The transcription factor EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL-31 induction.
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ABSTRACT:
SUBMITTER: Yamamura K
PROVIDER: S-EPMC5228069 | biostudies-literature | 2017 Jan
REPOSITORIES: biostudies-literature
Publications
The transcription factor EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL-31 induction.
Yamamura Kazuhiko K Uruno Takehito T Shiraishi Akira A Tanaka Yoshihiko Y Ushijima Miho M Nakahara Takeshi T Watanabe Mayuki M Kido-Nakahara Makiko M Tsuge Ikuya I Furue Masutaka M Fukui Yoshinori Y
Nature communications 20170109
Mutations of DOCK8 in humans cause a combined immunodeficiency characterized by atopic dermatitis with high serum IgE levels. However, the molecular link between DOCK8 deficiency and atopic skin inflammation is unknown. Here we show that CD4<sup>+</sup> T cells from DOCK8-deficient mice produce large amounts of IL-31, a major pruritogen associated with atopic dermatitis. IL-31 induction critically depends on the transcription factor EPAS1, and its conditional deletion in CD4<sup>+</sup> T cells ...[more]
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Project description:Dedicator of cytokinesis 8 deficiency is an autosomal recessive primary immune deficiency disease belonging to the group of hyperimmunoglobulinemia E syndrome (HIES). The clinical phenotype of dedicator of cytokinesis 8 (DOCK8) deficiency, characterized by allergic manifestations, increased infections, and increased IgE levels, overlaps with the clinical presentation of atopic dermatitis (AD). Despite the identification of metabolomics and cytokine biomarkers, distinguishing between the two conditions remains clinically challenging. The present study used a label-free untargeted proteomics approach using liquid-chromatography mass spectrometry with network pathway analysis to identify the differentially regulated serum proteins and the associated metabolic pathways altered between the groups. Serum samples from DOCK8 (n = 10), AD (n = 9) patients and healthy control (Ctrl) groups (n = 5) were analyzed. Based on the proteomics profile, the PLS-DA score plot between the three groups showed a clear group separation and sample clustering (R2 = 0.957, Q2 = 0.732). Significantly differentially abundant proteins (p < 0.05, FC cut off 2) were identified between DOCK8-deficient and AD groups relative to Ctrl (n = 105, and n = 109) and between DOCK8-deficient and AD groups (n = 85). Venn diagram analysis revealed a differential regulation of 24 distinct proteins from among the 85 between DOCK8-deficient and AD groups, including claspin, haptoglobin-related protein, immunoglobulins, complement proteins, fibulin, and others. Receiver-operating characteristic curve (ROC) analysis identified claspin and haptoglobin-related protein, as potential biomarkers with the highest sensitivity and specificity (AUC = 1), capable of distinguishing between patients with DOCK8 deficiency and AD. Network pathway analysis between DOCK8-deficiency and AD groups revealed that the identified proteins centered around the dysregulation of ERK1/2 signaling pathway. Herein, proteomic profiling of DOCK8-deficiency and AD groups was carried out to determine alterations in the proteomic profiles and identify a panel of the potential proteomics biomarker with possible diagnostic applications. Distinguishing between DOCK8-deficiency and AD will help in the early initiation of treatment and preventing complications.
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Project description:DOCK8 deficiency is a primary immunodeficiency characterized by recurrent sinopulmonary infections, dermatitis with cutaneous infections, elevated serum IgE levels, eosinophilia, and a high incidence of food allergy. Given the seriousness of DOCK8 deficiency, it is important to recognize it early and initiate appropriate therapy. Diagnosis relies on examining DOCK8 protein expression and sequencing of the 48 exons in the DOCK8 gene, but these assays are not always readily available. A major problem facing clinicians is that DOCK8 deficiency shares many clinical and laboratory features with severe atopic dermatitis. Here, we have identified biomarkers routinely measured by flow cytometry on whole blood in clinical immunology laboratories that may be used in distinguishing DOCK8 deficiency from severe atopic dermatitis. The use of these biomarkers may help the clinician identify those patients who are most likely to have DOCK8 mutations and would benefit from further specialized diagnostic testing.
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