An international team of researchers led by a physician from the Karl Landsteiner University for Health Sciences in Krems, Austria, has identified a duplication of the Interleukin 33 (IL-33) gene that causes a previously unidentified allergic and autoimmune disease. The diagnosis was provided to the 12-year-old boy who suffers from the disease after presenting to physicians with inflammation of the skin and the esophagus, food allergy, and asthma among other symptoms. IL-33 has been identified as a central upstream regulator of human immune responses.
The case is considered a breakthrough as it provides insights to the function of IL-33, as previous studies of the gene have been limited to in vitro cellular or animal models. With new insights from this case on the effects of the dysregulation of IL-33 in humans, the team is hopeful this new information will open avenues to explore the development of new therapeutic options for patients affected by this mutation.
“One of the most striking symptoms of the patient is chronic inflammation of the esophagus, an eosinophilic esophagitis, as well as chronic inflammatory changes of the skin,” said Prof. Thomas Eiwegger, head of the Department of Pediatrics and Adolescent Medicine at St. Pölten University Hospital, which is part of Karl Landsteiner University for Health Sciences. This resulted in a high number of eosinophilic granulocytes (hypereosinophilia), elevated levels of IgE antibodies, and recurrent eosinophil-dominated inflammation of the skin, he noted. “Especially the skin reactions and the inflammation of the esophagus confirm the central role of IL-33 in type-2 immune reactions in tissues exposed to the external environment.”
The human body’s type-2 immune response serves to defend against larger pathogens, but also represents the hallmark of allergic inflammation. IL-33 plays a central role in the initiation and regulation of allergic inflammation. Studies in animal models in which its production is genetically up- or down-regulated have contributed to the understanding and suggested functions beyond allergic inflammation, while allowing only a limited view of how this affects human. The disease symptoms of a patient with a duplicated IL-33 gene now provide such insight for the first time.
Much of the work for the publication of these new findings were conducted in studies at The Hospital for Sick Children in Toronto. Other symptoms in the diagnosed child beyond inflammation included physical abnormalities such as in the cranial bones, the jaw and the face, delayed weight gain and growth in length with hypermobility of the joints, short-sightedness, and a moderate developmental delay.
A curious finding of the research was that the gene duplication showed no increase in the concentration of the cytokine IL-33 in the blood. Yet, there were significant increases of it in the tissues of the gastrointestinal tract as well as the skin.
“The different subcellular localizations of IL-33 in different tissues were also striking,” noted Eiwegger. “For example, it showed up in the nucleus in inflamed skin tissue, but in the cytoplasm in inflammation-free intestinal tissue.”
The team suggests that these results show how tightly IL-33 is regulated locally and points to new explanations for the patient’s tissue-specific disease patterns that could be critical for targeted therapies for diseases in which IL-33 plays a role. The team points to a number of different potential monoclonal antibodies current in Phase II trials for conditions such as asthma, atopic dermatitis, and food allergies as one that could potentially be effective.
