Key Points
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Pruritus and chronic or relapsing eczematous dermatitis with typical distribution are essential for diagnosis of atopic dermatitis (AD).
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Interactions between susceptibility genes, the host’s environment, pharmacologic abnormalities and immunologic factors contribute to the pathogenesis of AD.
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Recent genome-wide association studies have confirmed the association of single-nucleotide polymorphisms (SNPs) of loci of the epidermal differentiation complex (EDC) with AD.
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Bacterial and viral antigens as well as allergens and autoantigens play a role in the pathogenesis of AD.
Atopic dermatitis is a highly pruritic chronic inflammatory skin disease that commonly presents during early childhood. It is frequently associated with a personal or family history of respiratory allergy, i.e. allergic asthma and/or rhinitis, and can have profound effects on patients’ lives, career choices and social interactions. Recent interest in AD has been sparked by reports of its increasing prevalence. Management approaches in AD have evolved from our rapidly increased understanding of the mechanisms underlying this skin disease and novel therapeutic avenues.
Epidemiology
Atopic dermatitis is a common skin disease with a lifetime prevalence in children of 10% to 20% in the USA, Northern and Western Europe, Japan, and other westernized countries. Environmental factors are critical in determining disease expression. Some of the potential risk factors that have received attention as being associated with the rise in atopic disease include small family size, increased income and education both in whites and blacks, migration from rural to urban environments, and increased use of antibiotics, that is, the so-called ‘western lifestyle’. These observations are supported by observations that allergic responses are driven by T helper cell type 2 (Th2) immune responses, whereas infections are induced by Th1 responses. Since Th1 responses antagonize the development of Th2 cells, a decreased number of infections or the lack of Th1 signals during early childhood could predispose to Th2 allergic responses (see Chapters 1 and 2 ).
Diagnosis and Differential Diagnosis
Clinical features of AD are listed in Box 50-1 . Of the major features, pruritus and chronic or relapsing eczematous dermatitis with typical distribution are essential for diagnosis. Intense pruritus and cutaneous reactivity are cardinal features of AD. Pruritus may be intermittent throughout the day but is usually worse at night. Its consequences are scratching, prurigo papules, lichenification and eczematous skin lesions. Patients with AD have a reduced threshold for pruritus. As a result, allergens, reduced humidity, excessive sweating and low concentrations of irritants (e.g. wool, acrylic, soaps and detergents) can exacerbate itching and scratching.
* Other skin conditions that may mimic atopic dermatitis should be excluded (see Box 51-1 ).
Essential Features
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Pruritus
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Facial and extensor eczema in infants and children
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Flexural eczema in adults
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Chronic or relapsing dermatitis
Frequently Associated Features
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Personal or family history of atopic disease
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Xerosis
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Cutaneous infections
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Nonspecific dermatitis of the hands or feet
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Elevated serum IgE levels
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Positive immediate-type allergy skin tests
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Early age of onset
Other Features
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Ichthyosis, palmar hyperlinearity, keratosis pilaris
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Pityriasis alba
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Nipple eczema
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White dermatographism and delayed blanch response
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Anterior subcapsular cataracts, keratoconus
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Dennie-Morgan infraorbital folds, orbital darkening
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Facial erythema or pallor
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Perifollicular accentuation
During infancy AD is generally more acute with excoriation, vesicles over erythematous skin and serous exudate. The rash primarily involves the face, scalp and extensor surfaces of the extremities ( Figure 50-1 ). In the patient with chronic AD, skin lesions become lichenified ( Figure 50-2 ) and the rash localizes to the flexural folds of the extremities. Approximately half of children with AD continue to have persistent skin disease as adults. At all stages of AD, patients usually have dry, lackluster skin. Chronic hand eczema, the most common form of occupational skin disease, may be the primary manifestation in many adults with AD. Other features, including exogenous allergy or elevated IgE, are variable although commonly seen in AD.
