# The Immunogenetic Landscape of Allergic Rhinitis: from Cellular Effectors to Gene Regulation and Targeted Therapies

## TL;DR

This review explores the immunogenetic basis of allergic rhinitis, covering immune pathways, genetic factors, and targeted therapies for better understanding and treatment.

## Contribution

The paper provides a comprehensive framework linking immunology, genetics, and epigenetics to allergic rhinitis pathogenesis and personalized therapies.

## Key findings

- Allergic rhinitis involves Th2 cell-driven adaptive immunity and innate pathways via epithelial alarmins like TSLP and IL-33.
- Genetic risk loci include HLA, FLG, and cytokine-related genes, with epigenetic regulation involving DNA methylation and miRNAs.
- Targeted therapies like omalizumab and dupilumab demonstrate successful translation of immunogenetic insights into treatment.

## Abstract

Allergic Rhinitis (AR) is a highly prevalent type 2 inflammatory disease driven by a complex immunogenetic background. This review aims to systematically delineate the immunogenetic landscape of AR, elucidating the complete knowledge chain from macroscopic cellular interactions and microscopic molecular regulation to precision targeted therapies. The article first dissects the two core immune axes driving the pathological process of AR: one is the classic adaptive immune pathway, centered on Th2 cells, which mediates IgE production, eosinophil infiltration, and mucus hypersecretion through the secretion of cytokines such as IL-4, IL-5, and IL-13; the other is the innate immune initiation pathway, in which nasal epithelial cells act as "sentinels" by releasing "alarmins" like TSLP and IL-33, leading to the rapid activation of type 2 innate lymphoid cells (ILC2s). The review then delves into the sophisticated signaling networks that regulate these immune responses, with a particular focus on the classic IL-4/STAT6/GATA3 signaling axis and its negative regulatory mechanisms. Building on this, the article further elaborates on the genetic susceptibility architecture of AR, highlighting key risk loci identified by genome-wide association studies (GWAS), such as variants in antigen presentation genes (HLA), epithelial barrier genes (FLG), and genes related to cytokine signaling pathways. To connect genetics with the environment, this review systematically summarizes epigenetic regulatory mechanisms, including DNA methylation, histone modifications, and microRNAs (miRNAs), and discusses the long-range immunomodulatory effects of nasal and gut microbiota dysbiosis on AR via the "gut-nasal axis". Finally, from a translational medicine perspective, the article demonstrates how a profound understanding of these pathophysiological mechanisms has successfully spurred the development of highly effective targeted biologics, such as omalizumab (targeting IgE), dupilumab (targeting the IL-4Rα receptor, thus blocking IL-4/IL-13 signaling), and tezepelumab (targeting TSLP). This review integrates the latest multidimensional research advances in immunology, genetics, epigenetics, and microbiome studies of AR, providing a comprehensive theoretical framework for understanding its complex pathogenesis and for the development of future personalized treatment strategies.