Abstract
BackgroundThe atopic syndrome consists of heterogeneous manifestations, in which multiple associated genetic loci have recently been identified. It is hypothesized that immune dysregulation plays a role in the pathogenesis. In primary immunodeficiency diseases (PIDs), which are often monogenic immunodysregulation disorders, the atopic syndrome is a frequently occurring comorbidity. Based on the genetic defects in PIDs, novel gene/pathway-targeted therapies have been evaluated, which could be relevant in the atopic syndrome as well. Therefore, we aimed to define subclasses within the atopic syndrome based on the expression profiles of immune cell lineages of healthy mice.MethodsOverlap between known atopy-related genes as described in the Human Gene Mutation Database and disease-causing genes of monogenic PIDs was evaluated. Clusters of atopy-related genes were based on the overlap in their co-expressed genes using the gene expression profiles of immune cell lineages of healthy mice from the Immunological Genome Project. We analyzed pathways involved in the atopic syndrome using Ingenuity Pathway Analysis.ResultsTwenty-two (5.3%) genes were overlapping between the atopy-related genes (n = 160) and PID-related genes (n = 278). We identified seven distinct clusters of atopy-related genes. Functional pathway analysis of all atopy-related genes showed relevance of T helper cell-mediated pathways.ConclusionsThis study shows a model to define clusters within the atopic syndrome based on gene expression profiles of immune cell lineages. Our results support the hypothesis that both genetic mechanisms and immune dysregulation play a role in the pathogenesis. It also opens up the possibility for novel therapeutic targets and a more tailored approach towards personalized medicine.
Highlights
The atopic syndrome consists of heterogeneous manifestations, in which multiple associated genetic loci have recently been identified
Content of data The search in Human Gene Mutation Database (HGMD) on atopic manifestations retrieved 159 atopy-related genes known in human (Additional file 1: Table S1)
Twenty-two (5.3%) genes of the atopy (n = 160) and primary immunodeficiency disease (PID) (n = 278) lists were overlapping, including ARPC1B, BTK, CASP8, CFTR, CTLA4, DOCK8, ICOS, IL10, IL12B, IL12RB1, IL17F, IL21, IL21R, IL7R, ITK, ORAI1, PGM3, SPINK5, STAT3, TNFRSF13B, TRAF3IP2 and TYK2 (Fig. 1 and Additional file 1: Table S1)
Summary
The atopic syndrome consists of heterogeneous manifestations, in which multiple associated genetic loci have recently been identified. Atopy is the genetic predilection to produce specific immunoglobulin (Ig) E following exposure to allergens This predisposition results in the development of atopic dermatitis (AD), food allergy (FA), asthma and allergic rhinitis (AR): the atopic syndrome [1]. Atopic manifestations share a common mechanism involving allergen-specific IgE, which triggers the release of inflammatory mediators, like histamine, in the skin, gastrointestinal tract, lungs and nose. The course of these manifestations over time is characterized by the atopic march, generally starting with AD in infancy and followed by FA, asthma and AR later in childhood [7]. Patients with atopic manifestations are mostly uniformly treated with topical or systemic immunosuppressive agents and/or antihistamines resulting in varying therapeutic responses as well [10,11,12,13]
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