Box 51-1 lists a number of inflammatory skin diseases, immunodeficiencies, skin malignancies, metabolic disorders, and infectious diseases that share features of AD. The differential diagnosis of AD should be considered particularly in patients with refractory AD. Infants presenting in the first year of life with failure to thrive, diarrhea, a generalized scaling erythematous rash and recurrent cutaneous and/or systemic infections should be evaluated for severe combined immunodeficiency syndrome (see Chapter 9 ). Wiskott-Aldrich syndrome is an X-linked recessive disorder characterized by thrombocytopenia, defects in humoral and cellular immunity and recurrent bacterial infections. The hyperimmunoglobulin E (hyper-IgE) syndrome is characterized by elevated serum IgE levels, defective T and B cell function, recurrent deep-seated bacterial infections including cutaneous abscesses caused by Staphylococcus aureus and/or pruritic skin disease caused by S. aureus , such as pustulosis, or recalcitrant dermatophytosis, reported with human immunodeficiency virus as well as with a variety of infestations such as scabies. Dock8 deficiency should be considered in patients with severe recurrent eczema herpeticum. Other conditions that can be confused with AD include psoriasis, ichthyosis, and seborrheic dermatitis.
Adolescents or adults who present with an eczematous dermatitis with no history of childhood eczema, respiratory allergy or atopic family history may have allergic contact dermatitis (see Chapter 53 ). Of note, topical glucocorticoid contact allergy has been reported increasingly in patients with chronic dermatitis on topical corticosteroid therapy.
Pathogenesis
Interactions between susceptibility genes, the host’s environment, pharmacologic abnormalities and immunologic factors contribute to the pathogenesis of AD. There are two disease models: first, that AD is a skin disease that primarily derives from an intrinsic defect of epithelial cells and skin barrier, thereby facilitating as a second step numerous modifications of innate and adaptive immunity (the outside-inside hypothesis); second, that AD is primarily an immunologic disease with mechanisms related to the overactivation of the immune system and Th2 dominated immune responses that impact secondarily on skin barrier function (the inside-outside hypothesis). However, it is most likely that a combination of both hypotheses and a continuous interplay contributes to the complexity of AD.
Genetics
The fact that AD and atopic disorders frequently affect more than one family member accounts for the strong genetic background of this disease. Several genetic factors contribute to the complex pathophysiology of AD, indicating that it is not a monogenic but a genetically complex disorder. It seems most likely that not only AD itself but, in particular, different subtypes of AD such as AD with early onset, childhood AD versus adulthood AD or AD with IgE mediated allergic reactions might be based on distinct genetic constellations. Therefore, one approach to achieve clarity could be systematic distinction of genetic modifications associated with (1) skin barrier dysfunction, (2) deficient innate immune responses and (3) modified adaptive immune reactions in AD.
Genetics and Skin Barrier Dysfunction
Dry skin, mirrored by increased transepidermal water loss, reduced skin hydration and decreased amounts of natural moisturizing factor indicate skin barrier impairment in AD. A candidate gene region for AD, localized on chromosome 1q21, contains a selection of genes encoding structural proteins of epidermal cornification, such as S100A proteins, profilaggrin, small proline-rich region proteins (SPRRs) and late envelope proteins (LEP), which form the so-called ‘epidermal differentiation complex’ (EDC). Filaggrin is an essential protein in maintenance of the formation of the stratum corneum barrier. In recent years, loss-of function mutations in the filaggrin gene have been shown to be strongly associated with AD. This finding was replicated and confirmed by an impressive series of independent studies. Moreover, a closer look at the filaggrin loss-of-function carriers within the group of AD patients revealed that specific clinical features and subtypes of AD are highly associated, including AD with early onset and a high number of allergen sensitizations. Moreover, specific interactions between genetic predisposition and environmental factors such as cat exposure at the time of birth seem to increase the risk for manifestations of eczema during the first year of life, in particular in children with filaggrin mutations. In addition, in the context of a genetically determined disturbed skin barrier in AD, there are reports of associations of polymorphisms in the SPINK5 gene, which encodes the lymphoepithelial kazal-type related inhibitor (LEKTI), an inhibitor of serine proteases. Other studies have reported on the association with AD of genetic modifications in the gene region encoding the stratum corneum chymotryptic enzyme (SCCE), leading to impaired stratum corneum integrity and function. Studies have also reported on gene associations with other epidermal components, such as collagen 29 (COL29) , or a genetic variant on chromosome. In addition to these genetically predetermined factors, highly active endogenous proteases such as mast cell chymase (MCC), as well as exogenous proteases derived from house dust mite allergens or S. aureus , cleave corneodesmosomes and accelerate desquamation of corneocytes. They may also delay epithelial regeneration by binding proteinase-activated receptors (PAR)-2 and thereby contribute to skin barrier impairment in AD. Recent genome-wide association studies have confirmed the association of SNPs of loci of the EDC with AD. As well as from these genetic changes, epigenetic modifications have been demonstrated in lesional skin of AD patients and are another putative factor impacting on epidermal skin barrier function.
