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Getting more and more complex: the pathophysiology of atopic eczema

European Journal of Dermatology. Volume 17, Number 4, 267-83, July-August 2007, Review article

DOI : 10.1684/ejd.2007.0200

Summary

Author(s) : Laura Maintz, Natalija Novak , Department of Dermatology, Sigmund-Freud-Str. 25, 53105 Bonn, University of Bonn.

Summary : Atopic eczema (AE) is a multifactorial chronic inflammatory skin disease characterized by pruritic, typically distributed eczematous skin lesions. Deficiencies in innate and adaptive immunity based on a genetic predisposition result in skin barrier dysfunction with hyperreactivity to environmental stimuli and susceptibility to skin infections which influence the course and severity of AE. In this review, we provide an overview of the complex pathophysiology of AE with a focus on recent advances published in this field.

Keywords : AE, Atopic eczema, AMP, Antimicrobial peptides, APC, Antigen-presenting cells, BDNF, brain-derived neurotrophic factor, DC, Dendritic cells, pDC, plasmacytoid dendritic cells, DCD, Dermcidin, EDC, Epidermal differentiation complex, EH, Eczema herpeticatum, FLG, Filaggrin gene, GM-CSF, Granulocyte macrophage colony-stimulating factor, HBD, Human β-defensin, IDEC, Inflammatory dendritic epidermal cells, IgE, Immunglobulin E, IL, Interleukin, LC, Langerhans cells, LPS, Lipopolysaccharide, LTA, Lipoteichoic acid, NOD, Nucleotide-binding oligomerization domain, NK, Natural killer cell, NGF, nerve growth factor, NT, Neurotrophin, P75 ^NTR, Pan-neurotrophin receptor (NTR) p75, PAMP, Pathogen associated molecular pattern, PGN, Peptidoglycan, PRR, Pattern recognition receptor, PAR, Proteinase-activated receptor, RANTES, Regulated upon activation, normally T cell expressed and secreted/CCL5, S. aureus, Staphylococcus aureus, SC, Stratum corneum, SNP, Single nucleotide polymorphism, SP, Serine protease, TARC, Thymus and activation regulated chemokine/CCL17, TG, Transglutaminase, trk, tyrosine kinase receptor, Th, Helper T lymphocyte, TLR, Toll-like receptor, TNF-α, Tumor-necrosis factor (TNF)-α

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Auteur(s) : Laura Maintz, Natalija Novak

Department of Dermatology, Sigmund-Freud-Str. 25, 53105 Bonn, University of Bonn

accepté le 31 Janvier 2007

Atopic eczema (AE) is one of the most frequent chronic inflammatory skin diseases with an increasing prevalence [1, 2], affecting 10-20% of children and 1-3% of adults in industrialized countries [3]. Complex interactions of deficient innate and adaptive immune responses underlie this multifactorial disease based on a strong genetic predisposition and triggered by environmental factors. Skin barrier dysfunction contributes to susceptibility to infections and hyperreactivity of distinct immune cells.According to the revised nomenclature of AE, only eczema of patients with elevated total serum IgE (> 150 kU/l) and specific IgE responses to aero- and food-derived allergens should be called atopic eczema whereas the previously called intrinsic eczema was redefined as non-atopic eczema [4].80% of adult AE patients suffer from concomitant sensitizations, allergic rhinitis or asthma. Conversely, 20% of adult AE patients with clinically and histologically indistinguishable eczematous skin lesions lack sensitizations and other clinical manifestations of the atopic triad. Despite the clinical similarity, AE patients exhibit a higher tissue eosinophilia [5, 6], enhanced lesional cytokine expression, including interleukin (IL)-5, -13, -1β and CCL11 [5, 6] and higher surface expression of the high-affinity receptor for IgE (FcεRI) on epidermal dendritic cells [7] compared to non-atopic eczema patients.

Genetic predisposition to AE

AE has a strong genetic background with a phenotype concordance of 0.72-0.77 in monozygotic and 0.15-0.23 in dizygotic twin pairs [1, 8]. Many genetic and epidemiologic studies have been carried out to identify susceptibility genes for AE. Genome screenings investigate families with affected individuals independent of hypotheses about disease cause. They search for any chromosome region co-inherited with disease (linkage mapping). In contrast, candidate gene studies founded on pre-existing knowledge of disease pathomechanisms evaluate the association of polymorphisms within these already known linkage regions [9].

Four genome screens for AE have been carried out so far and have identified significant linkage on chromosomes 1q21 [10], 3q21 [11], 3q24-22 [12], 3p26-24 [13] and 17q25 [10]. Supplementary loci have been found for AE with increased allergen-specific IgE levels (3p26-24, 4p15-14, 18q11-12 [13], 18q21 [12]), total serum IgE levels (16q) [10] and for AE with concomitant asthma (20p) [10]. Interestingly, only some of the loci overlap with known regions of linkage to asthma (13q [14], 20q [10]), whereas a greater degree of coincidence was observed for other inflammatory skin diseases such as psoriasis (1q, 3q, 17q, 20q) [10], leprosy (20p12) [15] and inflammatory bowel disease (chromosome 16) [16]. Based on these observations, a general effect of particular genes or gene families on immune reactions in the skin and mucosa [17] has been supposed to underlie defective barrier defenses [9].

Various candidate gene studies [9, 18-57] have identified AE-associated polymorphisms in genes important for epidermal differentiation, inflammation and atopy (table 1) and running text) such as the cytokine gene cluster located on chromosome 5q31-33. A maternal inheritance of atopic IgE responsiveness on chromosome 11q13 [58] has been found according to the observation that infant disease risk was often [59-61] although not always [62, 63], found to be more closely related to maternal than paternal disease status [9]. However, a high percentage of genetic studies on AE have reported conflicting results on the association of polymorphisms in different candidate gene regions with AE. These discrepancies might result from varying statistical power and sampling design of the studies such as ethnic groups, individual-based and population-level models etc. Moreover, well-defined and detailed inclusion criteria to characterize the specific phenotype of the AE patients are indispensable to investigate the genotype- phenotype correlation. Furthermore, other limitations of the recent advances concerning the genetic background of AE remain. For example, only very few SNPs have been identified so far on the module level and we are far away to understand the pathophysiological consequences of such mutations. Still, the development of novel technologies, improvement of epidemiological methodology and increasing knowledge of the human genome and human genetic diversity provides new insights into this complex disorder and will potentially allow the subsequent development of therapeutic interventions based upon a better understanding of the pathophysiology of AE.
Table 1 Overview of the candidate gene studies on atopic eczemaTable is adapted from references [9], [56] and [57].

