Brick and mortar model of the SC 1,2 NORMAL SKIN BARRIER FUNCTION INTRODUCTION. Physical barrier 3. Structure of the skin. Chemical barrier 4-6

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1 Skin barrier function and atopic eczema Fatema Thawer-Esmail, MD, FCDerm(SA) Division of Dermatology, University of Cape Town, and New Groote Schuur Hospital, Observatory, Cape Town, South Africa ABSTRACT The skin provides a semipermeable barrier, an antimicrobial barrier and an immunological barrier. The current view on the pathogenesis of atopic dermatitis (AD) suggests the outside-inside-outside model, which emphasises that barrier disruption due to environmental or genetic insults drives the disease process in AD, thereby stimulating the immune system which then further disrupts the skin barrier. This article summarises the different aspects of normal skin barrier function. It describes how they are affected in AD and the clinical implications for the management of AD. INTRODUCTION The skin is the largest organ of the human body. An important function of the skin is that of barrier maintenance. To appreciate the complexity of this function it is important to first understand the basic structure of this perfectly constructed interface between air and water. Structure of the skin The skin is made up of three main layers: epidermis, dermis and subcutis. The epidermis is subdivided into four layers. The outermost interface between the air and the body is the stratum corneum (SC). This overlies the stratum granulosum while the stratum spinulosa is interposed between it and the replicating basal layer. The epidermis sits on another semipermeable structure, the basal membrane zone at the dermal interface (Fig. 1). The epidermis provides the barrier function of the skin. Each layer has specifically structured cells, keratinocytes (KCs) that enable it to fulfill a unique function. The basal layer constantly undergoes cell division. The spinous layer is responsible for the protein and lipid synthesis necessary for construction of the barrier function. The lipid and hydrolysing enzymes are stored and organised into organelles called lamellar bodies and secreted by exocytosis in the upper granular layer. Filaggrin, a protein from profilaggrin, gets stored in keratohyaline granules and secreted in the granular layer, giving it its name. KCs of the spinous layer contain an increased number of intermediate filaments that make up their cytoskeleton. These intermediated filaments provide the structural support for the cell and attach to specialised cell junctions (desmosomes) that connect one cell to the other giving a spinous look under the microscope, hence the name. The lipids (free fatty acids (FFA), ceramides and cholesterol) and proteins (filaggrin, involucrin, loricin, transglutaminase enzymes) get released at the upper granular layer from the organelles and act together to form the corneal envelope, through processes of selective apoptosis (programmed cell death), aggregation of keratin filaments, and crosslinking of proteins with lipid molecules. As a result of apoptosis, the only components to survive in the KCs are the keratin filaments which get aggregated, resulting in flattening of the anuclear KCs. The desmosomes are modified to corneodesmosomes that bind the corneocytes together in the SC. Brick and mortar model of the SC 1,2 The SC has been described as having a two-compartment model with a brick and mortar arrangement. This model consists of multiple layers of anucleated cells (corneocytes) which form the bricks embedded in an extracellular matrix that is enriched with lipids organised in bi-layers. The anuclear corneocytes contain approximately 20-35% water. They function by limiting water loss from the body, and increase water retention. The lipid matrix acts as a semipermeable barrier against hydrophilic molecules, chemicals and microbes and also functions as a reservoir for topical drugs. NORMAL SKIN BARRIER FUNCTION The skin functions as a physical, chemical and an immunological barrier. Physical barrier 3 The SC forms the principal barrier against the percutaneous penetration of microbes and chemicals. Protein-rich, anucleated corneocytes are embedded in a lipid-rich matrix in the SC and surrounded by a cell envelope composed of cross-linked proteins, the corneal envelope. Nucleated cells with their cytoskeleton, tight and gap junctions also contribute to the physical barrier. The physical barrier functions by preventing water loss, prevents entry of