Aair 10 207 PDF
Aair 10 207 PDF
Aair 10 207 PDF
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits
unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
The epidermis contains epithelial cells, immune cells, and microbes which provides a physical and functional barrier to the protection of human skin.
It plays critical roles in preventing environmental allergen penetration into the human body and responsing to microbial pathogens. Atopic dermati-
tis (AD) is the most common, complex chronic inflammatory skin disease. Skin barrier dysfunction is the initial step in the development of AD. Multi-
ple factors, including immune dysregulation, filaggrin mutations, deficiency of antimicrobial peptides, and skin dysbiosis contribute to skin barrier
defects. In the initial phase of AD, treatment with moisturizers improves skin barrier function and prevents the development of AD. With the pro-
gression of AD, effective topical and systemic therapies are needed to reduce immune pathway activation and general inflammation. Targeted mi-
crobiome therapy is also being developed to correct skin dysbiosis associated with AD. Improved identification and characterization of AD pheno-
types and endotypes are required to optimize the precision medicine approach to AD.
Key Words: Atopic dermatitis; epidermal barrier; antimicrobial peptide; microbiome; moisturizer
© Copyright The Korean Academy of Asthma, Allergy and Clinical Immunology • The Korean Academy of Pediatric Allergy and Respiratory Disease http://e-aair.org 207
Kim et al. Volume 10, Number 3, May 2018
Fig. 1. Impaired skin barrier enhances allergen penetration and activates the innate immune system. Multiple factors, including immune dysregulation, defects in
terminal epithelial differentiation such as lack of filaggrin (FLG), deficiency of antimicrobial peptides (AMPs), altered composition of stratum corneum intercellular
lipids, and altered skin microbiome cause skin barrier defects. Source: Czarnowicki et al. J Allergy Clin Immunol 2017;139:1723-34.
ly, and each process is characterized by the expression specific function in AD.36 HBD-3 improves the function of the epithelial
proteins, including occludin, claudins, keratins, transglutamin- TJ barrier by inducing expression of several claudins.34 HBDs
ases (TGs), loricrin, and FLG.22,23,26,27 Keratinocytes express spe- and LL-37 also induce production of IL-18 through p38 and Erk
cific differentiation markers according to their stage of epider- mitogen-activated protein kinase activation in human kerati-
mal differentiation.22 For instance, keratin 5 and TG2, which are nocytes.37 Additionally, they induce expression of IL-6, IL-10,
expressed in the basal layer, represent early differentiation macrophage inflammatory protein-3 alpha, and RANTES.38
markers. In contrast, FLG, which is expressed in the upper Furthermore, it has been reported that HBDs and LL-37 induce
granular and cornified layers, is a late differentiation marker. keratinocyte migration, proliferation, re-epithelialization, neo-
Tight junctions (TJs), desmosomes, and adherens junctions are vascularization, and wound healing.31,35,38,39
paracellular proteins that form a permeability barrier between The cornified layer is surrounded by a continuous lipid matrix
adjacent cells and involve cell adhesion.26-29 which provides a barrier against water and prevent water
Keratinocytes also produce AMPs including cathelicidin (LL- loss.24,40,41 The lipid matrix mainly consists of 3 lipid classes:
37) and beta-defensins (HBDs), which kill microbes and play cholesterol, free fatty acids, and ceramides.23,42 Therefore, the
important roles in maintaining skin homeostasis.30,31 In addi- lipid matrix in the cornified layer may play crucial roles as a
tion to their antibacterial activity, AMPs kill viruses and fungi part of skin barrier and shows altered composition in AD skin.
through multiple modes of action.31 The levels of AMPs, such as It has also recently been reported that the epidermal microbi-
HBDs and LL-37 in epidermis, are low in normal health condi- ome may also play crucial roles in maintaining skin barrier
tions, but are highly expressed upon infection and inflamma- function.4,16,43 Previously, the biogeography of the skin microbi-
tion.31,32 AMPs form an innate epithelial chemical barrier and ome has been reported in children and adults.44,45 Several stud-
have pleiotropic functions.31,33 They not only kill microbes, but ies have shown that human skin microbiome is site-specific.44-46
also control inflammation and regulate the skin barrier.31,34,35 Recently, it has been reported that the gut and cutaneous com-
Impaired TJ protein expression contributes to skin barrier dys- mensal bacteria, including Staphylococcus (S.) epidermidis, and
208
http://e-aair.org Allergy Asthma Immunol Res. 2018 May;10(3):207-215. https://doi.org/10.4168/aair.2018.10.3.207
AAIR The Significance of Skin Barrier Dysfunction
S. hominis, play important roles in skin homeostasis and host not sufficient to generate AD. There are other factors that result
defense against microbial penetration.47-50 in AD development. Intercellular proteins, including TJs, des-
mosomes, and adherens junctions, form a permeability barrier
Dysregulation of the skin barrier in AD between adjacent cells and aids with cell adhesion.26-29 Th2 cy-
Epidermal barrier proteins, including FLG, TGs, keratins, lo- tokines down-regulate TJs, and impaired TJs contribute to ab-
ricrin and intercellular proteins, are cross-linked to form an im- normal skin barrier function in AD.36,75 Corneodesmosin
permeable skin barrier.22,23 Skin barrier defects facilitate aller- (CDSN) is an intercellular protein that plays a critical role in
gen sensitization and lead to systemic allergic responses, such maintaining skin barrier function.29,76 Recently, Lee et al.77 have
as increased IgE levels and airway hyperreactivity.36,51-53 Tran- reported that CDSN expression is down-regulated by cytokines,
sepidermal water loss (TEWL) is a noninvasive measurement including IL-4, IL-13, IL-22, IL-25, and IL-31. Additionally,
used to evaluate skin barrier function.54 Patients with AD have CDSN deficiency resulted in lethal-skin barrier disruption in a
increased TEWL, which reflects skin barrier dysfunction in AD, mouse model,76 and enhanced viral penetration in an organo-
and can precede clinical AD.55,56 typic skin model.77 Therefore, a variety of cytokines modulate
AD skin is characterized by overexpression of Th2 and Th22 epidermal barrier proteins, and cause skin barrier defects.
