calpain and Eosinophilic-Esophagitis

Eosinophilic esophagitis (EoE) is an emerging chronic inflammatory disease of the oesophagus and is clinically characterized by upper gastrointestinal (GI) symptoms including dysphagia and esophageal food impaction. Histopathologic manifestations, which include intraepithelial eosinophilic inflammation and alterations of the esophageal squamous epithelium, such as basal zone hyperplasia (BZH) and dilated intercellular spaces (DIS), are thought to contribute to esophageal dysfunction and disease symptoms. Corroborative clinical and discovery science-based studies have established that EoE is characterized by an underlying allergic inflammatory response, in part, related to the IL-13/CCL26/eosinophil axis driving dysregulation of several key epithelial barrier and proliferative regulatory genes including kallikrein (KLK) serine proteases, calpain 14 (CAPN14) and anoctamin 1 (ANO1). The contribution of these inflammatory and proliferative processes to the clinical and histological manifestations of disease are not fully elucidated. Herein, we discuss the immune molecules and cells that are thought to underlie the clinical and pathologic manifestations of EoE and the emerging therapeutics targeting these processes for the treatment of EoE.

Topics: Anoctamin-1; Calpain; Eosinophilic Esophagitis; Eosinophils; Humans; Interleukin-13; Kallikreins; Serine Proteases

Eosinophilic esophagitis (EoE) is a relatively new condition described as an allergic-mediated disease of the esophagus. Clinically, it is characterized by dysphagia, food impaction, and reflux-like symptoms. Multiple genome-wide association studies (GWAS) have been conducted to identify genetic loci associated with EoE. The integration of numerous studies investigating the genetic polymorphisms in EoE and the Mendelian diseases associated with EoE are discussed to provide insights into the genetic risk of EoE, notably focusing on

Topics: Calpain; Chemokine CCL26; Cytokines; Eosinophilic Esophagitis; Esophagus; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Hypersensitivity; Interleukin-13; Th2 Cells; Transforming Growth Factor beta1

Calpains are a family of intracellular, calcium-dependent cysteine proteases involved in a variety of regulatory processes, including cytoskeletal dynamics, cell-cycle progression, signal transduction, gene expression, and apoptosis. These enzymes have been implicated in a number of disease processes, notably for this review involving eosinophilic tissue inflammation, such as eosinophilic esophagitis (EoE), a chronic inflammatory disorder triggered by allergic hypersensitivity to food and associated with genetic variants in calpain 14 (CAPN14). Herein we review the genetic, structural, and biochemical properties of CAPN14 and its gene product CAPN14, and its emerging role in patients with EoE. The CAPN14 gene is localized at chromosome 2p23.1-p21 and is most homologous to CAPN13 (36% sequence identity), which is located 365 kb downstream of CAPN14. Structurally, CAPN14 has classical calpain motifs, including a cysteine protease core. In comparison with other human calpains, CAPN14 has a unique expression pattern, with the highest levels in the upper gastrointestinal tract, particularly in the squamous epithelium of the esophagus. The CAPN14 gene is positioned in an epigenetic hotspot regulated by IL-13, a T

Topics: Animals; Calpain; Eosinophilic Esophagitis; Humans; Protein Conformation

Eosinophilic esophagitis (EoE) is a chronic, allergic disease associated with marked mucosal eosinophil accumulation. EoE disease risk is multifactorial and includes environmental and genetic factors. This review will focus on the contribution of genetic variation to EoE risk, as well as the experimental tools and statistical methodology used to identify EoE risk loci. Specific disease-risk loci that are shared between EoE and other allergic diseases (TSLP, LRRC32) or unique to EoE (CAPN14), as well as Mendellian Disorders associated with EoE, will be reviewed in the context of the insight that they provide into the molecular pathoetiology of EoE. We will also discuss the clinical opportunities that genetic analyses provide in the form of decision support tools, molecular diagnostics, and novel therapeutic approaches.