microbes, allergens and irritants and provides mechanical support. Chemical barrier 4-6 This is formed by lipids, an acid mantle (provided by FFA, lactic acid from sweat excretion and urocanic acid from filaggrin protein break down), the antimicrobial peptides (human beta defensins (HBD) and cathelicidins) secreted by KCs lamellar bodies and filaggrin protein that aggregates keratin filaments and produces natural moisturising substances. These components together act to ensure normal keratinisation and lipid synthesis, provide antimicrobial protection and ensure proper hydration of the skin. Immunological barrier 1 The innate immunity of the skin consists of the physical barrier, cells, secretory elements like antimicrobial peptides, cytokines and encoded proteins called pattern recognition receptors (PRR). 4 The cells include KCs, dendritic cells, Langerhans cells, neutrophils and natural killer cells. 4 Antimicrobial peptides (AMP) are produced by KCs. They are induced by inflammation or inury 4 with the exception of HBD1 (which is always present in the KC). HBD and cathelicidin LL-37 are examples of AMP. AMP directly kill a broad range of bacteria, fungi and certain viruses. HBD2, HBD3 and LL-37 have been shown to Correspondence: Dr F Thawer-Esmail, fatemaht@gmail.com Current Allergy & Clinical Immunology, November 2011 Vol 24, No.4 193

2 KERATOHYALINE GRANULES LAMELLAR BODIES CORNIFIED LAYER GRANULAR LAYER SPINOUS LAYER DESMOSOME KERATIN FILAMENTS BASAL LAYER BASEMENT MEMBRANE DERMIS HEMIDESMOSOME SUBCUTIS Fig. 1. Structure of the skin. have antistaphylococcal activity. LL-37 is also known to have antiviral activity against Herpes simplex virus-1, H. simplex virus-2 and Vaccinia virus. 4 The PRR can be transmembrane and intracellular receptors and include toll-like receptors (TLR) through which the KC senses microbes. The cells secrete cytokines like tumour necrosis factoralpha (TNF-α), interleukins (ILs) such as IL-6 and IL-1α that stimulate cell proliferation and lipid synthesis. 7 Barrier disruption causes an increase in the expression of these cytokines that is crucial for barrier repair. However, prolonged disruption causes a chronic release of cytokines leading to inflammation and epidermal proliferation. The components of adaptive immune response consist of cells that interact with lymph nodes through skin lymphatics and bring about a response. The antigenpresenting cells include Langerhans cells, dermal dendritic cells and KCs. T lymphocytes execute immune response through interaction with endothelial cells. The system has been called skin-associated lymphoid tissues (SALT). The immune response to an antigen depends on the type of the antigen which then directs the T cells either to produce T-helper (Th)1 or Th2 cytokines. BARRIER DYSFUNCTION, A DRIVER OF DIS- EASE PROCESS IN ATOPIC DERMATITIS (AD) The current view on the pathogenesis of AD suggests that barrier dysfunction drives the disease process. It is described as the outside-inside-outside model of AD; as opposed to the previous idea of the inside-outsideinside model where the immune system was thought to lead to barrier dysfunction. 1,7,8 In genetically predisposed skin, allergens, microbes and irritants disturb the skin barrier and lead to inflammation and alterations of epidermal structure and function. This leads to activation of the immune system which in turn further disrupts the barrier function and leads to inflammation. The above theory is based primarily on the association of filaggrin gene mutations and AD. 7,9,10 The following observations led to the development of the above theory: 11 Filaggrin gene mutations are seen in 14-56% of European patients with AD. 7,9,10 AD disease severity parallels the degree of barrier abnormality Transepidermal water loss (TEWL) is elevated in atopic skin because of the disrupted barrier AD skin has a decreased irritancy threshold Decreased lipid ceramides essential to a normal barrier are found in atopic skin Emollients form an effective ancillary therapy when used under nursing supervision, moisturisers have been shown to reduce topical steroid use. 12 Barrier damage induced experimentally by use of surfactants or tape stripping leads to the release of cytokines such as IL-1α, IL-1β, TNF-α and granulocyte-macrophage colony-stimulating factor, implying that barrier dysfunction alone can lead to inflammation Appropriate lipid replacement therapy corrects the permeability barrier and has anti-inflammatory actions Current Allergy & Clinical Immunology, November 2011 Vol 24, No.4

