The health consequences of climate change are being increasingly recognized. Herein, the climate change hypothesis is put forth as a substantial contributor to the growing global allergy epidemic. ...A call for deeper research and action on the impact of climate change on various aspects of allergic disease mechanisms, exacerbation, and prevalence is imperative.
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.
When eosinophilia was first associated with esophagitis, it was thought to reflect gastroesophageal reflux disease, especially given the efficacy of reflux medications to abate esophageal ...eosinophilia in many individuals. Subsequent studies demonstrated disease remittance with amino acid–based formulas and conversely induction of esophageal eosinophilia in mice following allergen challenge. These results, along with the finding that proton pump inhibitors alleviated esophageal eosinophilia by an anti-inflammatory mechanism, turned attention away from an acid-induced pathogenesis and established eosinophilic esophagitis (EoE) as a separate disease entity driven by allergic inflammation. The disease underpinnings were elucidated by analysis of esophageal transcriptomic profiling, revealing gene signatures orchestrated by type 2 cytokine signaling, mainly IL-13. Preclinical studies showed that IL-13 overproduction was sufficient to induce EoE-like changes in mice and human ex vivo systems and conversely that inhibiting IL-13 signaling attenuated these processes. An early proof-of-principle study with a humanized anti–IL-13 mAb in patients with EoE revealed correction of the EoE transcriptome and attenuation of esophageal eosinophilia, providing a rationale for advancing anti–type 2 cytokine therapy for EoE. Dupilumab, a precision therapeutic mAb that blocks the shared IL-13 and IL-4 receptor, is the first drug to advance through clinical trials and receive US Food and Drug Administration approval for EoE. The ability of dupilumab to improve clinical, histologic, endoscopic, and molecular features of EoE and garner US Food and Drug Administration approval is a victory for science, rare diseases, patients, and advocacy and provides a framework for developing additional EoE treatments and approved treatments for eosinophilic gastrointestinal disease beyond the esophagus.
MicroRNA Lu, Thomas X.; Rothenberg, Marc E.
Journal of allergy and clinical immunology,
04/2018, Volume:
141, Issue:
4
Journal Article
Peer reviewed
Open access
MicroRNAs (miRNAs) are small endogenous RNAs that regulate gene-expression posttranscriptionally. MiRNA research in allergy is expanding because miRNAs are crucial regulators of gene expression and ...promising candidates for biomarker development. MiRNA mimics and miRNA inhibitors currently in preclinical development have shown promise as novel therapeutic agents. Multiple technological platforms have been developed for miRNA isolation, miRNA quantitation, miRNA profiling, miRNA target detection, and modulating miRNA levels in vitro and in vivo. Here we will review the major technological platforms with consideration given for the advantages and disadvantages of each platform.
Eosinophilic esophagitis is a recently recognized but expanding disorder characterized by antigen-driven eosinophil accumulation in the esophagus. Symptoms frequently mimic those of gastroesophageal ...reflux disease, but the diseases are distinct in their histopathology, gene expression signature, response to therapy, hereditary risk, and association with allergies. The pathogenesis of eosinophilic esophagitis involves environmental and genetic factors, particularly food antigens and expression level of the eosinophil chemoattractant eotaxin-3, respectively. Analyses of gene expression signatures and animal models have indicated the importance of adaptive T-cell immunity that involves interleukin-5 and interleukin-13–induced esophageal epithelial cell responses. Symptoms, dysregulation of esophageal gene expression, and pathology are largely reversible following reduced exposure to specific food antigens as well as anti-inflammatory therapy, but chronic treatment is necessary to prevent relapse. Therefore, eosinophilic esophagitis is a disease with unique features that include chronic esophagitis, atopy, immune sensitization to oral antigens, reversibility, and familial association.
Eosinophils are circulating and tissue-resident leukocytes that have potent proinflammatory effects in a number of diseases. Recently, eosinophils have been shown to have various other functions, ...including immunoregulation and antiviral activity. Eosinophil levels vary dramatically in a number of clinical settings, especially following eosinophil-targeted therapy, which is now available to selectively deplete these cells. There are key coronavirus disease 2019 (COVID-19)-related questions concerning eosinophils whose answers affect recommended prevention and care. First, do patients with eosinophilia-associated diseases have an altered course of COVID-19? Second, do patients with eosinopenia (now intentionally induced by biological drugs) have unique COVID-19 susceptibility and/or disease course? This is a particularly relevant question because eosinopenia is associated with acute respiratory deterioration during infection with the severe acute respiratory syndrome coronavirus 2, the causative agent of COVID-19. Third, do eosinophils contribute to the lung pathology induced during COVID-19 and will they contribute to immunopotentiation potentially associated with emerging COVID-19 vaccines? Herein, we address these timely questions and project considerations during the emerging COVID-19 pandemic.
Allergic inflammation is accompanied by the coordinated expression of a myriad of genes and proteins that initiate, sustain, and propagate immune responses and tissue remodeling. MicroRNAs (miRNAs) ...are a class of short single-stranded RNA molecules that posttranscriptionally silence gene expression and have been shown to fine-tune gene transcriptional networks because single miRNAs can target hundreds of genes. Considerable attention has been focused on the key role of miRNAs in regulating homeostatic immune architecture and acquired immunity. Recent studies have identified miRNA profiles in multiple allergic inflammatory diseases, including asthma, eosinophilic esophagitis, allergic rhinitis, and atopic dermatitis. Specific miRNAs have been found to have critical roles in regulating key pathogenic mechanisms in allergic inflammation, including polarization of adaptive immune responses and activation of T cells (eg, miR-21 and miR-146), regulation of eosinophil development (eg, miR-21 and miR-223), and modulation of IL-13–driven epithelial responses (eg, miR-375). This review discusses recent advances in our understanding of the expression and function of miRNAs in patients with allergic inflammation, their role as disease biomarkers, and perspectives for future investigation and clinical utility.
Eosinophils have historically been considered to be destructive end-stage effector cells that have a role in parasitic infections and allergic reactions by the release of their granule-derived ...cytotoxic proteins. However, an increasing number of experimental observations indicate that eosinophils also are multifunctional leukocytes involved in diverse inflammatory and physiologic immune responses. Under homeostatic conditions, eosinophils are particularly abundant in the lamina propria of the gastrointestinal tract, where their involvement in various biological processes within the gastrointestinal tract has been posited. In this review, we summarize the molecular steps involved in eosinophil development and describe eosinophil trafficking to the gastrointestinal tract. We synthesize the current findings on the phenotypic and functional properties of gastrointestinal eosinophils and the accumulating evidence that they have a contributory role in gastrointestinal disorders, with a focus on primary eosinophilic gastrointestinal disorders. Finally, we discuss the potential role of eosinophils as modulators of the intestinal immune system.
Eosinophilic esophagitis is an emerging disease that is distinguished from gastroesophageal reflux disease by the expression of a unique esophageal transcriptome and the interplay of early life ...environmental factors with distinct genetic susceptibility elements at 5q22 (TSLP) and 2p23 (CAPN14). Rare genetic syndromes have uncovered the contribution of barrier disruption, mediated in part by defective desmosomes and dysregulated transforming growth factor beta production and signaling, to eosinophilic esophagitis pathophysiology. Experimental modeling has defined a cooperative role of activated eosinophils, mast cells, and the cytokines IL-5 and IL-13, mediated by allergic sensitization to multiple foods. Understanding these processes is opening the way to better treatment based on disrupting allergic inflammatory and type 2 cytokine–mediated responses, including anti-cytokine therapeutics and dietary therapy.
PDF
