Targets for Eosinophilic Esophagitis

Eosinophilic Esophagitis (EoE) is a chronic, immune-mediated esophageal disorder characterized by eosinophil-predominant inflammation. Understanding the molecular targets involved in EoE pathogenesis is critical for elucidating disease mechanisms, identifying novel therapeutic interventions, and supporting drug development. The key targets in EoE are predominantly related to Type 2 (Th2) immune responses, cytokine signaling, and eosinophil recruitment and activation. Central to EoE are cytokines such as Interleukin 13 (IL13), Interleukin 4 (IL4), and Thymic Stromal Lymphopoietin (TSLP), which drive the Th2 inflammatory milieu, promote eosinophil trafficking, and upregulate eotaxin-3, a major chemoattractant for eosinophils. Colony Stimulating Factor 2 (CSF2/GM-CSF) further supports eosinophil survival and activation. Downstream signaling molecules such as Janus kinase 1 (JAK1) and nuclear receptor subfamily 3 group C member 1 (NR3C1, the glucocorticoid receptor) modulate cytokine signaling and anti-inflammatory responses, respectively. Prostaglandin D2 receptor 2 (PTGDR2/CRTH2) mediates chemotaxis of Th2 cells and eosinophils, while KIT proto-oncogene (KIT) is involved in mast cell function, another key player in EoE pathology. These targets collectively provide a comprehensive understanding of EoE pathogenesis and highlight multiple intervention points for therapeutic development, including monoclonal antibodies, small-molecule inhibitors, and biologics targeting cytokines, their receptors, or downstream signaling pathways. The identification and characterization of these targets have directly led to the development of targeted therapies such as anti-IL-13 and anti-TSLP antibodies, and JAK inhibitors, which are in various stages of clinical development for EoE.

Th2 Cytokines And Upstream Drivers

This category encompasses cytokines and upstream mediators that orchestrate the Th2 immune response, which is central to EoE pathogenesis. The primary targets are Interleukin 13 (IL13), Interleukin 4 (IL4), and Thymic Stromal Lymphopoietin (TSLP). These molecules drive eosinophil recruitment, activation, and tissue remodeling through the induction of eotaxin-3 (CCL26) and other downstream effectors. Their collective impact is the initiation and maintenance of chronic eosinophilic inflammation in the esophagus.

Interleukin 13 (IL13)

Interleukin 13 (IL13) is a Th2 cytokine with a central role in EoE pathogenesis. Structurally, IL13 is a four-helix bundle cytokine that signals via the IL13Rα1/IL4Rα receptor complex, activating the JAK/STAT6 pathway. IL13 upregulates eotaxin-3 (CCL26) in esophageal epithelial cells, a critical chemokine for eosinophil recruitment. IL13 also promotes tissue remodeling and fibrosis by stimulating periostin and collagen production. Elevated IL13 expression is consistently observed in EoE biopsies (Blanchard et al., Nat Immunol 2006), and anti-IL13 therapies (e.g., lirentelimab, cendakimab) have shown clinical efficacy in reducing eosinophil counts and improving symptoms. IL13 is a validated therapeutic target and a potential biomarker for disease activity. (Entrez: 3596, KEGG: 3596, UniProt: P35225)

Interleukin 4 (IL4)

Interleukin 4 (IL4) is a key Th2 cytokine structurally related to IL13, sharing the IL4Rα receptor subunit and activating STAT6 signaling. IL4 drives Th2 cell differentiation, B cell class switching to IgE, and upregulates eotaxin-3 in esophageal epithelial cells. Like IL13, IL4 is upregulated in EoE tissue and contributes to eosinophil recruitment and local inflammation. Dupilumab, a monoclonal antibody targeting IL4Rα and blocking both IL4 and IL13 signaling, is FDA-approved for EoE, demonstrating the clinical relevance of this pathway. IL4 is a direct mediator of EoE pathogenesis and a validated therapeutic target. (Entrez: 3565, KEGG: 3565, UniProt: P05112)

Thymic Stromal Lymphopoietin (TSLP)

Thymic Stromal Lymphopoietin (TSLP) is an epithelial-derived cytokine that acts as a master regulator of Th2 inflammation. Structurally, TSLP is a four-helix bundle cytokine binding to a heterodimeric receptor (TSLPR/IL7Rα), activating STAT5 via JAK1/2. TSLP is highly expressed in the esophageal epithelium of EoE patients, where it activates dendritic cells to promote Th2 polarization and induces IL4 and IL13 secretion. TSLP genetic variants are associated with EoE susceptibility. Tezepelumab, a monoclonal antibody against TSLP, is in clinical development for EoE and other Th2 diseases. TSLP is a validated upstream driver and a promising therapeutic target. (Entrez: 85480, KEGG: 85480, UniProt: Q969D9)

Eosinophil And Mast Cell Activation And Survival

This category includes targets that directly promote the survival, activation, and recruitment of eosinophils and mast cells, which are the hallmark effector cells in EoE. The key targets are Colony Stimulating Factor 2 (CSF2/GM-CSF), KIT proto-oncogene (KIT), and Prostaglandin D2 receptor 2 (PTGDR2/CRTH2). These molecules sustain local inflammation and tissue remodeling by supporting effector cell function.

