Targets for Food Allergy

Food allergy is a complex immunological disorder characterized by inappropriate immune responses to otherwise harmless food antigens, leading to acute and chronic inflammation, tissue damage, and potentially life-threatening anaphylaxis. The molecular targets identified here—Bruton tyrosine kinase (BTK), C-C motif chemokine receptor 9 (CCR9), histamine receptor H1 (HRH1), immunoglobulin heavy constant epsilon (IGHE), interleukin 13 (IL13), interleukin 17A (IL17A), interleukin 17F (IL17F), microRNA 155 (MIR155), TNF receptor superfamily member 1B (TNFRSF1B), toll like receptor 4 (TLR4), and toll like receptor 9 (TLR9)—collectively map the immunopathogenic landscape of food allergy. These targets are integral to the initiation, amplification, and effector phases of allergic responses, encompassing antigen presentation, T-cell polarization, B-cell class switching, IgE production, mast cell degranulation, cytokine/chemokine signaling, and tissue inflammation. Understanding these molecular players elucidates the mechanisms underlying disease onset and progression, reveals novel biomarkers for diagnosis and monitoring, and highlights actionable nodes for therapeutic intervention. The strategic targeting of these molecules—via small molecules, monoclonal antibodies, or nucleic acid-based therapies—has the potential to modulate key pathogenic pathways, offering opportunities for disease modification, symptom control, and prevention of severe allergic reactions. This integrated mechanistic insight is foundational for rational drug development and precision medicine approaches in food allergy.

Ige-Mediated Effector Phase And Mast Cell Activation

This category encompasses targets directly responsible for the classical effector mechanisms of food allergy, particularly those that mediate IgE production, mast cell/basophil activation, and histamine release. The key targets are immunoglobulin heavy constant epsilon (IGHE) and histamine receptor H1 (HRH1), which are central to the acute allergic response. These molecules are essential for the onset of allergic symptoms, including urticaria, bronchoconstriction, and anaphylaxis. Their activity is tightly linked to disease severity, and they serve as both biomarkers and therapeutic targets in clinical management.

Immunoglobulin Heavy Constant Epsilon (IGHE)

The immunoglobulin heavy constant epsilon (IGHE) gene encodes the constant region of the IgE heavy chain, which is a hallmark of allergic sensitization and the central mediator of type I hypersensitivity reactions. Structurally, IgE consists of two heavy (epsilon) and two light chains, with the Fc region binding to high-affinity FcεRI receptors on mast cells and basophils. Allergen-induced crosslinking of IgE-FcεRI complexes triggers degranulation and release of histamine, prostaglandins, and cytokines. Regulation of IGHE expression is controlled by class-switch recombination in B cells under the influence of Th2 cytokines, notably IL-4 and IL-13. Elevated serum IgE is a diagnostic and prognostic biomarker for food allergy. Therapeutically, anti-IgE monoclonal antibodies (e.g., omalizumab) have shown efficacy in reducing allergic symptoms and lowering the threshold for anaphylaxis in food-allergic individuals. (Entrez: 3497, UniProt: P01854)

Histamine Receptor H1 (HRH1)

Histamine receptor H1 (HRH1) is a G protein-coupled receptor (GPCR) primarily expressed on smooth muscle, endothelial cells, and neurons. Upon mast cell/basophil degranulation, histamine binds to HRH1, mediating vasodilation, increased vascular permeability, bronchoconstriction, and pruritus—key features of the allergic response. The HRH1 protein contains seven transmembrane domains, with ligand binding leading to Gq/11 activation and downstream PLC-IP3-Ca2+ signaling. HRH1 antagonists (antihistamines) are first-line symptomatic treatments for allergic reactions, including those due to food allergens. HRH1 expression and function are upregulated in allergic tissues. (Entrez: 3269, KEGG: 3269, UniProt: P35367)

Th2/Th17 Cytokine And Inflammatory Pathways

This category includes cytokines and their downstream signaling molecules that orchestrate the differentiation and effector functions of T helper cell subsets implicated in food allergy, particularly Th2 and Th17 cells. The principal targets are interleukin 13 (IL13), interleukin 17A (IL17A), and interleukin 17F (IL17F). These cytokines drive IgE class switching, eosinophilia, barrier dysfunction, and tissue inflammation. Their dysregulation is associated with disease severity, chronicity, and comorbid atopic disorders. Targeting these pathways offers opportunities for disease-modifying therapies.

Interleukin 13 (IL13)

Interleukin 13 (IL13) is a secreted cytokine produced by Th2 cells and type 2 innate lymphoid cells (ILC2s). Structurally, IL13 is a four-helix bundle cytokine that signals via the IL-13Rα1/IL-4Rα receptor complex, activating STAT6. IL13 promotes IgE class switching in B cells, mucus hypersecretion, goblet cell metaplasia, and tissue fibrosis. In food allergy, IL13 is upregulated in gut mucosa and circulation, correlating with disease activity and severity. Monoclonal antibodies targeting IL13 (e.g., lebrikizumab, tralokinumab) and its receptor are under investigation for allergic diseases. (Entrez: 3596, KEGG: 3596, UniProt: P35225)

Interleukin 17A (IL17A)

