REVIEW URRENT C OPINION
Recent developments in atopic dermatitis Wenming Peng and Natalija Novak
Purpose of review Research on atopic dermatitis is actively growing and continuously completing our knowledge on the pathophysiology of this complex disease. Recent findings Genome-wide association studies revealed new susceptibility loci for atopic dermatitis. In addition, different tissue-specific patterns of DNA methylation have been identified as first evidence for the relevance of epigenetic modifications in atopic dermatitis. Moreover, interest is emerging on the role of the skin and gut microbiome in atopic dermatitis. Signals mediated via pattern recognition receptors of the innate immune system have been analyzed in more detail, and the role of cytokines, such as IL-22, IL-25, IL-31 and IL-33 as well as innate lymphoid cells, has been studied. Summary Taken together, better knowledge of atopic dermatitis pathways will form the basis for the development of rationale-based therapeutic approaches in the future. Keywords atopic dermatitis, epigenetics, innate lymphoid cells, microbiome
INTRODUCTION Atopic dermatitis is a chronic inflammatory skin disease, which results from a mixture of genetic and environmental factors, leading to skin barrier dysfunction as well as dysregulation of immune responses. During recent years, our understanding of the pathogenesis of atopic dermatitis has improved. Genetic studies have identified important new atopic dermatitis-associated genes, which provide potential targets for diagnostic and therapeutic purpose. Growing immunological studies elucidated characteristics of the tissue microenvironment and connected it with immune responses, in which interaction of the skin barrier with the microbiome, signaling of new cytokines and chemokines and new types of immune cells have been discovered. On the basis of these findings, rationale-based therapeutic approaches are in development. We will discuss some recent new findings in this review.
NEW GENETICS AND EPIGENETICS STUDIES ON ATOPIC DERMATITIS Recently, a genome-wide association study and immunochip analysis, have identified a total of 19 loci to be associated with atopic dermatitis. Immunochip analysis has been performed on 2425 German individuals and 5449 controls and replication followed in 7196 cases and 15 480 controls. Single nucleotide polymorphisms within five
known loci 1q21.3 (Late cornified envelope 3A), 5q31.1 (IL-13, Kinesin family member 3A, Solute carrier family 22, member 4), 11q13.5 (Chromosome 11 open reading frame 30) and 20q13.33 [Tumor necrosis factor receptor superfamily member 6B (TNFRSF6B)] as well as within four new loci 4q27 (IL-2, IL-21), 11p13 (Proline rich 5 like), 16p13 (C-type lectin domain family 16) and 17q21.32 (TNFRSF6B) reached the genome-wide study threshold for association with atopic dermatitis [1 ]. In addition, in a genome-wide association study [2] conducted in a Japanese population of a total of 3328 patients with atopic dermatitis and 14 992 controls, 36 single nucleotide polymorphisms within three chromosomal regions, that is 2q12, 6p21 and 11p15.4 were significantly associated with atopic dermatitis. Chromosomal regions, identified in these two studies as candidate genes, imply modifications in epidermal barrier function as well as in innate and adaptive immunity in atopic dermatitis, in particular, &&
Department of Dermatology and Allergy, University of Bonn, Bonn, Germany Correspondence to Natalija Novak, MD, Department of Dermatology and Allergy, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany. Tel: +49 228 287 15370; fax: +49 228 287 14333; e-mail: [email protected] Curr Opin Allergy Clin Immunol 2014, 14:417–422 DOI:10.1097/ACI.0000000000000094
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KEY POINTS
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Novel atopic dermatitis-associated genes and epigenetic modifications reflect the complex genetic and epigenetic pathogenesis of atopic dermatitis. New immunological players in atopic dermatitis have been identified as ILCs, skin microbiome, as well as cytokines and chemokines beyond typical Th1 and Th2 cytokines. Growing knowledge about atopic dermatitis pathophysiology may help to develop new approaches for diagnostic and therapeutic purposes.
IL-1 family signaling, the vitamin D pathway, nerve growth factor pathway, chemokine receptor 4 pathway, suppressor of cytokine signaling 1, major histocompatibility complex class I and II and regulatory T cell pathways. So far, genetic studies have recently identified association of atopic dermatitis with genes with a potential link to the epithelial barrier function [3], regulatory receptors of immune cells [4], pattern recognition receptors responsible for sensing of the environment [5], molecules acting on Th2 cell homing [6], and signal molecules important for neonatal regulatory T cells [7]. Diversity of atopic dermatitisassociated genes identified in these studies mirrors the complex pathogenesis of atopic dermatitis. Factors other than the individual’s DNA sequence, which might be associated with diseaserelated changes, have been recognized as epigenetic alterations. First evidence for putative functionally relevant DNA methylation differences in the epidermis of atopic dermatitis patients came from a recent study. Inter-individual and intra-individual DNA methylation differences were analyzed with the help of a human methylation bead chip and calculated pairwise between lesional and nonlesional atopic dermatitis skin of the same individual and lesional skin of atopic dermatitis patients and normal skin of healthy volunteers. Correlated transcripts with significant differences between lesional atopic dermatitis skin and skin of healthy individuals mapped to S100A genes of the epidermal differentiation complex and genes encoding keratins in the keratin cluster [8 ]. These results suggest epigenetic modifications of keratinocyte function and structures of the epithelial tissue as well as epigenetic modification of mechanisms of danger signaling and host defence. &
FUNCTIONS OF INNATE LYMPHOID CELLS IN ATOPIC DERMATITIS Innate lymphoid cells (ILCs) are a group of newly identified heterogeneous immune cells that are 418