Genetics and Innate Immunity
First-line host defense mechanisms of the innate immune system are maintained by pattern-recognition receptors (PRR) that sense the environment for invading pathogens. Toll-like receptors (TLR), intracellular nucleotide-binding oligomerization domain (NOD) proteins and the LPS receptor CD14 belong to the PRRs and discriminate between diverse pathogen associated molecular patterns. Deficient maturation of the immune system and decreased efficiency in responding to PRR stimulation are suspected to account not only for higher prevalence of atopy but also the greatly increased propensity of AD patients to microbial infections. Several studies have focussed on a putative association between variations within gene regions encoding components of the innate immune system and AD. A polymorphism within the TLR2 gene has been shown to be associated with severe forms of AD with recurrent bacterial infections and has been linked to functional modifications of TLR2. However, no association of polymorphisms in the TLR2 , TLR4 and TLR6 genes with AD could be shown in other studies. A polymorphism in the TLR9 gene of putative functional relevance on TLR9 promoter activity was associated with pure AD.
SNPs within five known loci (1q21.3 [ LCE3A ], 5q31.1 [ IL13 , KIF3A , SLC22A4 ], 11q13.5 [ C11orf30 ] and 20q13.33 [ TNFRSF6B ]) as well as four new loci (4q27 [ IL2 , IL21 ], 11p13 [ PRR5L ], 16p3 [ CLEC16A ] and 17q21.32 [ TNFRSF6B ]) were detected in genome-wide study thresholds for association with AD in a recent study. Moreover, 36 SNPs within three chromosomal regions, i.e. 2q12, 6p21 and 11p15.4, were significantly associated with AD in another study.
Genetics and Adaptive Immunity
Induction of different receptors on effector cells, dendritic cells or other cells after passage of allergens and microbial pathogens into the skin contributes to numerous other mechanisms involving the adaptive immune system. To date, a wide repertoire of genetic modifications of gene regions encoding components of adaptive immunity has been associated with AD. Soluble factors such as cytokines and chemokines, which play a crucial role as soluble mediators of the adaptive immune system, show profound variations in AD, and it is more than likely that some of these deviations are already genetically encoded. These comprise genetic variations on chromosome 5q31-33 that cover genes of the Th2 cytokine cluster such as interleukin (IL)-3, IL-4, IL-5, IL-13 and granulocyte-macrophage colony stimulating factor (GM-CSF), functional mutations of the promoter region of RANTES/CCL5 (17q11) and gain-of-function polymorphisms in the IL4RA gene (16q12). Interestingly, polymorphisms in the IL4RA gene region were associated with AD with low IgE serum levels and no allergen sensitization. Beyond this, polymorphisms in the IL18 gene associated with AD might contribute to modified IL-18 production of peripheral blood mononuclear cells (PBMC) of patients with AD after stimulation with microbial components.