Gene	Gene product	Chromosomal location	Associated phenotype	Potential role in the pathophysiology of AE	Reference
				Innate immunity
FLG	Filaggrin	1q21	Extrinsic AE, Early onset of AE, AE with concomitant Asthma Ichthyosis vulgaris	Transepidermal water loss, Xerosis cutis, Systemic sensitization to allergens through the skin	[18-20]
SCCE	Stratum corneum chymotryptic enzyme	19q13.3	AE	Impaired stratum corneum integrity and function	[21]
SPINK5	LEKTI	5q31	AE Netherton syndrome	Serin protease inhibitor resulting in altered stratum corneum cohesion and lipid processing	[22, 23]
NOD1 = CARD 4	Nucleotide-binding oligomerization domain protein 1	7p14-15	AE, transmission distortion of serum IgE levels	Cytosolic receptor for gram-negative bacterial peptidoglycans	[24]
NOD2= CARD15	Caspase recruitment domain-containing protein 15	16q12	AE Modified risk for the development of asthma and allergic rhinitis Increased total IgE levels Crohn’s disease	Intracellular LPS receptor protein, Impaired recognition of microbial exposures might lead to insufficient downregulation of excessive immune responses	[25, 26]
TLR2	TLR-2	4q32	Severe AE with high total serum IgE levels and recurrent bacterial infections	Response to microbial stimuli such as the staphylococcal cell-wall components Lipoteichoic acid and peptidoglycan	[27]
TLR9	TLR-9	3p21.3	Non-atopic eczema	Recognition of bacterial and viral antigens Induction of Th1-biased immune response via IFN α and IL-12.	[28] (Novak et al, Unpublished data)
IRF2	IFN regulatory factor 2	4q35.1	Japanese children with AE	Transcriptional factor involved in the modulation of cellular responses to interferons (IFN) and viral infection; Regulation of cell growth and transformation	[29]
CD 14	CD 14 = LPS receptor	5q31.1	Lower prevalence of AE, Lower LPS induced IL-13 production	Binds complex of LPS and LPS-binding protein; required for LPS-induced macrophage activation	[30]
CCL5	RANTES =Regulated upon activation, normally T cell expressed and secreted	17q11.2	German children with AE, AE with enhanced RANTES production	Upregulation of CC chemokine expression, Elevated IgE production, stimulation of histamine secretion from basophils, increased recruitment of eosinophils, monocytes, and T_H-lymphocytes	[31, 32]
CCL11	Eotaxin	17q11.2	No association to susceptibility to AE, but to levels of serum IgE in AE patients	Potent chemoattractant and activator of eosinophils, basophils and T_H2 lymphocytes, indirect negative regulator of neutrophil recruitment	[33]
IL 12	IL-12	5q31-33	Susceptibility to AE	Induction of Th1-biased immune responses, deficiency of IL-12 mediated inhibition of IgE synthesis	[34]
GSTT1	Glutathione S-transferase, Theta-1	22q11.2	Predisposition and resistance to AE	Cellular defence against reactive oxygen species	[35, 36]
				Adaptive immunity
MS4A2	FCεRIβ= β chain of the high-affinity receptor for IgE	11q12-13	AE, asthma	Increased degranulation of mast cells	[37, 38]
IL4	IL-4	5q31-33	AE	B-cell isotype switch to IgE; Th2 differentiation and proliferation; proliferation of mast cells, Induction of the expression of FcεRI on LC, inhibition of IFN-γ mediated macrophage activation	[39]
ILRA	IL-4 receptor α chain	16p12-p11	Adult AE	See IL-4	[40, 41]
IL13	IL-13	5q31-33	AE with high total serum IgE levels No association to disease severity	B-cell isotype switch to IgE, inhibition of macrophages	[42, 43]
IL 18	IL-18	11q22	AE; no association to concomitant allergic rhinitis or asthma	Stimulation of IgE synthesis by enhancement of IL-4 and IL-13 production in response to microbial components	[44]
GM-CSF	Granulocyte-macrophage colony-stimulating factor	5q31.3	Absence of severe AE phenotype in children with AE	Increased production of neutrophils, monocytes; macrophage-activating factor; Promotion of the differentiation of Langerhans cells into mature dendritic cells; Inhibition of eosinophil apoptosis	[45]
STAT6	Signal transducer and activator of transcription 6	12q13-24	Elevated Serum IgE	Proximal promoter of RANTES, IL-4, IL-4R and important for the activity of IL-13	[46]
CMA 1	MCC1=Mast cell chymase 1	14q11.2	Pure adult and childhood AE with low serum IgE levels and without asthma or rhinitis	Increased microvascular permeability with accumulation of inflammatory cells, tissue remodelling; Release of TGF-β; induction of pruritus	[47-51]
TGFβ1	Transforming growth factor β	19q13.1	Children with AE	Inhibition of macrophages and B- and T-cell responses	[52]
TIM1	T-cell immunoglobulin- and mucin domain-containing molecule 1	12q12-13	AE, susceptibility to asthma	Th2-biased immune responses	[53]
CTLA4	Cytotoxic T lymphocyte -associated 4 receptor	2q33	Early onset infant AE	Recognition and killing of infected host cells	[54]
PHF11	Plant homology domain finger protein 11	13q14	Childhood AE with increased total serum IgE; Asthma	Proteins expressed on immune cells with a suspected role in transcriptional regulation	[55]

Modified skin barrier in AE

Transepidermal water loss

The epidermis functions both as a physical barrier and as an active immunological organ. It represents an effective protective shield which maintains to some degree resistance to environmental agents such as allergens, microbes or various irritants.

A modified skin barrier with an increased transepidermal water loss and reduced hydration of the skin is a characteristic feature of AE patients. AE patients exhibit an impaired barrier function and an inherently abnormal stratum corneum (SC) in both lesional and nonlesional skin [64]. Skin barrier dysfunction is regarded to set the course of AE allowing antigens, bacterias and viruses to invade the skin and gain access to immunocompetent cells in the upper parts of the epidermis and dermis. Epidermal allergen exposure may therefore lead to inflammation and systemic sensitization [65].