Topics: Animals; Calpain; Clinical Decision-Making; Cytokines; Eosinophilic Esophagitis; Eosinophils; Gene-Environment Interaction; Genetic Predisposition to Disease; Genetic Testing; Genotype; Humans; Membrane Proteins; Mucous Membrane; Polymorphism, Genetic; Thymic Stromal Lymphopoietin

Eosinophilic esophagitis (EoE) was historically distinguished from gastroesophageal reflux disease on the basis of histology and lack of responsiveness to acid suppressive therapy, but it is now appreciated that esophageal eosinophilia can respond to proton pump inhibitors. Genetic and environmental factors contribute to risk for EoE, particularly early-life events. Disease pathogenesis involves activation of epithelial inflammatory pathways (production of eotaxin-3 [encoded by CCL26]), impaired barrier function (mediated by loss of desmoglein-1), increased production and/or activity of transforming growth factor-β, and induction of allergic inflammation by eosinophils and mast cells. Susceptibility has been associated with variants at 5q22 (TSLP) and 2p23 (CAPN14), indicating roles for allergic sensitization and esophageal specific protease pathways. We propose that EoE is a unique disease characterized by food hypersensitivity; strong hereditability influenced by early-life exposures and esophageal-specific genetic risk variants; and allergic inflammation and that the disease is remitted by disrupting inflammatory and T-helper type 2 cytokine-mediated responses and through dietary elimination therapy.

Topics: Allergens; Animals; Calpain; Cytokines; Diet; Environment; Eosinophilic Esophagitis; Food Hypersensitivity; Gene Expression Regulation; Genetic Markers; Genetic Predisposition to Disease; Genetic Variation; Heredity; Humans; Molecular Diagnostic Techniques; Phenotype; Precision Medicine; Predictive Value of Tests; Risk Factors; Th2 Cells; Thymic Stromal Lymphopoietin

Eosinophilic esophagitis (EoE) is a chronic allergic disease triggered by food allergens with an increasing prevalence. This review highlights recent research advances in EoE with a focus on the literature of the past 18 months.. The incidence of EoE in the black population is higher than previously suggested. A novel locus spanning CAPN14 is associated with EoE. Diagnostic tests utilizing an analysis of EoE-specific transcriptome have been improved. Standardized EoE symptom score systems have been established. Treatment trials show the promise and limitations of allergen avoidance, antiinflammatory reagents, and anti-interleukin-13 antibodies. Insights into disease mechanisms highlight the role of invariant natural killer T cells and group 2 innate immune cells. Epithelial barrier protein desmoglein 1, bone morphogenetic protein antagonist follistatin, neurotrophic tyrosine kinase receptor type 1, and CAPN14 have been defined as new potential therapeutic targets in EoE as regulators of the inflammatory interleukin-13-axis. The role of IgG4 in the disease mechanisms has been suggested.. Genetic predisposition influenced by environmental factors increases EoE susceptibility. Research identifying the critical events leading to allergen sensitization and the esophagus-specific responses that drive EoE is evolving, and will lead to a better understanding of EoE and new therapeutic approaches for the disease.

Topics: Adolescent; Allergens; Calpain; Child; Child, Preschool; Eosinophilic Esophagitis; Genetic Predisposition to Disease; Genotype; Humans; Incidence; United States

Eosinophilic esophagitis (EoE) is a chronic allergen-mediated inflammatory disease of the esophagus. This inflammation leads to feeding difficulties, failure to thrive and vomiting in young children, and causes food impaction and esophageal stricture in adolescents and adults. In the 20 years since EoE was first described, we have gained a great deal of knowledge regarding the genetic predisposition of disease, the inflammatory milieu associated with EoE and the long-term complications of chronic inflammation. Herein, we summarize the important breakthroughs in the field including both in vitro and in vivo analysis. We discuss insights that we have gained from large-scale unbiased genetic analysis, a multitude of genetically and chemically altered mouse models of EoE and most importantly, the results of clinical trials of various pharmacologic agents. Understanding these successes and failures may be the key to developing more effective therapeutic strategies.