Systemic Immune Response
Most patients with AD have peripheral blood eosinophilia and increased serum IgE levels. Nearly 80% of children with AD develop allergic rhinitis or asthma. Serum IgE level is strongly associated with the prevalence of asthma, which suggests that allergen sensitization through the skin predisposes the patient to respiratory disease because of its effects on the systemic allergic response. Indeed, epicutaneous sensitization of mice with protein antigen induces allergic dermatitis, elevated serum IgE, airway eosinophilia and hyperresponsiveness to methacholine. This suggests that epicutaneous exposure to allergen in AD enhances the development of allergic asthma.
An increased frequency of skin-homing T cells producing IL-4, IL-5 and IL-13 but little interferon (IFN)-γ has been found in the peripheral blood of patients with AD. There is evidence that this predominance of Th2 cells results partially from selective apoptosis of circulating memory/effector Th1 cells. These immunologic alterations are important because IL-4 and IL-13 are the only cytokines that induce germline transcription at the C ε exon, thereby promoting isotype switching to IgE. IL-4 and IL-13 also induce the expression of vascular adhesion molecules, such as vascular cell adhesion molecule-1 involved in eosinophil infiltration, and down-regulate Th1-type cytokine activity. IL-5 plays a key role in the development, activation and cell survival of eosinophils. In contrast, IFN-γ inhibits IgE synthesis as well as the proliferation of Th2 cells and expression of the IL-4 receptor on T cells. The decreased IFN-γ produced by T cells from AD patients may be the result of reduced production of IL-18. Furthermore, an inverse relationship between skin colonization with S. aureus and spontaneous IFN-γ production of CD4 + T cells as well as induced IFN-γ production of CD8 + T cells has been observed.
A number of determinants support Th2 cell development in AD. These include the cytokine milieu in which T cell development is taking place, pharmacologic factors, the costimulatory signals used during T cell activation, and the antigen-presenting cells (APCs). In this regard, IL-4 promotes Th2 cell development, whereas IL-12, produced by macrophages, dendritic cells or eosinophils, induces Th1 cells. Mononuclear cells from patients with AD have increased cyclic adenosine monophosphate (cAMP)-phosphodiesterase (PDE) enzyme activity. This cellular abnormality contributes to the increased IgE synthesis by B cells and IL-4 production by T cells in AD as IgE and IL-4 production is decreased in vitro by PDE inhibitors.
Skin Immunopathology
Pathology
Clinically unaffected skin of AD patients exhibits mild epidermal hyperplasia and a sparse perivascular T cell infiltrate. Furthermore, increased transepidermal water loss and reduced skin hydration is detectable even in nonlesional AD skin. AD has a biphasic nature, characterized by an acute phase, which is predominated by Th2 cytokines, followed by a chronic phase, featuring Th1 cytokines. Acute eczematous skin lesions are characterized by marked intercellular edema (spongiosis) of the epidermis. Dendritic APCs such as Langerhans cells (LCs) and macrophages in lesional and, to a lesser extent, in nonlesional skin of AD patients have surface-bound IgE molecules. Within 24 to 48 hours after allergen application rapid influx of IgE-receptor bearing inflammatory dendritic epidermal cells (IDEC) and up-regulation of FcεRI expression are detectable in the epidermis of atopy patch test lesions. In the dermis of the acute lesion there is a marked perivenular T cell infiltrate with occasional monocyte-macrophages. The critical role of T cells in AD is suggested by the obligate role of T cells in mouse models of AD. The lymphocytic infiltrate consists predominantly of activated memory T cells bearing CD3, CD4 and CD45RO. Eosinophils, basophils and neutrophils are rarely present in acute AD; mast cells are found in normal numbers but in various stages of degranulation. There is an increase in S100A7 , S100A8 and S100A9 gene expression together with activation of Th2 and Th22 cytokines during the acute phase of AD.
