Materiały źródłowe

• #1 Mechanisms of Disease of Eosinophilic Esophagitis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4918086/

  Eosinophilic esophagitis (EoE) is a recently recognized inflammatory disease of the esophagus with clinical symptoms derived from esophageal dysfunction. The etiology of EoE is now being elucidated, and food hypersensitivity is emerging as the central cornerstone of disease pathogenesis. […] The primary histologic feature used in diagnosing EoE is an esophageal biopsy with at least 15 eosinophils per high-power field; this is referred to as the peak eosinophil count. Other histopathologic changes consistent with EoE include basal layer hyperplasia, papillary lengthening, and lamina propria fibrosis. […] EoE is a disease that is associated with food antigen-driven hypersensitivity, as evidenced by its response to dietary therapy. Hypersensitivity reactions can occur via multiple immune mechanisms including IgE (immediate type) and/or T cell-mediated (delayed type).

• #1 Pathogenesis of Eosinophilic Esophagitis: A Comprehensive Review of the Genetic and Molecular Aspects

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7582808/

  Eosinophilic esophagitis (EoE) is a relatively new condition described as an allergic-mediated disease of the esophagus. […] The pathophysiology of EoE is described by separately presenting the known function of each cell and molecule, with the major contributors being eosinophils, Th2 cells, thymic stromal lymphopoietin (TSLP), transforming growth factor (TGF)-1, and interleukin (IL)-13. […] Overexpression of several critical genes, including thymic stromal lymphopoietin (TSLP) and calpain 14 (CAPN-14), was found to disrupt the esophageal barrier and enhance immune-mediated inflammation. […] When allergens are exposed to the esophageal epithelium, epithelial cells and basophils produce TSLP. […] TSLP plays an important role in promoting Th2 cell differentiation by inducing the Th2-polarizing capacity of dendritic cells.

• #1 Pathogenesis of Eosinophilic Esophagitis: A Comprehensive Review of the Genetic and Molecular Aspects

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7582808/

  Activated Th2 cells produce cytokines such as IL-4, IL-5, and IL-13. […] IL-13 also reduces the expression levels of genes in the epidermal differentiation complex such as filaggrin and involucrin, thus weakening the barrier function of the squamous epithelium. […] At the same time, locally activated eosinophils and mast cells produce TGF-1, which triggers fibrotic changes in the esophageal wall, which in turn is mediated by fibroblasts and periostin, thus leading to smooth muscle dysfunction. […] CAPN encodes a proteolytic enzyme specifically in the esophagus. […] IL-13 induces the activity of this enzyme, and CAPN14 invokes a pathway that alters basic epithelial cell functions, including barrier integrity. […] EoE is caused by an allergic inflammation reaction in patients that have genetic and environmental risks of EoE, and it relies on both the innate and adaptive immune pathways.

• #1 Pathology Outlines – Eosinophilic esophagitis

  https://www.pathologyoutlines.com/topic/esophaguseosinophilic.html

  Recruited T cells differentiate into Th2 T cells and secrete IL4, IL5 and IL13 (Arch Pediatr 2019;26:182) […] IL4 promotes the differentiation of naïve T cells into Th2 T cells (Arch Pediatr 2019;26:182) […] IL5 promotes eosinophil survival (Arch Pediatr 2019;26:182) […] IL13 leads to expression of eotaxin3, which is a chemokine that induces eosinophilic activation and infiltration (Med Clin North Am 2019;103:29) […] Activated eosinophils produce TGF beta that promotes tissue remodeling and leads to fibrosis (Med Clin North Am 2019;103:29)

• #1 Eosinophilic esophagitis (EoE): Genetics and immunopathogenesis – UpToDate

  https://www.uptodate.com/contents/eosinophilic-esophagitis-eoe-genetics-and-immunopathogenesis/print

  Antigenic proteins, typically derived from food and less commonly from inhaled proteins, trigger an adaptive T helper type 2 (Th2) cell-mediated response that produces cytokines, such as interleukin (IL) 5 and IL-13. IL-13 subsequently triggers resident cells, such as esophageal epithelial cells, to produce a large set of proteins. The most strongly induced gene in this process is eotaxin 3, which in turn recruits eosinophils from the peripheral blood into the tissue. Antigen-driven Th2 cells also produce IL-5 and IL-13. IL-5 is a chief eosinophil growth and activation factor that primes eosinophils to have enhanced responsiveness to eotaxin 3 and prolongs their cellular survival. IL-13 induces other key mediators of EoE including eotaxin 3 and calpain 14 (CAPN14; the gene product of the primary EoE susceptibility locus).

• #1 Mechanisms of Disease of Eosinophilic Esophagitis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4918086/

  Eosinophils also have the capacity to initiate antigen-specific immune responses by acting as antigen-presenting cells (APCs). […] The esophagus is normally devoid of eosinophils, and the presence of esophageal eosinophilia is a defining pathologic feature of EoE. […] EoE is associated with esophageal dysmotility and dysphagia, which may be related to motor dysfunction of the esophagus rather than to physical narrowing. […] EoE is a disease that is associated with food antigen-driven hypersensitivity, as evidenced by its response to dietary therapy.

• #1

  https://link.springer.com/article/10.1007/s10620-013-2679-9

  Eosinophils are multifunctional cells which when activated secrete a wide variety of inflammatory mediators, cytokines, chemokines, neuromediators, and cytotoxic granule proteins. Eosinophil activation and degranulation may mediate the pathogenesis of EoE. […] In particular, eosinophils induce esophageal remodeling via a TGF- pathway resulting in subepithelial fibrosis, epithelial-mesenchymal transition, and smooth muscle dysfunction, and increase the rate of epithelial proliferation in the esophagus. This provides a possible explanation for clinical features of EoE such as dysphagia, esophageal rings, strictures, and dysmotility. […] The current model of EoE pathogenesis holds that antigens, either food allergens or aeroallergens, are presented to the esophagus and stimulate a Th2 response. IL-13 and IL-5, produced by lymphocytes, stimulate the esophageal epithelium to produce eotaxin-3, a potent chemokine, which then recruits and activates eosinophils. Eotaxin-3 is associated strongly with the pathogenesis of EoE since it is the most upregulated gene and bears a disease-associated single nucleotide polymorphism (SNP).