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essential for the development of inflammatory diseases [9]. Very recent studies [10 –12 ] suggest that ILCs might also play a role in the pathogenesis of atopic dermatitis. Salimi et al. [11 ] demonstrated presence of type 2 ILC2 in the skin of both human and mice. In human, Cluster of differentiation (CD)45þIL-7RaþChemoattractant receptor-homologous molecule expressed on Th2 cellsþILC2 expressed ILC2-specific transcription factors RARrelated orphan receptor a and GATA binding protein 3, although they did not express lineage markers, such as CD3, CD4, CD8, CD14, CD19, CD56, CD11c, CD11b, FceRI, T cell receptor gd heterodimer, T cell receptor ab heterodimer and CD123. After stimulation with allergen, ILC2 infiltrated the skin and produced IL-5 and IL-13. Furthermore, skin ILC2 produced high levels of IL-5, IL-6 and IL-13, but little IL-4 in response to IL-33 stimulation [13]. Moreover, ILC2 interacted with skin resident mast cells [14 ]. In addition, IL-33, a cytokine released by activated epithelial cells and degranulated mast cells, induced ILC2 migration [11 ]. A role of IL-33 or thymic stromal lymphopoietin (TSLP) in stimulation of human and murine ILC2 in atopic dermatitis [12 ] and infiltration of ILC2 in atopic dermatitis-like inflammatory skin was also confirmed in another transgenic mouse model [10 ]. Together, current studies suggest that ILC2 are important but not the only cellular players in atopic dermatitis. More knowledge about interaction of ILC2 with other cell types in the skin of atopic dermatitis has to be gained. &&
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IMPACT OF SKIN MICROBIOME ON ATOPIC DERMATITIS The skin and gut microrbiome came more and more into the center of interest. The composition of commensal organisms and pathogenic microbes on the skin and in the gut is supposed to play an important role in health and disease. Therefore, current research focuses on the interaction of resident microbes with the host and its impact on the physiological homeostasis as well as chronic diseases such as atopic dermatitis [13]. In the context of an intensive debate about the role of the skin barrier in atopic dermatitis, it came to our attention that not the mechanical skin barrier of the host, that is stratum corneum, but already the microbes residing on the host’s skin represent important components of the first line of the barrier. Consequently, better knowledge about the characteristics of the skin and gut microbiome in healthy individuals and patients with atopic dermatitis is essential to understand differences in their composition, to counteract microbiota with negative Volume 14 Number 5 October 2014
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effects and support microbiota with protective functions. In this regard, it has been observed in one recent study that birth mode, breast feeding and order of birth represent important factors with impact on the composition of the gut microbiome. Colonization with Lactobacilli and Bacteroides increased with the number of siblings, while colonization with Clostridia decreased. Clostridia colonization of the gut at early time points of life was linked to an increased risk of developing atopic dermatitis [14 ]. While the intestinal microbiome is most likely rather indirectly involved in the development of atopic dermatitis through interaction with the gut immune system, the skin microbiome could exert direct effects on the skin immune system [15]. High-throughput DNA sequencing of the bacterial 16S rRNA from lesional atopic dermatitis skin further revealed increased amounts of both skin commensal Staphylococcus epidermidis and S. aureus. Additionally, increased numbers of Streptococci, Propionbacteriae and Corynebacteriae species were detectable on the skin of atopic dermatitis patients after treatment [16]. Bacteriae have been regarded as promoters of tissue inflammation for a long time, although accumulating evidence suggests that microbiota may have regulatory functions in inflammatory skin. Lai et al. [17] demonstrated that staphylococcal lipoteichoic acid suppressed inflammation and inflammation initiated injury through a Toll-like receptor (TLR)2-dependent way. More recently, Yockey et al. [18] observed that loss of Notch signaling might lead to atopic dermatitis in a mouse model. As compared with normal controls, the mutant mice displayed elevated white blood cell counts and increased levels of TSLP in serum and skin. The study [18] demonstrated that removal of microbiota did not improve atopic dermatitis-like symptoms, which implies that microbiota might have immune regulatory functions. In line with this concept, Volz et al. [19 ] reported that extracts of Vitreoscilla filiformis, a nonpathogenic bacteria, suppressed cutaneous inflammation in an atopic dermatitis mouse model through IL-10 production in dendritic cells and priming of type 1 regulatory T cells. Although detailed information about how microbiota interacts with immune cells is still missing, these studies provide evidence that the microbiome might represent a novel target for therapeutic strategies. &&
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CYTOKINES BEYOND TH1 AND TH2 IN ATOPIC DERMATITIS Extrinsic (or allergic) type of atopic dermatitis is characterized by strong IgE-mediated allergic responses, whereas intrinsic (or nonallergic) type of atopic
dermatitis goes along with normal IgE levels and low ˜as et al. levels of Th2 cytokines. Recently, Sua´rez-Farin [20 ] compared types of immune responses in extrinsic and intrinsic atopic dermatitis. Higher mRNA levels of Th17 and Th22 cytokines were found in the lesional skin of intrinsic atopic dermatitis patients as compared with extrinsic atopic dermatitis patients. Interestingly, severity score of extrinsic atopic dermatitis patients correlated with the amount of Th2 cytokines IL-4 and IL-5 in the skin and negatively correlated with expression of barrier proteins such as loricrin, periplakin, and Filaggrin. The severity score of intrinsic atopic dermatitis patients correlated with the amount of Th1-related genes such as IL-1b and IFN-a as well as the IL-17related chemokine Chemokine (C-C motif) ligand 20, suggesting that different types of immune reactions exist in extrinsic and intrinsic atopic dermatitis [20 ]. Recently, it has been shown that IL-33 serum levels were enhanced in atopic dermatitis, correlated with severity of atopic dermatitis and significantly decreased after treatment [21], suggesting involvement of IL-33 in the pathophysiology of atopic dermatitis. The role of IL-17 in atopic dermatitis is still a matter of debate. Numbers of IL-17þ cells infiltrating the dermis of atopic dermatitis patients correlated with disease severity. In Filaggrin-deficient flaky tail (ft) mice (Flgft/ft mice), increased expression of IL-17, Th17-promoting cytokines IL-6 and IL-23 as well as the IL-17-inducible chemokine Chemokine (C-X-C motif) ligand 2 was