cytokines that contribute to skin barrier dysfunction by altering AMPs, such as LL-37 and HBD-3, are highly expressed by ke-
protein and lipid content in the skin (Table 1).2,4,57,58 FLG is a key ratinocytes during infection, inflammation, and wounding.30,31
epidermal barrier protein.22,59 It is degraded into free amino ac- AMPs form an innate multidimensional epithelial chemical
ids and these amino acids are essential for maintaining skin pH barrier.31,33 They not only have antimicrobial activities, but also
and the retention of water contributing to osmolarity in the cor-
nified layer.60-62 FLG deficiency alters the shape of corneocytes
*** ***
in the skin and enhances skin inflammation by facilitating epi-
*** *
cutaneous sensitization in murine models of eczema.41,63 FLG *** ***
4
deficiency also causes paracellular skin barrier abnormality
that reduces inflammatory thresholds to irritants and hap- Media
3 IL-4/13 (50 ng/mL)
Filaggrin (mg) protein
regulate the skin barrier.31,34,35 AMP expressions are inhibited in homeostasis. Increased skin pH also facilitates microbial skin
AD skin by Th2 cytokines, which are overexpressed in AD infections and skin barrier defects.4,98,99 Additionally, Brauweiler
skin.32,78-80 The deficiency of AMPs and over-expressed Th2 cy- et al.100 have demonstrated that staphylococcal alpha toxin, a
tokines in AD skin is associated with a higher propensity to S. primary toxin of S. aureus, causes cell death and consequently
aureus infection, which is known to play critical roles in the ex- skin barrier defects. Thus, decreased levels of AMPs may cause
acerbation of AD.30,31,81 Son et al.82 have reported that S. aureus skin dysbiosis and skin barrier defects. In summary, the skin
inhibited expression of terminal differentiation markers, in- dysbiosis and deficiency of AMPs may affect skin homeostasis
cluding FLG, loricrin, and keratina 1 and 10. Recently, Brauwei- and cause skin barrier defects in AD skin.4,16,47,49 However, addi-
ler et al.83 have also demonstrated that S. aureus lipoteichoic tional studies are needed to elucidate how dysbiosis affects epi-
acid inhibits keratinocyte differentiation markers, including dermal barrier function.
keratins 1 and 10, and desmocollin1, through a p63-mediated
pathway. Therefore, deficiency of AMPs and overexpressed Th2 Clinical implications in the treatment of AD
cytokines in AD skin may lead to frequent microbial skin infec- Moisturizers, including petrolatum, physiological lipid mix-
tions and skin barrier defects.32,84,85 tures, and ceramide-dominant triple-physiolosic lipid (ceramide:
AD skin also has a defective lipid matrix. This causes impaired cholesterol:free fatty acids at a 3:1:1 molar ratio), play critical
skin barrier function.18,86,87 Stratum corneum intercellular lipid roles in AD management.1,101,102 They improve clinical symp-
composition in AD skin is characterized by altered expression toms and skin barrier function, and reduces bacterial coloniza-
of enzymes involved in the biosynthesis of free fatty acids and tion.4,102-107 Petrolatum improves skin barrier functions by up-
ceramides.86,88 Researchers have demonstrated that altered regulation of AMPs, including LL-37, HBD-2, elafin, and S100
composition of stratum corneum intercellular lipids correlates proteins.101 Additionally, epidermal differentiation markers,
with S. aureus colonization status in AD.89 Additionally, it has such as FLG and loricrin, are induced by moisturizers.4,101
been reported that a synthetic omega-hydroxyceramides en- Moreover, petrolatum significantly reduces T-cell and dendritic
hanced the integrity of the stratum corneum, and accelerated cell infiltration in AD skin.101 Glatz et al.108 have reported that
the recovery of damaged skin barrier function by stimulating early emollient therapy alters the skin barrier and microbes in
differentiation processes.90 Lowe et al.91 also reported that rou- high-risk newborns. Of note, Nakatsuji et al.16 have demonstrat-
tine lipid replacement reduced the incidence of AD during the ed that application of coagulase-negative Staphylococcus
active treatment period by approximately fifty percent. There- strains to the skin of patients with AD decreases colonization by
fore, the lipid matrix in the cornified layer may play a crucial S. aureus.