• #1 Eosinophilic Esophagitis (EoE) Pathology: Definition, Etiology, Epidemiology

  https://emedicine.medscape.com/article/1610470-overview

  Eosinophils play an integral role in the remodeling of esophageal tissues, which is observed histologically as subepithelial fibrosis and manifests clinically as dysphagia in adults and vomiting in children. […] Eosinophils cause fibrosis through degranulation and secretion of their granule cationic proteins, particularly major basic protein (MBP) and eosinophil peroxidase (EPO) and the elaboration of fibrogenic growth factors such as transforming growth factor-, platelet-derived growth factor-BB, and IL-1. […] The association of degranulating eosinophils and deposition of their granule cationic proteins in tissues with pathologic fibrosis is a recurrent finding in a broad group of eosinophilic illnesses other than EoE such as hypereosinophilic syndrome and asthma.

• #1 Pathogenesis of Eosinophilic Esophagitis: A Comprehensive Review of the Genetic and Molecular Aspects

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7582808/

  Eosinophils are recruited from the blood with local chemotaxis and they seem to be integral to EoE disease pathogenesis. […] Eosinophils release eosinophilic peroxidase (EPO), eosinophil cationic protein (ECP), and major binding protein (MBP), which directly causes tissue damage and esophageal dysmotility. […] Eosinophils also serve as antigen-presenting cells (APCs) with MHC-II presentation as well as co-stimulatory molecules (CD40, CD28, CD86, and CD27). […] Eosinophils secrete a variety of cytokines (IL-2, IL-4, IL-6, IL-10, IL-12) which together can activate T cells. […] Eosinophils also produce IL-1, IL-3, IL-4, IL-5, IL-13, TGF-, eotaxin-3, RANTES, macrophage inflammatory protein 1 (MIP-1), tumor necrosis factor (TNF)-, granulocyte-macrophage colony-stimulating factor (GM-CSF), platelet-activating factor (PAF), and leukotriene C4 (LTC4).

• #1 From Pathogenesis to Treatment: Targeting Type-2 Inflammation in Eosinophilic Esophagitis

  https://www.mdpi.com/2218-273X/14/9/1080

  Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder of the esophagus. EoE shares a common pathogenetic mechanism with other chronic disorders pertaining to the type 2 inflammatory spectrum, such as atopic dermatitis (AD), allergic rhinitis (AR), asthma, and chronic rhinosinusitis with nasal polyps (CRSwNP). The recent advancements in EoE pathogenesis understanding have unveiled new molecular targets implied within the “atopic march” picture as well as specific to EoE. These discoveries have led to the clinical evaluation of several novel drugs (monoclonal antibodies and immune modulators), specifically aimed at the modulation of Th2 inflammation. EoE is characterized by the T helper 2 (Th2) inflammatory pathway, driving the eosinophilic infiltration of the esophageal wall, leading to obstructive symptoms, mainly dysphagia and food impaction. EoE pathogenesis has been intensively studied in recent years. EoE has an underlying genetic susceptibility, widely proven. Blanchard et al. identified a section of the human genome, termed the “EoE transcriptome”, with a conserved expression of multiple gene loci, in the esophagus of EoE patients. Among the conservatively expressed genes, CCL26, encoding for eotaxin 3 (an eosinophil chemoattractant and activator), resulted to be the most correlated among other gene loci comprising the EDC, a transcriptional “hot spot” in the atopic diseases’ genetic drive. One of the largest GWASs revealed how the Calpain 14 (CAPN14) gene, encoding for an IL-13-induced cysteine protease, resulted to be the highest correlated gene with active EoE. Furthermore, based on previously confirmed risk loci for allergic sensitization, the authors found a strong association of some genes implied in Th2 allergic responses in EoE compared to healthy individuals (particularly, TSLP, LRRC32, and LPP). The exposure to aero- or food antigens is pivotal in initiating the Th2 response. The first proof of the crucial role of the Th2 immune response and related cytokines in EoE pathogenesis came from animal studies. Akei et al. injected wild-type mice with epicutaneous antigens (ovalbumin or Aspergillus fumigatus), evidencing the role of IL-5 (via STAT5) in eosinophil production and recruitment with a determinant contribution by IL-4 and IL-13 via STAT6. The relevance of IL-5 in EoE has been widely re-estimated after the incomplete reduction in esophageal eosinophilia and the inefficacy in the clinical activity of IL-5-targeted monoclonal antibodies (mAbs). Blanchard and colleagues further explored the role of IL-13 in EoE, documenting the induction of a transcription profile overlapping with EoE patients in esophageal epithelial cells treated with the injection of IL-13. Eotaxins are determinants for eosinophil recruitment, as demonstrated by earlier studies on eotaxin-deficient mice. The absence of eotaxin production is characterized by a reduced eosinophil accumulation in GI tissues. Among eotaxins, eotaxin 3, encoded by the abovementioned CCL26 gene, appears to be prominently stimulated by IL-13. IL-13 (via STAT6) also contributes to eosinophilic chemotaxis, goblet cell hyperplasia, and smooth muscle contractility and terminally to collagen apposition and esophageal remodeling. The overexpression of IL-13 in transgenic mice with the stimulation of the Th2 immune response via doxycycline administration caused significant epithelial thickness, with augmented esophageal epithelial proliferation, increased angiogenesis, and collagen deposition. Esophageal remodeling seems to be highly dependent on the IL-13 induction of Transforming Growth Factor (TGFβ), capable of determining periostin induction, smooth muscle contraction, collagen deposition, and myofibroblast differentiation (via SMAD signaling). Furthermore, IL-13 has been related to epithelial barrier disruption. Davis and colleagues demonstrated that the epithelial loss of permeability in EoE follows an IL-13-induced CAPN14-dependent pathway. CAPN14 seems to induce Desmoglein-1 (DSG-1) and/or Desmoplakin (DSP) downregulation, leading to loose intercellular spaces. The type 2 response, with an increased production of Th2-related cytokines (IL-4, Il-5, and IL-13), fuels this vicious cycle, further hindering barrier permeability. The current picture of EoE treatments is constantly evolving, distancing from a mere anti-inflammatory and anti-eosinophil purpose to approach the Th2 immune environment.