3 AD affects the physical, chemical and immune barrier function of the skin. Physical and chemical barrier defects interact to disrupt the permeability and antimicrobial functions in AD skin. The permeability function disruption is due to an interaction between genetic abnormalities and environmental insults. DISRUPTION OF PERMEABILITY FUNCTION IN AD Inherited abnormalities causing abnormal barrier in AD The genes affected in AD include those encoding the filaggrin protein, serine protease (SP) and protease inhibitors (e.g. SPINK-5): Filaggrin gene 6,8,11 This gene encodes for filaggrin protein produced in the granular layer. Filaggrin is a keratin filament aggregating protein that results in flattening of the anuclear corneocytes. Degradation of filaggrin produces hygroscopic polycarboxylic acids and urocanic acid that act as natural moisturising factors (NMF), osmotically drawing water into corneocytes and holding it there. The acids also contribute towards the acid mantle. Urocanic acid acts as a natural chromophore, absorbing UV light and providing sun protection. Deficiency of filaggrin in AD leads to loss of all the above functions with disruption of structural integrity of the SC and a defective skin barrier. Association of filaggrin gene mutations and AD Filaggrin gene mutations were first described in ichthyosis vulgaris (IV). Since IV and AD often occur together, gene mutations were looked for in this subgroup of AD patients and found in 44% of patents with mild IV who were heterozygous for filaggrin null allelles, and in 76% of those with severe IV who were homozygous for filaggrin null allelles. 14 The association of filaggrin gene mutations with AD has since been extensively explored in Europe with the following findings: A null mutation (i.e. loss of function mutation) in the filaggrin gene is a major risk factor for predisposition to AD and AD-associated asthma 15 A carrier of 1 null mutation has a 4x increased chance of early-onset persistent eczema, while for carriers of 2 mutations the risk increases 80x 16 About 50% of children with moderate to severe AD carry either one or two filaggrin null alleles. 7 Mutations are associated with early-onset infant eczema which persists into adulthood 9 A correlation with severity of filaggrin-associated eczema due to: 11 decreased SC hydration that leads to a steeper water gradient across the SC which may drive increased transcutaneous water loss decreased production of acidic metabolites activates SP, an enzyme that degrades corneodesmosomes Individuals with filaggrin gene mutations have elevated levels of IgE. Filaggrin-deficient skin has a disrupted barrier, increasing TEWL and allowing chronic exposure to insults which triggers inflammation in AD. 7 Since not all patients with IV have inflammation, there must be other factors interacting with filaggrin-deficient skin in order to cause AD. Genes that upregulate SPs 1,11 Genetic defects due to gain of function mutations in the KLK7 gene that encodes SPs upregulate SP. Increased SP damages and degrades corneodesmosomes throughout the SC. It also degrades lipid-processing enzymes resulting in decreased production of ceramides. SP activates protease activator type 2 receptor (PAR-2) by direct cleavage of PAR-2 and inducing its signalling cascade. This results in downregulation of lamellar body secretion, decreasing SC total lipids. It also causes increased generation of IL-1α and IL-1β from corneocytes leading to inflammation. Protease inhibitors 1,8,11 These substances inhibit proteases. Cystatin A is a cysteine protease inhibitor secreted by the sweat glands that helps to protect the skin from degradation by exogenous sources of proteases such as those from house-dust mite (HDM) faeces. Gene mutations in CSTA, which encodes for cystatin A, have been found in AD skin. SPINK-5 encodes LEKTI (lympho-epithelial Kazal type inhibitor), that is also a protease inhibitor. Loss of function mutation of SPINK-5 is found in Netherton syndrome, which is characterised by severe AD, mucosal atopy and severe food allergies. Lipid composition in AD 1,5 Lipid is secreted and processed in the lamellar bodies that reside in the upper spinous and granular layer. For normal barrier function the lipid composition should contain 50% ceramides, 10-20% fatty acids and 25% cholesterol. 