observed in the atopic dermatitis mouse model [22]. IL-17deficient mice show suppressed Th2 type immune response in both a repeated hapten applicationinduced atopic dermatitis model and a flaky-tail (Flgft/ftma/ma) mouse model. Vg4þgd T cells in the draining Lymph nodes and Vg5 dermal gd T cells in the skin were identified as the major source of IL-17A [23]. The function of IL-17 in atopic dermatitis was further emphasized by a very recent study [24] which demonstrated that epidermal growth factor has protective functions in atopic dermatitis and alleviates atopic dermatitis symptoms by suppressing allergen-stimulated IL-6 and IL-17A production. Although significantly elevated gene expression of Th22 cytokines was observed in atopic dermatitis skin [25], the source of IL-22 in the atopic dermatitis skin is not clear. Teraki et al. [26] observed significantly higher numbers of circulating IL-22-producing CD4þ and CD8þ T cells in atopic dermatitis patients than in healthy controls. Furthermore, IL-13 or IL-22-coexpressing T cells were identified as the primary source of IL-22 in atopic dermatitis
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patients [26]. Because of its important functions in skin homeostasis and pathogenesis of skin diseases, IL-22 is also a potential target for treatment of atopic dermatitis. It has been shown that Cyclosporine treatment significantly improved clinical manifestation of atopic dermatitis patients by suppressing inflammation-related signaling pathways, including Th22 [27]. Because of the dominant Th2 responses, severe atopic dermatitis patients are prone to pathogen infection and develop recurrent bacterial and viral infection. Indeed, IL-25 is an important pro-Th2 cytokine and involved in local inflammation of the human gastrointestinal tract. The question of whether IL-25 contributes to Th2 responses and viral infections in atopic dermatitis skin is largely unanswered. Higher expression of IL-25 has been observed in the lesional skin of eczema herpeticum patients (ADEH) than in lesional skin of atopic dermatitis patients without any history of eczema herpeticum. Interestingly, IL-25 together with IL-4 and IL-13 enhances Herpes simplex virus type 1 replication through the mechanism that IL-25 inhibits filaggrin expression and reduces levels of filaggrin breakdown products to promote herpes simplex virus and vaccinia virus replication [28]. Additionally, increased levels of functional peripheral Treg (Regulatory T) cells and CD14dimCD16þ monocytes were detected in ADEH patients at the onset of eczema herpeticum. CD14dimCD16þ monocytes of ADEH patients displayed elevated potential to produce IL-10 and induced Treg cells, while they produced less proinflammatory cytokines. Therefore, increased levels of functional Tregs together with dysfunction of CD14dimCD16þ monocytes might be another reason for ADEH in a subgroup of patients [29].
INNATE AND ADAPTIVE IMMUNITY Pattern recognition receptors can help the immune system to sense and eliminate invading pathogens and therefore play essential roles in autoimmune and allergic diseases such as atopic dermatitis. In line with previous observations, monocytes and macrophages from atopic dermatitis patients might display modified expression of Toll-like receptor (TLR2) [30,31]. Kuo et al. [32 ] demonstrated that activation of TLR2 is necessary for normal skin barrier function in murine and human skin. Reduced epidermal TLR2 expression is involved in the dysfunction of the tight junction barrier of atopic dermatitis patients and might thereby contribute to chronic skin inflammation [32 ]. Activation of TLR4 by gram-negative bacteria initiates the Myeloid differentiation primary response gene &
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(88) and Toll–IL-1R domain-containing adapterinducing IFN-b-mediated signaling pathways. Brandt et al. [33] demonstrated that signaling through the TLR4 and toll–IL-1R domain-containing adapter-inducing IFN-b pathways alleviates skin barrier dysfunction, allergic sensitization and secretion of proinflammatory cytokines. Activation of the inflammasome suppresses TSLP expression and Th2 cell fate in the skin [34]. Roth et al. [35] demonstrated that S. aureus activates Nucleotide-binding oligomerization domain-containing protein 2 in keratinocytes, resulting in an increased expression of IL-17C. These studies provided evidence that other innate immune sensors apart from TLRs contribute to the development of atopic dermatitis by influencing skin barrier function, cytokine secretion and Th cell (T helper cell) fate. Cytokine signaling greatly modulates immune responses in atopic dermatitis. Impaired IFN-g signaling in epidermal Dendritic cells, monocytes and Monocyte-derived dendritic cells as well as impaired TGF-b signaling in monocytes from patients with atopic dermatitis [36,37] has been shown. Increased levels of Chemokine (C-X3-C motif) ligand 1Chemokine (C-X3-C motif) ligand 1 (CX3CL1) on endothelial cells, as well as elevated mRNA expression of its receptor, CX3C chemokine receptor (CX3CR)1, have been observed in human atopic dermatitis. Interestingly, either inhibition of CX3CR1 expression or blocking of CX3CL1–CX3CR1 interaction resulted in the alleviation of atopic dermatitis-like symptoms [38]. Moreover, both mast cells and antigen-presenting cells, such as monocytes of atopic dermatitis patients, express the high affinity receptor for IgE (FceRI). It was demonstrated that FceRI stimulation promotes the generation of Histamine H1 receptor (H1R)-expressing macrophage-like cells with enhanced histamine biosynthesis and H1R-mediated proinflammatory properties. In line with the in-vitro findings, high numbers of H1R-expressing CD68þ macrophages were detected in the dermis of atopic dermatitis skin lesions. The study [39 ] suggests a close histamine-mediated or Histamine receptor (HR)-mediated activation of dermal macrophages, leading to modified cell differentiation and responsiveness via H1R, which might contribute to the aggravation of allergic skin inflammation in atopic dermatitis. Fibroblasts are able to alter proliferation and differentiation of keratinocytes, but their role in atopic dermatitis is not yet fully understood. Berroth et al. [40] observed that fibroblasts from atopic dermatitis patients influenced the proliferation of keratinocytes and the terminal differentiation &
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process, resulting in an in-vivo-like morphology of atopic dermatitis. Subsequently, healthy fibroblasts were able to restore the structural deficits of atopic keratinocytes [40].