• #1 Pathogenesis of Eosinophilic Esophagitis: A Comprehensive Review of the Genetic and Molecular Aspects

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7582808/

  TGF-1, produced by mast cells, eosinophils, and esophageal epithelial cells, is a key cytokine for epithelial fibrosis and epithelial cell transformation. […] IL-13, a key cytokine and the most studied cytokine in EoE pathogenesis, is secreted by Th2 cells and activates eosinophils. […] Eotaxin-3, mainly produced by esophageal epithelial cells through the IL-13 signaling pathway, is implicated in eosinophil trafficking to the esophagus in patients with EoE.

• #1 Understanding eosinophilic esophagitis: the cellular and molecular mechanisms of an emerging disease | Mucosal Immunology

  https://www.nature.com/articles/mi201088

  Eotaxin-deficient animals exposed to the same allergens did not develop experimental EoE. […] IL-13 appears to activate the local tissue inflammatory response in Th2-associated diseases. […] IL-13 decreases esophageal epithelial cell differentiation, a process that may be critical for maintaining the barrier function of the esophageal mucosa. […] Eosinophils in EoE also express transforming growth factor-1 (TGF-1), which is known to induce fibrosis. […] This growth factor activates SMAD2/3 signaling in epithelial and lamina propria cells. […] Thus, it appears that eosinophils can contribute to the tissue changes associated with EoE. […] Despite the current knowledge, many questions remain. What causes EoE? What is the role of food and environmental allergens? Why are we seeing increasing numbers of patients with this disease?

• #1 Eosinophilic oesophagitis – A guide for primary care

  https://www.racgp.org.au/afp/2015/october/eosinophilic-oesophagitis-a-guide-for-primary-care

  Eosinophilic oesophagitis (EoE) is a chronic inflammatory disorder of the oesophagus that leads to oesophageal dysfunction and symptoms including dysphagia and heartburn. […] The current understanding of EoE pathogenesis is limited. It is a chronic disease that involves an interrelationship between genetic and environmental factors. Alteration in the hosts immune response manifests as an allergic oesophageal reaction to food-based proteins consumed in the diet. Antigens from various foods (eg milk, wheat, soy, eggs and seafood) have been implicated. […] Chronic inflammation and eosinophilic infiltration of the oesophagus leads to deposition of subepithelial fibrous tissue. Oesophageal remodelling and dysfunction follow with time. At end-stage, the disease may progress to a strictured lumen, which causes dysphagia and produces food bolus obstruction. […] EoE is a distinct clinical and pathological entity that is not analogous to GORD. It is different from GORD as it is not associated with acid reflux.

• #1

  https://link.springer.com/article/10.1007/s10620-013-2679-9

  Over the past two decades, eosinophilic esophagitis (EoE) has undergone a remarkable transformation. […] In parallel with this has been a rapid increase in our understanding of the pathogenesis and genetic basis of EoE. […] While the consensus is that EoE is an allergic/immune-mediated condition in which the eosinophil plays a central role, recent data suggest that non-eosinophil cell types play important, and possibly crucial, roles as well. […] The allergic basis for the disease is based on several lines of evidence. […] Prompted by the review by Zhang and colleagues in this issue of Digestive Diseases and Sciences, this editorial summarizes the role of the eosinophil and several other cell types in the pathogenesis of EoE, including lymphocytes, mast cells, fibroblasts, and epithelial cells. Recognizing and characterizing the role of the non-eosinophil cell types is likely to be central to future advances in the diagnosis and treatment of EoE.

• #1 Pathogenesis of Eosinophilic Esophagitis: A Comprehensive Review of the Genetic and Molecular Aspects

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7582808/

  Eosinophils have been studied in both mouse and human models, showing that an EoE-like disease is not completely dependent on eosinophils. […] In EoE, the numbers of CD3+, CD4+, and CD8+ T cells, as well as the CD8+/CD4+ T cell ratio, increase in the esophageal mucosa. […] Th2 cells produce type 2 cytokines such as IL-4, IL-5, and IL-13, which play a key role in the pathogenesis of EoE. […] The esophageal mast cell content increased significantly, and mast cell degranulation was detected in nearly all patients with EoE. […] Basophils are known to play a key role in allergic responses. […] Dendritic cells normally reside in the esophageal epithelium and an increased number of these cells were found in patients with EoE. […] Group 2 ILCs (ILC2s) expressed CRTH2 and secreted large quantities of type 2 cytokines in response to IL-25, IL-33, and TSLP.

• #1 Eosinophilic esophagitis (EoE): Genetics and immunopathogenesis – UpToDate

  https://www.uptodate.com/contents/eosinophilic-esophagitis-eoe-genetics-and-immunopathogenesis/print

  Eosinophilic esophagitis (EoE) is a chronic, immune/antigen-mediated esophageal disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation. The pathogenesis of EoE is the result of an interplay among genetic, environmental, and host immune system factors. […] The pathogenesis of EoE is incompletely understood but involves genetic, environmental, and host immune system factors. The esophagus of EoE patients has an impairment of epithelial cell differentiation and barrier function, which is consistent with molecular analysis that has elucidated that EoE is caused by a primary defect in esophageal epithelial function rather than an eosinophil defect. This is best illustrated by the finding that genetic susceptibility is mediated by genes expressed by the esophageal epithelia rather than eosinophils.