The impaired epidermal barrier in AE has been supposed to be caused by a primary defect of epidermal differentiation [17]. During differentiation, keratinocytes move from a proliferative cell type in the basal cell layer of the epidermis through the granular layer where the cornified envelope is formed, to an association of flattened, dead cell remnants (corneocytes) in the uppermost layer of the skin, the stratum corneum. The cornified envelope is an insoluble protein structure that is crosslinked by transglutaminases (TG) to replace the plasma membrane in corneocytes where it functions as a scaffold for lipid attachment. This structure prevents epidermal water loss and also impedes the entry of allergens, toxic chemicals and infectious organisms. A matrix of lipids such as ceramides, cholesterol, fatty acids and cholesterol esters compasses the corneocytes and builds the critical barrier to transepidermal water loss [66].

Dysregulated serine protease activity due to a higher pH in AE

Several proteases, especially the serine proteases (SP) stratum corneum chymotryptic enzyme (SCCE), stratum corneum tryptic enzyme (SCTE) and stratum corneum cathepsin-L-like enzyme (SCCL), are involved in the proteolytic degradation of corneodesmosomes, lipid processing enzymes such as β-glucocerebrosidase and acidic sphingomyelinase [67] and the resulting desquamation of corneocytes from the SC surface [68, 69]. Acid and neutral sphingomyelinase generate ceramides with structural and signal transduction functions in epidermal proliferation and differentiation [70]. The activity of the SPs is controlled by localized changes in pH and water concentrations [71]. Sustained SP activity by a slight, prolonged alkanization in pH from pH 5.0 to pH 5.5 in AE patients is suspected to induce abnormalities in both SC integrity, cohesion and permeability barrier homeostasis [65]. Decreased epidermal acid and neutral sphingomyelinase activity has been found in lesional and non-lesional skin of AE patients, correlated with reduced SC ceramide content and with impaired expression of the cornified envelope proteins involucrin, loricrin, filaggrin and keratins K5 and K16 leading to disturbed barrier function. Changes in K10, K6, and K17 were found only in lesional skin [70].

Mutations of the SPINK5 gene (5q32) encoding the lymphoepitheliala Kazal-type-related inhibitor (LEKTI), a SP inhibitor expressed by keratinocytes, have been shown to be linked to Netherton syndrome, a autosomal recessive disorder characterized by congenital ichthyosis, a hair-shaft defect (trichorrhexis invaginata), and atopic manifestations [72]. LEKTI co-localizes within the stratum corneum with kallikreins 5 and 7 and inhibits both SCTE and SCCE. A barrier dysfunction with disorganization of lamellar lipid membranes, altered lamellar body secretion, accelerated degradation of desmoglein-1 and overdesquamation of corneocytes represent characteristic features of the Netherton syndrome [73, 74]. The magnitude of SP activation has been shown to correlate with the barrier defect, clinical severity and inversely with residual LEKTI expression [74]. Maternally derived [75] polymorphisms of the SPINK5 gene have later also been associated with atopy and AE and are supposed to be involved in the development of high serum IgE and atopic diseases [75, 76].

SP can mediate pro-inflammatory effects via the proteinase-activated receptor-2 (PAR-2) which is highly expressed on epidermal keratinocytes and dermal endothelial cells. These cell populations respond to PAR-2 signalling with hyperproliferation and enhanced expression of proinflammatory cytokines and chemokines. PAR-2 is also expressed on human skin mast cells inducing the release of histamine upon activation [77]. Acute barrier disruption has been shown to increase SP activity and provoke PAR-2 activation. Endogenous PAR-2 activators may include mast cell-derived tryptase, and other trypsin-like enzymes such as SCTE, whereas exogenous activators could be tryptic enzymes released by Staphylococcus aureus (S. aureus) and house dust mites (HDM). Via their SP activity, HDM can sustain a non-immune specific inflammatory reaction in non-sensitized and sensitized persons in parallel with the elicitation of an allergen-specific response.

Another explanation of the decreased content of ceramide in the stratum corneum of AE patients is the high colonization of the atopic skin with ceramidase-secreting S. aureus. The bacterial flora of lesional and non-lesional skin of AE has been shown to secret significant more ceramidase compared to controls therefore contributing to ceramide deficiency. Conversely, sphingomyelinase, which breaks sphingomyelin down into ceramide and phosphorylcholine, was secreted from the bacterial flora obtained from all types of skin at similar levels for the patients with AD and healthy controls [78].

Genetically based modifications of the cornified envelope in AE

Genes encoding structural proteins of the epidermal cornification and S100 calcium-binding proteins form the so-called “epidermal differentiation complex” (EDC) localized on chromosome 1q21 [79]. The EDC includes a selection of genes encoding proteins involved in the formation of the cornified cell envelope such as S100A proteins, small proline-rich region proteins (SPRRs) and late envelope proteins (LEP), which are over-expressed in the skin of patients with AE and psoriasis [17, 80]. Filaggrin, which consolidates the keratin filaments into dense bundles, represents an integral part of the epidermis and is crucial for the development of the cornified envelope to engineer and maintain the barrier function of the uppermost layer of the skin [66]. The filaggrin (FLG) gene mutations 228del4 and R501X seem to be the major filaggrin variants in populations of European origin and are carried by about 9% of Europeans. Ichthyosis vulgaris, which is one of the most common inherited skin disorders of keratinization, is caused by FLG mutations [18] and is frequently associated with AE [81].

Recently, two loss-of function FLG mutations (R510X and 228del4) have been shown to be predisposing factors for AE and for AE with concomitant asthma, but not for asthma without AE [19, 20]. These FLG mutations led to deficiency of filaggrin peptides in the upper part of the epidermis. Associations of the FLG mutations have been observed in particular in AE patients with high total serum IgE levels and concomitant allergic sensitizations and early age of onset of AE with chronic persistent course until adulthood [82]. Therefore, an impaired epidermal barrier in AE caused by FLG variants has been supposed to represent an important risk factor for severe AE cases [20].

Deficiency of the innate immune system

Innate immunity consists of cellular and biochemical defense mechanisms that provide a rapid response to invasion of microbes after their recognition by pattern-recognition receptors (PRR). Defense against microbes is mediated by the early reactions of innate immunity and the later responses of adaptive immunity. Alterations in both innate and adaptive immunity have been described in AE.

Genetic susceptibility to insufficient innate immune responses in AE based on polymorphisms in pattern-recognition receptors?

