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Update on the structure and function of the skin barrier: atopic dermatitis as an exemplar of clinical implications.

ABSTRACT The healthy stratum corneum allows optimum permeability of water and provides the first line of defense against pathogenic and environmental assaults. The barrier functions of the stratum corneum are interrelated, coregulated, and interdependent. Research has demonstrated that three lipid species, which usually comprise 10% of the stratum corneum, are crucial to both its structure and its function; these must be present in sufficient quantities and in the correct proportions to provide optimum barrier function. The clinical implications of how the skin barrier works--and is supported and restored--can be seen in the current and emerging understanding of atopic dermatitis management.

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The effectiveness of the skin as a protective organ is made possible by a set of critical defensive and protective functions known collectively as "barrier function" (Table). Of these, the permeability barrier is the most critical because it allows humans to live in our dry terrestrial environment. The other functions all are defensive in nature. The most recent research has demonstrated that these defensive functions are not completely discrete; they are interrelated, coregulated, and interdependent to such a degree that if one function is perturbed, the others also are affected. These functions are possible because of the structure and properties of the stratum corneum.

Stratum Corneum Structure

It was first proposed 3 decades ago and now is widely appreciated that the structure of the stratum corneum is analogous to that of a brick wall, with corneocyte "bricks" held in place by the extracellular matrix "mortar." (1-3) The stratum corneum barrier relies predominantly on the extracellular matrix, where lamellar bilayers block the outflow of water into the environment and prevent the ingress of toxic substances, allergens, and microbial pathogens into the body. (2,3)

The lamellar bilayers that fill the intercellular spaces are formed of extracellular lipids, of which three species are key: cholesterol; a family of long-chained, free fatty acids; and ceramides. Normally, they comprise about 10% of the mass of the stratum corneum. Each of these three lipid species is equally important and must be present in sufficient quantities. In addition, they must be present in the correct proportions for the lamellar bilayers to form. (2,3)

The key lipids are derived from a unique secretory vesicle, the epidermal lamellar body, which is produced by the epidermis. The lamellar bodies produce the precursor elements--including phospholipids, glucosylceramides, cholesterol, and proteins that are essential to the cohesion, desquamation, and conversion of the lipid precursors into the more waterproof lipid products. Epidermal lamellar bodies also deliver at least two critical proteins that are important for antimicrobial defense: human [beta]-defensin 2 and the cathelicidin protein LL-37. (2,3)

Structurally, ceramides can be considered as two fatty-acid chain links joined together by an amide group. The ceramides in the stratum corneum barrier are highly saturated, with few unsaturated groups; thus, these ceramides are highly hydrophobic and are essential for the waterproofing of the skin--that is, forming a permeability barrier. (2-4)

A normal permeability barrier is also an effective antimicrobial barrier. It resists not only the egress of water but also the penetration into the body of pathogenic microbes, allergens, and other noxious substances. (2,4)

Clinical Implications of Skin Barrier Function: The Atopic Dermatitis (AD) Exemplar

The decades of basic science research have led to the present and growing recognition that barrier function is clinically relevant. It is becoming increasingly clear that many of the important inflammatory dermatoses seen in clinical practice are associated with primary inherited abnormalities in barrier function. Moreover, this understanding has led to the realization that the treatment of these disorders cannot be limited solely to anti-inflammatory therapy. AD provides a clear illustration of how our knowledge and strategies have progressed.

Molecular Background of AD

Filaggrin is the key protein that causes aggregation of keratin filaments in the corneocyte cytosol. As the corneocytes move up through the stratum corneum, filaggrin begins to be degraded into its constituent amino acid components. Next, these amino acids are further de-emanated into a family of organic acids that comprise natural moisturizing factor, a compound that is crucial for corneocyte hydration.

Many patients with AD have an inherited defect in filaggrin, but it is intriguing that AD associated with filaggrin deficiency is found predominantly in individuals of northern European ancestry. Thyssen and Elias (5) recently proposed a new theory to explain why filaggrin mutations have persisted and are becoming more common in this population; namely, that it might be related to a need for additional vitamin D production in the skin. It has been commonly believed that less skin pigment found in northern populations allows greater ultraviolet B (UVB) penetration and, thus, generation of additional vitamin D; new evidence suggests instead that it is filaggrin deficiency that allows greater UVB penetration and increased production of vitamin D in the epidermis. (5)

The fact that AD is attributable to inherited abnormalities in barrier function has important and broad implications for the therapy and prevention of AD.

The absence of sufficient quantities of filaggrin results in a defect in corneocyte hydration and a severe dry skin abnormality. In turn, the dry skin itself creates and contributes to the barrier abnormality by increasing the water gradient across the skin (Figure 1).