• #1 Eosinophilic esophagitis: From pathophysiology to treatment

  https://www.wjgnet.com/2150-5330/full/v6/i4/150.htm

  The incidence of EoE is higher in monozygotic twins (41%), but the observation that the disease also occurs in 21% of dizygotic twins suggests a role for environmental factors, especially in the early-life. […] The EoE is characterized by a prevalent eosinophilic infiltrate in the lamina propria and submucosa of the esophagus. […] The precise mechanisms of such localized inflammatory reactions are not recognized yet, but it is suggested that different cytokines are involved in the maturation and migration of eosinophils. […] The increased release of these cytokines in both the esophagus and the blood of EoE patients has been demonstrated in different studies, and, although need to be further clarified, their role in the pathogenesis of EoE appears to be fundamental. […] Eosinophils synthetize and release many proteins and mediators, in particular major basic protein (MBP), eosinophil cationic protein, eosinophil peroxidase, eosinophil-derived neurotoxin, TGF-, IL-13 and platelet-activating factor. […] Although all these mediators play a key role in the tissue damage and remodeling, the most robust data are about MBP and TGF-. […] These mechanisms act synergistically, determining the altered synthesis of extracellular matrix proteins, such as collagen, tenascin-C and metalloproteinases.

• #1 Eosinophilic esophagitis – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/eosinophilic-esophagitis/symptoms-causes/syc-20372197

  Researchers think that eosinophilic esophagitis may have a genetic component because the condition sometimes runs in families. […] If you have food or environmental allergies, asthma, atopic dermatitis, or a chronic respiratory disease, you’re more likely to be diagnosed with eosinophilic esophagitis.

• #1 Eosinophilic esophagitis | Allergy, Asthma & Clinical Immunology | Full Text

  https://aacijournal.biomedcentral.com/articles/10.1186/s13223-018-0287-0

  Eosinophils contribute to fibrosis through degranulation and secretion of their granule cationic proteins, particularly major basic protein (MBP), and elaboration of fibrogenic growth factors such as TGF-. […] The male predominance of EoE, as well as family history, twin concordance and genome-wide association studies, suggest that there is a genetic predisposition to EoE. […] EoE is also believed to represent a mixed IgE- and non-IgE-mediated allergic response to food and environmental allergens. […] Current thinking is that non-IgE-mediated mechanisms predominate in EoE. […] The majority of patients with EoE have been found to have positive skin prick tests and atopy patch tests to foods and/or aeroallergens. […] However, it is also clear that such testing does not accurately identify causative foods in most EoE patients.

• #1

  https://link.springer.com/article/10.1007/s00281-021-00855-y

  Despite dramatic advances in our understanding of the pathogenesis and course of disease in the relatively short timeframe since the discovery and first description of eosinophilic esophagitis (EoE) less than three decades ago, many open questions remain to be elucidated. […] The association of EoE with atopic disease has been repetitively confirmed, with at least 60% of EoE patients currently or previously suffering from concomitant atopic diseases. […] A multitude of factors are assumed to play a role in EoE’s etiopathogenesis, including genetics, altered immune response, and alterations in the dietary composition in specific and environmental factors in general. […] The accelerated emergence of EoE within a relatively short interval of less than three decades in itself is a strong advocate for a crucial role of environmental factors in chronic immune-mediated diseases (including IBD, psoriasis, or asthma) in general, so as specifically in EoE.

• #1

  https://link.springer.com/article/10.1007/s10620-013-2679-9

  Fibroblasts are also important in EoE, leading to the collagen deposition and esophageal scarring responsible for many of the clinical manifestations of EoE. This process appears to be mediated by TGF-, which is produced by eosinophils and mast cells. A recently recognized mechanism for fibroblast differentiation and activation is the epithelial-mesenchymal transition, whereby epithelial cells transform to and acquire mesenchymal-type features. […] Esophageal epithelial cells are another non-eosinophil cell involved in the pathogenesis of EoE. […] Defects in barrier function can facilitate penetration of luminal antigens into the tissue, serving as the initial trigger for EoE. […] It is an immunologically active tissue involved in the multiple inflammatory pathways in EoE. […] There have been rapid developments in our understanding of the pathogenesis of EoE over the past decade, with an increasing recognition that cell types beyond the eosinophil are likely critical to disease development. […] The current model holds that food or environmental allergens contact a possibly leaky esophageal epithelium, triggering a Th2-mediated cytokine response where IL-5 and IL-13 stimulate the esophageal epithelium to produce eotaxin-3. Eotaxin-3, in turn, recruits eosinophils to the esophageal epithelium where they are activated. IL-13 down-regulates epidermal differentiation complex genes, further impairing the esophageal epithelial barrier. Th2 lymphocytes additionally produce IL-9 which recruits mast cells into the esophagus. Eosinophils and mast cells produce TGF-, which induces the epithelial-mesenchymal transition and esophageal remodeling.

• #1 Understanding eosinophilic esophagitis: the cellular and molecular mechanisms of an emerging disease | Mucosal Immunology

  https://www.nature.com/articles/mi201088

  A comprehensive understanding of the etiology and pathogenesis of EoE will help direct future therapeutic strategies. […] EoE appears to be increasing in incidence, along with other immunologic diseases. […] Eosinophils display signs of activation and degranulation even as they extravasate into the esophageal mucosa. […] The recruitment of eosinophils and subsequent release of granule mediators are likely responsible for the accrued injury to the esophagus in EoE, which in turn leads to symptoms. […] A highly conserved gene expression profile, which includes increased eotaxin-3, is seen in EoE patients, independent of other clinical variables such as age, gender, and atopic status. […] Eotaxin induction followed by esophageal eosinophilia was also observed in mice exposed to aerosolized insect allergens.

• #1 Biomarkers and therapeutic targets: microRNA roles in the pathophysiology, diagnosis and management of eosinophilic esophagitis

  https://www.oaepublish.com/articles/jtgg.2018.11

  These immune cells are capable of producing Th2 cytokines and eotaxin family chemokines that sustain chronic inflammation. […] Ultimately, inflammation leads to narrowing of the esophageal lumen and symptoms of solid-food and liquid dysphagia, chest pain, food impaction, acid-reflux and even feeding disorders in children. […] While symptoms are currently managed by dietary elimination of offending foods, swallowed steroids, or some combination of both, there are no FDA-approved treatments that currently exist for EoE. […] Consequently, there is a need to identify novel therapeutics and biomarkers to guide therapy. […] Recent work has defined three main disease endotypes that associate with phenotypic and clinical features of EoE. […] Molecular profiling of esophageal biopsies from a recent cohort of nearly 200 adult and pediatric patients was correlated with other clinical features of EoE in order to identify three clusters or distinct groups of disease. […] The three groups or endotypes range in severity from mild (Endotype 1) to severe (Endotype 3).