role as part of the skin barrier. It has been reported that use of dilute bleach (sodium hypo-
chlorite) baths and intranasal mupirocin treatment improves
Microbiome AD symptoms.109 Other investigators have reported that topical
AD is associated with abnormal skin colonization of patho- use of bleach inhibites S. aureus and show beneficial effects on
gens, such as S. aureus.4,92 Commensal bacteria induce AMPs AD skin possibly through intrinsic anti-inflammatory ef-
and inhibit S. aureus on the human skin.16 In contrast, cutane- fects.110,111
ous dysbiosis affects skin immune responses and causes skin Hyung et al.112 reported Lactobacillus strain, CJLP55, isolated
inflammation.49,93,94 Moreover, skin dysbiosis may cause skin from kimchi, reduced infiltration of mast cells, eosinophils, and
barrier defects.95,96 Species-level investigation of AD flares dem- production of Th2 cytokines in AD-induced mouse skin. Addi-
onstrated greater S. aureus predominance in patients with tionally, Notay et al.113 analyzed 315 articles and reported that
more severe disease, and S. epidermidis predominates in pa- probiotics and prebiotics improved AD symptoms including
tients with less severe disease.49 Additionally, S. aureus isolates quality of life and clinical severity.
from AD patients with more severe flares induced epidermal Recently, various types of immune therapy have been devel-
thickening and expansion of cutaneous Th2 and Th17 cells.49 oped (Table 2). Clinical studies with broad and targeted thera-
However, Kennedy et al.97 reported that commensal staphylo- pies have been applied for patients with moderate-to-severe
cocci were significantly less abundant in infants with AD. This AD.1 Cyclosporine and oral glucocorticoids have been used, but
finding suggests that commensal bacteria might protect against there are limitations due to multiple adverse reactions. Dupil-
the development of AD. umab, anti-IL-4 Rα monoclonal antibody, improved clinical
AMPs, such as HBD-3 and LL-37, are highly expressed after findings in adults with moderate-to-severe atopic dermatitis,
various exposures in the normal healthy skin.31 Down-regulat- without significant safety concerns.114-117 Additionally, dupilum-
ed AMPs by Th2 cytokines in AD skin causes recurrent micro- ab up-regulated genes involved in skin barrier function.117 It
bial infections and may affect skin pH.41,85,98 Several factors, in- will be interesting to learn if early treatment of AD with dupil-
cluding FLG, cytokines, proteases, enzymes, and microbes, al- umab could prevent progression of the atopic march.
ter skin pH.42,98,99 Skin pH is an important factor controlling skin
210
http://e-aair.org Allergy Asthma Immunol Res. 2018 May;10(3):207-215. https://doi.org/10.4168/aair.2018.10.3.207
AAIR The Significance of Skin Barrier Dysfunction
Prevention of AD development mutations, deficiency of AMPs, and skin dysbiosis, may interact
Recent studies have demonstrated that moisturizers reduce with each other and cause skin barrier defects. Several strate-
rates of AD development4,104,105 and that probiotic supplemen- gies have been utilized to improve skin barrier function and to
tation may prevent AD.118,119 Additionally, investigators have re- control AD. Recently, moisturizers, probiotics, and targeted mi-
ported that skin commensal bacteria, including S. epidermidis crobiome therapy have been suggested to prevent AD develop-
and S. hominis, play crucial roles in skin homeostasis and de- ment in early life. Additionally, broad-spectrum and targeted
fense against microbial penetration.47-49 It has also been sug- therapies have been considered to control AD and prevent the
gested that colonization by commensal staphylococci can atopic march in patients with moderate-to-severe AD. Further
modulate skin immunity and might prevent development of studies are warranted to determine the efficacy of these diverse
AD.16,97 Therefore, correcting dysbiosis in AD skin may improve strategies, including emollients, probiotics, and commensal
skin barrier function and prevent AD development. Recently, bacteria, to prevent development of AD. It is noteworthy that
Kelleher et al.120 have demonstrated that increased TEWL at 2 recent data suggests AD is not just a local skin disease, but a
days and 2 months predates and predicts AD at 1 year. Kim et systemic immune disease because nonlesional skin and blood
al.121 have also reported that thymic stromal lymphopoietin profile show inflammatory findings. Therefore, we may need to
(TSLP) predicts the development of AD during infancy. These expand our scope of management, in the future, to systemic
data suggest that detection of increased TEWL, TSLP, and skin treatment in patients with moderate-to-severe AD.
dysbiosis in early life might predict AD and facilitate introduc-
tion of strategies to prevent AD development. These would in- ACKNOWLEDGMENTS
clude early use of moisturizers, topical anti-inflammatory
agents, probiotics as well as correction of microbial dysbiosis. The authors wish to acknowledge The Edelstein Family Foun-
dation of Pediatric Allergy-Immunology for their generous sup-
CONCLUSIONS AND FUTURE DIRECTIONS port of this work. This work was also supported by USPHS grant
R01 AR41256.
Factors, including immune dysregulation, epidermal gene
REFERENCES 18. van Smeden J, Bouwstra JA. Stratum corneum lipids: their role for
the skin barrier function in healthy subjects and atopic dermatitis
1. Brunner PM, Guttman-Yassky E, Leung DY. The immunology of patients. Curr Probl Dermatol 2016;49:8-26.
atopic dermatitis and its reversibility with broad-spectrum and 19. Busse D, Kudella P, Grüning NM, Gisselmann G, Ständer S, Luger T,
targeted therapies. J Allergy Clin Immunol 2017;139:S65-76. et al. A synthetic sandalwood odorant induces wound-healing
2. Bieber T, D’Erme AM, Akdis CA, Traidl-Hoffmann C, Lauener R, processes in human keratinocytes via the olfactory receptor
Schäppi G, et al. Clinical phenotypes and endophenotypes of OR2AT4. J Invest Dermatol 2014;134:2823-32.
atopic dermatitis: where are we, and where should we go? J Allergy 20. Erkoçoğlu M, Kocabaş CN. Role of IgA and IgM in severity of atop-
Clin Immunol 2017;139:S58-64. ic dermatitis. Ann Allergy Asthma Immunol 2015;114:433.