In addition, lack of sufficient organic acids results in an adverse change in the pH of the stratum corneum. The surface pH of the skin is normally highly acidic, a condition necessary for many critical functions. In the absence of sufficient filaggrin breakdown products, the pH rises, which has several dramatic and important consequences for stratum corneum function, including perturbation of the permeability barrier, hydration, antimicrobial defense, and skin cohesion (Figure 2). In addition, trans-urocanic acid, a critical filter for UVB radiation, is not formed, a finding that explains the recently reported increased incidence of nonmelanoma skin cancers in patients with a history of AD. (6)

Finally, these abnormalities in the availability of filaggrin breakdown products are accompanied by an activation and initiation of a cytokine cascade.

The epidermal cytokines have two functions. Of benefit to barrier function is that their synthesis and release upregulate necessary processes, such as lipid and DNA synthesis, which help restore the barrier function after it has been perturbed. However, if the barrier abnormality persists, the result is what is called an "outside-inside" cytokine cascade--recruitment of an inflammatory infiltrate into the skin and the initiation of inflammation. (7)

pH and the Pathogenesis of AD

Study of Netherton syndrome has provided important insights into the pathogenesis of AD. Netherton syndrome is a rare condition associated with a severe type of AD. In Netherton syndrome, mutations occur in SPINK5, a serine protease inhibitor that encodes a critical serine protease inhibitor, lymphoepithelial-Kazal-type 5 inhibitor (LEKTI). In the absence of LEKTI, serine proteases increase markedly and attack structures in the stratum corneum and the underlying epidermis. The result is abnormal barrier function, increased incidence of infection, a thin and poorly cohesive stratum corneum, and a direct initiation of helper T-cell subtype 2 ([T.sub.H]2) inflammation, (8)

As noted above, an increase in pH also increases serine protease activity. Therefore, in individuals with filaggrin deficiency, the abnormalities associated with Netherton syndrome (including the increases in pH and serine protease activity) are replicated. Conversely, if the pH of the skin can be lowered into an acidic range, many of the features of AD--and, perhaps, the disease itself--can be prevented. (8)

Lipid Abnormalities in AD

Most clinicians who manage patients with AD are aware of the lipid abnormalities inherent in this disease. However, the mechanisms of serine protease and pH increase underlying these abnormalities have been described only recently and may not be as widely understood.

It is now known that the increase in serine proteases blocks lamellar body secretion, so the lipids become trapped in the corneocytes. Because these lipids are not secreted, a global deficiency occurs in all three key lipids (ie, cholesterol, free fatty acids, and ceramides). (9)

A further decrease occurs specifically in ceramide content because the serine proteases attack the enzymes that generate ceramides. In addition, the [T.sub.H]2 cytokines in AD downregulate ceramide synthesis on a transcriptional level. Finally, the increased pH deactivates the serine proteases, which are mainly active when pH is neutral. (9)

Barrier-Repair Strategies in AD

The understanding of these underlying mechanisms of lipid abnormalities provides a rationale for therapy with corrective mixtures of physiologic lipids. Corrective barrier-repair therapy can use either nonphysiologic lipids (such as petrolatum and lanolin) or physiologic lipid-based formulations.

Applications of nonphysiologic lipids ("greasing the skin") has been the mainstay of basic skin care in patients with AD. The mechanism of action is the formation of a coating on the outer layer of the stratum corneum. (10,11) In contrast, physiologic lipids rapidly traverse the stratum corneum and enter the nucleated layers of the epidermis, where they combine with lipids that are being synthesized in the underlying epidermal cells and are then secreted into the intercellular spaces of the stratum corneum (Figure 3). (10)

To be optimal, physiologic lipid formulations must include all three key lipids, which must be delivered in a 3:1:1 molar ratio. The dominant species in any given formulation depends on the disease being treated. In AD, a global deficiency exists in all three key lipids, with a further decline in ceramides; thus, a ceramide-dominant version of the optimal molar ratio should be used to treat this disorder. Such a formulation has been shown to be highly effective--as effective as a midpotency corticosteroid agent--in treating moderate and severe AD. (12,13)

Physiologic lipid formulations are effective for barrier repair because, in addition to emollient and hydrating effects, these formulations are anti-inflammatory. A number of anti-inflammatory mechanisms have been identified. By normalizing the barrier, the cytokine cascade is decreased and the entry of allergens and haptens into the skin is reduced. In addition, improvement in the permeability barrier results in improved antimicrobial defense function. Also, many of the free fatty acids that are used in these formulations are potent activators of nuclear hormone receptors such as peroxisome proliferator-activated receptor (PPAR)-[alpha] and PPAR-[beta]/[delta]. In animal models of AD, these hormone receptors have been shown to exert anti-inflammatory effects as potent as that seen with clobetasol. Finally, physiologic lipid formulations with a low pH cause a decrease in serine protease activity. (12)