Chronic lichenified lesions are characterized by a hyperplastic epidermis with elongation of the rete ridges and prominent hyperkeratosis. There is an increased number of IgE-bearing DCs in the epidermis, and macrophages dominate the dermal mononuclear cell infiltrate. Mast cells are increased in number. Increased numbers of eosinophils are observed in chronic AD skin lesions. Eosinophils secrete cytokines and mediators that augment allergic inflammation and induce tissue injury in AD through the production of reactive oxygen intermediates and release of toxic granule proteins.
After topical treatment with calcineurin inhibitors, there is a decreased number of infiltrating T cells, B cells and eosinophils as well as expression of Th2 cytokines in addition to frequency of CD8 + T cells expressing the Th1 cytokine IFN-γ has been observed. Later on, surface expression of FcεRI epidermal DCs and number of epidermal inflammatory DC subtypes decreased, while frequency of LCs increased.
Cytokine Expression
Th2- and Th1-type cytokines contribute to the pathogenesis of skin inflammation in AD. As compared with the skin of normal controls, unaffected skin of AD patients has an increased number of cells expressing IL-4 and IL-13, but not IL-5, IL-12, or IFN-γ, mRNA. Acute and chronic skin lesions, when compared to normal skin or uninvolved skin of AD patients, have significantly greater numbers of cells that are positive for IL-4, IL-5 and IL-13 mRNA. However, acute AD is not characterized by significant expression of IFN-γ or IL-12.
Chronic AD skin lesions have significantly fewer IL-4 and IL-13 mRNA-expressing cells, but greater numbers of IL-5, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-12 and IFN-γ mRNA-expressing cells than acute AD. IL-5 and GM-CSF probably contribute to the increased numbers of eosinophils and macrophages. The increased expression of IL-12 in chronic AD skin lesions is of interest in that cytokine plays a key role in IFN-γ induction. Its expression in eosinophils and/or macrophages may initiate the switch to Th1 or Th0 cell development in chronic AD.
Aside from Th2 cytokines, elevated expression of Th22 cytokines has been observed in AD skin and small numbers of IL-17 + cells have been demonstrated to infiltrate the dermis of AD skin lesions. Higher mRNA expression of Th17 and Th22 cytokines has been observed in intrinsic AD as compared to extrinsic AD. Severity score of AD positively correlated with mRNA expression of Th2 cytokines in the skin and negatively correlated with expression of barrier proteins.
Activated T cells infiltrating the skin of AD patients have also been found to induce keratinocyte apoptosis, which contributes to the spongiotic process found in AD skin lesions. This process is mediated by IFN-γ, which up-regulates Fas on keratinocytes. The lethal hit is delivered to keratinocytes by Fas -ligand expressed on the surface of T cells that invade the epidermis and soluble Fas -ligand released from T cells. Additionally, there is some evidence that caspase-3 cleavage in the spinous epidermal layer also contributes to spongiosis. Mechanisms of IFN-γ induced keratinocyte apoptosis in AD have been analyzed in more detail and three apoptosis-related genes ( NOD2 , DUSP1 and ADM ) and eight genes overexpressed in AD skin lesions ( CCDC109B , CCL5 , CCL8 , IFI35 , LYN , RAB31 , IFITM1 and IFITM2 ) have been identified as playing a key role in this process.
Another factor inducing keratinocyte cell death is alpha toxin released by S. aureus . The amount of the enzyme acid sphingomyelinase, which is capable of preventing Th2 mediated increase of alpha toxin induced cell death, is reduced in AD skin. Additionally, it has been demonstrated that filaggrin is able to inhibit S. aureus alpha toxin mediated keratinocyte cell death. Together these data provide evidence for increased keratinocyte cell death in AD due to lower filaggrin expression and the increased Th2 micromilieu in the skin.
The role of regulatory T cell subtypes in AD is still unclear. There is some evidence for functional deficiency of resident T REG cells in the skin, while other studies report increased local numbers of CD4 + CD25 + Foxp3 + T REG cells in patients with AD. In addition, it has been demonstrated that activated CD25-expressing T cells with a phenotype of regulatory T cells, lacking CCR6 expression, promote Th2 immune responses in patients with AD. However, additional studies are required to elucidate the role of T REG cells in AD.