3 AD skin has been shown to have increased sphingomyelindeacylase activity, resulting in decreased ceramides and abnormal barrier function. The acid mantle 1,5 The acidic environment is formed by FFA, filaggrin degradation products, and sweat gland secretions containing lactic acid. An acid mantle is important for optimal function of lipidprocessing enzymes and those involved in keratinisation. An acid ph prevents activation of SPs that degrade corneodesmosomes and generate active primary cytokines that initiate the cytokine cascade leading to inflammation. The acid mantle prevents pathogen invasion and favours adhesion of non-pathogenic bacteria to the SC. AD patients are found to have increased ph in lesional and non-lesional skin. Disruption of antimicrobial functions (innate immunity defects) in AD 4 AMP are important intrinsic defences against infections. Atopic skin has decreased amounts of HBD2 and HBD3 which are usually induced during inflammation or injury. This increases susceptibility to staphylococcal and fungal infections. AD skin has decreased human cathelicidin LL-37 that predisposes to eczema herpeticum and eczema vaccinatum following smallpox vaccine. AD skin has been found to have TLR2 defects and decreased recruitment of innate immune cells. TLR2 provides for a broad range of antimicrobial recognition including Gram-positive and negative bacteria, fungi and potentially herpes viruses. Weak TLR2 and TLR4 responses have been shown to promote a Th2 response. TLR2 defects are thought to be responsible for susceptibility to Staphylococcus aureus and H. simplex virus infections. Current Allergy & Clinical Immunology, November 2011 Vol 24, No.4 195

4 ACQUIRED CAUSES ( ph, SP) GENETIC CAUSES ( FILAGGRIN, SP) PROLONGED BARRIER DISRUPTION CERAMIDE AMP S. AUREUS COLONISATION + INFECTION TOXINS/ SUPERANTIGENS SCRATCHING + EXCORIATION PRURITUS Fig. 2. The role of S. aureus in the pathogenesis of AD (SP serine proteinase, AMP antimicrobial peptides). A raised ph is due to filaggrin deficiency and decreased amount of FFA, providing a favourable environment for the bacteria to survive. AD skin has reduced levels of sphingosine, a precursor of ceramides that predisposes to staphylococcal infections. Adaptive immune dysfunction in AD Multiple gene mutations, such as gain of function polymorphisms in the α subunit of IL-4 receptor, have been identified in AD that switches the immune profile towards a Th2-dominant immune response leading to IL-4, IL-5 and IL-13 production which then upregulate IgE production. 16 These cytokines damage the barrier by decreasing ceramide production, decreasing filaggrin and desmoglein expression. Acquired/environmental stressors that affect barrier function in AD These include irritants, infections and allergens. Irritants Physical rough fabrics, extreme temperatures, extremes of humidity, wind, sun Chemical detergents, soaps, fragrances, alcohol, water, preservatives Essentially anything in excess can be irritating to the skin. Soaps and detergents Detergents and soaps are the commonest cause of irritant contact dermatitis of the hands. Their excess use on atopic skin with its barrier defect can cause further barrier damage and precipitate flares of AD. They are known to: 1 Emulsify skin surface lipids, disrupting the barrier, thereby leading to increased water loss Increase ph and therefore alter protease activity causing desquamation Activate PAR-2 receptors through proteases, thereby mediating inflammation and pruritus. Infections Colonisation by S. aureus is common in AD in both lesional and non-lesional skin. 17,18 Over time nonpathogenic strains of S. aureus that colonise AD skin can be replaced by toxin-producing strains. 8 More than half of AD patients with S. aureus secrete toxins with superantigen properties. 4 The exotoxins, namely S. aureus enterotoxin A (SEA), S. aureus enterotoxin B (SEB) and toxic shock syndrome toxin, can act as superantigens Superantigens non-specifically simulate T-cell activation by binding to antigen-presenting cells and T-cell receptors on regions which are not antigen binding. Therefore multiple clones of T cells may be stimulated, as no precise match is required, leading to massive release of cytokines, thereby causing flare of AD. Overt clinical infection manifesting as folliculitis, impetigo, echthyma and cellulitis are common in complicated AD as the barrier is defective. S. aureus colonisation leads to: Chronicity and severity of AD (through inflammation caused by superantigenic toxins). 19 Direct barrier damage by the toxins 196 Current Allergy & Clinical Immunology, November 2011 Vol 24, No.4