• #1 Mechanism of Action in EoE | DUPIXENT® (dupilumab)

  https://www.dupixenthcp.com/eoe/about/mechanism-of-action

  EoE is a chronic condition that is rapidly increasing in prevalence. It is caused primarily by type 2 inflammation, which can lead to remodeling of the esophagus and disease progression. Type 2 inflammation in EoE is driven by multiple cell types and mediators, and central to this pathway are Th2 cells. […] Th2 cells secrete IL-4 and IL-13, key cytokines that perpetuate type 2 inflammation in multiple ways. First, IL-4 drives Th2 cell differentiation and proliferation, amplifying the release of type 2 cytokines. Second, IL-4 and IL-13 facilitate the disruption of the junctions between epithelial cells, compromising epithelial barrier integrity. Third, IL-4 and IL-13 contribute to the recruitment of eosinophils into the tissue. In the inflammatory process, IL-4 binds to both type I and type II receptor complexes, while IL-13 binds to type II receptors located on the surface of multiple cell types, and upon receptor binding leads to unique intracellular signaling.

• #1 New genetic links in eosinophilic esophagitis | Genome Medicine | Full Text

  https://genomemedicine.biomedcentral.com/articles/10.1186/gm181

  A potential proposed mechanism is that Th2 cell activation leads to overexpression of CCL-26 and thereby to migration of eosinophils to the esophagus. […] Work by Aceves and colleagues showed that eosinophilic migration and activation in EoE lead to subepithelial fibrosis and to increased expression of transforming growth factor (TGF-) and its downstream signaling molecule phospho-SMAD2/3 compared with patients with GERD and healthy controls. […] The recent identification of TSLP and its receptor as key components in the EoE pathogenesis suggests that blockage of the TSLP-TSLP receptor activation could provide an attractive approach to treating the cause of EoE. […] These findings suggest a unique potential mechanism for the induction of EoE. Could food allergens trigger the TLR-3 receptor, inducing TSLP and causing the activation of the Th2 pathway, leading to eosinophilic inflammation in the esophagus? Or is there a 'second hit’, a virus that makes susceptible people develop EoE?

• #1 Eosinophilic Esophagitis

  https://medlineplus.gov/eosinophilicesophagitis.html

  Eosinophilic esophagitis (EoE) is a chronic disease of the esophagus. If you have EoE, white blood cells called eosinophils build up in your esophagus. This causes damage and inflammation, which can cause pain, trouble swallowing, and food getting stuck in your throat. […] Researchers are not certain about the exact cause of EoE. They think that it is an immune system/allergic reaction to foods or to substances in your environment, such as dust mites, animal dander, pollen, and molds. Certain genes may also play a role in EoE. […] There is no cure for EoE. Treatments can manage your symptoms and prevent further damage. The two main types of treatments are medicines and diet. […] Researchers are still trying to understand EoE and how best to treat it.

• #2 Eosinophilic esophagitis (EoE): Genetics and immunopathogenesis – UpToDate

  https://www.uptodate.com/contents/eosinophilic-esophagitis-eoe-genetics-and-immunopathogenesis/print

  Eosinophilic esophagitis (EoE) is a chronic, immune/antigen-mediated esophageal disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation. The pathogenesis of EoE is the result of an interplay among genetic, environmental, and host immune system factors. […] The pathogenesis of EoE is incompletely understood but involves genetic, environmental, and host immune system factors. The esophagus of EoE patients has an impairment of epithelial cell differentiation and barrier function, which is consistent with molecular analysis that has elucidated that EoE is caused by a primary defect in esophageal epithelial function rather than an eosinophil defect. This is best illustrated by the finding that genetic susceptibility is mediated by genes expressed by the esophageal epithelia rather than eosinophils.

• #2 Understanding eosinophilic esophagitis: the cellular and molecular mechanisms of an emerging disease | Mucosal Immunology

  https://www.nature.com/articles/mi201088

  Eosinophilic esophagitis (EoE) has been increasingly recognized as a unique clinicopathological entity over the past two decades. […] Patient studies suggest that EoE is an immunologic disease related to atopy. At the cellular level, eosinophils, mast cells, and B and T lymphocytes are increased in the esophageal mucosa in a patchy distribution throughout the length of the esophagus. […] Laboratory investigations have implicated aeroallergens, food allergens, and a unique T helper type 2 cytokine profile. EoE appears to be an antigen-driven hypersensitivity reaction characterized by a mixed IgE-dependent/delayed-type reaction and a distinct cascade of cytokines and growth factors. […] The causative events that lead to EoE in humans remain unknown. […] The molecular mechanisms of this disease are the subject of much ongoing investigation. Multiple cytokine-driven mechanisms specific to EoE have been identified along with a unique gene expression profile.

• #2 Eosinophilic esophagitis – Wikipedia

  https://en.wikipedia.org/wiki/Eosinophilic_esophagitis

  Eosinophilic esophagitis (EoE) is an allergic inflammatory condition of the esophagus that involves eosinophils, a type of white blood cell. In EoE, eosinophils migrate to the esophagus in large numbers. When a trigger food is eaten, the eosinophils contribute to tissue damage and inflammation. […] The pathophysiology of eosinophilic esophagitis is incompletely understood. Still, it is thought to involve some type of antigen exposure (coupled with a pre-existing genetic susceptibility), which causes a hyperactive immune response from immune cells in the esophagus. […] The antigenic exposure is thought to stimulate the esophageal epithelial cells to release the inflammatory cytokines IL-33 and thymic stromal lymphopoietin, which attract and activate Th2 helper T-cells. […] These helper T-cells the release pro-inflammatory cytokines including IL-13, IL-4 and IL-5.