Interleukin 17A (IL17A) is a pro-inflammatory cytokine produced by Th17 cells, γδ T cells, and ILC3s. IL17A forms homodimers or heterodimers with IL17F and binds to the IL17RA/IL17RC receptor complex, triggering NF-κB and MAPK signaling. In food allergy, IL17A contributes to neutrophilic inflammation, epithelial barrier disruption, and chronicity, particularly in severe or non-IgE-mediated phenotypes. Elevated IL17A has been detected in the gut and serum of allergic patients. Therapeutic targeting of IL17A is established in other inflammatory diseases and is being explored in allergy. (Entrez: 3605, KEGG: 3605, UniProt: Q16552)

Interleukin 17F (IL17F)

Interleukin 17F (IL17F) is closely related to IL17A and is co-expressed by Th17 cells. IL17F signals via the same receptor complex as IL17A, inducing production of chemokines, antimicrobial peptides, and matrix metalloproteinases. In food allergy, IL17F is implicated in mucosal inflammation and barrier dysfunction, and its levels are elevated in affected tissues. IL17F may act synergistically with IL17A to exacerbate disease. (Entrez: 112744, KEGG: 112744, UniProt: Q96PD4)

Innate Immune Sensing And Amplification

This category includes targets that mediate innate immune recognition of food antigens and potentiate adaptive immune responses. Toll like receptor 4 (TLR4) and toll like receptor 9 (TLR9) are pattern recognition receptors that detect microbial and endogenous danger signals, modulating dendritic cell activation, cytokine production, and T-cell polarization. Their activation can exacerbate allergic sensitization, promote Th2/Th17 skewing, and amplify mucosal inflammation.

Toll Like Receptor 4 (TLR4)

Toll like receptor 4 (TLR4) is a transmembrane pattern recognition receptor that senses lipopolysaccharide (LPS) and endogenous alarmins. TLR4 signaling via MyD88 and TRIF pathways leads to NF-κB and IRF3 activation, inducing pro-inflammatory cytokines and type I interferons. In food allergy, TLR4 is upregulated in intestinal epithelial and immune cells, and its activation enhances dendritic cell maturation, Th2 polarization, and IgE production. Animal models show that TLR4 deficiency reduces allergic sensitization. TLR4 antagonists are being explored as anti-inflammatory agents. (Entrez: 7099, KEGG: 7099, UniProt: O00206)

Toll Like Receptor 9 (TLR9)

Toll like receptor 9 (TLR9) recognizes unmethylated CpG DNA motifs from bacteria and viruses. TLR9 is localized in endosomal compartments of dendritic cells, B cells, and epithelial cells. Its activation induces type I interferons and pro-inflammatory cytokines, shaping immune responses. In food allergy, TLR9 signaling contributes to Th2/Th17 skewing and may exacerbate allergic inflammation. Synthetic TLR9 agonists and antagonists are under investigation for immune modulation. (Entrez: 54106, KEGG: 54106, UniProt: Q9NR96)

Adaptive Immune Regulation And Sensitization

This category includes targets involved in the regulation and amplification of adaptive immune responses, especially those that modulate T and B cell activation, differentiation, and cytokine production. Bruton tyrosine kinase (BTK), microRNA 155 (MIR155), TNF receptor superfamily member 1B (TNFRSF1B), and C-C motif chemokine receptor 9 (CCR9) play key roles in B cell receptor signaling, T cell function, migration, and inflammatory amplification. Dysregulation of these molecules promotes allergic sensitization, IgE production, and tissue inflammation.

Bruton Tyrosine Kinase (BTK)

Bruton tyrosine kinase (BTK) is a cytoplasmic non-receptor tyrosine kinase critical for B cell receptor (BCR) signaling, survival, and differentiation. The BTK protein features PH, SH2, SH3, and kinase domains. BTK is essential for B cell development and IgE class switching. Inhibition of BTK reduces B cell activation, mast cell degranulation, and allergic responses in preclinical models. BTK inhibitors (e.g., ibrutinib, acalabrutinib) are being evaluated for allergic and autoimmune diseases. (Entrez: 695, KEGG: 695, UniProt: Q06187)

MicroRNA 155 (MIR155)

MicroRNA 155 (MIR155) is a non-coding RNA that post-transcriptionally regulates gene expression in immune cells. MIR155 is upregulated upon allergen exposure and controls differentiation of Th2 and Th17 cells, B cell class switching, and cytokine production. MIR155 knockout mice are resistant to allergic sensitization and anaphylaxis. Therapeutic inhibition of MIR155 attenuates IgE responses and inflammation in models of food allergy. (Entrez: 406947)

TNF Receptor Superfamily Member 1B (TNFRSF1B)

TNF receptor superfamily member 1B (TNFRSF1B, also known as TNFR2) is a cell surface receptor for TNF-α. It is expressed on Tregs, effector T cells, and endothelial cells, mediating cell survival, proliferation, and inflammation. In food allergy, TNFRSF1B signaling amplifies Th2 responses, enhances mast cell activity, and promotes tissue inflammation. TNFRSF1B antagonists are being investigated for immune modulation. (Entrez: 7133, KEGG: 7133, UniProt: P20333)

C-C Motif Chemokine Receptor 9 (CCR9)

C-C motif chemokine receptor 9 (CCR9) is a GPCR expressed on T cells and involved in their homing to the gut via interaction with its ligand CCL25. In food allergy, CCR9 expression is upregulated on allergen-specific T cells, facilitating their migration to the intestinal mucosa and contributing to local inflammation. CCR9 antagonists are in development for inflammatory gut diseases and may have potential in food allergy. (Entrez: 10803, KEGG: 10803, UniProt: P51686)