The human immune system is a marvel of intricate interactions among countless finely-tuned components. It operates harmoniously to ensure that, ideally, we feel nothing at all. Our bodies are in a constant battleground, efficiently eliminating damaged cells and warding off viruses and bacteria.
Immune Reactions Gone Awry
Often, immune responses go unnoticed. However, symptoms such as a runny nose or joint pain signal their activity. In healthy individuals, these reactions are well-regulated. Fever rises but remains manageable, localized inflammation occurs without excessive damage, and the immune system focuses solely on foreign invaders.
Yet, sometimes, this delicate balance is disrupted. The immune system can overreact, leading to severe consequences for those affected—acute or chronic organ inflammation and autoimmune diseases like rheumatoid arthritis or multiple sclerosis may arise.
The Role of Interleukin-1
Researchers, notably Lorenz Thurner and his team at the José Carreras Center for Immunology and Gene Therapy, investigate these complex processes. They focus on a key messenger called Interleukin-1 and its antagonist, Interleukin-1 receptor antagonist (IL-1Ra). When Interleukin-1 is released, an inflammatory response ensues, often accompanied by fever, to combat foreign substances like viruses. In contrast, IL-1Ra blocks binding sites for Interleukin-1, curtailing the inflammatory response to prevent it from spiraling out of control.
However, some individuals’ immune systems react poorly to IL-1Ra. “The immune system produces antibodies to this antagonist, attacking and neutralizing it,” explains Professor Christoph Kessel from the University of Münster, who studies autoimmune and inflammatory processes.
Disruption of Immune Balance
With the blockage of IL-1Ra, Interleukin-1 has free rein to bind to its targets, triggering inflammation. The natural equilibrium between inflammatory responses and their inhibition is disturbed. This phenomenon has been known to Thurner and Kessel’s research team for some time, but the specific actions of IL-1Ra were previously unclear. Recently, they deciphered this mechanism in COVID-19 patients during the pandemic, revealing crucial insights published in the prestigious journal *Nature Communications*.
They identified specific sites on IL-1Ra from severely ill COVID patients where abnormal biochemical changes occurred. According to researchers Evi Regitz and Natalie Fadle from Thurner’s team, these changes, unknown to the adaptive immune system, result in a break in tolerance towards IL-1Ra, triggering an immune and ultimately inflammatory cascade. These findings pinpoint previously unknown weaknesses in the immune response.
Insights from the NAPKON Project
Dr. Bernhard Thurner, a co-author of the study, highlights further findings: “The threshold for these atypical protein modifications is significantly lower in former patients with severe COVID compared to healthy individuals.” However, questions remain: Is COVID-19 a catalyst for these reactions, or were they pre-existing in the patients’ immune systems? Furthermore, why were these patients more susceptible to such reactions? These inquiries could be addressed by the well-coordinated research team in the future.
The data supporting this study chiefly stem from Germany’s NAPKON project, a collective initiative born from decentralized national research efforts during the COVID-19 pandemic in 2020. Known as the “National Pandemic Cohort Network,” it aimed to consolidate COVID-related research activities and make those data accessible to all research institutions.
New Perspectives on Inflammatory Diseases
“This data is invaluable,” asserts Lorenz Thurner, indicating that the immune dysregulation observed is a temporary effect. Over time, the antibody count against IL-1Ra decreases in affected individuals. The mechanism unraveled by the research team is also relevant for other diseases. In a simultaneously released short report in the *Annals of the Rheumatic Diseases*, researchers Zanir Abdi, Lorenz Thurner, and Christoph Kessel demonstrated that similar hyperphosphorylation processes could lead to axial spondyloarthritis, a chronic inflammatory rheumatic disease.
Thus, the scientists’ findings hold significant implications extending beyond a singular condition like COVID-19, potentially guiding future treatments for various inflammatory diseases.
Source: Saarland University
Original Publications:
- Lorenz Thurner et al.; Autoantibodies to IL-1Ra and PGRN in severe COVID-19 are associated with inflammation-induced hyperphosphorylated antigen isoforms; Nat Commun 17, 4768, 2026, DOI: 10.1038/s41467-026-73316-5
- Zanir Abdi et al.; Proinflammatory autoantibodies enhancing tumor necrosis factor and RANKL signaling in axial spondyloarthritis associate with hyperphosphorylated progranulin and osteoprotegerin; Annals of the Rheumatic Diseases, 2026, DOI: 10.1016/j.ard.2026.04.008