• #2 Pathology Outlines – Eosinophilic esophagitis

  https://www.pathologyoutlines.com/topic/esophaguseosinophilic.html

  Recruited T cells differentiate into Th2 T cells and secrete IL4, IL5 and IL13 (Arch Pediatr 2019;26:182) […] IL4 promotes the differentiation of naïve T cells into Th2 T cells (Arch Pediatr 2019;26:182) […] IL5 promotes eosinophil survival (Arch Pediatr 2019;26:182) […] IL13 leads to expression of eotaxin3, which is a chemokine that induces eosinophilic activation and infiltration (Med Clin North Am 2019;103:29) […] Activated eosinophils produce TGF beta that promotes tissue remodeling and leads to fibrosis (Med Clin North Am 2019;103:29)

• #2 Eosinophilic esophagitis: Current concepts of pathophysiology, diagnosis, and treatment | Revista de Gastroenterología de México

  https://www.revistagastroenterologiamexico.org/en-eosinophilic-esophagitis-current-concepts-pathophysiology-articulo-S2255534X25000143

  Eosinophilic esophagitis (EoE) is a chronic, immune-mediated disease characterized by the infiltration of eosinophils into the esophageal mucosa. It is the most frequent cause of dysphagia and food impaction in adults. Due to its similar pathophysiology to allergic rhinitis, asthma, and atopic dermatitis, it has been considered the esophageal manifestation of allergy. […] Its pathophysiology has been better understood and endoscopic and clinical procedures have been refined for making the diagnosis. In addition, new drugs and special formulations of existing ones have been introduced for treating the disease. Simpler and more effective dietary treatment strategies have also been evaluated. […] Epithelial barrier dysfunction, inflammation mediated by Th2 lymphocytes and different cytokines, and tissue remodeling are the distinctive pathophysiologic characteristics of EoE. Under normal conditions, there are no eosinophils in the esophageal mucosa. In EoE, the exposure to environmental allergens increases the endogenous activity of the proteases in the esophagus. This results in the disruption of the epithelial intercellular junctions, facilitating the main access of food allergens into the deep layers of the mucosa. As a consequence, a Th2 lymphocyte-mediated inflammatory immune response is triggered. Those lymphocytes are sensitized, releasing proinflammatory cytokines, such as IL-4, IL-5, and IL-13 that induce the eosinophilic infiltration into the esophageal mucosa. IL-5 promotes the differentiation, maturation, and release of eosinophils from the bone marrow and facilitates the transport of eosinophils to the esophagus. IL-4 promotes the proliferation and differentiation of the Th2 lymphocytes and also has an inhibitory effect on apoptosis. On the other hand, IL-13 induces eotaxin 1 and 3 secretion. Said agent is a potent recruiter of eosinophils and mast cells, whose presence causes mucosal inflammation. The persistence of inflammation stimulates the production of fibrosis due to the activity of TGF- in a process known as esophageal remodeling.

• #2 Esophagitis pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Esophagitis_pathophysiology

  IL-5 prolongs the survival of the eosinophils. […] Eosinophils cause inflammation in the EoE patients by the following mechanisms: Upon the stimulation and the degranulation, the eosinophils release the granule proteins into the tissues. […] Granule proteins from eosinophils recruits the inflammatory cells and increase the vascularity. […] Increased vascularity stimulates fibrogenic mediators such as TGF-1 and matrix metalloproteinase 9 (MMP)-9. […] TGF- and eosinophilic granule proteins MBP and EPO are the key eosinophil effector proteins. […] MBP and MMP-9 disrupt the integrity of the epithelial cells of the esophagus through their involvement in the smooth muscles, fibroblasts, and cell-adhesion molecules. […] Eventually resulting in tissue remodeling and esophageal dysfunction.

• #2

  https://link.springer.com/article/10.1007/s10620-013-2679-9

  Eosinophils are multifunctional cells which when activated secrete a wide variety of inflammatory mediators, cytokines, chemokines, neuromediators, and cytotoxic granule proteins. Eosinophil activation and degranulation may mediate the pathogenesis of EoE. […] In particular, eosinophils induce esophageal remodeling via a TGF- pathway resulting in subepithelial fibrosis, epithelial-mesenchymal transition, and smooth muscle dysfunction, and increase the rate of epithelial proliferation in the esophagus. This provides a possible explanation for clinical features of EoE such as dysphagia, esophageal rings, strictures, and dysmotility. […] The current model of EoE pathogenesis holds that antigens, either food allergens or aeroallergens, are presented to the esophagus and stimulate a Th2 response. IL-13 and IL-5, produced by lymphocytes, stimulate the esophageal epithelium to produce eotaxin-3, a potent chemokine, which then recruits and activates eosinophils. Eotaxin-3 is associated strongly with the pathogenesis of EoE since it is the most upregulated gene and bears a disease-associated single nucleotide polymorphism (SNP).

• #2 Eosinophilic esophagitis (EoE): Genetics and immunopathogenesis – UpToDate

  https://www.uptodate.com/contents/eosinophilic-esophagitis-eoe-genetics-and-immunopathogenesis/print

  These type 2 cytokines are largely produced by activated effector memory pathogenic CD4+ T cells and mast cells that accumulate in the esophagus. IL-13 also decreases the expression of genes that encode proteins involved in barrier function such as filaggrin and components of esophageal desmosomes, such as desmoglein 1. Rare genetic loss-of-function variants in other desmosome genes, including those encoding periplakin and desmoplakin, are also associated with EoE.

• #2 Eosinophilic esophagitis – Wikipedia

  https://en.wikipedia.org/wiki/Eosinophilic_esophagitis

  These inflammatory cytokines, coupled with the T-cell response cause inflammation in the esophagus as well as stimulate basal cell hyperplasia and dilated intracellular spaces of the esophageal cells, characteristic histologic changes of the disease. […] The IL-5 released by the helper T-cells and eotaxin-3 act as chemotaxins, attracting granulocytes to the esophagus, including basophils, mast cells and eosinophils, with the eosinophilic infiltration giving the disease its characteristic histological changes. […] Eosinophils are inflammatory cells that release a variety of chemical signals which inflame the surrounding esophageal tissue. […] The migration of eosinophils to the esophagus may be due to genetic, environmental, and host immune system factors. […] At a tissue level, EoE is characterized by a dense infiltrate with white blood cells of the eosinophil type into the epithelial lining of the esophagus. This is considered an allergic reaction against ingested food, based on eosinophils’ important role in allergic reactions. The eosinophils are recruited into the tissue in response to the local production of eotaxin-3 by IL-13-stimulated esophageal epithelial cells.