CONCLUSION To restore modified immune responses is essential for the treatment of atopic dermatitis. In this regard, it is important to understand how Th1/Th2/Th17/ Th22-type responses are regulated. On one hand, it is essential to identify stimulatory or regulatory functions of specific skin-residing immune cells such as dendritic cell subpopulations; on the other hand, it is also important to identify bacterial components with regulatory functions in atopic dermatitis for therapeutic purposes. Acknowledgements This work was supported by SFB 704 of Germany Research Council and BONFOR. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Ellinghaus D, Baurecht H, Esparza-Gordillo J, et al. High-density genotyping study identifies four new susceptibility loci for atopic dermatitis. Nat Genet 2013; 45:808–812. The study identified important new susceptibility loci for atopic dermatitis. 2. Hirota T, Takahashi A, Kubo M, et al. Genome-wide association study identifies eight new susceptibility loci for atopic dermatitis in the Japanese population. Nat Genet 2012; 44:1222–1226. 3. Margolis DJ, Kim B, Apter AJ, et al. Thymic stromal lymphopoietin variation, filaggrin loss of function, and the persistence of atopic dermatitis. JAMA Dermatol 2014; 150:254–259. 4. Niepiekło-Miniewska W, Majorczyk E, Matusiak L, et al. Protective effect of the KIR2DS1 gene in atopic dermatitis. Gene 2013; 527:594–600. 5. Bivik C, Verma D, Winge MC, et al. Genetic variation in the inflammasome and atopic dermatitis susceptibility. J Invest Dermatol 2013; 133:2486–2489. 6. Knight JM, Lee SH, Roberts L, et al. CD11a polymorphisms regulate TH2 cell homing and TH2-related disease. J Allergy Clin Immunol 2014; 133:189– 197. 7. Casaca VI, Illi S, Klucker E, et al. STAT6 polymorphisms are associated with neonatal regulatory T cells and cytokines and atopic diseases at 3 years. Allergy 2013; 68:1249–1258. 8. Rodrı´guez E, Baurecht H, Wahn AF, et al. An integrated epigenetic and & transcriptomic analysis reveals distinct tissue-specific patterns of DNA methylation associated with atopic dermatitis. J Invest Dermatol 2014; 134:1873– 1883. The study observed modified DNA methylation in the lesional epidermis of atopic dermatitis patients as comared with healthy control skin. 9. Spits H, Artis D, Colonna M, et al. Innate lymphoid cells: a proposal for uniform nomenclature. Nat Rev Immunol 2013; 13:145–149. 10. Imai Y, Yasuda K, Sakaguchi Y, et al. Skin-specific expression of IL-33 && activates group 2 innate lymphoid cells and elicits atopic dermatitis-like inflammation in mice. Proc Natl Acad Sci U S A 2013; 110:13921–13926. The study showed that transgenic mice selectively expressing IL-33 in the skin developed atopic dermatitis-like syndrome in which ILC2 were involved. 11. Salimi M, Barlow JL, Saunders SP, et al. A role for IL-25 and IL-33-driven type&& 2 innate lymphoid cells in atopic dermatitis. J Exp Med 2013; 210:2939– 2950. The study observed that human ILC2 infiltrates the skin after allergen challenge.
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12. Kim BS, Siracusa MC, Saenz SA, et al. TSLP elicits IL-33-independent innate lymphoid cell responses to promote skin inflammation. Sci Transl Med 2013; 5:170ra16. The study showed enrichment of ILC2 in the lesional skin of atopic dermatitis patients and demonstrated IL-25 and IL-33-independent activation of ILC2 in inflammatory skin. 13. Schommer NN, Gallo RL. Structure and function of the human skin microbiome. Trends Microbiol 2013; 21:660–668. 14. Penders J, Gerhold K, Stobberingh EE, et al. Establishment of the intestinal && microbiota and its role for atopic dermatitis in early childhood. J Allergy Clin Immunol 2013; 132:601–607. The study showed that intestinal microbiota plays a role in the development of atopic dermatitis. 15. Naik S, Bouladoux N, Wilhelm C, et al. Compartmentalized control of skin immunity by resident commensals. Science 2012; 337:1115–1119. 16. Kong HH, Oh J, Deming C, et al. Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis. Genome Res 2012; 22:850–859. 17. Lai Y, Di Nardo A, Nakatsuji T, et al. Commensal bacteria regulate Toll-like receptor 3-dependent inflammation after skin injury. Nat Med 2009; 15:1377–1382. 18. Yockey LJ, Demehri S, Turkoz M, et al. The absence of a microbiota enhances TSLP expression in mice with defective skin barrier but does not affect the severity of their allergic inflammation. J Invest Dermatol 2013; 133:2714– 2721. 19. Volz T, Skabytska Y, Guenova E, et al. Nonpathogenic bacteria alleviating && atopic dermatitis inflammation induce IL-10-producing dendritic cells and regulatory Tr1 cells. J Invest Dermatol 2014; 134:96–104. The study showed that nonpathogenic bacteria exert regulatory functions in atopic dermatitis. 20. Sua´rez-Farin˜as M, Dhingra N, Gittler J, et al. Intrinsic atopic dermatitis shows && similar TH2 and higher TH17 immune activation compared with extrinsic atopic dermatitis. J Allergy Clin Immunol 2013; 132:361–370. The study demonstrated that different types of immune responses exist in extrinsic and intrinsic atopic dermatitis patients pointing to a central role of T cell activation in both atopic dermatitis variants. 21. Tamagawa-Mineoka R, Okuzawa Y, Masuda K, et al. Increased serum levels of interleukin 33 in patients with atopic dermatitis. J Am Acad Dermatol 2014; 70:882–888. 22. Leisten S, Oyoshi MK, Galand C, et al. Development of skin lesions in filaggrin-deficient mice is dependent on adaptive immunity. J Allergy Clin Immunol 2013; 131:1247–1250. 23. Nakajima S, Kitoh A, Egawa G, et al. IL-17A as an inducer for Th2 immune responses in murine atopic dermatitis models. J Invest Dermatol 2014; 51. [Epub ahead of print] 24. Zhang Z, Xiao C, Gibson AM, et al. EGFR signaling blunts allergen-induced IL-6 production and Th17 responses in the skin and attenuates development and relapse of atopic dermatitis. J Immunol 2014; 192:859–866. 25. Gittler JK, Shemer A, Sua´rez-Farin˜as M, et al. Progressive activation of T(H)2/ T(H)22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis. J Allergy Clin Immunol 2012; 130:1344–1354. 26. Teraki Y, Sakurai A, Izaki S. IL-13/IL-22-coproducing T cells, a novel subset, are increased in atopic dermatitis. J Allergy Clin Immunol 2013; 132:971– 974. 27. Khattri S, Shemer A, Rozenblit M, et al. Cyclosporine in patients with atopic dermatitis modulates activated inflammatory pathways and reverses epidermal pathology. J Allergy Clin Immunol 2014; 133:1626–1634. 28. Kim BE, Bin L, Ye YM, et al. IL-25 enhances HSV-1 replication by inhibiting filaggrin expression, and acts synergistically with Th2 cytokines to enhance HSV-1 replication. J Invest Dermatol 2013; 133:2678–2685. 29. Takahashi R, Sato Y, Kurata M, et al. Pathological role of regulatory T cells in the initiation and maintenance of eczema herpeticum lesions. J Immunol 2014; 192:969–978. 