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May 27, 2022
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Discovery of a gene defect that causes allergies and autoimmune diseases

Discovery of gene defect that causes allergies and autoimmune diseases

An international team led by a physician from the Karl Landsteiner University, Krems, has for the first time described the mutation of the IL-33 gene in the human genome, which leads to numerous manifestations of allergic diseases and autoimmune diseases.

Inflammation of the skin and esophagus, food allergies and asthma are just some of the symptoms of a 12-year-old boy who was first diagnosed with an IL-33 gene mutation. An international team led by a physician from the Karl Landsteiner University, Krems, has discovered this new disease.

The description of a single case allows a completely new look at the functions of IL-33, which is considered the central regulator of human immune responses. So far, studies of its function have been limited to in vitro cellular models or human-derived animal models. The discovery of overexpression of IL-33 in humans provides new insight into the implications of its dysregulation in humans. At the same time, this opens up potential therapeutic possibilities for patients suffering from this disease.

The human body’s type 2 immune response serves to protect against large pathogens, but is also a hallmark of allergic inflammation. Interleukin 33 (IL-33), the so-called “alarmin” released when cells are damaged, plays a central role in the initiation and regulation of allergic inflammation.

Animal models in which its production is genetically regulated up or down have contributed to understanding and putative functions beyond allergic inflammation, but they provide only limited insight into the human condition. The symptoms of the disease in a patient with a duplicated IL-33 gene provided the first such insight.

An international team from the Hospital for Sick Children, led by Prof. Thomas Eiwegger of the Private Karl Landsteiner University in Krems (KL Krems), was able to establish the diagnosis and give the first description.

“One of the patient’s most striking symptoms is chronic inflammation of the esophagus – eosinophilic esophagitis, as well as chronic inflammatory skin changes,” explains Prof. Thomas Eiwegger, who recently became head of the Department of Pediatrics and Adolescent Medicine at the University Hospital St. Pölten, part of KL Krems.

Thus, a high number of eosinophilic granulocytes (hypereosinophilia), elevated levels of IgE antibodies, and recurrent skin inflammation with a predominance of eosinophils occurred. According to Prof. Eiwegger: “Especially skin reactions and inflammation of the esophagus confirm the central role of IL-33 in type 2 immune responses in exposed tissues.” In addition, food allergies and asthma, as well as inflammatory complications of the wider gastrointestinal tract, also appear in terms of an autoimmune response.

Numerous studies in the study published in the journal Gastroenterology were conducted at the Hospital for Sick Children in Toronto, Canada, in collaboration with the university there. In addition to the symptoms of inflammation, physical abnormalities in patients were also recorded. These include changes in the cranial bones, jaw, and face, as well as delayed weight gain and growth in length with joint hypermobility, myopia, and mild developmental delay. For Prof. Eiwegger, these are signs of a pleiotropic role for IL-33 that goes beyond classic type 2 inflammation.

It is very interesting how the gene duplication affected the actual concentration of the cytokine IL-33 in the blood and various tissues. Although no increase in IL-33 concentration was observed in the blood, it increased significantly in the tissues of the gastrointestinal tract and skin. “The different subcellular localizations of IL-33 in different tissues were also striking,” notes Prof. Eiwegger. “For example, in inflamed skin tissues it is found in the nucleus, and in non-inflammatory intestinal tissues it is found in the cytoplasm.” The team believes these results show how tightly IL-33 is locally regulated and point to new explanations for tissue-specific features of a patient’s disease that may be critical for targeted therapies for diseases in which IL-33 plays a role.

Monoclonal antibodies that bind and remove IL-33 are being explored as therapeutic options in phase II trials for asthma, atopic dermatitis, and food allergies – an option that the team also considers worthy of evaluation in this case. Thus, this study is an example of modern precision medicine in which basic science directly influences clinical decision making.

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