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Atopic Dermatitis

Pathogenesis

Jonathan I. Silverberg, MD, PhD, MPH 
Reviewed on July 01, 2024
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Introduction

Atopic Dermatitis (AD) is a chronic, pruritic, inflammatory skin and potentially multisystem disorder associated with considerable morbidity. AD is associated with heterogeneous morphology, severity, disease course, lesional distribution patterns, disease features, triggers and comorbidities. As such, the pathogenesis of AD is multifactorial, involving the complex interplay between epidermal barrier dysfunction, systemic inflammation and immune dysregulation.

A fundamental debate exists as to whether AD is driven primarily by barrier dysfunction (“outside-in” hypothesis) or by an inflammatory response to irritants and environmental allergens (“inside-out” hypothesis). The outside-in hypothesis posits that epidermal barrier dysfunction precedes AD and is required for the disease to manifest. Skin barrier dysfunction may result due to genetic mutations, such as in the filaggrin (FLG) gene, or may be acquired secondary to irritants and mechanical…

Introduction

Atopic Dermatitis (AD) is a chronic, pruritic, inflammatory skin and potentially multisystem disorder associated with considerable morbidity. AD is associated with heterogeneous morphology, severity, disease course, lesional distribution patterns, disease features, triggers and comorbidities. As such, the pathogenesis of AD is multifactorial, involving the complex interplay between epidermal barrier dysfunction, systemic inflammation and immune dysregulation.

A fundamental debate exists as to whether AD is driven primarily by barrier dysfunction (“outside-in” hypothesis) or by an inflammatory response to irritants and environmental allergens (“inside-out” hypothesis). The outside-in hypothesis posits that epidermal barrier dysfunction precedes AD and is required for the disease to manifest. Skin barrier dysfunction may result due to genetic mutations, such as in the filaggrin (FLG) gene, or may be acquired secondary to irritants and mechanical disruption.4 A poor epidermal barrier results in increased transepidermal water loss (TEWL), decreased skin hydration and vulnerability to exogenous insults.5 These lead to keratinocyte damage and release of thymic stromal lymphopoietin (TSLP), as well as increased allergen penetration and binding to Langerhans cells, both of which then trigger Th2 inflammation in the skin and systemically.

The inside-out hypothesis posits that inflammation precedes and even causes barrier dysfunction in AD. Recent studies identified multiple polymorphisms of inflammatory genes in patients with AD, including IL-4, IL-13, IL-31 and others.1 These polymorphisms may lead to immune dysregulation and cutaneous inflammation, resulting in impaired keratinocyte differentiation and function, followed by downregulated expression of filaggrin and antimicrobial peptides (AMPs), thereby allowing penetration of exogenous allergens.

It is possible that the outside-in hypothesis applies to a subset of patients, such as those with FLG polymorphisms, whereas the inside-out hypothesis applies to patients with polymorphisms of immune-related genes. Regardless, both hypotheses agree that all patients have a combination of immune dysregulation, inflammation and skin-barrier dysfunction. 

Skin Barrier Dysfunction

The stratum corneum is composed of corneocytes that help create a barrier protecting the epidermis against physical and environmental insults. Corneocytes accomplish this through the secretion of substances that act as natural moisturizing factors (e.g., amino acids and lipids). Deficiencies in a variety of the proteins and lipids of the stratum corneum (e.g., ceramides, FLG) have been identified in the skin of patients with AD. Importantly, patients with and without active disease have altered barrier function and experience increased TEWL. For instance, AD patients manifest dry skin diffusely, even when active inflammatory lesions are not appreciable. Skin- and mucosal barrier-based abnormalities have been proposed to be a possible mechanism by which disease expands to food allergies, environmental allergies and asthma (i.e., the “atopic march”).