30. Hasannejad H, Takahashi R, Kimishima M, et al. Selective impairment of Tolllike receptor 2-mediated proinflammatory cytokine production by monocytes from patients with atopic dermatitis. J Allergy Clin Immunol 2007; 120:69– 75. 31. Niebuhr M, Lutat C, Sigel S, et al. Impaired TLR-2 expression and TLR-2mediated cytokine secretion in macrophages from patients with atopic dermatitis. Allergy 2009; 64:1580–1587. 32. Kuo IH, Carpenter-Mendini A, Yoshida T, et al. Activation of epidermal toll-like & receptor 2 enhances tight junction function: implications for atopic dermatitis and skin barrier repair. J Invest Dermatol 2013; 133:988–998. The study demonstrated that TLR2 signaling is required for the normal skin barrier function that might be impaired because of the decreased expression of epidermal TLR2 in atopic dermatitis patients. 33. Brandt EB, Gibson AM, Bass S, et al. Exacerbation of allergen-induced eczema in TLR4- and TRIF-deficient mice. J Immunol 2013; 191:3519–3525. 34. Schuepbach-Mallepell S, Philippe V, Bru¨ggen MC, et al. Antagonistic effect of the inflammasome on thymic stromal lymphopoietin expression in the skin. J Allergy Clin Immunol 2013; 132:1348–1357. 35. Roth SA, Simanski M, Rademacher F, et al. The pattern recognition receptor NOD2 mediates Staphylococcus aureus-induced IL-17C expression in keratinocytes. J Invest Dermatol 2014; 134:374–380. &&
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Skin allergy 36. Gros E, Petzold S, Maintz L, et al. Reduced IFN-g receptor expression and attenuated IFN-g response by dendritic cells in patients with atopic dermatitis. J Allergy Clin Immunol 2011; 128:1015–1021. 37. Peng WM, Maintz L, Allam JP, et al. Attenuated TGF-b1 responsiveness of dendritic cells and their precursors in atopic dermatitis. Eur J Immunol 2013; 43:1374–1382. 38. Staumont-Salle´ D, Fleury S, Lazzari A. CX3CL1 (fractalkine) and its receptor CX3CR1 regulate atopic dermatitis by controlling effector T cell retention in inflamed skin. J Exp Med 2014; 211:1185–1196.
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39. Novak N, Peng WM, Bieber T, et al. FceRI stimulation promotes the differentiation of histamine receptor 1-expressing inflammatory macrophages. Allergy 2013; 68:454–461. The study showed that FceRI stimulation promoted the generation of H1Rexpressing macrophage-like cells with enhanced histamine biosynthesis and H1R-mediated proinflammatory properties, suggesting a close histaminemediated or HR-mediated activation of dermal macrophages. 40. Berroth A, Ku¨hnl J, Kurschat N, et al. Role of fibroblasts in the pathogenesis of atopic dermatitis. J Allergy Clin Immunol 2013; 131:1547–1554.
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Recent developments in atopic dermatitis Wenming Peng and Natalija Novak
Purpose of review Research on atopic dermatitis is actively growing and continuously completing our knowledge on the pathophysiology of this complex disease. Recent findings Genome-wide association studies revealed new susceptibility loci for atopic dermatitis. In addition, different tissue-specific patterns of DNA methylation have been identified as first evidence for the relevance of epigenetic modifications in atopic dermatitis. Moreover, interest is emerging on the role of the skin and gut microbiome in atopic dermatitis. Signals mediated via pattern recognition receptors of the innate immune system have been analyzed in more detail, and the role of cytokines, such as IL-22, IL-25, IL-31 and IL-33 as well as innate lymphoid cells, has been studied. Summary Taken together, better knowledge of atopic dermatitis pathways will form the basis for the development of rationale-based therapeutic approaches in the future. Keywords atopic dermatitis, epigenetics, innate lymphoid cells, microbiome
INTRODUCTION Atopic dermatitis is a chronic inflammatory skin disease, which results from a mixture of genetic and environmental factors, leading to skin barrier dysfunction as well as dysregulation of immune responses. During recent years, our understanding of the pathogenesis of atopic dermatitis has improved. Genetic studies have identified important new atopic dermatitis-associated genes, which provide potential targets for diagnostic and therapeutic purpose. Growing immunological studies elucidated characteristics of the tissue microenvironment and connected it with immune responses, in which interaction of the skin barrier with the microbiome, signaling of new cytokines and chemokines and new types of immune cells have been discovered. On the basis of these findings, rationale-based therapeutic approaches are in development. We will discuss some recent new findings in this review.
NEW GENETICS AND EPIGENETICS STUDIES ON ATOPIC DERMATITIS Recently, a genome-wide association study and immunochip analysis, have identified a total of 19 loci to be associated with atopic dermatitis. Immunochip analysis has been performed on 2425 German individuals and 5449 controls and replication followed in 7196 cases and 15 480 controls. Single nucleotide polymorphisms within five
known loci 1q21.3 (Late cornified envelope 3A), 5q31.1 (IL-13, Kinesin family member 3A, Solute carrier family 22, member 4), 11q13.5 (Chromosome 11 open reading frame 30) and 20q13.33 [Tumor necrosis factor receptor superfamily member 6B (TNFRSF6B)] as well as within four new loci 4q27 (IL-2, IL-21), 11p13 (Proline rich 5 like), 16p13 (C-type lectin domain family 16) and 17q21.32 (TNFRSF6B) reached the genome-wide study threshold for association with atopic dermatitis [1 ]. In addition, in a genome-wide association study [2] conducted in a Japanese population of a total of 3328 patients with atopic dermatitis and 14 992 controls, 36 single nucleotide polymorphisms within three chromosomal regions, that is 2q12, 6p21 and 11p15.4 were significantly associated with atopic dermatitis. Chromosomal regions, identified in these two studies as candidate genes, imply modifications in epidermal barrier function as well as in innate and adaptive immunity in atopic dermatitis, in particular, &&
Department of Dermatology and Allergy, University of Bonn, Bonn, Germany Correspondence to Natalija Novak, MD, Department of Dermatology and Allergy, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany. Tel: +49 228 287 15370; fax: +49 228 287 14333; e-mail: [email protected] Curr Opin Allergy Clin Immunol 2014, 14:417–422 DOI:10.1097/ACI.0000000000000094
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KEY POINTS
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Novel atopic dermatitis-associated genes and epigenetic modifications reflect the complex genetic and epigenetic pathogenesis of atopic dermatitis. New immunological players in atopic dermatitis have been identified as ILCs, skin microbiome, as well as cytokines and chemokines beyond typical Th1 and Th2 cytokines. Growing knowledge about atopic dermatitis pathophysiology may help to develop new approaches for diagnostic and therapeutic purposes.
