Review article
Skin barrier function, epidermal proliferation and differentiation in eczema

https://doi.org/10.1016/j.jdermsci.2006.06.003Get rights and content

Summary

Skin permeability barrier function is impaired in eczema, particularly in contact and atopic dermatitis (AD). In contact dermatitis disruption of the barrier by irritants and allergens is the primary event, followed by sensitization, inflammation, increased epidermal proliferation and changes in differentiation. Genetically impaired skin barrier function is already present in non-lesional and more pronounced in lesional skin in AD. Increased epidermal proliferation and disturbed differentiation, including changes in lipid composition, cause impaired barrier function in AD. Defective permeability barrier function enables the enhanced penetration of environmental allergens into the skin and initiates immunological reactions and inflammation. Barrier dysfunction is therefore crucially involved in the pathogenesis of AD. The atopic syndrome represents a genetically impaired skin barrier function as well as impaired nasal, bronchial, and intestinal mucous membranes leading to AD, allergic rhinitis, bronchial asthma or aggravation of AD. Common treatment strategies for eczema include the application of lipid-based creams and ointments, which aim toward the restoration of the defective permeability barrier, thus helping to normalize proliferation and differentiation.

Introduction

The existence of a defect in skin permeability barrier function in eczema is well accepted. The skin is composed of several different types of barrier including the physical barrier, located in the outermost epidermal layer, the stratum corneum [1], the chemical/biochemical or antimicrobial barrier of the innate immune system, composed of lipids, acids, lysozymes and antimicrobial peptides [2], and the immune barrier, consisting of the humeral (Ig-antibodies) and cellular immune system (lymphocytes, dendritic cells, macrophages) [3]. Epidermal abnormalities are often viewed as a consequence of inflammation. In contrast, we propose that the impaired barrier function in atopic dermatitis is crucially involved in the pathogenesis of eczema. This review focuses on the role of the physical barrier and also points to interactions with the chemical/biochemical barrier and the immune barrier in contact dermatitis and AD.

Section snippets

Skin permeability barrier

The stratum corneum, composed of protein-enriched cells, the corneocytes, and lipid-enriched intercellular domains, is most important in the formation of the physical barrier. The barrier is formed during epidermal proliferation and differentiation which begins in the basal layer. Numerous biochemical reactions take place during the transition from the basal layer to the stratum corneum, including the synthesis of specific basal (K5 and K14) and suprabasal (K1 and K10) keratins and cornified

Barrier disruption in contact dermatitis

The important role of skin barrier function in contact dermatitis is obvious: irritating chemicals which come in contact with the skin lead to acute or chronic irritant contact dermatitis, depending on the strength of the irritant, the duration and number of contacts. Irritants like water containing detergents or solvents impair skin barrier function by removing lipids or disturbing the lipid organization of stratum corneum intercellular bilayers. Subsequently, these irritants penetrate into

Barrier function and the immune system in contact dermatitis

We have previously shown that experimental barrier disruption in human skin through application of acetone or sodium lauryl sulfate results in an increase in Langerhans cell density in the epidermis. We also found an increase in Langerhans cell density and proliferation during standard patch testing using an occlusive patch test chamber, which leads to barrier disruption because of hyperhydration and increased irritant capacity of the allergen [8]. It has also been shown that barrier disruption

Barrier function and hydration in atopic dermatitis

We recently determined skin barrier function and epidermal hydration in AD using biophysical methods. Transepidermal water loss (TEWL), as a marker of barrier function, was already two-fold increased in non-lesional and four-fold increased in lesional skin, compared with the skin of normal controls. This shows that the inside-out barrier is already impaired in non-lesional and is more pronouncedly impaired in lesional skin of AD. The outside-in barrier is also disturbed in AD, which may allow

Metabolism of essential free fatty acids in AD

It has been known for more than 70 years that a deficiency in n-6 essential fatty acids (EFAs) leads to inflammatory skin conditions in both animals and humans. Mice fed an EFA-deficient diet showed red scaly skin and an up to 10-fold increase in transepidermal water loss. The symptoms of EFA deficiency in animals can easily be reversed with systemic or topical application of n-6 EFAs, linoleic acid, γ-linolenic acid, or columbinic acid. In atopic dermatitis there is no deficiency of linoleic