3. Leung DY, Guttman-Yassky E. Assessing the current treatment of 21. Kim BE, Leung DY. Epidermal barrier in atopic dermatitis. Allergy
atopic dermatitis: unmet needs. J Allergy Clin Immunol 2017;139: Asthma Immunol Res 2012;4:12-6.
S47-8. 22. Candi E, Schmidt R, Melino G. The cornified envelope: a model of
4. Czarnowicki T, Krueger JG, Guttman-Yassky E. Novel concepts of cell death in the skin. Nat Rev Mol Cell Biol 2005;6:328-40.
prevention and treatment of atopic dermatitis through barrier and 23. Kalinin A, Marekov LN, Steinert PM. Assembly of the epidermal
immune manipulations with implications for the atopic march. J cornified cell envelope. J Cell Sci 2001;114:3069-70.
Allergy Clin Immunol 2017;139:1723-34. 24. Proksch E, Brandner JM, Jensen JM. The skin: an indispensable
5. Ahn K. The prevalence of atopic dermatitis in Korean children. Al- barrier. Exp Dermatol 2008;17:1063-72.
lergy Asthma Immunol Res 2016;8:1-2. 25. Potten CS. Cell replacement in epidermis (keratopoiesis) via dis-
6. Beattie PE, Lewis-Jones MS. A comparative study of impairment of crete units of proliferation. Int Rev Cytol 1981;69:271-318.
quality of life in children with skin disease and children with other 26. Furuse M, Hata M, Furuse K, Yoshida Y, Haratake A, Sugitani Y, et
chronic childhood diseases. Br J Dermatol 2006;155:145-51. al. Claudin-based tight junctions are crucial for the mammalian
7. Rao DR, Sordillo JE, Kopel LS, Gaffin JM, Sheehan WJ, Hoffman E, epidermal barrier: a lesson from claudin-1-deficient mice. J Cell
et al. Association between allergic sensitization and exhaled nitric Biol 2002;156:1099-111.
oxide in children in the School Inner-city Asthma Study. Ann Al- 27. Wan H, Winton HL, Soeller C, Taylor GW, Gruenert DC, Thomp-
lergy Asthma Immunol 2015;114:256-257.e1. son PJ, et al. The transmembrane protein occludin of epithelial
8. Boguniewicz M, Abramovits W, Paller A, Whitaker-Worth DL, tight junctions is a functional target for serine peptidases from fae-
Prendergast M, Cheng JW, et al. A multiple-domain framework of cal pellets of Dermatophagoides pteronyssinus. Clin Exp Allergy
clinical, economic, and patient-reported outcomes for evaluating 2001;31:279-94.
benefits of intervention in atopic dermatitis. J Drugs Dermatol 28. Schneeberger EE, Lynch RD. Structure, function, and regulation of
2007;6:416-23. cellular tight junctions. Am J Physiol 1992;262:L647-61.
9. Mancini AJ, Kaulback K, Chamlin SL. The socioeconomic impact 29. Jonca N, Guerrin M, Hadjiolova K, Caubet C, Gallinaro H, Simon
of atopic dermatitis in the United States: a systematic review. Pedi- M, et al. Corneodesmosin, a component of epidermal corneocyte
atr Dermatol 2008;25:1-6. desmosomes, displays homophilic adhesive properties. J Biol
10. Leung DY, Guttman-Yassky E. Deciphering the complexities of Chem 2002;277:5024-9.
atopic dermatitis: shifting paradigms in treatment approaches. J 30. Lai Y, Gallo RL. AMPed up immunity: how antimicrobial peptides
Allergy Clin Immunol 2014;134:769-79. have multiple roles in immune defense. Trends Immunol 2009;30:
11. Mahdavinia M, Rasmussen HE, Engen P, Van den Berg JP, Davis E, 131-41.
Engen K, et al. Atopic dermatitis and food sensitization in South 31. Nakatsuji T, Gallo RL. Antimicrobial peptides: old molecules with
African toddlers: role of fiber and gut microbiota. Ann Allergy new ideas. J Invest Dermatol 2012;132:887-95.
Asthma Immunol 2017;118:742-743.e3. 32. Howell MD, Gallo RL, Boguniewicz M, Jones JF, Wong C, Streib JE,
12. Visitsunthorn N, Chatpornvorarux S, Pacharn P, Jirapongsananu- et al. Cytokine milieu of atopic dermatitis skin subverts the innate
ruk O. Atopy patch test in children with atopic dermatitis. Ann Al- immune response to vaccinia virus. Immunity 2006;24:341-8.
lergy Asthma Immunol 2016;117:668-73. 33. Niyonsaba F, Nagaoka I, Ogawa H, Okumura K. Multifunctional
13. Roerdink EM, Flokstra-de Blok BM, Blok JL, Schuttelaar ML, antimicrobial proteins and peptides: natural activators of immune
Niggemann B, Werfel T, et al. Association of food allergy and atop- systems. Curr Pharm Des 2009;15:2393-413.
