**Background:** Toll-like receptors (TLRs) are pattern recognition receptors that link innate and adaptive immunity by recognizing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Allergic diseases, such as asthma and allergic rhinitis, are increasing globally, and both genetic variations in TLR-related genes and environmental factors influence their development. This review aims to provide a holistic view of TLR involvement in IgE-mediated allergic diseases, covering TLR expression, genetic associations, environmental modulation, allergen–TLR interactions, and therapeutic targeting.
**Methods:** The authors conducted a narrative review of the literature, synthesizing findings from in vitro studies, animal models, genetic association studies (GWAS and target sequencing), and clinical trials. They focused on TLR expression in organs and cells involved in allergic responses, differential expression between allergic and non-allergic individuals, the role of TLRs in inducing or protecting against Th2 responses, genetic polymorphisms in TLR genes, environmental factors (microbial exposure, virome, smoking, air pollution), and direct/indirect interactions of allergens with TLRs. Therapeutic approaches using TLR ligands, TLR-ligand allergen fusion proteins, TLR antagonists, and probiotics were also reviewed.
**Key Results:** TLR expression varies by cell type and tissue; for example, human nasal epithelial cells express high levels of TLR3, TLR6, TLR7, and TLR10, while alveolar macrophages express TLR1, TLR2, TLR4, and TLR7 most highly. In allergic individuals, TLR2 and TLR4 mRNA and protein levels are increased in the nasal epithelium of patients with persistent allergic rhinitis, and TLR4 expression on neutrophils is elevated during pollen season. TLR3 mRNA increases in nasal tissue of birch and grass pollen allergic patients during season. Genetic studies have identified numerous SNPs in TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, and TLR10 associated with asthma, allergic rhinitis, atopic dermatitis, and allergic sensitization. For instance, the TLR2 SNP rs7656411 (GT/TT genotype) was significantly associated with increased risk of allergic rhinitis in a Chinese case-control study (452 patients, 495 controls). Environmental factors such as farming exposure upregulate TLR2, TLR4, and CD14 expression in children, protecting against allergic sensitization. In a murine model, maternal intranasal exposure to Acinetobacter lwoffii F78 upregulated TLR2, TLR3, TLR6, TLR7, and TLR9 mRNA in the mother's lung and protected offspring from allergic airway inflammation. Allergen sources interact with TLRs: Der p 2 from house dust mites mimics MD-2 and enhances TLR4 signaling; Fel d 1 from cat dander enhances LPS-induced TLR4 activation by approximately 15-fold; ragweed pollen extracts induce TLR4-dependent neutrophil infiltration; and nickel directly activates human TLR4 via histidine residues H456 and H458. Therapeutic applications include the TLR4 agonist monophosphoryl lipid A (MPLA) used in allergen immunotherapy products in Europe, and TLR7 agonist AZD8848 which reduced nasal symptoms in birch and grass pollen allergic rhinitis patients after repeated intranasal administration. However, TLR9 agonist AZD1419 did not significantly improve asthma symptoms in a clinical trial despite reducing type 2-associated plasma cytokines.
**Clinical Implications:** The review underscores the central role of TLR4 in allergic sensitization, with most allergen sources interacting with this receptor, often via LPS or LPS-like molecules. This suggests that targeting TLR4 signaling could be a promising therapeutic strategy. The differential effects of TLR activation—low-dose LPS promoting Th2 responses and high-dose promoting Th1 responses—highlight the importance of dose and route in designing immunomodulatory therapies. Genetic polymorphisms in TLR genes may serve as biomarkers for allergy risk and guide personalized treatment. The protective effects of microbial exposure, particularly in farming environments, support the hygiene hypothesis and suggest that early-life TLR stimulation may prevent allergies. Current AIT products using MPLA demonstrate the feasibility of TLR-based adjuvants, but more clinical trials are needed to evaluate TLR agonists and antagonists. The review also identifies knowledge gaps, such as the role of the host microbiome and the pollen microbiome in modulating TLR responses, and the need for human studies under non-sterile conditions to better mimic natural sensitization.