Epidermal proliferation and differentiation in AD

Eczema represents a scaling dermatitis; epidermal changes are both clinically and histologically visible. Using the Ki-67 marker, we found an increase in epidermal proliferation already in non-lesional and a several fold increase in lesional skin, compared to healthy skin. Increased proliferation is often accompanied by disturbed differentiation. We recently determined keratins and cornified envelope proteins in atopic dermatitis by immunohistology and by western blotting, finding reduced

Cutaneous and mucocutaneous barrier dysfunction in the atopic syndrome

It is well known that atopic dermatitis is part of the atopic syndrome which also includes allergic rhinitis/conjunctivitis and allergic bronchial asthma. Therefore, Ogawa and Yoshiike have suggested that the atopic syndrome represents a mucocutaneous barrier dysfunction [10]. A mucocutaneous barrier defect readily allows for the penetration of multiple antigens, but also irritants. Increased skin irritant response in atopic subjects is well known. Disturbed skin barrier function not only

Genetics related to disturbed barrier function

A genetically impaired epidermal barrier has also been proposed as a cause of AD and respiratory atopy. Increased exposure to irritants and allergens postnatal in predisposed individuals would lead to a subset of specific TH2 cell activation favouring the development of IgE response [35]. Ichthyosis vulgaris, an autosomal dominant disorder causing defective epidermal filaggrin expression, occurs in 20–37% of patients with AD [36]. Concomitant atopic dermatitis in patients with ichthyosis

Increased rate of viral infections in AD

It is well known that recurrent herpes simplex infections in patients with AD may lead to eczema herpeticum. The occurrence of eczema herpeticum has been generally viewed as a consequence of reduced immune function. However, eczema herpeticum also occurs in Wiskott–Aldrich syndrome, Netherton's syndrome, Darier's disease and Hailey–Hailey's disease. These are without exception monogenetic diseases where mutations lead to epidermal defects including defects in skin barrier function. Therefore,

Chemical/biochemical barrier in eczema

The chemical/biochemical barrier, or innate immune system, contains several antimicrobial peptides known as cathelicidines (LL-37), β-defensins, psoriasin and RNAse7. Some of these antimicrobial peptides like cathelicidines and β-defensin-2 and -3 are only negligibly present in normal skin, but accumulate in skin affected by inflammatory diseases such as psoriasis. It has been shown that there is no increase in human β-defensin-2 and LL-37 mRNA in AD compared to normal skin, in contrast to

Climate and environmental aspects in the pathogenesis of AD

The increased incidence of AD might be explained by barrier dysfunction caused by changes in lifestyle or climate. Lifestyle-associated changes in physiological stress appear to enhance skin irritability [50], [51], [52]. Excessive use of soaps, liquid detergents and shampoos may lead to irritation of the skin and disturbed skin barrier function. Air conditioning and inadequate ventilation may increase exposure to environmental antigens such as household dust mites and pollens. Antigens may

Therapeutic implications

Treatment strategies in eczema often address immunogenic abnormalities and barrier function. Treatment with corticosteroids, cyclosporin, tacrolimus, pimecrolimus, and UV light has been shown to reduce cell inflammation as well as to improve barrier function. Application of creams and ointments containing lipids and lipid-like substances, hydrocarbons, fatty acids, cholesterol esters and triglycerides stimulates barrier repair and increases stratum corneum hydration. Hydrocarbons, most commonly

Ehrhardt Proksch received his PhD in chemistry from the University of Göttingen in 1977 and an MD from the Universities of Frankfurt and Göttingen in 1983. He was a visiting scientist at the Department of Dermatology, University of California at San Francisco and is currently Professor and Vice-Chairman of the Department of Dermatology, Venerology and Allergology at the University of Kiel. Professor Proksch's research areas include barrier function of the skin, ceramides, lipids, skin aging and

References (58)

  • O. Macheleidt et al.

    Deficiency of epidermal protein-bound ω-hydroxyceramides in atopic dermatitis

    J Invest Dermatol

    (2002)
  • S. Ekanayake-Mudiyanselage et al.