ic dermatitis exacerbations. Ann Allergy Asthma Immunol 2016; 34. Kiatsurayanon C, Niyonsaba F, Smithrithee R, Akiyama T, Ushio H,
116:334-8. Hara M, et al. Host defense (Antimicrobial) peptide, human
14. Pyun BY. Natural history and risk factors of atopic dermatitis in β-defensin-3, improves the function of the epithelial tight-junction
children. Allergy Asthma Immunol Res 2015;7:101-5. barrier in human keratinocytes. J Invest Dermatol 2014;134:2163-
15. Zheng T, Yu J, Oh MH, Zhu Z. The atopic march: progression from 73.
atopic dermatitis to allergic rhinitis and asthma. Allergy Asthma 35. Hirsch T, Spielmann M, Zuhaili B, Fossum M, Metzig M, Koehler T,
Immunol Res 2011;3:67-73. et al. Human beta-defensin-3 promotes wound healing in infected
16. Nakatsuji T, Chen TH, Narala S, Chun KA, Two AM, Yun T, et al. diabetic wounds. J Gene Med 2009;11:220-8.
Antimicrobials from human skin commensal bacteria protect 36. De Benedetto A, Rafaels NM, McGirt LY, Ivanov AI, Georas SN,
against Staphylococcus aureus and are deficient in atopic derma- Cheadle C, et al. Tight junction defects in patients with atopic der-
titis. Sci Transl Med 2017;9:eaah4680. matitis. J Allergy Clin Immunol 2011;127:773-786.e1-7.
17. Smith AR, Knaysi G, Wilson JM, Wisniewski JA. The skin as a route 37. Niyonsaba F, Ushio H, Nagaoka I, Okumura K, Ogawa H. The hu-
of allergen exposure: part I. Immune components and mecha- man beta-defensins (-1, -2, -3, -4) and cathelicidin LL-37 induce
nisms. Curr Allergy Asthma Rep 2017;17:6. IL-18 secretion through p38 and ERK MAPK activation in primary
212
http://e-aair.org Allergy Asthma Immunol Res. 2018 May;10(3):207-215. https://doi.org/10.4168/aair.2018.10.3.207
AAIR The Significance of Skin Barrier Dysfunction
human keratinocytes. J Immunol 2005;175:1776-84. with skin and allergic diseases. N Engl J Med 2011;365:1315-27.
38. Niyonsaba F, Ushio H, Nakano N, Ng W, Sayama K, Hashimoto K, 56. Flohr C, England K, Radulovic S, McLean WH, Campbel LE, Bark-
et al. Antimicrobial peptides human beta-defensins stimulate epi- er J, et al. Filaggrin loss-of-function mutations are associated with
dermal keratinocyte migration, proliferation and production of early-onset eczema, eczema severity and transepidermal water
proinflammatory cytokines and chemokines. J Invest Dermatol loss at 3 months of age. Br J Dermatol 2010;163:1333-6.
2007;127:594-604. 57. Kim BE, Bin L, Ye YM, Ramamoorthy P, Leung DY. IL-25 enhances
39. Golec M. Cathelicidin LL-37: LPS-neutralizing, pleiotropic pep- HSV-1 replication by inhibiting filaggrin expression, and acts syn-
tide. Ann Agric Environ Med 2007;14:1-4. ergistically with Th2 cytokines to enhance HSV-1 replication. J In-
40. Elias PM, Schmuth M. Abnormal skin barrier in the etiopathogen- vest Dermatol 2013;133:2678-85.
esis of atopic dermatitis. Curr Allergy Asthma Rep 2009;9:265-72. 58. Hamid Q, Boguniewicz M, Leung DY. Differential in situ cytokine
41. Elias PM, Hatano Y, Williams ML. Basis for the barrier abnormality gene expression in acute versus chronic atopic dermatitis. J Clin
in atopic dermatitis: outside-inside-outside pathogenic mecha- Invest 1994;94:870-6.
nisms. J Allergy Clin Immunol 2008;121:1337-43. 59. Howell MD, Kim BE, Gao P, Grant AV, Boguniewicz M, Debenedet-
42. Kezic S, Jakasa I. Filaggrin and skin barrier function. Curr Probl to A, et al. Cytokine modulation of atopic dermatitis filaggrin skin
Dermatol 2016;49:1-7. expression. J Allergy Clin Immunol 2007;120:150-5.
43. Chng KR, Tay AS, Li C, Ng AH, Wang J, Suri BK, et al. Whole 60. Jang H, Matsuda A, Jung K, Karasawa K, Matsuda K, Oida K, et al.
metagenome profiling reveals skin microbiome-dependent sus- Skin pH is the master switch of kallikrein 5-mediated skin barrier
ceptibility to atopic dermatitis flare. Nat Microbiol 2016;1:16106. destruction in a murine atopic dermatitis model. J Invest Derma-
44. Oh J, Conlan S, Polley EC, Segre JA, Kong HH. Shifts in human skin tol 2016;136:127-35.
and nares microbiota of healthy children and adults. Genome 61. Nicotera P, Melino G. Caspase-14 and epidermis maturation. Nat
Med 2012;4:77. Cell Biol 2007;9:621-2.
45. Oh J, Byrd AL, Deming C, Conlan S; NISC Comparative Sequenc- 62. Denecker G, Hoste E, Gilbert B, Hochepied T, Ovaere P, Lippens S,
ing Program, Kong HH, et al. Biogeography and individuality et al. Caspase-14 protects against epidermal UVB photodamage
shape function in the human skin metagenome. Nature 2014;514: and water loss. Nat Cell Biol 2007;9:666-74.