Genetic Risk Factors for AD

Two risk factors that appear to be consistently and strongly associated with the development of AD include a family history of atopy and loss-of-function mutations in the FLG gene. Approximately 70% of patients with AD have a positive family history of atopic disease. Children having one parent with atopic disease are at 2- to 3-fold higher risk of developing AD; this increases to 3- to 5-fold if both parents have atopic disease. Additional evidence comes from twin studies, where concordance rates among monozygotic twins were found to be 77% compared with 15% for dizygotic twins.

FLG Loss-of-Function Mutations

The FLG gene encodes profilaggrin. Upon degradation, profilaggrin forms FLG monomers, which have major roles in maintenance of hydration in the stratum corneum, especially in response to changing environmental factors, such as humidity. FLG null mutations are present in approximately 10% of the general population and they appear to confer risk for earlier-onset AD and for more severe, persistent disease.  In contrast, approximately 20% to 50% of patients with AD carry a FLG mutation. The causal relationship between FLG mutations and the development of AD is complex, since many patients with AD have no identifiable FLG mutations and among those with FLG null mutations, approximately 40% do not develop symptoms of AD. Reductions in FLG expression have also been reported in the absence of loss-of-function mutations, with environmental factors, mechanical damage and inflammatory factors (e.g., IL-4, TSLP) being proposed as potential regulators.

In addition to being a strong genetic factor for AD, null mutations in the filaggrin gene also cause another chronic skin disease, ichthyosis vulgaris, a disorder of keratinization. Both AD and ichthyosis vulgaris are associated with one another and have overlapping disease characteristics, including dry and scaly skin. Filaggrin mutations also confer susceptibility to asthma in individuals with AD,26 and have been associated with palmar hyperlinearity, keratosis pilaris, fine scaling and self-reported xerosis. When summed together, skin features known to be associated with FLG mutations (e.g., ichthyosis, keratosis pilaris, palmar hyperlinearity and flexural eczema) have 87.8% penetrance in children with one FLG mutation and 100% penetrance in children with two FLG mutations, compared to 46.5% in children without any FLG mutations.

Other Genetic Factors

The connection between AD and FLG mutations fueled research into the genetics of barrier dysfunction in AD. FLG was found to lie with a so-called epidermal differentiation complex (EDC), a complex of genes important to the maturation of the stratum corneum. Other genes in this complex include S100 calcium binding proteins (S100s), the small proline-rich proteins (SPRRs) and the late expressed cornified envelope proteins, trichohyalin, repetin and involucrin. Screening the EDC for mutations involved in the pathogenesis of AD revealed SPRR3 to be an additional risk factor for AD.

Interplay of Epidermal Barrier Dysfunction with Inflammation and Immune Dysregulation

The skin of patients with AD may be abnormal, even without visually appreciable active inflammatory lesions. For example, chronic mild inflammation may be present between flares. Lesional AD skin may also express fewer AMPs compared to healthy skin; however, elevated levels have also been reported. Resulting infections, such as by S aureus, may further decrease the integrity of the skin. Regardless of whether it is a primary or secondary defect, an impaired skin barrier makes it easier for antigens and pathogens to enter the subcutaneous space to contributes to sensitization, inflammation and infection.

Although, it is unknown what key events ultimately cause the onset of AD, dendritic cells are hypothesized to be the linking factor between skin-barrier disruption, allergen exposure and subsequent inflammatory lesions. Dendritic cells promote Th2 cell differentiation. In older studies of AD patients, dendritic cells were found to have elevated expression of high-affinity receptors for immunoglobulin E (IgE). Antigen and IgE binding to these receptors were once thought to crucial in triggering an inflammatory cascade, since they interact with T lymphocytes and produce chemokines to attract additional lymphocytes. However, recent studies showed that damaged keratinocytes produce IL-33 that binds to ST2 receptors on dendritic cells, thereby driving Th2 differentiation and resulting in subsequent AD lesions. Production of TSLP by keratinocytes also causes the attraction of inflammatory cells and drives an inflammatory state via a Th2 response. Cytokines produced by Th2 cells further contribute to an impaired barrier by inhibiting maturation of the stratum corneum, thus perpetuating a vicious cycle of damage.