It is important to note that numerous products are being marketed that use the terms barrier repair and ceramides to support claims of restoration of normal barrier function, but often with few scientific data behind such claims. Many of these products contain incomplete lipid mixtures, often with no ceramides included, and frequently they do not contain sufficient quantities of physiologic lipids; commonly, the lipids in these formulations are not present in the correct molar ratio. (12)

Conclusion

For many years, clinicians routinely have used a number of effective strategies that help repair the stratum corneum barrier. These measures were based largely on empiric and anecdotal evidence that they worked, although the underlying mechanisms for why and how they worked were not always fully understood. For example, in AD, clinicians educated parents and patients about strategies to break the itch-scratch cycle, including avoiding harsh soaps and exposure to potential allergens, the importance of hydration in the form of baths followed by applications of emollient moisturizers, decreasing psychological stress in the family, using antihistamines and topical and systemic corticostefolds when needed, and attention to reducing exposure to microbes, especially staphylococci.

Newer approaches do not replace but enhance these traditional strategies for maintaining and restoring the optimal function of the stratum corneum barrier. These include keeping the skin pH sufficiently acidic, using topical antihistamines (particularly [H.sub.2]-blockers such as cimetidine), and applying appropriately formulated physiologic lipid amines. In addition, the results of recent research advances in understanding stratum corneum function in diseases such as AD may, in the near future, lead to the availability of agents that target specific molecular pathways. These include PPAR and liver X receptor activators (which are highly anti-inflammatory and improve barrier function), serine protease inhibitors (which may prevent stratum corneum damage and, ultimately, clinical expression of AD), and protease-activated receptor-2 inhibitors (to inhibit itching and inflammation).

Caption: Figure 1. Filaggrin deficiency leading to barrier dysfunction in atopic dermatitis. Filaggrin gene (FLG) mutations in patients with atopic dermatitis result in inadequate production of profilaggrin and filaggrin and in reduced corneocyte osmolytes. The consequent defect in corneocyte hydration causes severe dry skin, which, in turn, creates and contributes to abnormal barrier function by increasing the water gradient across the skin. Figure courtesy of Peter M. Elias, MD.

Caption: Figure 2. Filaggrin deficiency predisposes to both atopic dermatitis and skin cancer. When filaggrin deficiency is present, trans urocanic acid (UCA) does not form. Trans-UCA is a critical filter for ultraviolet B (UVB) radiation--more important, in fact, than melanin pigment for protection against UVB radiation. This finding explains the increased incidence of nonmelanoma skin cancers in patients with a history of atopic dermatitis. Figure courtesy of Peter M. Elias, MD.

Caption: Figure 3. Barrier repair lipids. Nonphysiologic--lipids--such as petrolatum--remain on the surface stratum corneum layers. In contrast, physiologic lipids traverse the stratum corneum and enter the nucleated cell layers. Adapted from Man M-Q et al. (10)

References

(1.) Elias PM. Epidermal lipids, barrier function, and desquamation. J Invest Dermatol. 1983;80(suppl):445-495.

(2.) Elias PM. Stratum corneum defensive functions: An integrated view. J Invest Dermatol. 2005:125:183-200.

(3.) Elias PM Structure and function of the stratum corneum extracellular matrix. J Invest Dermatol. 2012;132:2131-2133.

(4.) Elias PM. The epidermal permeability barrier: From the early days at Harvard to emerging concepts. J Invest Dermatol. 2004;122:xxxvi-xxxix.

(5.) Thyssen J P, Elias PM Did latitude-dependent differences in prevalence of filaggrin mutations evolve to support cutaneous vitamin D production? J Invest Dermatol. 2013:133:S107.

(6.) Elias PM, Williams ML. Comment on "Does a History of Eczema Predict a Future Basal Cell Carcinoma?" J Invest Dermatol. 2013;133:1676-1677.

(7.) Elias PM, Steinhoff M. "Outside-to-inside" (and now back to "outside") pathogenic mechanisms in atopic dermatitis. J Invest Dermatol. 2008;128:1067-1070.

(8.) Hachem JP, Wagberg F, Schmuth M, et al. Serine protease activity and residual LEKTI expression determine phenotype in Netherton syndrome. J Invest Dcrmatol. 2006;126:1609-1621.

(9.) Gruber R, Elias PM, Crumrine D, et al. Filaggrin genotype in ichthyosis vulgaris predicts abnormalities in epidermal structure and function. AmJ Pathol 2011;178:2252-2263.