IL-1 family signaling, the vitamin D pathway, nerve growth factor pathway, chemokine receptor 4 pathway, suppressor of cytokine signaling 1, major histocompatibility complex class I and II and regulatory T cell pathways. So far, genetic studies have recently identified association of atopic dermatitis with genes with a potential link to the epithelial barrier function [3], regulatory receptors of immune cells [4], pattern recognition receptors responsible for sensing of the environment [5], molecules acting on Th2 cell homing [6], and signal molecules important for neonatal regulatory T cells [7]. Diversity of atopic dermatitisassociated genes identified in these studies mirrors the complex pathogenesis of atopic dermatitis. Factors other than the individual’s DNA sequence, which might be associated with diseaserelated changes, have been recognized as epigenetic alterations. First evidence for putative functionally relevant DNA methylation differences in the epidermis of atopic dermatitis patients came from a recent study. Inter-individual and intra-individual DNA methylation differences were analyzed with the help of a human methylation bead chip and calculated pairwise between lesional and nonlesional atopic dermatitis skin of the same individual and lesional skin of atopic dermatitis patients and normal skin of healthy volunteers. Correlated transcripts with significant differences between lesional atopic dermatitis skin and skin of healthy individuals mapped to S100A genes of the epidermal differentiation complex and genes encoding keratins in the keratin cluster [8 ]. These results suggest epigenetic modifications of keratinocyte function and structures of the epithelial tissue as well as epigenetic modification of mechanisms of danger signaling and host defence. &
FUNCTIONS OF INNATE LYMPHOID CELLS IN ATOPIC DERMATITIS Innate lymphoid cells (ILCs) are a group of newly identified heterogeneous immune cells that are 418
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essential for the development of inflammatory diseases [9]. Very recent studies [10 –12 ] suggest that ILCs might also play a role in the pathogenesis of atopic dermatitis. Salimi et al. [11 ] demonstrated presence of type 2 ILC2 in the skin of both human and mice. In human, Cluster of differentiation (CD)45þIL-7RaþChemoattractant receptor-homologous molecule expressed on Th2 cellsþILC2 expressed ILC2-specific transcription factors RARrelated orphan receptor a and GATA binding protein 3, although they did not express lineage markers, such as CD3, CD4, CD8, CD14, CD19, CD56, CD11c, CD11b, FceRI, T cell receptor gd heterodimer, T cell receptor ab heterodimer and CD123. After stimulation with allergen, ILC2 infiltrated the skin and produced IL-5 and IL-13. Furthermore, skin ILC2 produced high levels of IL-5, IL-6 and IL-13, but little IL-4 in response to IL-33 stimulation [13]. Moreover, ILC2 interacted with skin resident mast cells [14 ]. In addition, IL-33, a cytokine released by activated epithelial cells and degranulated mast cells, induced ILC2 migration [11 ]. A role of IL-33 or thymic stromal lymphopoietin (TSLP) in stimulation of human and murine ILC2 in atopic dermatitis [12 ] and infiltration of ILC2 in atopic dermatitis-like inflammatory skin was also confirmed in another transgenic mouse model [10 ]. Together, current studies suggest that ILC2 are important but not the only cellular players in atopic dermatitis. More knowledge about interaction of ILC2 with other cell types in the skin of atopic dermatitis has to be gained. &&
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IMPACT OF SKIN MICROBIOME ON ATOPIC DERMATITIS The skin and gut microrbiome came more and more into the center of interest. The composition of commensal organisms and pathogenic microbes on the skin and in the gut is supposed to play an important role in health and disease. Therefore, current research focuses on the interaction of resident microbes with the host and its impact on the physiological homeostasis as well as chronic diseases such as atopic dermatitis [13]. In the context of an intensive debate about the role of the skin barrier in atopic dermatitis, it came to our attention that not the mechanical skin barrier of the host, that is stratum corneum, but already the microbes residing on the host’s skin represent important components of the first line of the barrier. Consequently, better knowledge about the characteristics of the skin and gut microbiome in healthy individuals and patients with atopic dermatitis is essential to understand differences in their composition, to counteract microbiota with negative Volume 14 Number 5 October 2014
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effects and support microbiota with protective functions. In this regard, it has been observed in one recent study that birth mode, breast feeding and order of birth represent important factors with impact on the composition of the gut microbiome. Colonization with Lactobacilli and Bacteroides increased with the number of siblings, while colonization with Clostridia decreased. Clostridia colonization of the gut at early time points of life was linked to an increased risk of developing atopic dermatitis [14 ]. While the intestinal microbiome is most likely rather indirectly involved in the development of atopic dermatitis through interaction with the gut immune system, the skin microbiome could exert direct effects on the skin immune system [15]. High-throughput DNA sequencing of the bacterial 16S rRNA from lesional atopic dermatitis skin further revealed increased amounts of both skin commensal Staphylococcus epidermidis and S. aureus. Additionally, increased numbers of Streptococci, Propionbacteriae and Corynebacteriae species were detectable on the skin of atopic dermatitis patients after treatment [16]. Bacteriae have been regarded as promoters of tissue inflammation for a long time, although