To examine the mechanisms whereby allergen exposure through the epidermis could initiate systemic allergy and predispose individuals to the development of 1 or more atopic diseases via the so-called ...atopic march.
PubMed databases from 1950 to the present were searched for relevant articles pertaining to epidemiologic and genetic evidence of the progression of the atopic march.
Articles concerning pathophysiologic conditions that link atopic dermatitis, allergic rhinitis, and asthma were examined.
The data suggest that a sequence of atopic manifestations occurs, typically atopic dermatitis in infancy followed by allergic rhinitis and/or asthma in later stages. Reduced filaggrin expression is implicated as a major predisposing factor for atopy in multiple lines of evidence, including genome-wide analysis and microarray investigations. Other gene products have an important role. Cross-sectional and longitudinal studies provide preliminary epidemiologic support for the sequential development of allergic diseases.
The mechanisms by which allergen exposure through the epidermis can initiate systemic allergy and predispose individuals to atopic dermatitis, allergic rhinitis, and asthma have become clearer in recent years. Longitudinal studies of individuals carrying loss-of-function filaggrin gene mutations are needed to further define the risks associated with epidermal barrier dysfunction and potentially identify specific targets for barrier repair and prevention of atopic dermatitis and other atopic disease. The effects of preventive and treatment strategies have been inconsistent across studies, and further research is warranted before any definitive recommendations can be made.
The atopic march recognizes the increased occurrence of asthma, allergic rhinitis, or both after atopic dermatitis (AD) onset. Mechanisms for developing atopic comorbidities after AD onset are poorly ...understood but can involve the impaired cutaneous barrier, which facilitates cutaneous sensitization. The association can also be driven or amplified in susceptible subjects by a systemic TH2-dominant immune response to cutaneous inflammation. However, these associations might merely involve shared genetic loci and environmental triggers, including microbiome dysregulation, with the temporal sequence reflecting tissue-specific peak time of occurrence of each disease, suggesting more of a clustering of disorders than a march. Prospective longitudinal cohort studies provide an opportunity to explore the relationships between postdermatitis development of atopic disorders and potential predictive phenotypic, genotypic, and environmental factors. Recent investigations implicate disease severity and persistence, age of onset, parental atopic history, filaggrin (FLG) mutations, polysensitization, and the nonrural environment among risk factors for development of multiple atopic comorbidities in young children with AD. Early intervention studies to repair the epidermal barrier or alter exposure to the microbiome or allergens might elucidate the relative roles of barrier defects, genetic locus alterations, and environmental exposures in the risk and sequence of occurrence of TH2 activation disorders.
Eosinophilic gastrointestinal diseases are a constellation of conditions categorized by the location of eosinophilic infiltration in the gastrointestinal tract. Symptoms vary based on location of ...eosinophils and age of the patient. There are no approved medications at the current time with individuals using off-label steroids or dietary therapy. Translational research has identified potential pathways to target in the treatment of eosinophilic esophagitis (EoE), gastritis (EoG), and enteritis (EoN), including type 2 pathways, mast cells, and eosinophils. Preliminary studies found cendakimab (anti-interleukin IL-13) and dupilumab (anti-IL-4 receptor alpha) to have an effect on eosinophil count and symptoms with dupilumab recently approved. In addition, mepolizumab (anti-IL-5), reslizumab (anti-IL-5), and lirentelimab (anti-Siglec 8) were found to have reduction in eosinophils without reduction of symptoms. For EoG and EoN, both benralizumab (anti-IL-5 receptor) and lirentelimab were found to have histologic and symptom improvement. There are no agents studied for eosinophilic colitis. Results of ongoing phase 3 trials in EoE and EoG/EoN are also anticipated.
Pathophysiology of Eosinophilic Esophagitis O’Shea, Kelly M.; Aceves, Seema S.; Dellon, Evan S. ...
Gastroenterology (New York, N.Y. 1943),
01/2018, Volume:
154, Issue:
2
Journal Article
Peer reviewed
Open access
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.