5 Inteference with lipid lamellae formation due to microbe secretion of sphingosinedeacylase and glycerophosphylase Desquamation due to microbe-secreted proteases Upregulation of the expression of cutaneous lymphocyte-associated antigen on T cells and production of KC-derived cytokines. The role of S. aureus in the pathogenesis of AD 8,11 Figure 2 illustrates how S. aureus aggravates AD. Failed barrier function caused by an increased ph, decreased AMP and decreased amounts of FFA and sphingosine (precursor of ceramides) predisposes to infection and colonisation with S. aureus. Both colonisation and infection further worsen barrier dysfunction. Surface proteins of S. aureus downregulate FFA production. Toxigenic strains are more likely to cause clinical infection, stimulate pruritus via enterotoxins and induce IgE production. Toxins that act as superantigens stimulate T-cell proliferation. IL-31 produced by activated T cells causes pruritus. An itch-scratch cycle is initiated, further disrupting the barrier with excoriations allowing additional entry of pathogens. Studies have shown that using antistaphylococcal measures decreases the amount of colonisation of S. aureus on the skin but does not seem to show a convincing improvement in eczema activity. 22,23 Allergens These penetrate through a defective barrier in AD, stimulating a Th2-dominant infiltrate and inflammation which further aggravates barrier dysfunction. Various protein allergens have been implicated in IgE responses in AD including insects (HDM, cockroach), pollens, danders, food allergens, plants, seafoods and drugs. HDM. These survive in humid, warm environments. Modern living environments with carpets, reduced ventilation with central heating and en suite bathroom facilities provide a perfect environment for HDM to survive. HDM are thought to aggravate AD by disrupting the barrier function via SP production and IgE stimulation. 1 Derp 1, the allergen in HDM, is found in faecal matter. However, systemic reviews on avoidance measures have not been shown to improve AD. 22 Cockroach. Allergens are thought to activate PAR-2 receptors thereby causing barrier dysfunction, inflammation and pruritus. 1 Other endogenous and exogenous stressors 8,11,24 Prolonged exposure to increased demand of decreased environmental humidity accelerates water loss especially from a defective SC Psychological stress leads to increased demand of endogenous glucocorticoid production that alters permeability, affects SC integrity and decreases lipids production Exogenous application of IL-4 (Th2 cytokine) has been shown to delay barrier recovery, decreases ceramide secretion in vitro, inhibits filaggrin gene and desmoglein expression (protein found on desmosomes). Hence any allergen which can provoke a Th2 response can lead to barrier disruption. CLINICAL IMPLICATIONS The mainstay of AD treatment and control therefore would include restoration of barrier function, avoidance of triggers and treatment of inflammation. Restoration of barrier function This includes using bland (colour-free, fragrance-free, least amount of preservatives) emollients that would provide both occlusive (forms a greasy film thereby preventing evaporation, such as petroleum) and humectant (retains water, such as glycerin and urea) properties, 25 and also maintain an acidic ph and restore the specific types of lipids in their correct ratio. In cases where there is a strong genetic barrier disruption, it might not be possible to restore the barrier completely. Correcting the barrier abnormality has been found to be anti-inflammatory: 13 i t decreases ingress of allergens and immunogens, thereby downregulating the Th2 pathway lipid ratio restoration decreases the ph, therefore stops overactivation of SP, thereby preventing an inflammatory reaction through the PAR-2 receptors downregulates signalling mechanisms that lead to inflammation. Avoidance of triggers Limit irritants Soaps and detergents (use emollient for washing where possible) Rough fabric clothing Fragrances such as wet wipes, nappy powders, bubble baths, creams Aggressive use of antiseptics Excessive use of shampoos Excess heat and sweating Excess dry climates (central heating, air-conditioned rooms) Limit allergen exposure (controversial) Cat dander, HDM, pollen Infections (treatment of clinically evident infection) Treatment of inflammation Early use of topical steroids during a flare is advised in order to treat inflammation and prevent further barrier damage and infection. CONCLUSION Atopic eczema is due to abnormalities of the skin barrier which results from an interplay