Antigen-Presenting Cells
Atopic dermatitis skin contains an increased number of IgE-bearing LCs, which appear to play an important role in cutaneous allergen presentation to Th2 cells. Binding of IgE to LCs occurs primarily via high-affinity IgE receptors. The clinical importance of these IgE receptors on LCs is supported by the observation that the presence of FcεRI-expressing LCs bearing IgE molecules is required to provoke eczematous skin lesions by application of aeroallergens on uninvolved skin of AD patients. In contrast to mast cells and basophils where the FcεRI is a tetrameric structure constitutively expressed at high levels, this receptor on APCs consists of the α-chain, which binds IgE and γ-chain dimers containing an immunoreceptor tyrosine-based activation motif (ITAM) for downstream signaling, but lacks the classic β-chain. It is assumed that allergens which invade the skin are taken up by IgE molecules bound to FcεRI-expressing DCs. In the epidermis, FcεRI expression on DCs is related to the atopic state of the individual, with higher expression in AD lesions as compared to nonlesional skin of AD patients or epidermal skin of nonatopic individuals. Different FcεRI-bearing DC subtypes have been identified in lesional AD skin. CD207 + /CD1a + , i.e. LCs, as well as CD207 − /CD1a + /FcεRI + DCs are located in the epidermis. CD1c + /FcεRI + DCs represent the major DC subpopulation of the dermal compartment, while low numbers of CD207 + /FcεRI + /CD1a + DCs are also detectable in the dermis.
Furthermore it has been demonstrated that the ability of cutaneous DC subsets to prime Th1, Th2, Th17 and Th22 immune responses in vitro is the same for DC derived from skin lesions of patients with AD or patients with other inflammatory skin diseases such as psoriasis. This indicates that chemokine expression and release together with other soluble and cellular factors of the skin micromilieu might be crucial for the outcome of T cell responses and disease-specific T cell responses in the skin.
Besides myeloid DCs, macrophage-like cells with high histamine receptor 1 expression are detectable in the dermis of lesional AD skin and might amplify inflammation after stimulation with histamine released by mast cells and other cells.
Myeloid Dendritic Cells (mDC) Contribute to Allergic Sensitization and Maintenance of Inflammation with Th2-Th1 Switch
Langerhans cells bearing FcεRI are the main myeloid DC population present in nonlesional AD skin; upon allergen challenge and inflammation, FcεRI bearing myeloid DCs, so-called ‘inflammatory dendritic epidermal cells (IDECs)’ are detectable in the epidermis. After IgE binding and internalization of the allergen, LCs migrate to peripheral lymph nodes and present the processed allergen efficiently to naïve T cells, thus initiating a Th2 immune response with sensitization to the antigen. Beyond, the activated LCs can present the allergen-derived peptides locally to transiting antigen-specific T cells and induce a T cell mediated secondary immune response. Concomitantly, aggregation of FcεRI on the surface of LCs in vitro promotes the release of chemotactic factors, which in vivo supposedly contribute to the recruitment of IDECs into the epidermis. IDECs mainly present at inflammatory sites, produce high amounts of proinflammatory cytokines after FcεRI cross-linking, display a high stimulatory capacity toward T cells and serve as amplifiers of the allergic inflammatory immune response. Moreover, stimulation of FcεRI on the surface of IDECs induces the release of IL-12 and IL-18 and enhances the priming of naïve T cells into IFN-γ producing Th1 or Th0 cells. These mechanisms may contribute to the switch from the initial Th2 immune response in the acute phase to the Th1 immune responses in the chronic phase.
Precursor cells of myeloid DCs display lower responsiveness to TGF-β, which might contribute to a lower number of LCs in favor of higher numbers of DCs with inflammatory properties differentiating from precursor cells. Additionally, DCs and precursor cells of DCs of patients with AD show an attenuated response to IFN-γ stimulation, which in part results from a lower expression of IFN-γRI and IFN-γRII, leading to lower phosphorylation of STAT-1 and lower expression of IFN-γ inducible genes. Together this reduced IFN-γ response might contribute to the overbalance of the Th2 immune response in the acute phase of AD.
