Identification of novel gene signatures in patients with atopic dermatitis complicated by eczema herpeticum

• Published in: Journal of allergy and clinical immunology Vol. 134; no. 4; pp. 848 - 855
• Main Authors: Bin, Lianghua, MD, PhD, Edwards, Michael G., PhD, Heiser, Ryan, PhD, Streib, Joanne E., BA, Richers, Brittany, BS, Hall, Clifton F., MS, Leung, Donald Y.M., MD, PhD
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.10.2014; Elsevier; Elsevier Limited
• Subjects: Adolescent; Adult; Aged; Allergic diseases; Allergy and Immunology; Animals; Atopic dermatitis; Biological and medical sciences; Cells, Cultured; Child; Dermatitis; Dermatitis, Atopic - complications; Dermatitis, Atopic - genetics; Down-Regulation; eczema herpeticum; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene expression; Genetic Markers; herpes simplex virus; Herpes simplex virus 1; Herpesvirus 1, Human - immunology; Human subjects; Human viral diseases; Humans; Immune system; Immunity, Innate; Immunopathology; Infections; Infectious diseases; interferon regulatory factor 3; interferon regulatory factor 7; Interferon Regulatory Factor-3 - genetics; Interferon Regulatory Factor-7 - genetics; Interferon Type I - metabolism; Interferons; Interleukins - genetics; Kaposi Varicelliform Eruption - etiology; Kaposi Varicelliform Eruption - genetics; Leukocytes, Mononuclear - immunology; Leukocytes, Mononuclear - virology; Male; Medical sciences; Middle Aged; Patients; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Skin allergic diseases. Stinging insect allergies; Smallpox; Studies; Transcriptome; type I interferon; type III interferon; Viral diseases; Viral diseases with cutaneous or mucosal lesions and viral diseases of the eye; Viral infections; Young Adult; RPKM; eczema herpeticum; herpes simplex virus; HSV-1; type III interferon; RNA-seq; Atopic dermatitis; FDR; Atopic dermatitis with a history of eczema herpeticum; ADEH; qPCR; HSE; TLR; Toll-like receptor; RNA sequencing; Atopic dermatitis without a history of eczema herpeticum; Ingenuity Pathway Analysis; AD; Reads per kilobase per million mapped reads; interferon regulatory factor 3; interferon regulatory factor 7; Quantitative PCR; PCA; type I interferon; Herpes simplex virus 1; False discovery rate; IPA; IRF; Herpes simplex encephalitis; Interferon regulatory factor; Principal component analysis; Allergy; Skin disease; Kaposi-Juliusberg syndrome; Pustulosis dermatosis; Alphaherpesvirinae; Identification; Atopy; Immunology; Complication; Herpesvirus hominis; Human; Immunopathology; Herpesviridae; Cytokine; Herpes; Gene expression profile; Infection; Virus; Interferon regulatory factor 3; Viral disease; Interferon
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2014.07.018

Background A subset of patients with atopic dermatitis (AD) is prone to disseminated herpes simplex virus (HSV) infection (ie, atopic dermatitis with a history of eczema herpeticum [ADEH+]). Biomarkers that identify ADEH+ are lacking. Objective We sought to search for novel ADEH+ gene signatures in PBMCs. Methods An RNA-sequencing approach was applied to evaluate global transcriptional changes by using PBMCs from patients with ADEH+ and patients with atopic dermatitis without a history of eczema herpeticum (ADEH−). Candidate genes were confirmed by means of quantitative PCR or ELISA. Results PBMCs from patients with ADEH+ had distinct changes to the transcriptome when compared with those from patients with ADEH− after HSV-1 stimulation: 792 genes were differentially expressed at a false discovery rate of less than 0.05 (ANOVA), and 15 type I and type III interferon genes were among the top 20 most downregulated genes in patients with ADEH+. We further validated that IFN-α and IL-29 mRNA and protein levels were significantly decreased in HSV-1–stimulated PBMCs from patients with ADEH+ compared with those from patients with ADEH– and healthy subjects. Ingenuity Pathway Analysis demonstrated that the upstream regulators of type I and type III interferons, interferon regulatory factor (IRF) 3 and IRF7, were significantly inhibited in patients with ADEH+ based on the downregulation of their target genes. Furthermore, we found that gene expression of IRF3 and IRF7 was significantly decreased in HSV-1–stimulated PBMCs from patients with ADEH+. Conclusions PBMCs from patients with ADEH+ have a distinct immune response after HSV-1 exposure compared with those from patients with ADEH−. Inhibition of the IRF3 and IRF7 innate immune pathways in patients with ADEH+ might be an important mechanism for increased susceptibility to disseminated viral infection.