PRR play a pivotal role in the induction of first-line defense mechanisms of the innate immune system and trigger adaptive immune responses to a wide range of microbial pathogens. They respond to highly conserved pathogen associated molecular patterns (PAMPs) shared by groups of related microbes. To discriminate between the diverse PAMPs, our innate immune system provides a variety of PRR such as toll-like receptors (TLRs) expressed on the cell surface, intracellular nucleotide-binding oligomerization domain (NOD) or CD14 [83, 84]. Genetic variations in innate immunity genes have been reported to be associated with a range of inflammatory disorders. As exposure to microbial products, mainly to lipopolysaccharide (LPS), has been conjected to prevent from the development of asthma and atopy [85] and AE is often triggered by microbial infections, deficiencies of PRRs have been supposed to contribute to the dysbalance on the level of TH2 and TH1 immune responses in AE.

Toll-like receptors

Eleven different mammalian TLRs (TLR1-11) have so far been identified which are expressed on many cells important for the innate immune system, including macrophages, dendritic cells (DC), neutrophils, mucosal epithelial and endothelial cells. Ligand recognition induces a conserved host defense program via the nuclear factor κB (NFκB), leading to expression of inflammatory cytokines (TNF-α, IL-1, IL-12), endothelial adhesion molecules (E-selectin), costimulatory molecules, and antimicrobial defenses (AMPs, inducible nitric oxide synthase). Importantly, activation of dendritic cells by TLR ligands is necessary for their maturation and consequent ability to initiate adaptive immune responses [86]. TLR2 is important for the answer to diverse bacteria, mycobacteria, protozoans and fungi, recognizing the fungal zymosan, LPS and other PAMPs such as the staphylococcal cell-wall components lipoteichoic acid (LTA) and peptidoglycan (PGN). Associations of the TLR2 polymorphisms rs4696480 with asthma [87] and rs5743708 with severe forms of AE with high total serum IgE and recurrent bacterial infections (n = 78) [27] have been reported. Conversely, a recent study with 275 German nuclear families could not show an association of TLR2, TLR3 and TLR4 SNP with AE [88]. Likewise, no association of polymorphisms in the TLR6 [89] and TLR4 (LPS) gene [88, 89] associated to asthma [90] and modified endotoxin effects on asthma [91] gene with AE could be shown. The mRNA expression for TLRs 1, 2, 3, 5 and 6 did not differ significantly between skin biopsies of patients with AE and psoriasis [92]. Study results are controversial for TLR9 which recognizes unmethylated CpG DNA (bacteria, protozoans) and intracellular viral antigens. No relevant associations between TLR9 SNPs and atopy could be shown in a group of healthy subjects [93] in contrast to own study results showing a significant association of C-2337T, located within the promoter region of TLR9 with the non-atopic subtype of AE (Novak et al., unpublished data).

Nucletide-binding oligomerization domain (NOD)

Intracellular PAMPs, particularly peptidoglycan (PGN), are recognized by the NOD (also known as Caspase-recruitment-domain = CARD) family of proteins [94]. NOD1 and NOD2 expressing keratinocytes produced IL-6 after stimulation with PGN [95] and HBD2 after stimulation with the NOD2-specific ligand muramyl dipeptide [96]. Associated single nucleotide polymorphisms (SNP) of CARD4 (encoding NOD1) [24] have been observed with AE, whereas variants of CARD15/NOD2 modified the risk of developing asthma or allergic rhinoconjunctivitis [25]. Interestingly, SNP in CARD15 (encoding NOD2) have been associated to Crohn’s disease, a chronic inflammatory bowel disease. Therefore it has been speculated that a shared genetically based barrier defect [9] with impaired recognition of microbial exposures might result in an insufficient downregulation of excessive immune responses, giving rise to either Th2 dominated allergies or Th1 related Crohn’s disease [26].

CD14

Besides many other microbial compounds, CD14 binds the complex of LPS and LPS-binding protein and is required for LPS-induced macrophage activation via TLR 4. Because CD14 has also been found to induce cellular activation in response to LTA through a TLR2-dependent pathway [97] and has binding activity for peptidoglycans (PGN) [98], it is thought to play a role in host response to S. aureus as well [99]. Reduced levels of soluble CD14 (sCD14] have been observed in atopic children [100]. In breast-fed children, low levels of soluble CD14 in breast milk has been shown to be associated with an increased risk for AE and asthma [101, 102]. Thus, the exposure to high levels of sCD14 in the fetal and neonatal gastrointestinal tract via breastfeeding or exogenous supply might influence immunologic reactivity both locally and systemically in early life and thereby influence disease outcome [101]. A genotype at the CD14 gene locus has been shown to attenuate the development of AE in children at risk after exposure to dogs [103]. However, no difference could be observed between the CD14 expression on keratinocytes from the nonlesional skin of patients with AE, psoriasis and controls [104].

Deficiency of antimicrobial peptides contributes to the propensity to skin infections in AE

Recent evidence suggests that impaired innate immune mechanisms with deficiency of the antimicrobial peptides (AMP) human cathelicidin LL-37, human β-defensin (HBD)-2 and HBD-3 contribute to the susceptibility of atopic patients to skin infections.

Defensins are broad-spectrum antibiotics that kill a wide variety of bacterial and fungal pathogens. LL-37 has been shown to display antimicrobial activity against viral pathogens [105] additional to bactericidal and fungicidal actions, to neutralize LPS bioactivity, to induce the expression of the inflammatory mediators by keratinocytes [106] and thus to chemoattract neutrophils, monocytes, mast cells, and T cells. The combination of LL-37 and HBD2 has been shown to achieve synergistic antimicrobial activity by effectively killing S. aureus [107]. With the exception of the constitutively expressed HBD1, healthy skin exhibited only small amounts of AMP but synthesis of HBD2, 3 and LL-37 by keratinocytes was increased in response to inflammatory cytokines [92, 107, 108]. Therefore high amounts of AMP have been found in the skin of patients with chronic inflammatory skin diseases with high expression of these cytokines such as psoriasis or contact dermatitis. Conversely, both lesional and non-lesional skin of patients with AE [92] featured scarce expression of HBD2, 3 and LL-37 compared to psoriasis skin [92, 107, 109]. The Th2 cytokines interleukin (IL)-4 and IL-13 have been shown to downregulate AMP expression in AE skin [92, 105, 107]. Supplementary to the propensity to bacterial infections due to scarceness of HBD2 and HBD3, cathelicidin deficiency in AE might also predispose to severe viral infections such as eczema vaccinatum caused by orthopox virus [105, 110] and eczema herpeticatum (EH) [111].

