Skin and esophageal inflammation, food allergies, and asthma are just a few of the symptoms of a now 12-year-old kid who was the first to be diagnosed with an IL-33 gene mutation.

This disease was found by an international team of researchers led by a physician from the Karl Landsteiner University for Health Sciences, Krems.

Their description of a single case sheds light on the in vivo actions of IL-33, which is thought to be a key upstream regulator of human immune responses. Studies on its function have so far been limited to in vitro cellular or animal models derived from humans. The finding of IL-33 overexpression in humans advances the discovery of fresh information on the effects of its dysregulation in humans. It also brings up potential therapy alternatives for people who are impacted.

The type-2 immune response of the human body serves to defend against greater infections, but it is also the hallmark of allergic inflammation. Interleukin 33 (IL-33) is a key player in the start and regulation of allergic inflammation. It is known as an “alarmin” since it is released in response to cellular injury. Animal studies in which its production is genetically up-or down-regulated have contributed to the knowledge and indicated functions beyond allergic inflammation, but they only provide limited insight into the situations in humans. For the first time, the disease symptoms of a patient with a duplication of the IL-33 gene have revealed this information.

First-described

Prof. Thomas Eiwegger of the Karl Landsteiner Private University for Health Sciences Krems (KL Krems) led a multinational team at The Hospital for Sick Children to make the diagnosis and provide the first description. Prof. Thomas Eiwegger, who recently became head of the Department of Pediatrics and Adolescent Medicine at St. Pölten University Hospital, which is part of KL Krems, explains: “One of the most striking symptoms of the patient is a chronic inflammation of the esophagus, an eosinophilic esophagitis, as well as chronic inflammatory changes of the skin.”

Thus, hypereosinophilia, higher levels of IgE antibodies, and recurring eosinophil-dominated skin inflammation were seen.

“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,” says Prof. Eiwegger. In terms of an autoimmune response, food allergies, asthma, and inflammatory problems of the larger gastrointestinal tract also manifest.

The Hospital for Sick Children in Toronto, Canada, in collaboration with the university there, undertook numerous investigations for the now-published report. In addition to the inflammatory symptoms, the patient’s physical anomalies were documented. These include changes to the cranial bones, jaw, and face, as well as delayed weight gain and growth in length, hypermobility of the joints, myopia, and a moderate developmental delay. These findings, according to Prof. Eiwegger, show that IL-33 has a pleiotropic effect beyond typical type-2 inflammation.

There are more genes. Increased cytokine production

It was fascinating to see how this gene duplication altered the real concentration of the cytokine IL-33 in the blood and other tissues. Although IL-33 levels in the blood did not rise, they did rise significantly in the tissues of the gastrointestinal tract and the skin.

“The different subcellular localizations of IL-33 in different tissues were also striking. For example, it showed up in the nucleus in inflamed skin tissue, but in the cytoplasm in inflammation-free intestinal tissue,” Prof. Thomas Eiwegger adds.

These findings, according to the researchers, demonstrate how tightly IL-33 is regulated locally and hint at novel explanations for the patient’s tissue-specific illness patterns, which could be important for developing tailored therapeutics for diseases where IL-33 plays a role.

In phase 2 research, monoclonal antibodies that bind to and eliminate IL-33 are being examined as therapeutic possibilities for the treatment of asthma, atopic dermatitis, and food allergies — an option that the team believes is also worth considering here. So, this research is an example of modern precision medicine, where basic science has a direct effect on clinical decisions.

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