accumulating evidence suggests that microbiota may have regulatory functions in inflammatory skin. Lai et al. [17] demonstrated that staphylococcal lipoteichoic acid suppressed inflammation and inflammation initiated injury through a Toll-like receptor (TLR)2-dependent way. More recently, Yockey et al. [18] observed that loss of Notch signaling might lead to atopic dermatitis in a mouse model. As compared with normal controls, the mutant mice displayed elevated white blood cell counts and increased levels of TSLP in serum and skin. The study [18] demonstrated that removal of microbiota did not improve atopic dermatitis-like symptoms, which implies that microbiota might have immune regulatory functions. In line with this concept, Volz et al. [19 ] reported that extracts of Vitreoscilla filiformis, a nonpathogenic bacteria, suppressed cutaneous inflammation in an atopic dermatitis mouse model through IL-10 production in dendritic cells and priming of type 1 regulatory T cells. Although detailed information about how microbiota interacts with immune cells is still missing, these studies provide evidence that the microbiome might represent a novel target for therapeutic strategies. &&
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CYTOKINES BEYOND TH1 AND TH2 IN ATOPIC DERMATITIS Extrinsic (or allergic) type of atopic dermatitis is characterized by strong IgE-mediated allergic responses, whereas intrinsic (or nonallergic) type of atopic
dermatitis goes along with normal IgE levels and low ˜as et al. levels of Th2 cytokines. Recently, Sua´rez-Farin [20 ] compared types of immune responses in extrinsic and intrinsic atopic dermatitis. Higher mRNA levels of Th17 and Th22 cytokines were found in the lesional skin of intrinsic atopic dermatitis patients as compared with extrinsic atopic dermatitis patients. Interestingly, severity score of extrinsic atopic dermatitis patients correlated with the amount of Th2 cytokines IL-4 and IL-5 in the skin and negatively correlated with expression of barrier proteins such as loricrin, periplakin, and Filaggrin. The severity score of intrinsic atopic dermatitis patients correlated with the amount of Th1-related genes such as IL-1b and IFN-a as well as the IL-17related chemokine Chemokine (C-C motif) ligand 20, suggesting that different types of immune reactions exist in extrinsic and intrinsic atopic dermatitis [20 ]. Recently, it has been shown that IL-33 serum levels were enhanced in atopic dermatitis, correlated with severity of atopic dermatitis and significantly decreased after treatment [21], suggesting involvement of IL-33 in the pathophysiology of atopic dermatitis. The role of IL-17 in atopic dermatitis is still a matter of debate. Numbers of IL-17þ cells infiltrating the dermis of atopic dermatitis patients correlated with disease severity. In Filaggrin-deficient flaky tail (ft) mice (Flgft/ft mice), increased expression of IL-17, Th17-promoting cytokines IL-6 and IL-23 as well as the IL-17-inducible chemokine Chemokine (C-X-C motif) ligand 2 was observed in the atopic dermatitis mouse model [22]. IL-17deficient mice show suppressed Th2 type immune response in both a repeated hapten applicationinduced atopic dermatitis model and a flaky-tail (Flgft/ftma/ma) mouse model. Vg4þgd T cells in the draining Lymph nodes and Vg5 dermal gd T cells in the skin were identified as the major source of IL-17A [23]. The function of IL-17 in atopic dermatitis was further emphasized by a very recent study [24] which demonstrated that epidermal growth factor has protective functions in atopic dermatitis and alleviates atopic dermatitis symptoms by suppressing allergen-stimulated IL-6 and IL-17A production. Although significantly elevated gene expression of Th22 cytokines was observed in atopic dermatitis skin [25], the source of IL-22 in the atopic dermatitis skin is not clear. Teraki et al. [26] observed significantly higher numbers of circulating IL-22-producing CD4þ and CD8þ T cells in atopic dermatitis patients than in healthy controls. Furthermore, IL-13 or IL-22-coexpressing T cells were identified as the primary source of IL-22 in atopic dermatitis
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patients [26]. Because of its important functions in skin homeostasis and pathogenesis of skin diseases, IL-22 is also a potential target for treatment of atopic dermatitis. It has been shown that Cyclosporine treatment significantly improved clinical manifestation of atopic dermatitis patients by suppressing inflammation-related signaling pathways, including Th22 [27]. Because of the dominant Th2 responses, severe atopic dermatitis patients are prone to pathogen infection and develop recurrent bacterial and viral infection. Indeed, IL-25 is an important pro-Th2 cytokine and involved in local inflammation of the human gastrointestinal tract. The question of whether IL-25 contributes to Th2 responses and viral infections in atopic dermatitis skin is largely unanswered. Higher expression of IL-25 has been observed in the lesional skin of eczema herpeticum patients (ADEH) than in lesional skin of atopic dermatitis patients without any history of eczema herpeticum. Interestingly, IL-25 together with IL-4 and IL-13 enhances Herpes simplex virus type 1 replication through the mechanism that IL-25 inhibits filaggrin expression and reduces levels of filaggrin breakdown products to promote herpes simplex virus and vaccinia virus replication [28]. Additionally, increased levels of functional peripheral Treg (Regulatory T) cells and CD14dimCD16þ monocytes were detected in ADEH patients at the onset of eczema herpeticum. CD14dimCD16þ monocytes of ADEH patients displayed elevated potential to produce IL-10 and induced Treg cells, while they produced less proinflammatory cytokines. Therefore, increased levels of functional Tregs together with dysfunction of CD14dimCD16þ monocytes might be another reason for ADEH in a subgroup of patients [29].