EH is a disseminated herpes simplex virus (HSV) 1 or 2 infection with severe systemic illness that occurs in 10-20% of patients with AE [112] Risk factors for EH are an early onset of AE, severe and untreated AE [113], head and neck dermatitis [114], previous Herpes simplex infections and EHs, an elevated serum IgE [113] combined with higher level of specific sensitizations, especially against Malassezia sympodialis [114]. LL-37 exhibits potent antiviral activity against HSV [111]. Lower levels of cathelicidin have been shown in skin lesions of AE patients and EH compared to those of uncomplicated with EH [111].

Dermcidin (DCD) is another recently discovered AMP with antibacterial and antimycotic properties [115-117] which is constitutively expressed [118] in human eccrine sweat glands and secreted into sweat. The amount of several DCD derived peptides in sweat of patients with AE was found to be significantly reduced compared to healthy controls, especially in AE patients with a history of bacterial and viral infections [119]. In addition to the reduced DCD expression in atopic sweat, the overall reduced amount of sweat [120, 121] with reduced secretion of IgA [122] and altered sweat electrolyte concentrations [123] in AE are supposed to contribute to the proneness to skin infections in AE.

Deficiency in adaptive immunity and modifications on the cellular level

Intrinsic defect of keratinocytes in AE

Keratinocytes are crucial not only for innate immunity by expressing TLRs and producing AMP in response to invading microbes [124], but also produce cytokines which mediate both innate and adaptive inflammatory immune reactions. Keratinocytes from AE patients have been shown to produce increased amounts of proinflammatory mediators both constitutively and in response to a variety of stimuli, including epithelial injury, such as scratch-induced mechanical trauma [125]. AE keratinocytes also express high levels of the IL-7 like cytokine thymic stromal lymphopoietin (TSLP) which activates myeloid dendritic cells (DC) to increased expression of IL-5, IL-13 and of chemokines such as CCL17 and CCL22 active towards chemokine receptor (CCR)4⁺Th2 lymphocytes [126, 127]. Skin-specific overexpression of TSLP in a transgenic mouse resulted in an AE-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 [128], indicating that TSLP might play an important role in AE.

Promotion of leukocyte recruitment to sites of infection by chemokines

Chemokines that are expressed by endothelial cells act on leukocytes rolling on the endothelium and increase the affinity of leukocyte integrins for their ligands. Integrin activation is critical for the firm adherence of the leukocytes to the endothelium, as a prelude to subsequent migration toward a chemical gradient into extravascular tissue [129]. In acute AE, enhanced serum levels of the chemokines CCL2/MCP-1 (monocyte chemoattractant protein-1), CCL4/MIP-1β (macrophage inflammatory protein), CCL5/RANTES (regulated upon activation, normally T cell expressed and secreted), CCL11/Eotaxin [130], CCL17/TARC (Thymus and activation regulated chemokine), CCL22/MDC (macrophage-derived chemokine), CCL26/eotaxin-3, CCL27/CTACK (cutaneous T cell attracting chemokine) and CX₃CL1 /Fractalkine and other chemotactic factors such as IL-16 and soluble CD30 (sCD30) have been observed. These chemokines have been supposed to contribute to the chemotaxis of eosinophils and Th2 cells. Elevated CCL5 levels correlated to total serum IgE levels and eosinophilia [130]. An increased expression of CCL11 and its receptor CCR3 (expressed on eosinophils and T lymphocytes) have been detected in lesional skin of AE patients compared to controls [131]. The cytokine and chemokine-mediated leukocyte activation results in the release of inflammatory mediators, including effector cytokines (IL-31) and proteases (tryptase), which perpetuate pruritic signals together with stress-induced neuropeptides [132].

Because of the continuous activation of epidermal cytokines as a consequence of the underlying barrier dysfunction in AE only minimal exogenous skin trauma may be needed to amplify cytokine production and activate disease in clinically uninvolved skin [65].

B- and T-cell pathophysiology

T-cell skin homing

The migration of memory and effector T cells to the inflamed skin plays an essential role in the development of atopic skin inflammation. Cutaneous lymphocyte antigen (CLA) is a skin-homing receptor defining a subset of circulating memory T cells [133-135]. CLA interacts with the vascular ligand E-selectin and mediates the rolling of distinct leukocyte subsets along the vascular endothelium [132]. In response to microbial or antigenic invasion, epidermal keratinocytes produce a variety of proinflammatory mediators such as the skin-specific CCL27. The interaction of CCL27 with its receptor CCR10 mediates the recruitment of CLA+lymphocytes to the skin in vivo and in vitro [136] together with CCL17-CCR4 [137] and CCL18 [138]. AE patients have been shown to feature enhanced serum levels of CCL18, secreted by monocytes and DCs, which could be also observed only in atopic skin biopsies, but not in healthy controls or psoriasis [138, 139]. Other important cofactors in the skin homing process are α-6 integrin, vascular cell adhesion molecule 1, intercellular adhesion molecule 1 and IL-8, which can be found in higher levels in the peripheral blood of AE patients [135, 140].

The biphasic nature of AE

AE is a biphasic disease where the initial phase is predominated by T helper type 2 (Th2) cytokines that later switches to a more chronic Th1-dominated eczematous phase [135]. The effective production of IgE in atopic disease by B cells depends on support by Th2 cells, which produce interleukin-4 (IL-4), IL-5, IL-9 and IL-13. Barrier-disruption and exposure to antigen have been shown to induce production of IL-4 and IL-5 in the skin [141, 142]. AE patients show characteristic features of marked Th2 polarization such as high levels of IL-4, -5, and 13 in particular in the acute phase of AE in both lesional and non-lesional skin [143] in combination with a predominance of Th2 cytokines in the blood [144, 145] and enhanced IgE production [135]. IL-4 induces the differentiation of Th2 cells from naïve CD4+ precursors, IgE isotype switching in B cells together with IL-13 [146], alters the homeostasis of the skin and makes Langerhans cells more efficient in taking up and processing naive proteins [147], upregulates the expression of FcεRI and skin homing molecules on DCs [148] and suppresses interferon (IFN)-γ- dependent macrophage functions. IL-5 stimulates the growth, differentiation and survival of eosinophils and activates mature eosinophils. This results in peripheral blood eosinophilia and increased IgE serum levels found in the majority of AE patients. Moreover, circulating effector and memory Th1 cells selectively undergo apoptosis in AE patients, skewing the immune response towards Th2 cells. This could not be observed in non-atopic eczema or other inflammatory skin diseases such as psoriasis or contact dermatitis [149].