• #2 Diagnosing eosinophilic esophagitis: cytokine sizzle and fizzle – Mexican style | Revista de Gastroenterología de México

  https://www.revistagastroenterologiamexico.org/en-diagnosing-eosinophilic-esophagitis-cytokine-sizzle-articulo-S2255534X17300026

  Eotaxin-3 is a potent chemoattractant for activated eosinophils, causing them to home to the esophagus. […] Finally, degranulation products released by eosinophils contribute to the epithelial injury. […] Thus EoE results from an immune-induced, cytokine-mediated injury. […] Moreover, recent data suggest that reflux esophagitis is primarily a cytokine-mediated disease, as well. […] However, our studies in a rat model showed that reflux esophagitis started with T lymphocytes (not granulocytes) infiltrating the esophageal submucosa (not the surface epithelium), and with basal cell hyperplasia that preceded the loss of surface cells. […] Based on those findings, we proposed a new concept for reflux esophagitis pathogenesis, in which refluxed gastric juice does not kill esophageal epithelial cells directly, but rather stimulates them to secrete cytokines that induce proliferative changes and attract the T lymphocytes and other inflammatory cells that ultimately damage the mucosa.

• #2 Pathology Outlines – Eosinophilic esophagitis

  https://www.pathologyoutlines.com/topic/esophaguseosinophilic.html

  Multifactorial, chronic eosinophilic inflammatory condition affecting the esophagus in both adult and pediatric patients that occurs in the absence of identifiable secondary causes (Med Clin North Am 2019;103:29) […] Characterized by a chronic immune reaction to environmental and food allergens leading to a deficient esophageal mucosal barrier (Arch Pediatr 2019;26:182) […] Intraepithelial eosinophils recruited via chemotaxis act as antigen presenting cells (APCs) recruiting T cells, activating mast cells and activating basophils (Arch Pediatr 2019;26:182) […] Eosinophils secrete a cationic protein eosinophilic peroxidase (EPO) and major binding protein (MBP) causing cell damage leading to the symptom of esophageal dysmotility (Arch Pediatr 2019;26:182) […] Concentration of eosinophilic peroxidase (EPO) correlates to increased symptomology, not the number of intraepithelial eosinophils (Arch Pediatr 2019;26:182)

• #2 Pathogenesis of Eosinophilic Esophagitis: A Comprehensive Review of the Genetic and Molecular Aspects

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7582808/

  Eosinophils are recruited from the blood with local chemotaxis and they seem to be integral to EoE disease pathogenesis. […] Eosinophils release eosinophilic peroxidase (EPO), eosinophil cationic protein (ECP), and major binding protein (MBP), which directly causes tissue damage and esophageal dysmotility. […] Eosinophils also serve as antigen-presenting cells (APCs) with MHC-II presentation as well as co-stimulatory molecules (CD40, CD28, CD86, and CD27). […] Eosinophils secrete a variety of cytokines (IL-2, IL-4, IL-6, IL-10, IL-12) which together can activate T cells. […] Eosinophils also produce IL-1, IL-3, IL-4, IL-5, IL-13, TGF-, eotaxin-3, RANTES, macrophage inflammatory protein 1 (MIP-1), tumor necrosis factor (TNF)-, granulocyte-macrophage colony-stimulating factor (GM-CSF), platelet-activating factor (PAF), and leukotriene C4 (LTC4).

• #2 Understanding eosinophilic esophagitis: the cellular and molecular mechanisms of an emerging disease | Mucosal Immunology

  https://www.nature.com/articles/mi201088

  Eotaxin-deficient animals exposed to the same allergens did not develop experimental EoE. […] IL-13 appears to activate the local tissue inflammatory response in Th2-associated diseases. […] IL-13 decreases esophageal epithelial cell differentiation, a process that may be critical for maintaining the barrier function of the esophageal mucosa. […] Eosinophils in EoE also express transforming growth factor-1 (TGF-1), which is known to induce fibrosis. […] This growth factor activates SMAD2/3 signaling in epithelial and lamina propria cells. […] Thus, it appears that eosinophils can contribute to the tissue changes associated with EoE. […] Despite the current knowledge, many questions remain. What causes EoE? What is the role of food and environmental allergens? Why are we seeing increasing numbers of patients with this disease?

• #2

  https://link.springer.com/article/10.1007/s10620-013-2679-9

  Fibroblasts are also important in EoE, leading to the collagen deposition and esophageal scarring responsible for many of the clinical manifestations of EoE. This process appears to be mediated by TGF-, which is produced by eosinophils and mast cells. A recently recognized mechanism for fibroblast differentiation and activation is the epithelial-mesenchymal transition, whereby epithelial cells transform to and acquire mesenchymal-type features. […] Esophageal epithelial cells are another non-eosinophil cell involved in the pathogenesis of EoE. […] Defects in barrier function can facilitate penetration of luminal antigens into the tissue, serving as the initial trigger for EoE. […] It is an immunologically active tissue involved in the multiple inflammatory pathways in EoE. […] There have been rapid developments in our understanding of the pathogenesis of EoE over the past decade, with an increasing recognition that cell types beyond the eosinophil are likely critical to disease development. […] The current model holds that food or environmental allergens contact a possibly leaky esophageal epithelium, triggering a Th2-mediated cytokine response where IL-5 and IL-13 stimulate the esophageal epithelium to produce eotaxin-3. Eotaxin-3, in turn, recruits eosinophils to the esophageal epithelium where they are activated. IL-13 down-regulates epidermal differentiation complex genes, further impairing the esophageal epithelial barrier. Th2 lymphocytes additionally produce IL-9 which recruits mast cells into the esophagus. Eosinophils and mast cells produce TGF-, which induces the epithelial-mesenchymal transition and esophageal remodeling.