between the environment and genes. Early avoidance of environmental triggers and barrier maintenance/restoration leads to early resolution of AD in patients who have heterozygous gene mutations. Dry skin and itch might be the first sign of barrier disruption in an individual with a strong family history of AD. This should alert one to avoid triggers and use emollients. The correct choice and use of emollients are crucial to management in AD. Declaration of conflict of interest The author declares no conflict of interest. Acknowledgement I thank Prof Gail Todd for her guidance and support in writing this article. Current Allergy & Clinical Immunology, November 2011 Vol 24, No.4 197

6 REFERENCES 1. Cork MJ, Danby SG, Vasilopoulos Y, et al. Epidermal barrier dysfunction in atopic dermatitis. J Invest Dermatol 2009; 129: Nemes Z, Steinert PM. Bricks and mortar of the epidermal barrier. Exp Mol Med 1999; 31: Proksch E, Brandner J, Jensen J-M. The skin: an indispensable barrier. Exp Dermatol 2008; 17: Benedetto AD, Agnihothri R, McGirt LY, et al, Atopic dermatitis: a disease caused by innate immune defects? J Invest Dermatol 2009; 129: Hatano Y, Man MQ, Uchida Y, et al. Maintenance of an acidic stratum corneum prevents emergence of murine atopic dermatitis. J Invest Dermatol 2009; 129: Elias PM. Barrier repair trumps immunology in the pathogenesis and therapy of atopic dermatitis. Drug Discov Today Dis Mech 2008; 5(1):e33-e Irvine A, Mclean I. Breaking the sound barrier: filaggrin is a major gene for atopic dermatitis. J Invest Dermatol 2006; 126: Elias PM. Skin barrier function. Curr Allergy Asthma Rep 2008; 8(4): Barker JN, Palmer CN, Zhao Y, et al. 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Dry skin and moisturizers. Clin Dermatol 2001; 19: Chairman s report allergy in somalia I was privileged to recently accompany the charity Gift of the Givers (GOTG) on a humanitarian mission to Somalia. I was part of a medical team of 27 health professionals which comprised 3 paediatricians. Somalia is a country gripped in war and drought resulting in millions of internally displaced people. There is no central government or health authority to take care of the basic needs of society. This has had devastating consequences for the people of Somalia. The women and children of Somalia have been the main victims of the famine. We treated thousands of children in the few days that we were there. The children that we treated were severely growth stunted. We saw many children with kwashiorkor, marasmus, TB, malaria, acute and chronic diarrhoeal diseases, measles and other infectious diseases. Most of the children that we saw lived in appalling conditions and had no access to water, sanitation and basic health care. None of the children was immunised. Some of the children had never consulted a doctor before. It was also very heartbreaking to see some children with treatable diseases, but lack of resources prevented us offering them any treatment. These included children with congenital hydrocephalous, congenital heart disease (cyanotic and acyanotic), osteosarcoma, retinoblastoma, TB and malaria. What was remarkable however was that in the camps where GOTG provides meals, we found very few sick people. This was only after 1 month of starting the feeding scheme. GOTG feeds people on a daily basis and the numbers are growing. A striking observation was that we saw very few children with allergic diseases. My colleagues and I saw only two children with allergic rhinitis and conjunctivitis. We did not see any children with asthma, atopic eczema or food allergy. There is now a lot of debate about the validity of the hygiene hypothesis. Perhaps the hygiene hypothesis does apply to Somalian children. Back home we are busy preparing for our annual congress. This will be a joint meeting with the PMG. It promises to be an exciting event with many local and international experts in allergy, immunodeficiency and paediatrics. We look forward to hosting you. On a sad note we would like to express our condolences to the family of Ed Findley who passed away in September this year. Ed was a true friend of ALLSA. He supported the society and individuals in the society in many different ways. He was instrumental in establishing the UCB Allergy Research Award. Ed will be missed by the allergy fraternity and his contribution will not be forgotten. Our thoughts are with his family. May his soul rest in peace. Ahmed Manjra Chairman 198 Current Allergy & Clinical Immunology, November 2011 Vol 24, No.4