Interferon Responses in Eczema Herpeticum

National Institute of Allergy and Infectious Diseases (NIAID)84 enrolled

Overview

Atopic dermatitis (AD) is a chronic skin disorder characterized by recurrent viral skin infections. A small subset of patients with AD suffer from disseminated viral infections, e.g., eczema herpeticum (ADEH+), after herpes simplex infection (HSV) or eczema vaccinatum (EV) after smallpox vaccination. Interferon gamma (IFNγ) plays a critical role in the innate and acquired immune responses by activating macrophages, enhancing natural killer cell activation, and promoting T cell differentiation, as well as regulating B cell isotype switching to immunoglobulin (Ig) G2a. Recent studies have demonstrated that IFNγ generation was significantly decreased after stimulation with HSV ex vivo. The purpose of this study is to determine if deficient IFNγ induction leads to susceptibility to HSV infection in ADEH+ patients.

The investigators hypothesize that defective IFNγ responses in peripheral blood mononuclear cells (PBMCs) from ADEH+ patients results from aberrant pattern recognition receptors (PRR) signaling in antigen-presenting cells (APCs) resulting in low level production of IL-12, an essential cytokine for IFNγ generation. This study will compare results from 40 ADEH+, 40 ADEH-, and 40 non-atopic participants. Study procedures will typically be completed in one visit; however, participants may be asked to return for additional unscheduled visit(s) occurring as frequently as every 3 months for the duration of the study to provide an additional blood sample for further characterization of immune mechanisms leading to reduced IFNγ responses in ADEH+.

Study Type

OBSERVATIONAL

Enrollment

Conditions

Atopic Dermatitis Eczema Herpeticum Herpes Simplex Infections

Eligibility

Sex: ALLMin age: 6 YearsMax age: 65 YearsHealthy volunteers:

Medical Language ↔ Plain English

Participant Inclusion Criteria: Participants who meet all of the following criteria are eligible for enrollment: * have a history of AD with or without a history of Eczema Herpeticum (EH) as diagnosed using the Atopic Dermatitis Research Network (ADRN) Standard Diagnostic Criteria OR --are non-atopic as diagnosed using the ADRN Standard Diagnostic Criteria * are willing to sign the informed consent form or whose parent or legal guardian is willing to sign the informed consent form (age appropriate) prior to initiation of any study procedure * are willing to sign the assent form, if age appropriate. Participant Exclusion Criteria: Participants who meet any of the following criteria are not eligible for enrollment: * have a history of any systemic illness (e.g., immunodeficiency disorders such as human immunodeficiency virus \[HIV\] or lupus erythematosus) other than the condition being studied * have an active systemic malignancy, excluding uncomplicated non-melanoma skin cancer * have any skin disease other than AD that might compromise the stratum corneum barrier (e.g., bullous disease, psoriasis, cutaneous T cell lymphoma \[also called Mycosis Fungoides or Sezary syndrome\], dermatitis herpetiformis, Hailey-Hailey, or Darier's disease) * have a first degree relative already enrolled in the study * are determined not to be eligible in the opinion of the Investigator. Participants who meet any of the following criteria are not eligible for enrollment but may be reassessed: * have active eczema herpeticum at the Enrollment Visit * have taken systemic immunosuppressive drugs including cyclosporine or oral steroids within 30 days of the Enrollment Visit * have a fever ≥ 38.5 degrees Centigrade (ºC) (101.3 ºF) at the Enrollment Visit.

Outcomes

Primary Outcomes

Expression of IFNγ and Interleukin-12 (IL-12), in response to stimulation with Herpes Simplex Virus 1 (HSV-1), Vaccinia Virus (VV), and Pattern Recognition Receptors (PRR) agonists

Protein and messenger ribonucleic acid (mRNA) levels of IFNγ, and the IFN-γ promoting cytokine, IL-12, produced by Cluster of Differentiation 14 (CD14+) monocytes in response to stimulation with HSV-1, VV, and various PRR agonists

Time frame: Day 1

Secondary Outcomes

Cell surface expression of Major Histocompatibility complex (MHC) class I and class II and co-stimulatory molecules on CD14+ cells in response to IFNγ and Interferon-alpha (IFNα) stimulation

Time frame: Day 1

Production of IL-18 and IFNα protein and mRNA by CD14+ cells following stimulation with HSV-1, VV, or PRR agonists

Time frame: Day 1

Production of IFNγ protein by Cluster of Differentiation 8 (CD8+) T cells in response to stimulation with recombinant human cytokines including but not limited to IL-12, IL-18, and IFNα

Time frame: Day 1

Protein expression of IFNγ receptor and IFNα/β receptor on CD14+ cells

Time frame: Day 1

Immunodominant HSV-1 peptide repertoires

Analysis of immunodominant HSV-1 peptide repertoires with related Human Leukocyte Antigen (HLA) in ADEH+, ADEH-, and non-atopic participants

Time frame: Day 1

High-throughput gene expression profiling to analyze ribonucleic acid (RNA) from HSV-1 stimulated and sham stimulated CD14+ monocytes

Global transcriptional response of CD14+ monocytes to stimulation with HSV-1 as evaluated by GeneChip Profiling

Time frame: Day 1

Production of protein and RNA of IFN family members and any related pro- or anti-inflammatory cytokines/chemokines in response to stimulation of PBMCs or purified monocytes

IFN family members include IFNα, Interferon beta (IFNβ), and IFNγ. Related pro- or anti-inflammatory cytokines/chemokines include, but are not limited to IL-29 and IL-10

Time frame: Day 1

Expression of MHC and co-stimulatory molecules on CD14+ cells in response to stimulation with HSV-1, VV, or PRR agonists

Time frame: Day 1

Viral titer of VV as determined by plaque assay following incubation of virus with PBMCs

Time frame: Day 1

Gene expression profiles and gene variant profiles of PBMCs stimulated with HSV-1 as assayed by RNA-seq

Time frame: Day 1

Interferon Responses in Eczema Herpeticum

Overview

Conditions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes