Nonlesional atopic dermatitis skin is characterized by broad terminal differentiation defects and variable immune abnormalities

doi:10.1016/j.jaci.2010.12.1124

Journal of Allergy and Clinical Immunology

Volume 127, Issue 4, April 2011, Pages 954-964.e4

https://doi.org/10.1016/j.jaci.2010.12.1124 Get rights and content

Background

Atopic dermatitis (AD) is a common inflammatory skin disease with a T_H2 and “T22” immune polarity. Despite recent data showing a genetic predisposition to epidermal barrier defects in some patients, a fundamental debate still exists regarding the role of barrier abnormalities versus immune responses in initiating the disease. An extensive study of nonlesional AD (ANL) skin is necessary to explore whether there is an intrinsic predisposition to barrier abnormalities, background immune activation, or both in patients with AD.

Objective

We sought to characterize ANL skin by determining whether epidermal differentiation and immune abnormalities that characterize lesional AD (AL) skin are also reflected in ANL skin.

Methods

We performed genomic and histologic profiling of both ANL and AL skin lesions (n = 12 each) compared with normal human skin (n = 10).

Results

We found that ANL skin is clearly distinct from normal skin with respect to terminal differentiation and some immune abnormalities and that it has a cutaneous expansion of T cells. We also showed that ANL skin has a variable immune phenotype, which is largely determined by disease extent and severity. Whereas broad terminal differentiation abnormalities were largely similar between involved and uninvolved AD skin, perhaps accounting for the “background skin phenotype,” increased expression of immune-related genes was among the most obvious differences between AL and ANL skin, potentially reflecting the “clinical disease phenotype.”

Conclusion

Our study implies that systemic immune activation might play a role in alteration of the normal epidermal phenotype, as suggested by the high correlation in expression of immune genes in ANL skin with the disease severity index.

Section snippets

Patients and skin samples

Skin biopsy specimens were collected from 15 patients with moderate-to-severe AD (10 male and 5 female patients; age, 16-81 years; median age, 38 years) and 10 healthy volunteers under institutional review board–approved protocols, and written consent was obtained. Patients with an acute exacerbation of chronic AD and without any therapy for more than 4 weeks were included (see Table E1 in this article’s Online Repository at www.jacionline.org). Biopsy specimens were obtained from both AL and

Patients’ characteristics

We studied nonlesional and lesional skin biopsy specimens from 15 adult patients with moderate-to-severe chronic AD, SCORAD scores ranging from 28 to 97.5 (mean, 60), and a body surface area (BSA) involvement of 11% to 63% (mean, 36%; see Table E1). A single-copy R501X mutation in the FLG gene was observed in 1 patient (see Table E1 and the Methods section in this article’s Online Repository).

ANL skin shows abnormal proliferation and immune infiltration compared with normal skin

To determine whether ANL skin maintains specific features of diseased skin, we compared epidermal

Discussion

In contrast to psoriasis, in which nonlesional skin is largely similar to normal skin²⁵ and disease tendency cannot be determined based on abnormalities in nonlesional skin,³¹ ANL skin is viewed as abnormal by most authors,10, 12, 13, 14, 15, 16 although conflicting results have been observed.³² Prior studies have analyzed alterations in only a few genes of interest,³³ in a small number of patients,12, 34 or both, so that a global characterization of gene and protein expression in ANL skin was

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: Supported by grant no. 5UL1RR024143-02 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and the NIH Roadmap for Medical Research.

: Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest.

^∗: These authors contributed equally to this work.

View full text

Atopic dermatitis and skin diseaseNonlesional atopic dermatitis skin is characterized by broad terminal differentiation defects and variable immune abnormalities

Background

Objective

Methods

Results

Conclusion

Section snippets

Patients and skin samples

Patients’ characteristics

ANL skin shows abnormal proliferation and immune infiltration compared with normal skin

Discussion

Lancet

J Invest Dermatol

J Invest Dermatol

J Invest Dermatol

J Invest Dermatol

J Allergy Clin Immunol

Clin Dermatol

J Dermatol Sci

Mol Immunol

J Invest Dermatol

Clin Immunol

Immunity

Atopic dermatitis

N Engl J Med

Abnormal skin barrier in the etiopathogenesis of atopic dermatitis

Curr Opin Allergy Clin Immunol

IL-22-producing “T22” T cells account for upregulated IL-22 in atopic dermatitis despite reduced IL-17-producing TH17 T cells

J Allergy Clin Immunol

Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling

J Clin Invest

Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis

Nat Genet

The skin barrier as an innate immune element

Semin Immunopathol

Broad defects in epidermal cornification in atopic dermatitis identified through genomic analysis

J Allergy Clin Immunol

Differential in situ cytokine gene expression in acute versus chronic atopic dermatitis

J Clin Invest

New insights into atopic dermatitis

J Clin Invest

Ceramide and cholesterol composition of the skin of patients with atopic dermatitis

Acta Derm Venereol

Transepidermal water loss in dry and clinically normal skin in patients with atopic dermatitis

Acta Derm Venereol

Atopic dermatitis and skin disease
Nonlesional atopic dermatitis skin is characterized by broad terminal differentiation defects and variable immune abnormalities