Topics: Animals; Basophils; Calpain; Cellular Microenvironment; Cytokines; Dysbiosis; Eosinophilic Esophagitis; Esophagus; Fibrosis; Genetic Predisposition to Disease; Humans; Immunoglobulin E; Interleukin-13; Interleukin-5; Mast Cells; Mucous Membrane; Neoplasm Proteins; Nuclear Proteins; Receptors, Cytokine; Repressor Proteins; Th2 Cells; Thymic Stromal Lymphopoietin

Eosinophilic esophagitis is characterized by destructive responses of the immune system to environmental allergens, including food, on the human esophagus. EoE is now reported as a major cause of upper gastrointestinal morbidity in children and adults and the incidence is reported to be on the increase. It is known that EoE has a high degree of heritability, with a majority of the phenotypic variation believed to be genetic in origin as shown by genetic epidemiology studies of twins and families. Prior to 2010, there were no known genetic risk factors for the disease. Three GWAS have since been published identifying 5 loci which influence risk for EoE in both children and adults. The information gained from GWAS has been of value in elucidating the pathways involved, such as IL4/STAT6, and more unexpected pathways such as epithelial apical transport and wound healing. We will review the results of the EoE GWAS and the known associated genes, concluding with a discussion of some future directions for genetic studies in EoE.

Topics: Calpain; Eosinophilic Esophagitis; Guanine Nucleotide Exchange Factors; Humans; Neoplasm Proteins; Nuclear Proteins; Repressor Proteins; STAT6 Transcription Factor

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.

Topics: Adolescent; Biopsy; Calpain; Case-Control Studies; Child; Desmoplakins; Desmosomes; DNA Mutational Analysis; Eosinophilic Esophagitis; Esophageal Mucosa; Exome Sequencing; Female; HaCaT Cells; HEK293 Cells; Heterozygote; Humans; Male; Mutation, Missense; Plakins; Proteolysis; RNA-Seq; Single-Cell Analysis

Eosinophilic esophagitis (EoE) is a chronic, food antigen-mediated disease characterized by esophageal dysfunction and intraepithelial eosinophil accumulation.. We hypothesized that very early onset EoE (V-EoE) would be enriched for early-life and genetic factors and have worse presentation and prognosis than later-onset pediatric EoE (L-EoE).. We conducted a single-site, retrospective review comparing patients diagnosed at age 12 months or less (V-EoE, n = 57) and age 14 to 18 years (L-EoE, n = 70). These patients underwent medical record, EoE Histology Scoring System, Endoscopic Reference Score, and EoE Diagnostic Panel assessment when sample availability permitted. Genetic association used 2 EoE genotype repositories. Data were analyzed using chi-square tests, t tests, Wilcoxon rank-sum tests, Spearman correlations, cluster analysis, and logistic regression.. Among pediatric patients with EoE, diagnosis most commonly occurred within early life (0-24 months, 17%). V-EoE was more likely to attain histologic remission via dietary restriction (P < .0001). Basal zone hyperplasia and eosinophil inflammation were greater in V-EoE (P < .05). Esophageal strictures more commonly occurred in L-EoE (P = .03). V-EoE had lower endoscopic scores (P < .05). Molecular expression was very similar between groups. Cesarean delivery was more common in patients with V-EoE (P = .03). Patients with V-EoE demonstrated enrichment of CAPN14 common genetic variants.. Early-life diagnosis of EoE is a common occurrence. V-EoE responds to standard therapy without early evidence for complications, suggesting a less severe prognosis than hypothesized. Molecular pathogenesis is preserved between V-EoE and L-EoE. Cesarean delivery and CAPN14 genetic variation likely promote earlier disease development.

Topics: Adolescent; Age of Onset; Calpain; Eosinophilic Esophagitis; Female; Genetic Variation; Humans; Male; Retrospective Studies

