these participants were more likely to experience life-threatening complications. They were also more likely to experience symptoms similar to those of known autoinflammatory, interferon-mediated diseases, such as SAVI, CANDLE and Aicardi-Goutières syndrome.
Eighteen participants had unusual inflammatory “fingerprints” that—together with next generation genetic sequencing—identified three novel diseases. Eight study participants with high levels of an inflammatory cytokine known as IL-18, clubbing of the fingernails and lung disease and a potentially fatal inflammatory complication known as macrophage activation syndrome (MAS)—but no disease-causing genetic mutation—had a disease dubbed IL-18PAP-MAS. Four other participants with cone-shaped teeth and rashes had novel mutations in the gene IKGKB/NEMO and were diagnosed with NEMO-NDAS. Six participants with recurrent viral pneumonia and damaging mutations in the gene SAMD9L had a third new disease, SAMD9L-SAAD. The distinct genetic mutations that cause NEMO-NDAS and SAMD9L-SAAD allow clinicians to screen for these diseases.
Accurately diagnosing these patients allows physician-researchers to tailor treatment. In several cases, autoinflammatory diseases are associated with increased activation of some cellular molecules known as JAKs and STATs. Previously, Dr. Goldbach-Mansky’s team found that a rheumatoid arthritis medication that blocks the JAK-STAT signaling pathway reduced inflammation in people with CANDLE and SAVI, resulting in much-improved clinical outcomes.
Preliminary data indicated such JAK inhibitors may also help some participants in the new study. When given JAK inhibitors, participants with NEMO-NDAS and SAMD9L-SAAD still experienced elevated inflammation and accompanying symptoms while taking JAK inhibitors. Together with these participants’ unique inflammatory fingerprints, these data indicate that biological pathways other than JAK-STAT may be active in the newly identified diseases.
“As we continue to discover new genetic anomalies that cause never-before-seen autoinflammatory diseases, we learn more about how our bodies normally control inflammation,” said Adriana A. de Jesus, M.D., Ph.D., staff scientist in NIAID’s Translational Autoinflammatory Diseases Section in the Laboratory of Clinical Immunology & Microbiology and lead author on the new report. “Studying how these mutations lead to inflammation may help us discover supplemental treatments that may also benefit more common inflammatory problems, like autoimmune diseases and cancers.”
This research was supported in part by NIAID, NIH’s Intramural Research Program, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the NIH Clinical Center.
A. de Jesus et al. Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases. Journal of Clinical Investigation DOI: 10.1172/JCI129301 (2019).