Plasmacytoid Dendritic Cells
Human plasmacytoid DCs (PDCs) are the only professional interferon (IFN) producing cells and express the IL-3 receptor α-chain (CD123) and the blood dendritic cell antigen (BDCA)-2. Stimulation of PDCs with viral antigens induces the production of IFN-α/β, which is of crucial importance for the defense against viral infections. Human PDCs bear the PRRs TLR7 and TLR9 on their cell surface. Furthermore, they express the high-affinity receptor for IgE (FcεRI). Based on a close interaction of FcεRI with TLR9, the amount of IFN-α and IFN-β released in response to TLR9 stimulation is profoundly down-regulated in PDCs after FcεRI aggregation and allergen challenge in vitro. In view of frequent FcεRI aggregation induced by allergen challenge of PDCs of AD patients, this counterregulation might account for a profoundly reduced release of IFNs after viral antigen stimulation.
Furthermore, as compared to psoriasis, contact dermatitis or lupus erythematosus, the frequency of PDCs in the lesional epidermal skin of AD is low, although PDCs are recruited to the dermis during atopy patch test (APT). This might result from Th2 cytokines or IL-10 in the skin micromilieu, leading to apoptosis of PDCs and, together with the counterregulation of FcεRI with TLRs, promote enhanced susceptibility of AD patients to viral skin infections.
Inflammatory Cell Infiltration
Several chemokines have been linked to recruitment of inflammatory cell subtypes such as DCs, T cells eosinophils, etc. to the skin in AD, including CCL2, CCL3, CCL4, CCL5, CCL11, CCL13, CCL18, CCL20, CCL22, CCL26 and CCL27. Moreover, serum levels of some of these chemokines correlate directly with disease activity and decrease in response to successful topical treatment, as shown for CCL5 and CCL11 after tacrolimus treatment. A role of CCL18 in the amplification of allergic inflammation by increased homing of memory T cells has been demonstrated. Another chemokine shown to be selectively up-regulated in AD was CCL1, the ligand to C-C chemokine receptor (CCR)8, which in vitro promoted the recruitment of T cells and Langerhans cell-like DCs. IL-16, a chemoattractant for CD4 + T cells, is increased in acute AD skin lesions. The C-C chemokines, RANTES/CCL5, monocyte chemotactic protein-4 (MCP-4/CCL13) and eotaxin/CCL11 have also been found to be increased in AD skin lesions and likely contribute to the chemotaxis of eosinophils and Th2 lymphocytes into the skin.
IL-31 is a novel cytokine, preferentially expressed by Th2 cells, which signals through a heterodimeric receptor composed of IL-31 receptor A and oncostatin M receptor. Interestingly, up-regulated IL-31 expression has been observed in pruritic AD skin lesions and was inducible by both stimulation of cutaneous lymphocyte antigen bearing (CLA + ) T cells of AD patients with staphylococcal enterotoxin B (SEB) in vitro and application of SEB to the skin of AD patients in vivo. Furthermore, IL-31 induced the expression of the inflammatory chemokines CCL1, CCL17 and CCL22 in keratinocytes. Since IL-31 induces severe pruritus and dermatitis in transgenic mice and IL-31 receptor showed most abundant expression in dorsal root ganglia, these findings provide a new link between staphylococcal colonization, subsequent T cell recruitment and activation and pruritus induction in patients with AD.
In terms of T cells infiltrating the inflamed skin, it has been suggested that the so-called ‘Th17 cells’ may be of relevance not only in psoriasis but also in AD. Reports from animal models combined with studies using atopy patch tests or microarrays imply that Th17 may be induced in the skin by the topical application of allergens and may therefore assist skin infection in AD. However, as compared to psoriasis, Th17 most likely plays a rather minor role in AD skin.