Atopic dermatitis (AD) is one of the most common chronic childhood skin diseases affecting up to 17% of children in the United States. The point prevalence of AD has increased based on validated ...questionnaires in the most recent update of the International Study of Asthma and Allergies in Childhood. However, the increases are primarily in developing countries, whereas the rates have stabilized in countries with higher incomes. AD starts in early childhood with 65% of children affected by 18 months of age. Furthermore, less than half of the patients with AD have complete resolution by 7 years of age and only 60% have resolution by adulthood, indicating the chronic nature of AD. AD is a major risk factor for the development of asthma, with an increased odds ratio in children with AD in several longitudinal studies compared with children without AD, and about 30% of patients with AD develop asthma. Patients with atopic sensitization along with eczema are at a higher risk for progressing in the atopic march to asthma. The main risk factors for progression and persistence of asthma are early onset and severity of AD.
Eosinophilic esophagitis (EoE) is a clinicopathologic condition of increasing recognition and prevalence. In 2007, a consensus recommendation provided clinical and histopathologic guidance for the ...diagnosis and treatment of EoE; however, only a minority of physicians use the 2007 guidelines, which require fulfillment of both histologic and clinical features. Since 2007, the number of EoE publications has doubled, providing new disease insight. Accordingly, a panel of 33 physicians with expertise in pediatric and adult allergy/immunology, gastroenterology, and pathology conducted a systematic review of the EoE literature (since September 2006) using electronic databases. Based on the literature review and expertise of the panel, information and recommendations were provided in each of the following areas of EoE: diagnostics, genetics, allergy testing, therapeutics, and disease complications. Because accumulating animal and human data have provided evidence that EoE appears to be an antigen-driven immunologic process that involves multiple pathogenic pathways, a new conceptual definition is proposed highlighting that EoE represents a chronic, immune/antigen-mediated disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation. The diagnostic guidelines continue to define EoE as an isolated chronic disorder of the esophagus diagnosed by the need of both clinical and pathologic features. Patients commonly have high rates of concurrent allergic diatheses, especially food sensitization, compared with the general population. Proved therapeutic options include chronic dietary elimination, topical corticosteroids, and esophageal dilation. Important additions since 2007 include genetic underpinnings that implicate EoE susceptibility caused by polymorphisms in the thymic stromal lymphopoietin protein gene and the description of a new potential disease phenotype, proton pump inhibitor-responsive esophageal eosinophila. Further advances and controversies regarding diagnostic methods, surrogate disease markers, allergy testing, and treatment approaches are discussed.
Basophils and allergic inflammation Siracusa, Mark C., PhD; Kim, Brian S., MD; Spergel, Jonathan M., MD, PhD ...
Journal of allergy and clinical immunology,
10/2013, Volume:
132, Issue:
4
Journal Article
Peer reviewed
Open access
Basophils were discovered by Paul Ehrlich in 1879 and represent the least abundant granulocyte population in mammals. The relative rarity of basophils and their phenotypic similarities with mast ...cells resulted in this cell lineage being historically overlooked, both clinically and experimentally. However, recent studies in human subjects and murine systems have shown that basophils perform nonredundant effector functions and significantly contribute to the development and progression of TH 2 cytokine–mediated inflammation. Although the potential functions of murine and human basophils have provoked some controversy, recent genetic approaches indicate that basophils can migrate into lymphoid tissues and, in some circumstances, cooperate with other immune cells to promote optimal TH 2 cytokine responses in vivo . This article provides a brief historical perspective on basophil-related research and discusses recent studies that have identified previously unappreciated molecules and pathways that regulate basophil development, activation, and function in the context of allergic inflammation. Furthermore, we highlight the unique effector functions of basophils and discuss their contributions to the development and pathogenesis of allergic inflammation in human disease. Finally, we discuss the therapeutic potential of targeting basophils in preventing or alleviating the development and progression of allergic inflammation.
In an article reviewing the status of gastrointestinal allergy in the New England Journal of Medicine in 1949, Ingelfinger et al1 decried the reliance on patients' "incrimination" of specific foods, ...outcome of trial diets, or association of abdominal complaints with symptoms believed to be allergic in making the diagnosis of food allergy. Recently, the National Institutes of Health-sponsored expert panel "Guidelines for the diagnosis and management of food allergy," reaffirmed the utility of the DBPCFC for diagnosing food allergy after an extensive review of the current literature.11 However, the expert panel noted that open or single-blind challenges could also be acceptable when the challenge outcome is negative or when objective symptoms are elicited that exactly recapitulate the history of the reaction.
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