59-64. 63. Oyoshi MK, Murphy GF, Geha RS. Filaggrin-deficient mice exhibit
46. Capone KA, Dowd SE, Stamatas GN, Nikolovski J. Diversity of the TH17-dominated skin inflammation and permissiveness to epicu-
human skin microbiome early in life. J Invest Dermatol 2011;131: taneous sensitization with protein antigen. J Allergy Clin Immunol
2026-32. 2009;124:485-93, 493.e1.
47. Knaysi G, Smith AR, Wilson JM, Wisniewski JA. The skin as a route 64. Man MQ, Hatano Y, Lee SH, Man M, Chang S, Feingold KR, et al.
of allergen exposure: part II. Allergens and role of the microbiome Characterization of a hapten-induced, murine model with multi-
and environmental exposures. Curr Allergy Asthma Rep 2017;17:7. ple features of atopic dermatitis: structural, immunologic, and bio-
48. Nakamizo S, Egawa G, Honda T, Nakajima S, Belkaid Y, Kabashima chemical changes following single versus multiple oxazolone chal-
K. Commensal bacteria and cutaneous immunity. Semin Immu- lenges. J Invest Dermatol 2008;128:79-86.
nopathol 2015;37:73-80. 65. Scott IR, Harding CR. Filaggrin breakdown to water binding com-
49. Byrd AL, Deming C, Cassidy SK, Harrison OJ, Ng WI, Conlan S, et pounds during development of the rat stratum corneum is con-
al. Staphylococcus aureus and Staphylococcus epidermidis strain trolled by the water activity of the environment. Dev Biol 1986;115:
diversity underlying pediatric atopic dermatitis. Sci Transl Med 84-92.
2017;9:eaal4651. 66. Gutowska-Owsiak D, Schaupp AL, Salimi M, Taylor S, Ogg GS. In-
50. Lee E, Lee SY, Kang MJ, Kim K, Won S, Kim BJ, et al. Clostridia in terleukin-22 downregulates filaggrin expression and affects ex-
the gut and onset of atopic dermatitis via eosinophilic inflamma- pression of profilaggrin processing enzymes. Br J Dermatol 2011;
tion. Ann Allergy Asthma Immunol 2016;117:91-92.e1. 165:492-8.
51. Tang KT, Ku KC, Chen DY, Lin CH, Tsuang BJ, Chen YH. Adult 67. Gutowska-Owsiak D, Schaupp AL, Salimi M, Selvakumar TA,
atopic dermatitis and exposure to air pollutants-a nationwide McPherson T, Taylor S, et al. IL-17 downregulates filaggrin and af-
population-based study. Ann Allergy Asthma Immunol 2017;118: fects keratinocyte expression of genes associated with cellular ad-
351-5. hesion. Exp Dermatol 2012;21:104-10.
52. Knox SM, Erwin EA, Mosser-Goldfarb JL, Scherzer R. Sensitization 68. Kim BE, Leung DY, Boguniewicz M, Howell MD. Loricrin and in-
patterns among patients with atopic dermatitis evaluated in a volucrin expression is down-regulated by Th2 cytokines through
large tertiary care pediatric center. Ann Allergy Asthma Immunol STAT-6. Clin Immunol 2008;126:332-7.
2017;118:645-7. 69. Rodríguez E, Baurecht H, Herberich E, Wagenpfeil S, Brown SJ,
53. Spergel JM, Mizoguchi E, Brewer JP, Martin TR, Bhan AK, Geha RS. Cordell HJ, et al. Meta-analysis of filaggrin polymorphisms in ec-
Epicutaneous sensitization with protein antigen induces localized zema and asthma: robust risk factors in atopic disease. J Allergy
allergic dermatitis and hyperresponsiveness to methacholine after Clin Immunol 2009;123:1361-1370.e7.
single exposure to aerosolized antigen in mice. J Clin Invest 1998; 70. Stemmler S, Parwez Q, Petrasch-Parwez E, Epplen JT, Hoffjan S.
101:1614-22. Two common loss-of-function mutations within the filaggrin gene
54. Nikolovski J, Stamatas GN, Kollias N, Wiegand BC. Barrier function predispose for early onset of atopic dermatitis. J Invest Dermatol
and water-holding and transport properties of infant stratum cor- 2007;127:722-4.
neum are different from adult and continue to develop through 71. Wan J, Mitra N, Hoffstad OJ, Margolis DJ. Influence of FLG muta-
the first year of life. J Invest Dermatol 2008;128:1728-36. tions and TSLP polymorphisms on atopic dermatitis onset age.
55. Irvine AD, McLean WH, Leung DY. Filaggrin mutations associated Ann Allergy Asthma Immunol 2017;118:737-738.e1.
72. Yu HS, Kang MJ, Jung YH, Kim HY, Seo JH, Kim YJ, et al. Mutations tients with atopic dermatitis. J Eur Acad Dermatol Venereol 2017;
in the filaggrin are predisposing factor in Korean children with 31:135-41.