• #2 Eosinophilic oesophagitis: clinical manifestations and treatment options. The role of the allergologist | Allergologia et Immunopathologia

  https://www.elsevier.es/en-revista-allergologia-et-immunopathologia-105-articulo-eosinophilic-oesophagitis-clinical-manifestations-treatment-S0301054608758695

  Eosinophilic oesophagitis (EO) is an infrequent disorder that is currently underdiagnosed. The etiology of EO is not clear, though atopy has been suggested as playing an important role in the development of the disease. […] The association between EO and a type Th2 immune response appears clear, although recent studies postulate that Th1 helper lymphocytes also participate in the physiopathology of the disease suggesting a mixed-type immunological disorder. […] Both food allergens and aeroallergens appear to be implicated in the etiology of EO. […] There is evidence of a genetic predisposition in EO, specifically at the level of the gene encoding for eotaxin-3. […] Interleukin 5 also has been implicated in the etiopathogenesis of EO, since high IL-5 levels would favour development of the disease.

• #2 Eosinophilic esophagitis – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/eosinophilic-esophagitis/symptoms-causes/syc-20372197

  Eosinophilic esophagitis (e-o-sin-o-FILL-ik uh-sof-uh-JIE-tis) is a chronic immune system disease. […] This buildup, which is a reaction to foods, allergens or acid reflux, can inflame or injure the esophageal tissue. […] Eosinophils are a typical type of white blood cells present in your digestive tract. However, in eosinophilic esophagitis, you have an allergic reaction to an outside substance. The reaction may occur as follows: The lining of your esophagus reacts to allergens, such as food or pollen. The eosinophils multiply in your esophagus and produce a protein that causes inflammation. Inflammation can lead to scarring, narrowing and formation of excessive fibrous tissue in the lining of your esophagus. […] There has been a significant increase in numbers of people diagnosed with eosinophilic esophagitis in the past decade.

• #2 Mechanistic Insights into Eosinophilic Esophagitis: Therapies Targeting Pathophysiological Mechanisms

  https://www.mdpi.com/2073-4409/12/20/2473

  The role of the gut microbiota in immune regulation is increasingly recognized. Exploring therapies that modulate the composition of the microbiota to mitigate inflammation and allergen sensitization holds potential for the treatment of EoE. […] Understanding the central pathogenesis of EoE is critical to develop targeted therapeutic strategies that can reduce inflammation, restore esophageal function, and relieve symptoms. However, the complexity of the disease is underscored by the involvement of multiple cellular and molecular pathways, making the development of effective treatments a multifaceted challenge.

• #2 The Role of Medications in the Management of Eosinophilic Esophagitis (EoE): A Review of Current Treatment Options – Canadian Digestive Health Foundation

  https://cdhf.ca/en/the-role-of-medications-in-the-management-of-eosinophilic-esophagitis-eoe-a-review-of-current-treatment-options/

  Several medications that have been found to be effective in treating patients with eosinophilic esophagitis (EoE). Treatments are aimed at reducing esophageal inflammation, hoping to reduce the risk of fibrosis (scar tissue) and strictures (narrowing) forming in the esophagus. […] While these medications are very effective at suppressing stomach (gastric) acid production, this is not thought to be their main mode of action in EoE. In a normal esophagus we expect to find no eosinophils. PPIs appear to work in EoE by directly blocking or interacting with proteins that are responsible for attracting eosinophils into the tissue. […] Swallowed topical steroids work like other steroids, in that their main action is to improve inflammation. However, the steroids used in EoE act locally on the surface lining of the esophagus rather than having an effect throughout the body. […] It works by interacting with proteins (called interleukin 4 and interleukin 13) that are heavily involved in the EoE inflammatory pathway, and as a result they reduce the eosinophilic inflammation in the esophagus.

• #2

  https://link.springer.com/article/10.1007/s00281-021-00855-y

  Although the importance of environmental factors in the pathogenesis of EoE has increasingly received recognition in recent years, discrepantly little knowledge and research is currently available in comparison to for instance genetics. […] This indicates that a re-evaluation of the scientific community’s research priorities might be worthwhile and a more intensive exploration of environmental factors might harbor the potential to advance our understanding of EoE in general and its recent dramatic epidemiological rise in specific. […] The rapidly changing environment and complexity of EoE patients’ exposures to environmental influences throughout lifetime render it likely that an increased investigations of the environment might be fruitful to advance our understanding of the pathogenesis of EoE. […] In a disease as multifactorial as EoE, it certainly is plausible to increase our attention, dedication, and scientific focus on a key component of its pathogenesis, which is the environment.

• #3 Mechanisms of Disease of Eosinophilic Esophagitis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4918086/

  Eosinophilic esophagitis (EoE) is a recently recognized inflammatory disease of the esophagus with clinical symptoms derived from esophageal dysfunction. The etiology of EoE is now being elucidated, and food hypersensitivity is emerging as the central cornerstone of disease pathogenesis. […] The primary histologic feature used in diagnosing EoE is an esophageal biopsy with at least 15 eosinophils per high-power field; this is referred to as the peak eosinophil count. Other histopathologic changes consistent with EoE include basal layer hyperplasia, papillary lengthening, and lamina propria fibrosis. […] EoE is a disease that is associated with food antigen-driven hypersensitivity, as evidenced by its response to dietary therapy. Hypersensitivity reactions can occur via multiple immune mechanisms including IgE (immediate type) and/or T cell-mediated (delayed type).

• #4 Eosinophilic esophagitis: From pathophysiology to treatment

  https://www.wjgnet.com/2150-5330/full/v6/i4/150.htm

  Eosinophilic esophagitis (EoE) is a chronic immune disease, characterized by a dense eosinophilic infiltrate in the esophagus, leading to bolus impaction and reflux-like symptoms. […] The pathogenesis of EoE is unknown, but it is supposed to be multifactorial with genetic, immunologic and environmental factors being all involved. […] There is evidence that EoE is more prevalent in patients suffering from food-allergy, rhinitis, asthma or atopic dermatitis. […] Interestingly, all these pathologies share an altered immune response to common antigens, which determinates an aberrant Th2-response, and, hence, the uncontrolled activation of eosinophils, mast cells and basophils. […] The higher risk of EoE in familiars of affected patients supports the hypothesis of genetic predisposition.

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