Intrinsic Defect of Keratinocytes in Atopic Dermatitis
Keratinocytes play an important role in the production of antimicrobial protein and cytokines in response to stimulation by invading pathogens, mediating both innate and adaptive inflammatory immune reactions. In addition, AD keratinocytes express high levels of the IL-7 like cytokine thymic stromal lymphopoietin (TSLP), which activates myeloid dendritic cells (DCs) to increase expression of IL-5, IL-13, CCL17 and CCL22. Skin-specific overexpression of TSLP in a transgenic mouse resulted in an AD-like phenotype, with the development of eczematous lesions containing inflammatory dermal cellular infiltrates, an increase in Th2 CD4 + T cells expressing cutaneous homing receptors and elevated serum levels of IgE, pointing to an important role of TSLP in AD. DCs primed by TSLP may convert to strong inducers of T cell responses of the Th2 type in vitro, so that enhanced TSLP release triggered by frequent allergen challenge, microbial infections and inflammation might initiate and perpetuate Th2 immune responses in AD.
Chronic Skin Inflammation
Chronic AD is linked to the prolonged survival of inflammatory cells in atopic skin. IL-5 expression during chronic AD plays a role in prolonging survival of eosinophils and enhancement of their function. In chronic AD, increased GM-CSF expression maintains the survival and function of monocytes, LCs and eosinophils. Epidermal keratinocytes from AD patients have significantly higher levels of RANTES expression following stimulation with tumor necrosis factor (TNF)-α and IFN-γ than keratinocytes from psoriasis patients. This may serve as one mechanism by which cytokines such as TNF-α enhances the chronicity and severity of eczema. Mechanical trauma can also induce the release of TNF-α and many other proinflammatory cytokines from epidermal keratinocytes. Thus, chronic scratching plays a role in the perpetuation and elicitation of skin inflammation in AD.
Antimicrobial Peptides
The innate immune system provides a rapid response to invasion of microbes. Research results from recent years strongly imply that impaired innate immune mechanisms with deficiency of the antimicrobial peptides (AMPs), which are represented by human intracellular proteins, i.e. human cathelicidin LL-37, human β-defensin (HBD)2 and HBD3 as well as dermcidin-derived antimicrobial proteins in sweat, might contribute to the susceptibility of AD patients to skin infections. Defensins are broad-spectrum antibiotics that kill a wide variety of bacterial and fungal pathogens. Antimicrobial activity against viral pathogens is maintained by LL-37. Efficient killing of S. aureus is achieved by LL-37 together with HBD2 . Since inflammatory mediators up-regulate AMP expression, chronic inflammatory skin diseases such as psoriasis and contact dermatitis are characterized by increased amounts of AMP. Conversely, only weak up-regulation of HMD2, 3 and LL-37 is detectable in both lesional and nonlesional skin of patients with AD. The Th2 cytokines IL-4, IL-13 and IL-10 down-regulate AMP expression in vitro and might account for low AMP in AD skin. Moreover, reduced mobilization of human HBD3 accounts for defective killing of S. aureus in AD. In addition to the propensity to bacterial infections due to low HBD2, 3 and LL-37 expression, cathelicidin deficiency in AD might also predispose to severe viral infections such as eczema vaccinatum caused by orthopox virus and eczema herpeticum (EH). In support of this concept, lower levels of cathelicidin are detectable in skin lesions of AD patients with one or more episodes of EH in their history as compared to AD patients without EH. Dermcidin (DCD) is another recently discovered AMP with antibacterial and antimycotic properties and is constitutively expressed in human eccrine sweat glands. The amount of several DCD derived peptides in sweat was found to be significantly reduced in AD patients with a history of bacterial and viral infections and is another cause of higher susceptibility of AD patients to microbial infections. Interestingly, both incubation of keratinocytes with vitamin D 3 in vitro, as well as treatment of AD patients with oral vitamin D 3 , increases cathelicidin production of keratinocytes in AD patients, pointing to a novel opportunity to improve innate immune responses in AD patients therapeutically in the near future.
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