(10.) Man M-Q, Feingold KR, Elias PM. Exogenous lipids influence permeability barrier recovery in acetone-treated murine skin. Arch Dermatol. 1993;129:728-738.

(11.) Man M-Q, Brown BE, Wu-Pong S, Feingold KR, Elias PM. Exogenous nonphysiologic vs physiologic lipids: Divergent mechanisms for correction of permeability barrier dysfunction. Arch Dermatol. 1995;131:809-816.

(12.) Elias PM, Sun R, Eder AR, Wakefield JS, Man M-Q. Treating atopic dermatitis at the source: Corrective barrier repair therapy based upon new pathogenic insights. Exp Rev Dermatol. 2013;8:27-36.

(13.) Sajie S, Asiniwasis E, Skotnicki-Grant A. A look at epidermal barrier function in atopic dermatitis: Physiologic lipid replacement and the role of ceramides. Shin Ther Lett. 2012;17:6-9.

Peter M. Elias, MD, * Lawrence E Eichenfield, MD, ([dagger]) Joseph E Fowler, Jr, MD, ([double dagger]) Paul Horowitz, MD, ([section]) and Renee P. McLeod, PhD, APRN-BC, CPNP ([parallel])

* Professor Emeritus, Department of Dermatology, University of California, San Francisco, and Dermatology Service, VAMC, San Francisco, CA.

([dagger]) Professor of Clinical Pediatrics and Medicine (Dermatology), University of California, San Diego, Chief, Pediatric and Adolescent Dermatology, Rady Children's Hospital, San Diego, CA.

([double dagger]) Clinical Professor of Dermatology, Contact and Occupational Dermatology, University of Louisville, Louisville, KY.

([section]) Private Practice, Discovery Pediatrics, Inc., Valencia, CA.

([parallel]) Dean and Professor, Musco School of Nursing and Health Profession, Brandman University, Irvine, CA.

Publication of this CME article was jointly sponsored by the University of Louisville School of Medicine Continuing Medical Education and Global Academy for Medical Education, LLC, and is supported by an educational grant from Johnson & Johnson Consumer and Personal Products Worldwide, Division of Johnson & Johnson Consumer Companies, Inc.

The faculty have received an honorarium from Global Academy for Medical Education for their participation in this activity. They acknowledge the editorial assistance of Joanne Still, medical writer, and Global Academy for Medical Education in the development of this continuing medical education journal article. Joanne Still has no relevant financial relationships with any commercial interests.

Peter M. Elias, MD, has no relevant financial relationships with any commercial interests.

Lawrence F. Eichenfield, MD, has been an investigator and/or consultant for Galderma Laboratories, Stiefel a GSK company, and Valeant Pharmaceuticals International.

Joseph F. Fowler, Jr, MD, has been a consultant and/or speaker and/or investigator for 3M, Abbott Laboratories, Allerderm, Allergan, Amgen Astellas Pharma US, Inc, Centocor, Dermik, Dow Pharmaceutical Sciences, Inc., Eli Lilly and Company, Galderma Laboratories, L.E, GlaxoSmithKline, Johnson &Johnson Consumer Products Company, Medicis Pharmaceutical Corporation, Merck Pharmaceuticals, Merz Aesthetics, Novartis Pharmaceutical Corporation, OnSet, Promius, Pfizer, Quinnova, Ranbaxy, SmartPractice, Taisho, Taro, and Valeant Pharmaceuticals International.

Paul Horowitz, MD, FAAP, has been a speaker and/or consultant and/or researcher for Abbott Laboratories and Johnson & Johnson Consumer Personal Products Worldwide.

Renee P. McLeod, PhD, APRN-BC, CPNP, FAANP has been a speaker and/or consultant for Johnson &Johnson Consumer Personal Products Worldwide.

Address reprint requests to: Peter M. Elias, MD, Dermatology Service, VA Medical Center, 4150 Clement Street, MS 190, San Francisco, CA 94121; 415-750-2091; eliasp@derm.ucsf.edu

Table. Protective Functions of the Stratum Corneum Barrier

* Permeability barrier (life in a dry milieu)

* Exclusion of noxious chemicals and allergens

* Protection from mechanical insults

* Antimicrobial defense

* Integrity and cohesion (desquamation)

* Antioxidant defense

* Cytokine activation (outpost of immune system)

* Ultraviolet light barrier

* Hydration (pliability)


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Author:Elias, Peter M.; Eichenfield, Lawrence F.; Fowler, Joseph F., Jr.; Horowitz, Paul; McLeod, Renee P.
Publication:Family Practice News
Date:Aug 1, 2013
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