Immune Dysregulation in the Pathogenesis of AD

When activated by cytokines from antigen-presenting cells, CD4+ helper T lymphocytes differentiate into Th1 and Th2 lymphocytes. A biphasic response of cell-mediated immunity has been implicated in the pathogenesis of AD lesions, with Th2 cells having a role in both acute and chronic phases and Th1 cells contributing particularly in the chronic phase.

Th2 cytokines (IL-4, IL-5 and IL-13) are upregulated in the blood and cutaneous lesions of AD; these lead to itch and inflammation, and promote eosinophilia and the creation of IgE antibodies that play an important roles in atopy. Th2 cytokines have also been implicated in affecting the integrity of the epidermal barrier, including reducing the epidermal expression of FLG. Thus, epidermal inflammation may precede and be sufficient to cause skin-barrier disruption, even in those without preceding barrier defects. Th2 cytokines also impair antimicrobial peptide responses to pathogens, which, in conjunction with barrier disruption, allows for increased pathogen penetration.

Th1 cells produce IFN-γ and IL-12 to promote the destruction of intracellular pathogens while also suppressing the Th2-mediated humoral immunity to some extent. The Th1 response feeds chronic inflammation and can lead to apoptosis of keratinocytes through interaction of IFN-γ with the Fas receptor. The roles of several major immune factors are discussed below.

IL-4 and IL-13

IL-4 and IL-13 play prominent roles in inflammation, epidermal barrier dysfunction, itch and susceptibility to infection in AD (Figure 2-1). In 1994, Hamid and colleagues quantified IL-4 mRNA in skin biopsies of both acute and chronic lesions and nonlesional skin in AD patients and normal control skin. IL-4 gene expression was highest in acute AD lesions, but also increased in chronic AD lesions compared with nonlesional AD and normal control skin. In 2001, transgenic murine models expressing epidermal IL-4 produced an AD-like phenotype, including pruritus, xerosis, inflammatory skin lesions, S aureus infection and histopathology of chronic dermatitis. Other studies in both mice and humans substantiated the findings that IL-4 is increased in AD and that it may play a central role in pathogenesis.

Emerging evidence suggests that IL-13 may be of even greater pathophysiologic importance in AD than IL-4. Increased expression of IL-13 occurs in acute and chronic AD lesions in human skin, and transgenic mice with cutaneous IL-13 expression also develop an AD-like phenotype. A study of 147 deep-sequenced RNA samples from human skin found that the AD transcriptome is enriched in IL-13, while IL-4 is nearly undetectable. These findings are corroborated by data showing increased IL-13 protein levels in the plasma and interstitial fluid as well as the stratum corneum of patients with AD compared to healthy controls. Levels of IL-13 also correlate with AD severity. IL-13 is produced by multiple immune cells, and elevated IL-13 levels in AD lesions may initiate cutaneous inflammation and fibrotic remodeling. Collectively, these and other data suggest that AD may be primarily an IL-13-dominant disease.

Epidermal barrier dysfunction and keratinocyte damage are critical to the pathogenesis of AD. Howell and colleagues found that IL-4 and IL-13 inhibited FLG production in vitro during keratinocyte differentiation, suggesting that Th2 inflammation can result in acquired FLG deficiency and worsen barrier dysfunction overall. IL-4 and IL-13 were also found to downregulate keratinocyte expression of loricrin and involucrin, important proteins for skin barrier formation and integrity. Exposure to IL-4 in vitro was also found to reduce levels of ceramides and desmoglein-3 (a key protein in desmosomes). One study found that the composition of lipid species with important roles in skin barrier function (including ceramides, sphingomyelins and lysophosphatidylcholines) was altered in AD lesions of human patients and in skin-specific IL-13 overexpression transgenic mice. Similar changes were observed in cultured keratinocytes and found to be driven by an IL-13 and STAT-6 dependent decrease in fatty acid elongase expression, which shifted the lipid population toward short-chain species associated with increased barrier permeability.

