Scientists Identify Gene Region that Fuels Asthma Inflammation

Pollen and house dust mites are two common allergens that cause respiratory distress in asthma patients. However, type-2 helper T (Th2) cells and group-2 innate lymphoid cells (ILC2s) release a class of proteins known as type-2 cytokines in response to a variety of asthma triggers. GATA-binding protein 3 (GATA3) is essential for the maturation of Th2 and ILC2.

The human GATA3 gene expression is elevated by particular gene sequences known as enhancers. Research has shown that enhancers affect the development of Th2 and ILC2 by regulating the production of GATA3.

The function of the gene region G900, which is near the GATA3 gene, in the asthma inflammation pathway is presently being studied. Recent research has revealed that the mouse gene region corresponding to the human G900 is involved in Th2 differentiation and, as a result, in enhancing allergic responses, but not ILC2. The study has been published in the Proceedings of the National Academy of Sciences.

Multiple genome-wide association studies (GWAS) have aimed to elucidate the underlying biology and predict susceptibility to asthma. The importance of single nucleotide polymorphisms (SNPs) within the 10p14 locus has been indicated in several independent studies, not only in asthma susceptibility but also in a broad spectrum of allergic diseases, including allergic rhinitis, atopic dermatitis, and eosinophilic granulomatosis with polyangiitis.”

Hiroshi Nakajima, Professor and Study Lead Researcher, Chiba University

Researchers from the Graduate School of Medicine at Chiba University, including Arifumi Iwata, Takashi Kumagai, and Hiroki Furuya, created mice lacking the G900 region in their genomes to study the function of G900 in asthma-associated inflammatory pathways.

The mG900 "knockout mice" were later exposed to allergens like papain and house dust mites. Researchers observed that these mice exhibited a diminished inflammatory response compared to the control group with intact mG900 when exposed to house dust mites. Additionally, they noted a suppression of Th2 differentiation in the knockout mice compared to the controls.

One aspect we elucidate in our study is the role of the murine G900 region in Th2 differentiation and allergic airway inflammation. This region, homologous to the human G900 region associated with asthma, is shown to be essential for in vivo Th2 cell differentiation and allergic responses, particularly in the context of house dust mite (HDM)-induced allergic airway inflammation. Furthermore, we have demonstrated that this G900 region is crucial for optimizing the three-dimensional chromatin structure near GATA3 in Th2 cells.”

Hiroshi Nakajima, Professor and Study Lead Researcher, Chiba University

The results of the study have broad ramifications for treating other allergic diseases and treating asthma. Pharmacologically limiting GATA3 enhancers such as G900 can regulate Th2 differentiation and function in the future, potentially lowering the heightened immune responses that underlie allergic reactions. 

By identifying and understanding critical genetic regions that regulate immune responses, such as the mG900 region, it may be possible to develop precision medicine approaches tailored to individual genetic profiles. This could lead to more effective and personalized treatments, reducing the incidence and severity of allergic reactions and improving the quality of life for individuals suffering from these conditions.”

Hiroshi Nakajima, Professor and Study Lead Researcher, Chiba University