Although eosinophilic esophagitis (EoE) is associated with certain gene variants, the rapidly increasing incidence of EoE suggests that environmental factors contribute to disease development.. We tested for gene-environment interaction between EoE-predisposing polymorphisms (within TSLP, LOC283710/KLF13, CAPN14, CCL26, and TGFB) and implicated early-life factors (antibiotic use in infancy, cesarean delivery, breast-feeding, neonatal intensive care unit [NICU] admission, and absence of pets in the home).. We conducted a case-control study using hospital-based cases (n = 127) and control subjects representative of the hospital catchment area (n = 121). We computed case-only interaction tests and in secondary analyses evaluated the combined and independent effects of genotype and environmental factors on the risk of EoE.. Case-only analyses identified interactions between rs6736278 (CAPN14) and breast-feeding (P = .02) and rs17815905 (LOC283710/KLF13) and NICU admission (P = .02) but not with any of the factors examined. Case-control analyses suggested that disease risk might be modifiable in subjects with certain gene variants. In particular, breast-feeding in those with the susceptibility gene variant at rs6736278 (CAPN14) reduced the risk of EoE (adjusted odds ratio, 0.08; 95% CI, 0.01-0.59). Admission to the NICU in those without the susceptibility gene variant at rs17815905 (LOC283710/KLF13) significantly increased the risk of having disease (adjusted odds ratio, 4.83; 95% CI, 1.49-15.66).. The interplay of gene (CAPN14 and LOC283710/KLF13) and early-life environment factors (breast-feeding and NICU admission) might contribute to EoE susceptibility.

Topics: Adolescent; Calpain; Case-Control Studies; Cell Cycle Proteins; Child; Environmental Exposure; Eosinophilic Esophagitis; Female; Gene-Environment Interaction; Genetic Predisposition to Disease; Humans; Kruppel-Like Transcription Factors; Male; Polymorphism, Genetic; Repressor Proteins

Eosinophilic Esophagitis (EoE) is an emerging chronic atopic disease. Recent advances in understanding its genetic and molecular biology pathogenesis may lead to a better management of the disease. EoE is an atopic disease. Most of the patients affected by EoE have other atopic diseases such as allergic rhinitis, asthma, IgE-mediated food allergies and/or atopic dermatitis. The local inflammation is a T helper type 2 (Th2) flogosis, which most likely is driven by a mixed IgE and n-IgE-mediated reaction to food and/or environmental allergens. Epidemiological studies show that EoE is an atopic disease with a strong genetic component. Genetic studies have shown that EoE is associated with single nucleotide polymorphism on genes, which are released by the epithelium and important in atopic inflammation such as thymic stromal lymphopoietin located (TSLP) close to the Th2 cytokine cluster [interleukin (IL)-4, IL-5, IL-13] on chromosome 5q22, Calpain 14, EMSY, and Eotaxin3. When the EoE diagnosis is made, it is imperative to control the local eosinophilic inflammation not only to give symptomatic relief to the patient, but also to prevent complications such as esophageal stricture and food impaction.. EoE is treated like many other atopic diseases with a combination of topical steroids and/or food antigen avoidance. The new understanding of EoE may lead to more specific and definitive treatments of EoE.

Topics: Calpain; Cytokines; Eosinophilic Esophagitis; Epithelium; Genetic Predisposition to Disease; Humans; Immunotherapy; Neoplasm Proteins; Nuclear Proteins; Polymorphism, Genetic; Repressor Proteins; Steroids; Th2 Cells; Thymic Stromal Lymphopoietin

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)

Topics: Adolescent; Adult; Calpain; Child; Child, Preschool; Eosinophilic Esophagitis; Epithelial Cells; Esophagus; Female; Genetic Predisposition to Disease; Genetic Variation; Genome-Wide Association Study; Genotype; Haplotypes; Humans; Interleukin-13; Male; Meta-Analysis as Topic; Middle Aged; Models, Genetic; Organ Specificity; Up-Regulation; Young Adult

Eosinophilic esophagitis (EoE) is an allergic disorder characterized by infiltration of the oesophagus with eosinophils. We had previously reported association of the TSLP/WDR36 locus with EoE. Here we report genome-wide significant associations at four additional loci; c11orf30 and STAT6, which have been previously associated with both atopic and autoimmune diseases, and two EoE-specific loci, ANKRD27 that regulates the trafficking of melanogenic enzymes to epidermal melanocytes and CAPN14, that encodes a calpain whose expression is highly enriched in the oesophagus. The identification of five EoE loci, not only expands our aetiological understanding of the disease but may also represent new therapeutic targets to treat the most debilitating aspect of EoE, oesophageal inflammation and remodelling.

Topics: Adult; Calpain; Case-Control Studies; Eosinophilic Esophagitis; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Guanine Nucleotide Exchange Factors; Humans; Male; Neoplasm Proteins; Nuclear Proteins; Repressor Proteins; STAT6 Transcription Factor