INNATE AND ADAPTIVE IMMUNITY Pattern recognition receptors can help the immune system to sense and eliminate invading pathogens and therefore play essential roles in autoimmune and allergic diseases such as atopic dermatitis. In line with previous observations, monocytes and macrophages from atopic dermatitis patients might display modified expression of Toll-like receptor (TLR2) [30,31]. Kuo et al. [32 ] demonstrated that activation of TLR2 is necessary for normal skin barrier function in murine and human skin. Reduced epidermal TLR2 expression is involved in the dysfunction of the tight junction barrier of atopic dermatitis patients and might thereby contribute to chronic skin inflammation [32 ]. Activation of TLR4 by gram-negative bacteria initiates the Myeloid differentiation primary response gene &
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(88) and Toll–IL-1R domain-containing adapterinducing IFN-b-mediated signaling pathways. Brandt et al. [33] demonstrated that signaling through the TLR4 and toll–IL-1R domain-containing adapter-inducing IFN-b pathways alleviates skin barrier dysfunction, allergic sensitization and secretion of proinflammatory cytokines. Activation of the inflammasome suppresses TSLP expression and Th2 cell fate in the skin [34]. Roth et al. [35] demonstrated that S. aureus activates Nucleotide-binding oligomerization domain-containing protein 2 in keratinocytes, resulting in an increased expression of IL-17C. These studies provided evidence that other innate immune sensors apart from TLRs contribute to the development of atopic dermatitis by influencing skin barrier function, cytokine secretion and Th cell (T helper cell) fate. Cytokine signaling greatly modulates immune responses in atopic dermatitis. Impaired IFN-g signaling in epidermal Dendritic cells, monocytes and Monocyte-derived dendritic cells as well as impaired TGF-b signaling in monocytes from patients with atopic dermatitis [36,37] has been shown. Increased levels of Chemokine (C-X3-C motif) ligand 1Chemokine (C-X3-C motif) ligand 1 (CX3CL1) on endothelial cells, as well as elevated mRNA expression of its receptor, CX3C chemokine receptor (CX3CR)1, have been observed in human atopic dermatitis. Interestingly, either inhibition of CX3CR1 expression or blocking of CX3CL1–CX3CR1 interaction resulted in the alleviation of atopic dermatitis-like symptoms [38]. Moreover, both mast cells and antigen-presenting cells, such as monocytes of atopic dermatitis patients, express the high affinity receptor for IgE (FceRI). It was demonstrated that FceRI stimulation promotes the generation of Histamine H1 receptor (H1R)-expressing macrophage-like cells with enhanced histamine biosynthesis and H1R-mediated proinflammatory properties. In line with the in-vitro findings, high numbers of H1R-expressing CD68þ macrophages were detected in the dermis of atopic dermatitis skin lesions. The study [39 ] suggests a close histamine-mediated or Histamine receptor (HR)-mediated activation of dermal macrophages, leading to modified cell differentiation and responsiveness via H1R, which might contribute to the aggravation of allergic skin inflammation in atopic dermatitis. Fibroblasts are able to alter proliferation and differentiation of keratinocytes, but their role in atopic dermatitis is not yet fully understood. Berroth et al. [40] observed that fibroblasts from atopic dermatitis patients influenced the proliferation of keratinocytes and the terminal differentiation &
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process, resulting in an in-vivo-like morphology of atopic dermatitis. Subsequently, healthy fibroblasts were able to restore the structural deficits of atopic keratinocytes [40].
CONCLUSION To restore modified immune responses is essential for the treatment of atopic dermatitis. In this regard, it is important to understand how Th1/Th2/Th17/ Th22-type responses are regulated. On one hand, it is essential to identify stimulatory or regulatory functions of specific skin-residing immune cells such as dendritic cell subpopulations; on the other hand, it is also important to identify bacterial components with regulatory functions in atopic dermatitis for therapeutic purposes. Acknowledgements This work was supported by SFB 704 of Germany Research Council and BONFOR. Conflicts of interest There are no conflicts of interest.
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J Invest Dermatol 2013; 133:2678–2685. 29. Takahashi R, Sato Y, Kurata M, et al. Pathological role of regulatory T cells in the initiation and maintenance of eczema herpeticum lesions. J Immunol 2014; 192:969–978. 30. Hasannejad H, Takahashi R, Kimishima M, et al. Selective impairment of Tolllike receptor 2-mediated proinflammatory cytokine production by monocytes from patients with atopic dermatitis. J Allergy Clin Immunol 2007; 120:69– 75. 31. Niebuhr M, Lutat C, Sigel S, et al. Impaired TLR-2 expression and TLR-2mediated cytokine secretion in macrophages from patients with atopic dermatitis. Allergy 2009; 64:1580–1587. 32. Kuo IH, Carpenter-Mendini A, Yoshida T, et al. Activation of epidermal toll-like & receptor 2 enhances tight junction function: implications for atopic dermatitis and skin barrier repair. J Invest Dermatol 2013; 133:988–998. The study demonstrated that TLR2 signaling is required for the normal skin barrier function that might be impaired because of the decreased expression of epidermal TLR2 in atopic dermatitis patients. 33. Brandt EB, Gibson AM, Bass S, et al. Exacerbation of allergen-induced eczema in TLR4- and TRIF-deficient mice. J Immunol 2013; 191:3519–3525. 34. Schuepbach-Mallepell S, Philippe V, Bru¨ggen MC, et al. Antagonistic effect of the inflammasome on thymic stromal lymphopoietin expression in the skin. J Allergy Clin Immunol 2013; 132:1348–1357. 35. Roth SA, Simanski M, Rademacher F, et al. The pattern recognition receptor NOD2 mediates Staphylococcus aureus-induced IL-17C expression in keratinocytes. J Invest Dermatol 2014; 134:374–380. &&
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Skin allergy 36. Gros E, Petzold S, Maintz L, et al. Reduced IFN-g receptor expression and attenuated IFN-g response by dendritic cells in patients with atopic dermatitis. J Allergy Clin Immunol 2011; 128:1015–1021. 37. Peng WM, Maintz L, Allam JP, et al. Attenuated TGF-b1 responsiveness of dendritic cells and their precursors in atopic dermatitis. Eur J Immunol 2013; 43:1374–1382. 38. Staumont-Salle´ D, Fleury S, Lazzari A. CX3CL1 (fractalkine) and its receptor CX3CR1 regulate atopic dermatitis by controlling effector T cell retention in inflamed skin. J Exp Med 2014; 211:1185–1196.
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39. Novak N, Peng WM, Bieber T, et al. FceRI stimulation promotes the differentiation of histamine receptor 1-expressing inflammatory macrophages. Allergy 2013; 68:454–461. The study showed that FceRI stimulation promoted the generation of H1Rexpressing macrophage-like cells with enhanced histamine biosynthesis and H1R-mediated proinflammatory properties, suggesting a close histaminemediated or HR-mediated activation of dermal macrophages. 40. Berroth A, Ku¨hnl J, Kurschat N, et al. Role of fibroblasts in the pathogenesis of atopic dermatitis. J Allergy Clin Immunol 2013; 131:1547–1554.
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