Colony Stimulating Factor 2 (CSF2)

Colony Stimulating Factor 2 (CSF2), also known as GM-CSF, is a cytokine that promotes the survival, differentiation, and activation of eosinophils and other myeloid cells. CSF2 is a glycoprotein that binds to the GM-CSF receptor (CSF2RA/CSF2RB), activating JAK2/STAT5 signaling. Elevated CSF2 levels are found in EoE esophageal tissue, correlating with eosinophil infiltration. CSF2 enhances eosinophil viability and prolongs their inflammatory activity. Therapeutic targeting of CSF2 or its receptor is under investigation in eosinophilic disorders, though not yet approved for EoE. CSF2 is a direct effector in EoE pathogenesis. (Entrez: 1437, KEGG: 1437, UniProt: P04141)

KIT Proto-Oncogene, Receptor Tyrosine Kinase (KIT)

KIT is a type III receptor tyrosine kinase expressed on mast cells and some hematopoietic progenitors. It binds stem cell factor (SCF), leading to receptor dimerization and activation of PI3K/AKT, MAPK, and JAK/STAT pathways. Mast cells are increased in EoE tissue and contribute to fibrosis and barrier dysfunction. KIT signaling is essential for mast cell survival and activation. Inhibitors of KIT (e.g., imatinib) have shown efficacy in steroid-refractory EoE, supporting a pathogenic role for KIT+ mast cells. (Entrez: 3815, KEGG: 3815, UniProt: P10721, A0A8I5KS03)

Prostaglandin D2 Receptor 2 (PTGDR2)

Prostaglandin D2 receptor 2 (PTGDR2), also known as CRTH2, is a G-protein coupled receptor expressed on eosinophils, Th2 cells, and basophils. PTGDR2 binds prostaglandin D2 (PGD2), mediating chemotaxis and activation of Th2 cells and eosinophils. Increased PTGDR2 expression and PGD2 production are observed in EoE esophageal biopsies. Antagonists of PTGDR2 (e.g., fevipiprant) are in development for allergic diseases and may have potential in EoE. PTGDR2 is a direct mediator of eosinophil and Th2 cell recruitment in EoE. (Entrez: 11251, KEGG: 11251, UniProt: Q9Y5Y4)

Cytokine Signaling And Modulation

This category comprises intracellular signaling molecules and receptors that mediate or regulate cytokine signaling in EoE. Janus kinase 1 (JAK1) is essential for transducing signals from multiple Th2 cytokines, while Nuclear Receptor Subfamily 3 Group C Member 1 (NR3C1, the glucocorticoid receptor) mediates anti-inflammatory responses. These targets influence the intensity and duration of Th2 inflammation and are critical for therapeutic intervention.

Janus Kinase 1 (JAK1)

Janus kinase 1 (JAK1) is a non-receptor tyrosine kinase involved in the signaling of multiple cytokines, including IL4, IL13, and TSLP. JAK1 forms complexes with other JAKs to phosphorylate STAT proteins, leading to transcription of inflammatory genes. In EoE, JAK1 mediates Th2 cytokine-driven inflammation and tissue remodeling. JAK inhibitors (e.g., upadacitinib, tofacitinib) are in clinical trials for EoE and have shown efficacy in reducing eosinophilic inflammation. JAK1 is a central hub in cytokine signaling and a validated therapeutic target. (Entrez: 3716, KEGG: 3716, UniProt: P23458)

Nuclear Receptor Subfamily 3 Group C Member 1 (NR3C1)

Nuclear Receptor Subfamily 3 Group C Member 1 (NR3C1), also known as the glucocorticoid receptor, is a ligand-activated transcription factor that mediates the anti-inflammatory effects of corticosteroids. Upon ligand binding, NR3C1 translocates to the nucleus and represses pro-inflammatory gene expression, including Th2 cytokines and eotaxin-3. Corticosteroids are the mainstay of EoE therapy, and resistance or dysfunction of NR3C1 can lead to refractory disease. NR3C1 is a critical modulator of inflammation and a key therapeutic target in EoE. (Entrez: 2908, KEGG: 2908, UniProt: P04150)