An international team recently discovered a previously unnoticed syndrome related to COVID-19: MDA5-autoimmunity and Interstitial Pneumonitis Contemporaneous with COVID-19, or MIP-C for short.
Pradipta Ghosh, M.D., was sitting in her office at the University of California San Diego School of Medicine when she received a request from the other side of the world.
Ghosh, a professor in the Departments of Medicine and Cellular and Molecular Medicine at UC San Diego School of Medicine, got an email from Dennis McGonagle, Ph.D., who is a professor of investigative rheumatology at the Univer rnrnUniversity of Leeds in the UK. It initiated an international partnership that discovered a previously overlooked COVID-related syndrome and led to a publication in eBioMedicine, a journal of The Lancet.
McGonagle reached out to Ghosh to propose a collaboration on a COVID-related enigma. Ghosh recounted, “He informed me that they were observing mild COVID cases. They had immunized approximately 90% of the Yorkshire population, yet they were now encountering this extremely rare autoimmune disease known as MDA5 — autoantibody associated dermatomyositis (DM) in patients who may or may not have been infected with COVID, or even recall if they had.”
They were exposed to it.”
McGonagle talked about patients with severe lung scarring, some of whom had symptoms related to rheumatologic conditions such as rashes, arthritis, and muscle pain, which are often seen in interstitial lung disease. He wanted to investigate if there was a link between MDA5-positive dermatomyositis and COVID-19.
“Dermatomyositis is more prevalent in people of Asian descent, especially Japanese and Chinese individuals,” Ghosh explained. “However, Dr. McGonagle noticed a sudden increase in cases among Caucasians.”
“But that’s not the only issue,” Ghosh added. “Because he mentioned, ‘Oh, and by the way, some of these patients are deteriorating rapidly.The Institute for Network Medicine at UC San Diego School of Medicine, headed by Ghosh, focuses on precision computational systems network. The Center for Precision Computational Systems Network (PreCSN) is housed within this institute, with its main component being BoNE – the Boolean Network Explorer. BoNE is a robust computational framework that can derive practical insights from large datasets. According to Ghosh, BoNE is designed to overlook individual patient differences within a group and instead identify common factors shared by everyone in the group.BoNE has been used in the past to help Ghosh and her team identify lung and heart syndromes related to COVID in adults and children. McGonagle, a rheumatologist specializing in inflammatory and autoimmune conditions, collaborated with the Institute for Network Medicine to investigate the increase in post-pandemic inflammatory and autoimmune diagnoses. Ghosh mentioned that McGonagle’s patients, all within the U.K.’s National Health System (NHS), were instrumental in aiding the investigation.The database contains extensive medical records for a large population, making it easier to access and analyze health data for research purposes,” Ghosh explained.
Ghosh and McGonagle assembled a team to investigate what they discovered was indeed a brand new syndrome. The UC San Diego team consisted of Saptarshi Sinha, Ph.D., interim director of PreCSN, who was a co-first author on the paper, and Paula David Ramos, M.D., who was conducting research fellowship in experimental rheumatology at the Leeds Institute of Rheumatic and Musculoskeletal Medicine. The UC San Diego team also included two PreCSN-affiliated students, Ella McLaren, aAn undergraduate student and aspiring physician-scientist, and Sahar Taheri, a graduate student in the Jacobs School of Engineering Department of Computer Science and Engineering. The study started with McGonagle lab’s discovery of autoantibodies to MDA5 – an RNA-sensing enzyme that plays a role in detecting COVID-19 and other RNA viruses. Out of the 60 patients, 25 developed lung scarring, also known as interstitial lung disease. Ghosh mentioned that the severity of the lung scarring led to the deaths of eight individuals in the group due to progressive fibrosis. She stated that there are established clinical profiles of MDA5 autoimm.Ghosh mentioned that the disease they were studying was distinctive in its behavior, rate of progression, and the number of deaths it caused. The team from UC San Diego used BoNE to analyze McGonagle’s data and discovered that patients with a high MDA5 response also had elevated levels of interleukin-15. Ghosh explained that interleukin-15 is a cytokine that can activate two major types of immune cells, leading to cellular exhaustion and an immunologic phenotype commonly associated with progressive interstitial lung disease or fibrosis.
BoNE enabled the team to identify the cause of the Yorkshire syndrome and identify a specific single nucleotide polymorphism that provides protection. As a result of their discovery, the group was able to name the condition: MDA5-autoimmunity and Interstitial Pneumonitis Contemporaneous with COVID-19. It is abbreviated as MIP-C, pronounced as “mipsy.” Ghosh stated that the name was chosen to establish a connection with MIS-C, a separate COVID-related condition in children.
Ghosh mentioned that it is highly unlikely that MIP-C is limited to the United Kingdom. Symptoms of MIP-C are being reported from various regions around the world.
he expressed her desire that the team’s discovery of interleukin-15 as a potential cause will spark further research into potential treatments.
The University of California San Diego co-authors are all mentioned above.
This research was partially funded by the National Institute for Health Research (NIHR) Leeds Biomedical Research Centre (BRC), as well as by the National Institutes for Health (NIH) grant R01-AI155696 and pilot awards from the University of California Office of the President Research Grants Program Office (R00RG2628, R00RG2642 and R01RG3780) to Pradipta Ghosh. Saptarshi Sinha received partial support from R01-AI141630 (to Pradipta Ghosh) and in part byThis research was funded by the American Association of Immunologists (AAI) Intersect Fellowship Program for Computational Scientists and Immunologists.