Although chronic itch is often an overlooked symptom of AD, it has a profound negative impact on patient quality of life. IL-4 and IL-13 are critical in disease pathogenesis and in the eventual development of chronic itch. However, the mechanisms by which inflammatory pathways induce itch remain unclear. A study by Oetjen and colleagues demonstrated that activation of IL-4 Receptor α (IL-4Rα) directly stimulates sensory neurons, sensitizing them to multiple other pruritogens, a process dependent on Janus kinase (JAK) signaling. They also found that activation of this pathway is required for chronic itch in inflammatory and non-inflammatory settings, since both pharmacologic JAK inhibition and sensory neuron-specific genetic deletion of JAK1 resulted in abatement of chronic itch in mice. One study showed significant increases in acute pruritus and scratching behavior in mice injected with either IL-4 or IL-13 alone, or both cytokines together, indicating these cytokines can act as pruritogens.

With improved understanding of AD pathophysiology, IL-4 and IL-13 pathways have emerged as candidates for targeted therapy. There are several biologics targeting IL-4 and/or IL-13 pathways in development. Dupilumab, a fully humanized monoclonal antibody targeting IL-4Ra, was approved by the FDA in March 2017 as the first biologic for the treatment of AD.

Enlarge  Figure 2-1: Role of IL-4 and IL-13 in the Pathogenesis of AD. Source: Adapted from Silverberg JI, et al. Dermatol Clin. 2017;35(3):327-334.
Figure 2-1: Role of IL-4 and IL-13 in the Pathogenesis of AD. Source: Adapted from Silverberg JI, et al. Dermatol Clin. 2017;35(3):327-334.

IL-31

IL-31 is an important regulator of itch. It is produced primarily by Th2 cells, but also by mast cells in response to antimicrobial peptides. Its levels are higher in lesional AD skin compared to non-lesional skin, and correlate with other immune factors, such as IL-4 and IL-13, as well as disease severity. IL-31 transgenic mice spontaneously develop pruritus and skin lesions independently of elevated IgE and T cells. Scratching behavior in these mice correlated with the level of IL-31 and treating them with anti–IL-31 antibodies successfully ablated the scratching response.

The receptor for IL-31 is a heterodimer of IL-31Rα and OSMR that is expressed in the skin. Interestingly, staphylococcal exotoxins can induce IL-31Rα expression on monocytes and macrophages. This has been proposed as a possible explanation for elevated infection rates in AD patients: elevated IL-31Rα expression could render these immune cells more sensitive to IL-31, leading to itching and disrupting of the skin barrier, thus facilitating pathogen colonization.

IL-33

IL-33 is an IL-1 family cytokine which binds the ST2 receptor expressed on Th2 cells, basophils, mast cells and group 2 innate lymphoid cells (ILC2s). Several lines of evidence suggest a role for IL-33 in AD. IL-33 is abundant in AD lesions. IL-33 binding stimulates the production of IL-5 and IL-13 in Th2 cells. In transgenic mouse models, IL-33 overexpression causes severe eczema. In an MC903-induced mouse AD model, IL-33 expression is enriched within the AD-like lesions following MC903 treatment. Furthermore, loss of IL-33 or its receptor ST2 significantly impairs the development of AD-like lesions in this MC903-induced mouse AD model.

Other studies have reported contrary results. In a calcipotriol-induced mouse model of AD, loss of IL-33 and/or its receptor ST2 did not prevent the development of AD-like disease, including inflammation and morphological changes (increased ear skin thickness). While a Phase 2a proof-of-concept study showed a significant improvement in Eczema Area and Severity Index 50 (EASI50) and EASI75 rates in patients receiving etokimab, an anti-IL-33 antibody, a subsequent Phase 2b trial failed to demonstrate a benefit of etokimab over placebo. Existing data thus present a mixed picture and additional studies are needed on the role of IL-33 in AD pathophysiology and as a potential therapeutic target.