Whereas mRNA-expression for Th1 cytokines such as IFN-γ and IL-12 were not significantly detectable in acute AE skin lesions, increased mRNA- expression of IFN-γ, IL-5, IL-12 and GM-CSF could be observed in chronic AE [150]. IL-12 is the key inducer of cell-mediated innate immune response to intracellular microbes. IL-12 together with IL-18 stimulates the IFN-γ production of natural killer (NK) and T cells, enhances the cytolytic activity of NK cells and CTLs and promotes the development of Th1 cells together with IFN-γ. IFN- γ induces macrophage activation, increased microbicidal activity, expression of class I and II MHC molecules and costimulators on APCs, promotes the Th-1 differention and inhibits the proliferation of Th2 cells. Based on the differing cytokines depending on the phase of disease, a biphasic cause of AE with the initiation of acute skin inflammation by Th2 cytokines and maintenance of chronic inflammation by Th1 cytokines such as IFN-γ and IL-12, but also eosinophils [150], probably inhibiting their apoptosis by autocrine release of GM-CSF and IL-5 [154], has been assumed. Another characteristic feature of AE is keratinocyte apoptosis [151-153]. This presumption has been confirmed by sequential skin biopsies from AE patients undergoing an atopy patch test [155]. In the atopy patch test, aero- and food allergens are applied to the skin for 48 hours and elicit an eczematoid reaction in sensitized patients [156-160].

Myeloid dendritic cells (mDC) contribute to allergic sensitization and maintenance of inflammation with Th2-Th1 switch

Dendritic cells (DC) are highly specialized APCs found in epithelial and lymphoid tissues which play a pivotal role in the generation and regulation of adaptive immune responses. Two subtypes of DC with different cell- surface markers and functional duties [161] have been shown to play an important role in the pathophysiology of AE: myeloid DC (mDC) and plasmacytoid DC (pDC) [162-164]. High amounts of Langerhans cells (LC) and inflammatory dendritic epidermal cells (IDEC), have been shown in lesional skin [165]. Both LC and IDEC express the high-affinity receptor for IgE (FcεRI) [165, 166]. After IgE binding and internalization of the allergen, LC migrate to peripheral lymph nodes, present the processed allergen efficiently to naïve T cells, thus initiating a Th2 immune response with sensitization to the antigen. Otherwise, the activated LC can present the allergen-derived pepides locally to transiting antigen-specific T cells and thereby induce a classic T cell- mediated secondary immune response [167]. Concomitantly, aggregation of FcεRI on the surface of LC induces the release of chemotactic factors such as IL-16, CCL22, CCL17 and CCL2 [148, 168] (figure 1). These cytokines are supposed to recruit IDEC into the skin. In contrast to LC, IDEC can be found exclusively at inflammatory sites, produce high amounts of proinflammatory cytokines after FcεRI cross-linking, display a high stimulatory capacity towards T cells and serve as amplifiers of the allergic inflammatory immune response [164]. Precursor cells of IDECs are most likely monocytes from the peripheral blood which differentiate into IDEC during the recruitment process into the skin. Selective decrease of the high affinity receptor for IgE (FcεRI) expressing CD14+CD16-CD64+ monocyte subsets during the exacerbation phase in the peripheral blood of AD patients and restorage of the CD14+CD16-CD64+ monocytes after successful topical treatment of AD underscore this hypothesis. Moreover, stimulation of FcεRI on the surface of IDEC induces the release of IL-12 and IL-18 and enhances the priming of naïve T cells into IFN-γ producing Th1 cells. These mechanisms may lead to the switch from the initial Th2 immune response in acute AE to the Th1 phenotype in the chronic phase of AE [164]. Invasion of high amounts of IDEC have been shown 72 hours after allergen challenge in the APT, underlining their crucial role for the development of eczema [169].

A lower amount of IFN-α- and β-producing plasmacytoid dendritic cells may account for the higher susceptibility of these patients to viral infections

Activated plasmacytoid DC (pDC) are able to produce antiviral type I interferons such as IFN-α and -β. Moreover, pDCs have been shown to express FcεRI, whereas the amount of IgE bound to FcεRI is related to the disease state and the serum IgE levels [170]. Thus, pDC can process allergens by FcεRI-IgE and promote Th2 type immune responses [167]. An increased number of pDC have been found in the peripheral blood of AE patients, but only a limited number of pDC are detectable in skin lesions of AE in contrast with other inflammatory skin diseases [162]. The paucity of pDC in the atopic skin has been supposed to result from a decreased expression of skin-homing molecules such as cutaneous lymphocyte antigen and the L-selectin CD62L on pDC in the peripheral blood of AE patients [170]. FcεRI-preactivated pDC produce lower amounts of type-I IFN after stimulation with virus DNA motifs [170], which, together with the deficiency of antimicrobial peptides may contribute to the enhanced susceptibility of AE patients to viral infections [113].

Modified function of T-regulatory cells in AE

Regulatory T cells (T reg) control the activation of autoreactive and T effector cells and are crucial for the maintenance of peripheral tolerance to self antigens. Two main groups of regulatory T cells have been defined: the natural CD4+CD25+ T regs (nTreg) and the adaptive T-regulatory cells type 1 (Tr1), characterized by the secretion of high levels of IL-10 with or without transforming growth factor (TGF)-β [171, 172]. The balance between allergen-specific Tr1 cells and Th2 cells appears to be decisive in the development of allergy [173, 174]. Increased numbers of peripheral blood CD4+CD25+ T cells have been found in AE patients compared to psoriasis and healthy controls [175]. A significant expression of Tr1, their suppressive cytokines IL-10 and TGF-β as well as their receptors has been observed in lesional and eczematous lesions of atopy patch tests, whereas nT regs were not detectable [176]. Both nTregs and Tr1 cells of AE patients efficiently suppressed activation of IL-4 secreting Th2 and IFN-γ-secreting Th1 cells stimulated with antigen in vitro. However, neither nTregs nor Tr1 cells and their cytokines IL-10 and TGF-β could impair keratinocyte apoptosis in AE as an effector function of preactivated T cells [176]. This might be explained by the finding that staphylococcal enterotoxin B inhibits nTregs [177, 178] in AE. The superantigens have been shown to upregulate glucocorticoid-induced TNF receptor-related protein ligand on monocytes. This resulted in the proliferation of nTregs and abrogation of their immunosuppressive activity via a cell-cell contact interaction [178].

