An international team of scientists from the Karl Landsteiner University for Health Sciences, Kremsstated in recent research that the mutation of the IL33 gene in the human genome is the cause of several manifestations of allergic diseases and autoimmune diseases.
The results of the study have been published in the scientific journal Gastroenterology.
IL33 gene mutation: this is what the research says
Inflammation of the skin and esophagus, food allergies and asthma are just some of the symptoms of a 12-year-old boy who was the first identified to have a mutation on the IL33 gene. An international team led by a doctor from Karl Landsteiner University for Health Sciences, Krems, has discovered this new pathological entity. Their single case description provides entirely new insights into the in vivo functions of the IL33 gene, which is considered a central regulator upstream of human immune responses.
To date, research on its function has been limited to human-derived in vitro cell or animal models. This discovery of an overexpression of the IL33 gene in humans is a step forward that helps to possess new knowledge about the consequences of its dysregulation in humans. At the same time, it also opens up new scenarios on better performing therapeutic treatments for individuals affected by allergies or autoimmune diseases.
The human body’s type 2 immune response serves to defend against larger pathogens, but it is also the hallmark of allergic inflammation. the IL33 gene, a so-called “alarmin”Due to its release following cell damage, it plays a central role in the initiation and regulation of allergic inflammation.
Animal models in which its production is genetically up or down regulated have contributed to understanding and suggested functions beyond allergic inflammation, but allow only a limited view of the conditions in humans. The disease symptoms of an individual with a duplicated IL33 gene now provide that insight for the first time.
An international team from the hospital for sick children led by the Professor Thomas Eiwegger of the Karl Landsteiner Private University for Health Sciences Krems (KL Krems) was able to formulate the diagnosis and provide the first description: “One of the patient’s most striking symptoms is chronic inflammation of the esophagus, esophagitis of the esophagus, as well as chronic inflammatory skin changes“Explained Professor Thomas Eiwegger, chief of the Department of Pediatrics and Adolescent Medicine at the University Hospital St. Pölten, which is part of the KL Krems.
Therefore, there was a high number of eosinophilic granulocytes (hypereosinophilia), elevated levels of IgE antibodies, and recurrent eosinophil-dominated skin inflammation. According to Professor Eiwegger: “Especially skin reactions and inflammation of the esophagus confirm the central role of IL-33 in type 2 immune reactions in tissues exposed to the external environment“. Furthermore, food allergies and asthma, as well as inflammatory complications of the broader gastrointestinal tract, also manifest themselves in terms of autoimmune responses.
Numerous investigations into the research have been conducted at the Hospital for Sick Children in Toronto, Canada, in collaboration with the local university. In addition to inflammatory symptoms, the patient’s physical abnormalities were also recorded.
These include: changes in the cranial bones, jaw and face, as well as delayed weight gain and growth in length with hypermobility of the joints, myopia and moderate developmental delay. According to Professor Eiwegger, these are indications of the pleiotropic role of the IL33 gene beyond classic type 2 inflammation.
The extent to which this gene duplication affected the effective concentration of the cytokine IL-33 in the blood and various tissues was very interesting. Although there was no increase in the IL33 gene in the blood, there were significant increases in the tissues of the gastrointestinal tract and in the skin.
“The different subcellular locations of IL-33 in different tissues were also striking“, Professor Eiwegger added:”For example, it appeared in the nucleus in the inflamed skin tissue, but in the cytoplasm in the intestinal tissue free of inflammation“. The team believes these findings show how tightly the IL33 gene is regulated locally and point to new explanations for patient tissue-specific disease patterns that could be critical for targeted therapies for diseases in which IL-33 plays a role.
Monoclonal antibodies that bind and remove the IL33 gene are being investigated as therapeutic options in Phase 2 studies for the treatment of asthma, atopic dermatitis and food allergies, an option the team also considers worthy of consideration here.. Therefore, this research exemplifies modern precision medicine where basic science has a direct impact on clinical decision making.
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