atopic dermatitis. Allergy Asthma Immunol Res 2013;5:211-5. 89. Li S, Villarreal M, Stewart S, Choi J, Ganguli-Indra G, Babineau DC,
73. O’Regan GM, Sandilands A, McLean WH, Irvine AD. Filaggrin in et al. Altered composition of epidermal lipids correlates with
atopic dermatitis. J Allergy Clin Immunol 2008;122:689-93. Staphylococcus aureus colonization status in atopic dermatitis. Br
74. Henderson J, Northstone K, Lee SP, Liao H, Zhao Y, Pembrey M, et J Dermatol 2017;177:e125-7.
al. The burden of disease associated with filaggrin mutations: a 90. Oh MJ, Nam JJ, Lee EO, Kim JW, Park CS. A synthetic C16 omega-
population-based, longitudinal birth cohort study. J Allergy Clin hydroxyphytoceramide improves skin barrier functions from di-
Immunol 2008;121:872-877.e9. versely perturbed epidermal conditions. Arch Dermatol Res 2016;
75. Gruber R, Börnchen C, Rose K, Daubmann A, Volksdorf T, Wlady- 308:563-74.
kowski E, et al. Diverse regulation of claudin-1 and claudin-4 in 91. Lowe AJ, Su JC, Allen KJ, Abramson MJ, Cranswick N, Robertson
atopic dermatitis. Am J Pathol 2015;185:2777-89. CF, et al. A randomized trial of a barrier lipid replacement strategy
76. Leclerc EA, Huchenq A, Mattiuzzo NR, Metzger D, Chambon P, for the prevention of atopic dermatitis and allergic sensitization:
Ghyselinck NB, et al. Corneodesmosin gene ablation induces le- the PEBBLES pilot study. Br J Dermatol. Forthcoming 2017.
thal skin-barrier disruption and hair-follicle degeneration related 92. Eyerich K, Eyerich S, Biedermann T. The multi-modal immune
to desmosome dysfunction. J Cell Sci 2009;122:2699-709. pathogenesis of atopic eczema. Trends Immunol 2015;36:788-801.
77. Lee UH, Kim BE, Kim DJ, Cho YG, Ye YM, Leung DY. Atopic der- 93. Kobayashi T, Glatz M, Horiuchi K, Kawasaki H, Akiyama H, Kaplan
matitis is associated with reduced corneodesmosin expression: DH, et al. Dysbiosis and Staphylococcus aureus colonization
role of cytokine modulation and effects on viral penetration. Br J drives inflammation in atopic dermatitis. Immunity 2015;42:756-
Dermatol 2017;176:537-40. 66.
78. Nomura I, Goleva E, Howell MD, Hamid QA, Ong PY, Hall CF, et al. 94. Naik S, Bouladoux N, Wilhelm C, Molloy MJ, Salcedo R, Kasten-
Cytokine milieu of atopic dermatitis, as compared to psoriasis, muller W, et al. Compartmentalized control of skin immunity by
skin prevents induction of innate immune response genes. J Im- resident commensals. Science 2012;337:1115-9.
munol 2003;171:3262-9. 95. Zeeuwen PL, Boekhorst J, van den Bogaard EH, de Koning HD,
79. Ong PY, Ohtake T, Brandt C, Strickland I, Boguniewicz M, Ganz T, van de Kerkhof PM, Saulnier DM, et al. Microbiome dynamics of
et al. Endogenous antimicrobial peptides and skin infections in human epidermis following skin barrier disruption. Genome Biol
atopic dermatitis. N Engl J Med 2002;347:1151-60. 2012;13:R101.
80. Hata TR, Kotol P, Boguniewicz M, Taylor P, Paik A, Jackson M, et al. 96. Wollina U. Microbiome in atopic dermatitis. Clin Cosmet Investig
History of eczema herpeticum is associated with the inability to in- Dermatol 2017;10:51-6.
duce human β-defensin (HBD)-2, HBD-3 and cathelicidin in the 97. Kennedy EA, Connolly J, Hourihane JO, Fallon PG, McLean WH,
skin of patients with atopic dermatitis. Br J Dermatol 2010;163:659- Murray D, et al. Skin microbiome before development of atopic
61. dermatitis: early colonization with commensal staphylococci at 2
81. Brauweiler AM, Goleva E, Leung DY. Th2 cytokines increase months is associated with a lower risk of atopic dermatitis at 1
Staphylococcus aureus alpha toxin-induced keratinocyte death year. J Allergy Clin Immunol 2017;139:166-72.
through the signal transducer and activator of transcription 6 98. Ali SM, Yosipovitch G. Skin pH: from basic science to basic skin
(STAT6). J Invest Dermatol 2014;134:2114-21. care. Acta Derm Venereol 2013;93:261-7.
82. Son ED, Kim HJ, Park T, Shin K, Bae IH, Lim KM, et al. Staphylo- 99. Rippke F, Schreiner V, Schwanitz HJ. The acidic milieu of the horny
coccus aureus inhibits terminal differentiation of normal human layer: new findings on the physiology and pathophysiology of skin
keratinocytes by stimulating interleukin-6 secretion. J Dermatol pH. Am J Clin Dermatol 2002;3:261-72.
Sci 2014;74:64-71. 100. Brauweiler AM, Goleva E, Leung DY. Interferon-γ protects from
83. Brauweiler AM, Hall CF, Goleva E, Leung DY. Staphylococcus au- staphylococcal alpha toxin-induced keratinocyte death through
reus lipoteichoic acid inhibits keratinocyte differentiation through apolipoprotein L1. J Invest Dermatol 2016;136:658-64.
a p63-mediated pathway. J Invest Dermatol 2017;137:2030-3. 101. Czarnowicki T, Malajian D, Khattri S, Correa da Rosa J, Dutt R,
84. Howell MD, Wollenberg A, Gallo RL, Flaig M, Streib JE, Wong C, et Finney R, et al. Petrolatum: barrier repair and antimicrobial re-
al. Cathelicidin deficiency predisposes to eczema herpeticum. J sponses underlying this “inert” moisturizer. J Allergy Clin Immu-
Allergy Clin Immunol 2006;117:836-41. nol 2016;137:1091-1102.e7.