OX40/OX40L

The tumor necrosis factor receptor OX40 and its ligand OX40L comprise an important immunomodulatory signaling axis. Primarily expressed on lymphocytes (OX40) and antigen presenting cells (OX40L), these molecules regulate effector T cell expansion and survival, and promote CD4+ and CD8+ T cell memory. The skin of AD patients contains a large number of OX40L-expressing dendritic cells, which suggests a role for OX40 signaling in AD, despite a lack of correlation between OX40/OX40L expression and disease severity. In an exploratory Phase 2a study, patients treated with GBR 830, a monoclonal antibody against OX40, exhibited a significantly greater reduction in EASI scores compared to placebo-treated patients, providing additional evidence of the causative importance of the OX40/OX40L signaling axis in AD.

ILC2s

Group 2 innate lymphoid cells (ILC2s) are effector lymphocytes derived from common lymphoid progenitors. They promote the differentiation of Th2 cells from CD4+ T cell precursors. ILC2s express IL-4, IL-5, IL-9, IL-13 and OX40L. Skin lesions of AD patients and mouse models of AD are enriched in ILC2s that express receptors for IL-33, IL-25 and TSLP and produce a large amount of IL-5 and IL-13.

A causal role for ILC2s in AD is suggested by several lines of evidence. First, depletion of ILC2 cells in lymphocyte-deficient AD model mice reduces IL-5 and IL-13 levels in the AD-like lesions and significantly decreases skin inflammation and swelling. Second, purified activated mouse ILC2s from MC903-induced AD-like lesions can induce IL-4, IL-4 and IL-13 expression and AD-like skin lesions when intradermally injected into the ears of MC903-naïve mice. Finally, treatment with SR1001, a reverse agonist of the receptor RORα which is essential for ILC2 development, alleviates AD-like phenotypes in M903- and TPA-triggered mouse AD models.

IL-5

IL-5 is a Th2 cytokine and a key promoter of eosinophil function, regulating their generation, chemotaxis, activation and survival. Produced by basophils, mast cells, and ILC2s in response to IL-33, TSLP and other signals, IL-5 binding to its receptor activates downstream signaling via JAK2. While eosinophils are enriched in the skin and blood of AD patients, the causative role of IL-5 in AD is not yet established. Its involvement is suggested by the observation that treatment with an anti-IL-5 antibody reduced the severity of AD-like phenotypes in a mouse AD model. However, mepolizumab, another anti-IL-5 antibody, failed to demonstrate increased efficacy over placebo in two clinical trials. Thus, the role of IL-5 as a therapeutic target in AD remains uncertain.

TSLP

Thymic stromal lymphopoietin (TSLP) is an epithelial-derived cytokine that is upregulated upon barrier dysfunction, with levels being correlated with disease severity. Some studies suggested that TSLP acts as a “master switch” responsible for the onset and maintenance of AD and the atopic march. Evidence for this comes from over-expression of TSLP in keratinocytes, which results in a scratching and an AD-like skin phenotype in mice, eventually leading to asthma-like lung inflammation. TSLP is released by keratinocytes and directly interacts with its receptors (heterodimer of TSLPR and IL-7Rα) on somatosensory nerves to illicit itching. Injection of TSLP in wild-type mice was found to promote itching and that this reaction is preserved in transgenic mice lacking T, B, or mast cells, thus demonstrating that immune recruitment is not required for TSLP-induced neural activation. TSLP is thought to bind to its receptor on peripheral afferent C-fibers, thereby activating the PLC signaling pathway. This opens TRPA1 ion channels, stimulates membrane depolarizationand initiates neural signaling that leads to the sensation of itch.