The contribution of mast cells to AE

Mast cells (MCs), critical effector cells in allergic inflammation and innate immunity to bacteria, are located in large numbers in tissues that interface the external environment, including the skin [179]. The number of dermal mast cells is increased during the early phase of AE [180]. MCs cells contribute to pruritus and inflammation in AE via release of histamine, tryptase, mast cell chymase (MCC) and other inflammatory mediators. Histamine induces pruritus by binding to the histamine H1- and H3-receptor on periphery sensory nerves. Mast cell-derived histamine also induces keratinocytes to upregulate the production of various inflammatory cytokines such as nerve growth factor (NGF) [181], IL-6, IL-8 [182] and granulocyte-macrophage colony stimulating factor (GM-CSF) [183] via binding to H1 receptors on the keratinocyte cell surface and subsequent activation of intracellular protein kinase C [184]. Moreover, an impaired histamine degradation capacity based on a reduced diamine oxidase activity has been shown in a subgroup of patients with AE and was mirrored by histamine intolerance-like symptoms and non-IgE mediated intolerance of histamine-rich food and alcohol [185]. Tryptase mediates itch sensation and neuropeptide release (substance P, CGRP and neurokinin A) through the activation of PAR-2. MC chymase-positive cells have been shown to be increased in both lesional and non-lesional skin of AE patients compared to psoriasis and controls [186, 187]. MCC gene (CMA 1) (14q11.2) variants have been linked to AE, in particular to pure adult and childhood AE with low serum IgE levels and without asthma or rhinitis AE [47-51] These findings indicate a contribution of MCC to skin inflammation and mast cell induced pruritus in AE [188], especially in non-atopic eczema. However, the association of MCC gene variants with AE could not be confirmed by all studies [189, 190] which might be due to variations in study design or population history.

Trigger factors

S. aureus triggers AE by both specific and nonspecific mechanisms

AE is often complicated by recurrent infections of skin lesions by bacterial, viral and fungal pathogens. Especially S. aureus with its cell wall components LTA and PGN is a frequent trigger for the exacerbation of AE. Healthy skin is colonized to less than 10% by S. aureus whereas the microbial flora of atopic skin shows striking differences, being colonized by S. aureus to > 90% in inflammatory lesions and 76% in non-lesional skin [191, 192]. Also the nose has been shown to be a major reservoir of S. aureus. The increased ceramidase secretion by S. aureus with a resulting ceramide deficiency contributes to the disturbed skin barrier in AE. A higher affinity and bond of S. aureus due to the modified fibrine and fibrinogen composition in the skin of AE has been supposed [56]. S. aureus PGN stimulates both the production of GM-CSF and CCL5 from keratinocytes [193] thus contributing to leukocyte recruitment and inflammation in AE. Moreover, up to 50% to 60% of the S. aureus found on patients with AE is producing enterotoxines like S. aureus enterotoxin A (SEA), B (SEB), C (SEC), D (SED), etc [194] and some of the patients are sensitized to them. S. aureus enterotoxines also function as superantigens. Eczematous inflammation could by provoked by application of S aureus or its enterotoxines on the skin of AE patients. Via induction of CCL1 and CCL18 production in DCs, keratinocytes and endothelial cells, they lead to recruitment of skin-homing CLA+ memory T cells and LCs into atopic skin [132]. Staphylococcal superantigen has been shown to induce the pruritic cytokine IL-31 both in vitro and in vivo [195]. The superantigens also have been supposed to neutralize the suppressive function of T regulatory cells [56]. Bacterial superantigens can also induce glucocorticoid resistance via production of the glucocorticoid receptor β [196]. These properties of S. aureus are mirrored by the correlation of disease severity with specific IgE levels of S. aureus enterotoxin [197, 198].

Food- and aeroallergens trigger acute eczema

Allergens may induce both allergic reactions of the immediate and of the delayed type in sensitized patients, and thus are well-known, unbeloved companions of most of the patients during their long-lasting atopic career manifesting as AE, food allergy, allergic bronchial asthma or allergic rhinoconjunctivitis. Food allergens may elicit skin rashes in about 35% of AE children [199]. This has been verified immunologically by the detection of T cells specific to food in blood and skin lesions of sensitized children [200]. Only 20% of young children develop tolerance to peanuts, whereas the other most important allergies in childhood, towards milk, egg, wheat and soy are normally outgrown [199]. From the age of 2 years on, aeroallergens come to the fore. They may impair allergic asthma, rhinoconjunctivitis and AE and frequently show cross-reactivity between pollen and the profilins of food. The atopy patch test, positive in 30-50% of AE patients [201], together with food-challenges has been proven to be of value as a useful diagnostic tool to verify the clinical relevance of sensitizations. Still, the APT with foods is not well standardized, and different methods in preparing the test materials are likely to cause controversial results [202]. Moreover, specific IgE and APT with foods have been shown to be often false positive, resulting in low positive predictive values (64% and 45%, respectively) [160]. Therefore, prospective multicenter studies on the clinical use of the APT are needed and double blind placebo controlled food challenges have still to be regarded as the gold standard for diagnosis of food responsive eczema in AE patients [57, 160, 202]. However, the need for challenges has to be decided on an individual basis [57]. The degree of IgE sensitisation to aeroallergens directly correlates to the severity of AE [203]. HDM are top-ranking indoor allergens due to the high rate of sensitisation against them and their enzymatic properties. Allergen reduction is difficult due to the nearly ubiquitary exposure to HDM and also encasing strategies do not always lead to significant improvement of clinical symptoms. However, there is growing evidence that specific immunotherapy might represent an attractive therapeutic option for long-time treatment not only of sensitized patients with allergic rhinoconjunctivitis or asthma, but also for AE, especially for severe forms [204, 205].

IgE autoreactivity contributes to severity and chronification of AE

Molecular analyses have revealed a high resemblance of environmental allergens to human proteins. These findings have led to the assumption that autoimmunity directed against partly denatured peptide epitopes cross-reacting to exogenous allergens, might be of relevance for AE [206]. The development of IgE autoreactivity has been supposed to be based on chronic tissue damage of skin, lung and intestinum due to repeated exposure to allergens in sensitized persons. Atopy related autoantigens (ARA), including Hom s 1-5 and DSF 70 have been detected not only in target organs of atopy, but also in effector cells such as basophils, mast cells and T cells. Thus, organ- specific manifestations (e.g. AE) have been assumed to be impaired by the transport to and deposition of IgE-reactive autoantigen in the skin rather than from a preferential expression of the autoantigens in the affected tissues [207]. Moreover, specific IgE against the stress inducible enzyme manganese superoxide dismutase (MnSOD) correlating with disease activity has been found to induce T cell reactivity in vitro and eczematous reactions in APT in MnSOD-sensitized patients with AE. MnSOD cross-reacts to Malassezia sympodialis, a skin-colonizing yeast [208]. The high colonization with Malassezia sympodialis in AE with considerable sensitization rates has been known as an important trigger factor for AE [209]. AE patients displaying IgE autoreactivity have been observed to feature high total serum IgE levels with a large amount of sensitizations to food- and aeroallergens and first disease manifestation already during the age of one [210]. Moreover, levels of IgE autoantibodies are associated with severity of disease [206, 211] Hom s-4 has been shown to induce Th1 responses accompanied by the release of IFN-γ, a cytokine involved in epithelial damage and chronic stages of skin inflammation [212]. Thus, IgE autoreactivity has been supposed to start in early infancy [210] and to contribute to very severe, therapy-resistant and chronic courses of disease [56].

