huIGHE Mouse

The immunoglobulin heavy constant epsilon region (IGHE), also known as the IgE heavy chain constant region, is a member of the immunoglobulin heavy chain gene family. It is the gene encoding the heavy chain constant region of immunoglobulin E (IgE) antibody and plays a central role in type I hypersensitivity reactions and allergic immune responses. The ε heavy chain constant region encoded by this gene specifically mediates the binding of IgE to the high-affinity receptor FcεRI and the low-affinity receptor FCER2/CD23. When IgE binds to receptors on the surface of effector cells via its Fc segment and is cross-linked by allergens, it initiates downstream signal transduction, leading to degranulation of mast cells and basophils, and the release of histamine, leukotrienes, cytokines, and other inflammatory mediators, thereby driving the classical immediate-type allergic reaction ^[1]. IGHE is primarily expressed after B cells differentiate and mature into plasma cells. The IgE it encodes is mainly distributed in the serum (in trace amounts) and tissues, where it binds to receptors on the surface of mast cells and basophils, indicating its critical role in the regulation of allergic inflammation ^[2].

Studies have shown that IGHE gene polymorphisms, such as the alleles IGHE01 and IGHE02, along with related regulatory variants, can influence IgE production levels and are closely associated with the susceptibility and severity of IgE-mediated allergic diseases, including asthma, allergic rhinitis, atopic dermatitis, and chronic urticaria ^[3]. Based on its central role in IgE-mediated allergic reactions, IGHE and the IgE molecule it encodes have become important molecular targets for biologic therapies in allergic diseases. Research has found that IGHE-targeted gene silencing therapy can successfully redirect transcripts from the secretory form to the membrane form, significantly reducing IgE secretion while inducing apoptosis of IgE+ plasma cells ^[4]. The first approved anti-IgE humanized monoclonal antibody, omalizumab, targets IgE to block the IgE-FcεRI pathway and is used to treat moderate-to-severe allergic asthma, chronic urticaria, and other diseases ^[5]. Ligelizumab and other novel anti-IgE candidate drugs, such as UB-221 and LP-003, are in Phase II or III clinical trials, primarily targeting chronic spontaneous urticaria, allergic asthma, and food allergies ^[6].

huIGHE mice are a humanized model constructed using gene editing technology. The sequences from TCT in exon 1 to the TAG stop codon in exon 6 of the endogenous mouse Ighe gene were replaced with the sequences from TCC in exon 1 to the TAG stop codon in exon 6 of the human IGHE gene. huIGHE mice can be used to study the pathogenesis of IgE-mediated allergic diseases, such as allergic asthma, allergic rhinitis, atopic dermatitis, and chronic urticaria. They are also suitable for preclinical pharmacodynamic evaluation of IgE-related antibody drugs and gene therapy strategies.