IgE

IgE is central to allergic diseases, such as asthma, hay fever and food allergy and is produced by plasma cells upon stimulation with IL-4 and IL-13. IgE binds to high-affinity receptors on mast cells and basophils and can trigger the release of inflammatory mediators leading to type 1 mediated hypersensitivity reactions in allergic disease. Patients with AD have significantly higher rates of asthma, hay fever, food allergy and other allergic disorders. As such, many previously thought that IgE played a critical role in the pathophysiology of AD. However, 20% to 50% of patients with AD have normal total and allergen-specific IgE levels, suggesting that IgE is not pathogenic in many AD patients. Additionally, studies using omalizumab and ligelizumab, humanized monoclonal antibodies directed against IgE, have shown no significant clinical improvement in patients with AD, even though serum IgE levels dramatically decreased following treatment. More recent paradigms have placed greater emphasis on the upstream T cells and Th2 inflammation, including IL-4 and IL-13, rather than the IgE downstream.

An important trigger of AD flares is exposure to aeroallergens (eg, dust mites, pollen, animal dander, fungi). IgE sensitization to these allergens is directly correlated with disease severity; however, elevated IgE levels may be attributed to barrier disruption and increase allergen sensitization in severe AD. In many patients, aeroallergens may aggravate AD via irritancy or other non-IgE mediated mechanisms, eg, directly stimulating TSLP production. Previous studies support that positive reactions to house dust mite allergens are related to irritant and enzymatic effects via protease-activated receptor 2 which induce TSLP. Since reducing exposure to aeroallergens has been shown to relieve symptoms of AD, an avoidance strategy may be recommended in select patients who report worsening AD from these allergens.

AD patients are at increased risk of several types of infections. Colonization of the skin by S aureus can lead to AD exacerbation due to increased IgE production, including IgE directed specifically against S aureus toxins. The yeast Malassezia furfur is also part of the normal skin flora, especially on the head and neck, and is equally common in AD patients and healthy controls; however, AD patients are more likely to have IgE antibodies directed against Malassezia. Thus, IgE may partially contribute to the pathogenesis of AD in a subset of AD patients.

Cyclic AMP (cAMP) and Phosphodiesterase 4 (PDE-4)

The intracellular level of cAMP, regulated through PDE activity, has a key role in the generation of proinflammatory and anti-inflammatory cytokines by immune cells. Elevated levels of cAMP (low PDE-4 activity) are associated with an anti-inflammatory state, whereas low levels of cAMP (high PDE-4 activity) are associated with a pro-inflammatory state. Since elevated PDE-4 levels have been reported in AD skin, PDE-4 inhibition has been an active area of research. PDE inhibitors block cAMP degradation and increase cAMP levels, which result in the inhibition of pro-inflammatory cytokine production. Crisaborole, a topical PDE-4 inhibitor, has recently been approved by the FDA for the treatment of mild to moderate AD in patients 2 years of age and older.

Th17 and Th22

In addition to Th2 cytokines, Th17 and Th22 cytokines may play a role in acute lesions. Th17 and Th22 cytokines may induce epidermal hyperplasia and/or alter terminal differentiation proteins. IL-17 promotes inflammation by stimulating keratinocytes to produce cytokines, including granulocyte macrophage colony-stimulating factor (GM-CSF), TNF-α, IL-8, C x C motif chemokine ligand 10 (CXCL10), and vascular epidermal growth factor (VEGF). IL-17 is well-established in the pathogenesis of psoriasis, and although Th17 cell levels are correlated with AD severity, its role in AD has yet to be conclusively demonstrated. One study found that IL-17 expression was upregulated in skin of Asian patients with AD who had more psoriasiform lesions, but not in patients of Northern European descent and classical eczematous lesion.