    Expression of epidermal keratins and the cornified envelope protein involucrin is influenced by permeability barrier disruption

    J Invest Dermatol

    (1998)
  • E.B. Mitchell et al.

    Basophils in allergen-induced patch test sites in atopic dermatitis

    Lancet

    (1982)
  • M.G. Pike et al.

    Increased intestinal permeability in atopic eczema

    J Invest Dermatol

    (1986)
  • A. Trautmann et al.

    The differential fate of cadherins during T-cell-induced keratinocyte apoptosis leads to spongiosis in eczematous dermatitis

    J Invest Dermatol

    (2001)
  • J.J. Chen et al.

    The gene for a rare autosomal dominant form of pompholyx maps to chromosome 18q22.1–18q22.3

    J Invest Dermatol

    (2006)
  • G.J. de Jongh et al.

    High expression levels of keratinocyte antimicrobial proteins in psoriasis compared with atopic dermatitis

    J Invest Dermatol

    (2005)
  • P.M. Elias et al.

    Epidermal pathogenesis of inflammatory dermatoses

    Am J Contact Derm

    (1999)
  • M. Altemus et al.

    Stress-induced changes in skin barrier function in healthy women

    J Invest Dermatol

    (2001)
  • R. Ghadially et al.

    Effects of petrolatum on stratum corneum structure and function

    J Am Acad Dermatol

    (1992)
  • J. Harder et al.

    Antimicrobial peptides in human skin

    Chem Immunol Allergy

    (2005)
  • T. Schwarz

    Skin immunity

    Br J Dermatol

    (2003)
  • W.M. Holleran et al.

    Sphingolipids are required for mammalian epidermal barrier function. Inhibition of sphingolipid synthesis delays barrier recovery after acute perturbation

    J Clin Invest

    (1991)
  • M. Fartasch et al.

    Structural relationship between epidermal lipid lamellae, lamellar bodies and desmosomes in human epidermis: an ultrastructural study

    Br J Dermatol

    (1993)
  • E. Proksch et al.

    Influence of epidermal permeability barrier disruption and Langerhans’ cell density on allergic contact dermatitis

    Acta Derm Venereol

    (1997)
  • D. Jakobza et al.

    Surface skin lipids in atopic dermatitis (author's translation)

    Dermatol Monatsschr

    (1981)
  • J. Barth et al.

    Skin surface lipids in atopic eczema and ichthyosis

    Chron Derm

    (1989)
  • A. Yamamoto et al.

    Stratum corneum lipid abnormalities in atopic dermatitis

    Arch Dermatol Res

    (1991)
  • A. Di Nardo et al.

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

    Acta Derm Venereol

    (1998)
  • Cited by (0)

    Ehrhardt Proksch received his PhD in chemistry from the University of Göttingen in 1977 and an MD from the Universities of Frankfurt and Göttingen in 1983. He was a visiting scientist at the Department of Dermatology, University of California at San Francisco and is currently Professor and Vice-Chairman of the Department of Dermatology, Venerology and Allergology at the University of Kiel. Professor Proksch's research areas include barrier function of the skin, ceramides, lipids, skin aging and antimicrobial defense of the skin, as well as occupational and environmental dermatology, skin pharmacology and toxicology.

    Regina Fölster-Holst received her MD from the University of Kiel in 1984. Since 1985, she has been a member of the clinical staff of the Department of Dermatology, Venerology and Allergology at the University of Kiel, currently holding the position of Senior Physician. Dr. Fölster-Holst specializes in pediatric dermatology and conducts research on the genetic variability and pathphysiology of atopic dermatitis.

    Jens-Michael Jensen received his MD from the University of Kiel in 1994 and completed his doctoral dissertation Tumor Necrosis Factor-a Signal Transduction through Sphingomyelinases and Ceramides in the Repair of the Skin's Permeability Barrier in 1998. He was a visiting scientist at the Harvard Skin Disease Research Center at Harvard University. Alongside his clinical duties at the Department of Dermatology, Venerology and Allergology at the University of Kiel, Dr. Jensen conducts research on barrier function, signal transduction in the epidermis, lipids, skin aging, antimicrobial defense, infectious and allergic diseases, and atopic dermatitis.

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