Pruritus and stress

The agonizing pruritus and cutaneous hyperreactivity to nonspecific stimuli are characteristic features of AE and generated by different pathomechanisms. Xerosis and skin inflammation cause the so-called pruritoceptive itch. Emotional stress triggers psychogenic itch. Stress has been shown to increase peripheral blood CD8+ T-lymphocytes, eosinophils [213], levels of IFN-γ, IL-5 and to decrease cortisol levels in AE patients [214]. This might be explained by a suppression of the hypothalamic-pituitary adrenal axis in response to mental stress [214]. Moreover, an altered response with increased numbers of CLA+ and CD8+ T lymphocytes and T cells expressing cytokines has been observed in AE patients with high total serum IgE [215]. An increased number and diameter of cutaneous nerve fibres has been shown in lesional AE skin [216, 217]. In addition, dermal contacts between mast cells and nerves are increased in AE skin compared with nonatopic controls, thus contributing to the maintenance of neurogenic inflammation through activation by substance P and CGRP [218]. Additionally to histamine, pruritus can be induced by several other mediators, such as neuromediators, prostaglandins, proteases, kinins and cytokines [219].

Neurotrophins and other neuromediators in AE

Neurotrophins are homologous growth factors which were initially discovered in the nervous system [220]. They play an important role in the proliferation, myelinisation, differentiation, survival and reconstruction of cutaneous nerve fibres. Neurotrophins can modulate afferent nerve function by stimulating the production of neuropeptides such as the tachykinin family substance P or neurokinin A and B [221]. These neuropeptides then modulate a wide range of functional responses of immune cells leading to activation and differentiation of these cells [222-224]. Neurotrophins can be produced by neurons, mast cells, T cells, B cells, endothelial cells, natural killer cells, macrophages, keratinocytes and epithelial cells [225]. The neurotrophin (NT) family in mammals includes NGF, brain-derived neurotrophic factor (BDNF) and the neurotrophins-3 (NT-3), -4 (NT-4) and -5 (NT-5) [225]. All neurotrophins bind with low affinity to the pan-neurotrophin receptor p75 (p75^NTR), a member of the TNF receptor/Fas/CD40 superfamily [224]. They also bind with high affinity and specificity to the tropomyosin-related kinase / tyrosine kinase (trk) family of receptors such as trkA for NGF, trkB for BDNF and NT-4, and trkC for NT-3 [226].

An increased expression of NGF and its receptors trkA and p75 NGFR has been found in AD lesions [227], in association with increased systemic plasma levels of NGF [228, 229], and substance P [229]. These levels correlated positively with AE disease activity [229]. Moreover, substance P has been shown to induce keratinocyte NGF production in vivo and in vitro [230]. Decreased levels of substance P [231, 232], but increased levels of substance P and calcitonine gene related peptide-positive nerve (CGRP) fibres [218] have been found in lesional skin.

An increased expression of NT-4 has been observed on keratinocytes of prurigo lesions of AE skin, most pronounced after IFN-γ injection [233]. Induction of NGF and NT-4 induced sensitization of nociceptors and neuronal hyperplasia, which might explain the increased innervation characteristic for these skin lesions [217]. Moreover, NGF enhanced the survival of peripheral blood eosinophils [234]. NGF also activates eosinophil functions through the release of eosinophil cytotoxic granule proteins and induction of eosinophil chemotaxis [235]. Interestingly, BDNF correlated positively to disease activity [236]. Increased levels of BDNF, playing a pivotal role in allergic asthma, have been observed in serum, plasma, eosinophils and supernatants of stimulated eosinophils from patients with AE [225]. BDNF has been shown to inhibit eosinophil apoptosis and to increase chemotaxis of eosinophils from patients with AE compared to nonatopic controls [225].

Though neurotrophins are physiologically important for the maintenance and regeneration of cutaneous nerves in the normal skin, their enhanced production in lesional AE skin and their function as inflammatory cytokines with promotion of mast cell and eosinophilic functions may amplificate the abnormal sensory innervation, pruritus and allergic inflammation in AE. In addition to neurotrophins, also other neuromediators, such as β-endorphin [237, 238], substance P [229], CGRP [218], vasoactive intestinal peptide (VIP) and acetylcholine [239] are supposed to play an important role in the induction and maintenance of pruritus.

Overexpression of IL-31 accounts for pruritus in AE

IL-31 is a novel cytokine preferentially expressed by Th2 cells with signals through a heterodimeric receptor composed of IL-31 receptor A and oncostatin M receptor. Overexpression of IL-31 has been shown to induce severe pruritus and dermatitis in transgenic mice [240]. Activated leukocytes of AE patients expressed increased levels of IL-31 compared to controls [195]. An upregulated IL-31 expression has been shown in pruritic AE skin lesions but also in non-lesional skin compared to nonpruritic psoriatic skin inflammation [195, 241]. In vivo and in vitro, staphylococcal enterotoxin B induced IL-31 expression in AE patients. In cultured keratinocytes, IL-31 induced the expression of the inflammatory chemokines CCL1, CCL17 and CCL22 important for monocyte, T cell and basophil recruitment into the skin [240]. IL-31 receptor A showed most abundant expression in dorsal root ganglia representing the site where the cell bodies of cutaneous sensory neurons reside [195]. These findings provide a new link between staphylococcal colonization, subsequent T cell recruitment and induction and activation of pruritus in patients with AE [195].

Conclusion

Taken together, the increasing knowledge of the genetics and pathophysiology of AE provide a better understanding of this chronic inflammatory disease and promise the development of new therapeutic options.

Acknowledgements

Natalija Novak is supported by a Heisenberg-Fellowship of the DFG NO454/3-1.

Conflict of interest: none.

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