Eosinophilic esophagitis (EoE) is a chronic allergic inflammatory disease with a complex underlying genetic etiology. Herein, we conduct whole-exome sequencing of a multigeneration EoE pedigree (discovery set) and 61 additional multiplex families with EoE (replication set). A series of rare, heterozygous, missense variants are identified in the genes encoding the desmosome-associated proteins DSP and PPL in 21% of the multiplex families. Esophageal biopsies from patients with these variants retain dilated intercellular spaces and decrease DSP and PPL expression even during disease remission. These variants affect barrier integrity, cell motility and RhoGTPase activity in esophageal epithelial cells and have increased susceptibility to calpain-14-mediated degradation. An acquired loss of esophageal DSP and PPL is present in non-familial EoE. Taken together, herein, we uncover a pathogenic role for desmosomal dysfunction in EoE, providing a deeper mechanistic understanding of tissue-specific allergic responses.

Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus triggered by immune hypersensitivity to food. Herein, we tested whether genetic risk factors for known, non-allergic, immune-mediated diseases, particularly those involving autoimmunity, were associated with EoE risk. We used the high-density Immunochip platform, encoding 200,000 genetic variants for major auto-immune disease. Accordingly, 1214 subjects with EoE of European ancestry and 3734 population controls were genotyped and assessed using data directly generated or imputed from the previously published GWAS. We found lack of association of EoE with the genetic variants in the major histocompatibility complex (MHC) class I, II, and III genes and nearly all other loci using a highly powered study design with dense genotyping throughout the locus. Importantly, we identified an EoE risk locus at 16p13 with genome-wide significance (Pcombined=2.05 × 10-9, odds ratio = 0.76-0.81). This region is known to encode for the genes CLEC16A, DEXI, and CIITI, which are expressed in immune cells and esophageal epithelial cells. Suggestive EoE risk were also seen 5q23 (intergenic) and 7p15 (JAZF1). Overall, we have identified an additional EoE risk locus at 16p13 and highlight a shared and unique genetic etiology of EoE with a spectrum of immune-associated diseases.

Eosinophilic esophagitis (EoE) can progress to fibrostenosis by unclear mechanisms. Herein, we investigated gene dysregulation in fibrostenotic EoE, its association with clinical parameters and specific pathways, and the functional consequences.

Patient-reported outcome metrics for eosinophilic esophagitis (EoE) have been developed and validated but not used in a multicenter pediatric population or systematically aligned with histology.

Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder associated with allergic hypersensitivity to food. We interrogated >1.5 million genetic variants in EoE cases of European ancestry and subsequently in a multi-site cohort with local and out-of-study control subjects. In addition to replicating association of the 5q22 locus (meta-analysis P=1.9×10(-16)), we identified an association at 2p23 spanning CAPN14 (P=2.5×10(-10)). CAPN14 was specifically expressed in the esophagus, was dynamically upregulated as a function of disease activity and genetic haplotype and after exposure of epithelial cells to interleukin (IL)-13, and was located in an epigenetic hotspot modified by IL-13. Genes neighboring the top 208 EoE-associated sequence variants were enriched for esophageal expression, and multiple loci for allergic sensitization were associated with EoE susceptibility (4.8×10(-2)

Eosinophilic esophagitis (EoE) is an esophageal inflammatory disease associated with atopic diseases. Thymic stromal lymphopoietin (TSLP) and calpain 14 (CAPN14) genetic variations contribute to EoE, but how this relates to atopy is unclear.

Mast cells (MCs) are pleiotropic cells that accumulate in the esophagus of patients with eosinophilic esophagitis (EoE) and are thought to contribute to disease pathogenesis, yet their properties and functions in this organ are largely unknown.

Infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) can lead to coronavirus-induced disease 2019 (COVID-19). The gastrointestinal (GI) tract is now an appreciated portal of infection. SARS-CoV-2 enters host cells via angiotensin-converting enzyme-2 (ACE2) and the serine protease TMPRSS2. Eosinophilic gastrointestinal disorders (EGIDs) are inflammatory conditions caused by chronic type 2 (T2) inflammation. the effects of the T2 atopic inflammatory milieu on SARS-COV-2 viral entry gene expression in the GI tract is poorly understood. We analyzed tissue ACE2 and TMPRSS2 gene expression in pediatric eosinophilic esophagitis (EoE), eosinophilic gastritis (EG), and in normal adult esophagi using publicly available RNA-sequencing datasets. Similar to findings evaluating the airway, there was no difference in tissue ACE2/TMPRSS2 expression in EoE or EG when compared with control non-EoE/EG esophagus/stomach. ACE2 gene expression was significantly lower in esophagi from children with or without EoE and from adults with EoE as compared with normal adult esophagi. Type 2 immunity and pediatric age could be protective for infection by SARS-CoV-2 in the gastrointestinal tract because of decreased expression of ACE2.