Proteomics Profiling to Distinguish DOCK8 Deficiency From Atopic Dermatitis.

Minnie Jacob,Zakiya Shinwari,Rand Arnaout,Hamoud Al-Mousa,Bandar Alsaud,Anas M Abdel Rahman,Afshan Masood,Majed Dasouki,Mai Abdel Jabbar,Ayodele A Alaiya

doi:10.3389/falgy.2021.774902

Abstract

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.

Highlights

Dedicator of cytokinesis 8 deficiency is a rare autosomal recessive combined immunodeficiency that forms part of the heterogeneous hyper immunoglobulin E syndrome (HIES). dedicator of cytokinesis 8 (DOCK8) is a guanine nucleotide exchange factor that regulates the activity of cell division cycle 42 (Cdc42) necessary for promoting actin binding, maintaining cytoskeletal integrity, and integrating signals from the cell membrane for appropriate cytoskeletal reorganization [1]
Eosinophilia was seen in all the patients, albeit the counts were higher in the DOCK8-deficient cohort than atopic dermatitis (AD); high counts in DOCK8 deficiency cannot be used as the only criterion for diagnosis eosinophils can be elevated in many other diseases
The Severity Scoring of Atopic Dermatitis (SCORAD) and the Visual Analog Scale (VAS) pruritus scores were comparable in both cohorts (Table 1)

Summary

Introduction

Dedicator of cytokinesis 8 deficiency is a rare autosomal recessive combined immunodeficiency that forms part of the heterogeneous hyper immunoglobulin E syndrome (HIES). dedicator of cytokinesis 8 (DOCK8) is a guanine nucleotide exchange factor that regulates the activity of cell division cycle 42 (Cdc42) necessary for promoting actin binding, maintaining cytoskeletal integrity, and integrating signals from the cell membrane for appropriate cytoskeletal reorganization [1]. Dedicator of cytokinesis 8 (DOCK8) is a guanine nucleotide exchange factor that regulates the activity of cell division cycle 42 (Cdc42) necessary for promoting actin binding, maintaining cytoskeletal integrity, and integrating signals from the cell membrane for appropriate cytoskeletal reorganization [1]. DOCK8 plays an important role in cell migration, morphology, adhesion, and growth [4]. The characteristic features associated with DOCK8 deficiency include elevated IgE levels, recurrent bacterial and viral infections, atopic dermatitis, mucocutaneous candidiasis, asthma, severe food and environmental antigens allergies, and an increased incidence of malignancy [5, 6]. Individuals with DOCK8 mutations exhibit recurrent sinopulmonary infections specific for humoral immunodeficiency and severe viral infections suggestive of T-cell dysfunctions [7]. Patients with DOCK8 deficiency characteristically manifest with dermatitis-like skin lesions resembling atopic dermatitis (AD)

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Conclusion