Other Cytokine Pathways

Several other immune factors have been implicated in the pathogenesis of AD. IL-9 promotes mast cell activity, eosinophils and innate immune cells. IL-9 levels have been shown to be increased in both pediatric and adult AD patients and correlate with AD severity. IL-9 also enhances the secretion of IL-13, a key cytokine in AD pathogenesis. A significant association between IL-9 and IL-9 receptor gene polymorphisms with AD was found in a Korean population. CD8+ cells may also be implicated in the pathogenesis of AD, through the production of IL-13 and IFN-γ in AD lesions. Future research will help identify missing components of the inflammatory cascade, some of which may represent promising drug targets.

JAK-STAT Pathway

JAKs are intracellular enzymes that transmit signals arising from cytokine- or growth factor-receptor interactions on the cellular membrane to influence hematopoiesis and immune cell function. Upon cytokine binding, JAKs form heterodimers with other JAKs (eg, JAK1/JAK3), then phosphorylate and activate signal transducers and activators of transcription (STATs), which modulate intracellular activity, including gene expression. The JAK/STAT pathway is therefore an important mechanism by which proinflammatory cytokines (e.g., IL-4, IL-5, IL-13 and IL-31) exert their effect on biological process, including those involved in the pathogenesis of AD (for the relationships of specific cytokines with downstream JAK-STAT pathway components, see Table 2-1). JAK1/3-STAT6 has been shown to be the dominant signaling pathway for IL-4. By contrast, JAK1/2- and TYK2-STAT6 signaling are involved in IL-4 and IL-13 signaling and JAK1/2-STAT1/3/5 are involved in IL-31 signaling. JAKs have specialized roles in hematopoiesis, with JAK1 and JAK3 promoting lymphopoiesis and JAK2 promoting myelopoiesis. This specialization is reflected in the hematological adverse event profiles associated with JAK inhibitors, as anemia and neutropenia are more commonly observed with agents targeting JAK2, whereas reduced CD8+ T cell function and natural killer cell lymphopenia are characteristic of anti-JAK3 agents. While selective JAK1 inhibitors generally have a better hematological adverse event profile than JAK2 or JAK3 targeted drugs, laboratory abnormalities in both the myeloid and lymphoid lineage have also been reported for these agents especially at higher doses.

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Infections in Patients with AD

The epidermis is an important barrier, protecting against TEWL and infections. One feature of the skin of AD patients is a reduced number of antimicrobial peptides, which contributes to elevated infection rates. S aureus can be cultured from >90% of patients with AD, compared to approximately 5% of the general population. Fortunately, most patients with AD and S aureus colonization do not show increased morbidity due to the colonization. Regardless, bacterial colonization can lead to AD exacerbation, which further disrupts the antimicrobial and barrier functions of the skin. This may occur through the production of degradative serine proteases by S aureus. Features of an impaired skin barrier, such as an increased pH of the stratum corneum and the loss of free fatty acids, ceramide metabolites and molecules with antimicrobial effects are also proposed to contribute to elevated infection rates in patients with AD.

AD patients are not only at elevated risk of cutaneous infections. An increased rate of extra-cutaneous, multi-organ and systemic infections have been identified in patients with AD.

Environmental Factors Affecting the Pathogenesis of AD

Environmental factors play an important role in the development of AD, as well as in triggering flare-ups. For example, exposure to low humidity accelerates TEWL, which can amplify barrier defects and potentially permit allergen penetration or enhance vulnerability to exogenous insults. Many other important environmental factors have been identified as playing a role in AD, such as maternal exposures during pregnancy, skin irritants, climate and ultraviolet exposure, pollutants, tobacco smoke, water hardness, urban and rural living and diet. Much research has been done to understand these factors, since they represent potentially modifiable factors that can be managed to prevent or mitigate disease exacerbations.

Atopic March

AD is thought to be the initial step in a phenomenon termed the “atopic march,” which is the propensity for AD to be followed later in life by the serial occurrence of allergic diseases, especially food allergies, asthma and allergic rhinoconjunctivitis. The mechanisms behind this allergic sensitization is highly debated.

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