85. Leung DY. New insights into atopic dermatitis: role of skin barrier 102. Lee HJ, Lee SH. Epidermal permeability barrier defects and barri-
and immune dysregulation. Allergol Int 2013;62:151-61. er repair therapy in atopic dermatitis. Allergy Asthma Immunol
86. Danso M, Boiten W, van Drongelen V, Gmelig Meijling K, Gooris G, Res 2014;6:276-87.
El Ghalbzouri A, et al. Altered expression of epidermal lipid bio- 103. Eichenfield LF, Ahluwalia J, Waldman A, Borok J, Udkoff J, Boguni-
synthesis enzymes in atopic dermatitis skin is accompanied by ewicz M. Current guidelines for the evaluation and management
changes in stratum corneum lipid composition. J Dermatol Sci of atopic dermatitis: a comparison of the Joint Task Force Practice
2017;88:57-66. Parameter and American Academy of Dermatology guidelines. J
87. Kim D, Lee NR, Park SY, Jun M, Lee K, Kim S, et al. As in atopic der- Allergy Clin Immunol 2017;139:S49-57.
matitis, nonlesional skin in allergic contact dermatitis displays ab- 104. Simpson EL, Berry TM, Brown PA, Hanifin JM. A pilot study of
normalities in barrier function and ceramide content. J Invest Der- emollient therapy for the primary prevention of atopic dermatitis.
matol 2017;137:748-50. J Am Acad Dermatol 2010;63:587-93.
88. Ito S, Ishikawa J, Naoe A, Yoshida H, Hachiya A, Fujimura T, et al. 105. Simpson EL, Chalmers JR, Hanifin JM, Thomas KS, Cork MJ,
Ceramide synthase 4 is highly expressed in involved skin of pa- McLean WH, et al. Emollient enhancement of the skin barrier
214
http://e-aair.org Allergy Asthma Immunol Res. 2018 May;10(3):207-215. https://doi.org/10.4168/aair.2018.10.3.207
AAIR The Significance of Skin Barrier Dysfunction
from birth offers effective atopic dermatitis prevention. J Allergy atopic dermatitis. N Engl J Med 2016;375:2335-48.
Clin Immunol 2014;134:818-23. 115. Thaçi D, Simpson EL, Beck LA, Bieber T, Blauvelt A, Papp K, et al.
106. Cardona ID, Stillman L, Jain N. Does bathing frequency matter in Efficacy and safety of dupilumab in adults with moderate-to-se-
pediatric atopic dermatitis? Ann Allergy Asthma Immunol 2016; vere atopic dermatitis inadequately controlled by topical treat-
117:9-13. ments: a randomised, placebo-controlled, dose-ranging phase 2b
107. Pabst RC, Starr KP, Qaiyumi S, Schwalbe RS, Gewolb IH. The effect trial. Lancet 2016;387:40-52.
of application of aquaphor on skin condition, fluid requirements, 116. Beck LA, Thaçi D, Hamilton JD, Graham NM, Bieber T, Rocklin R,
and bacterial colonization in very low birth weight infants. J Peri- et al. Dupilumab treatment in adults with moderate-to-severe
natol 1999;19:278-83. atopic dermatitis. N Engl J Med 2014;371:130-9.
108. Glatz M, Polley E, Simpson E, Kong H. Emollient therapy alters 117. Hamilton JD, Suárez-Fariñas M, Dhingra N, Cardinale I, Li X, Kos-
skin barrier and microbes in infants at risk for developing atopic tic A, et al. Dupilumab improves the molecular signature in skin of
dermatitis. J Invest Dermatol 2015;135:S31. patients with moderate-to-severe atopic dermatitis. J Allergy Clin
109. Huang JT, Abrams M, Tlougan B, Rademaker A, Paller AS. Treat- Immunol 2014;134:1293-300.
ment of Staphylococcus aureus colonization in atopic dermatitis 118. Rø AD, Simpson MR, Rø TB, Storrø O, Johnsen R, Videm V, et al.
decreases disease severity. Pediatrics 2009;123:e808-14. Reduced Th22 cell proportion and prevention of atopic dermatitis
110. Eriksson S, van der Plas MJ, Mörgelin M, Sonesson A. Antibacterial in infants following maternal probiotic supplementation. Clin Exp
and antibiofilm effects of sodium hypochlorite against Staphylo- Allergy 2017;47:1014-21.
coccus aureus isolates derived from patients with atopic dermati- 119. di Mauro G, Bernardini R, Barberi S, Capuano A, Correra A, De’
tis. Br J Dermatol 2017;177:513-21. Angelis GL, et al. Prevention of food and airway allergy: consensus
111. Myles IA, Williams KW, Reckhow JD, Jammeh ML, Pincus NB, Sas- of the Italian Society of Preventive and Social Paediatrics, the Ital-
talla I, et al. Transplantation of human skin microbiota in models ian Society of Paediatric Allergy and Immunology, and Italian So-
of atopic dermatitis. JCI Insight 2016;1:e86955. ciety of Pediatrics. World Allergy Organ J 2016;9:28.
112. Hyung KE, Kim SJ, Jang YW, Lee DK, Hyun KH, Moon BS, et al. 120. Kelleher M, Dunn-Galvin A, Hourihane JO, Murray D, Campbell
Therapeutic effects of orally administered CJLP55 for atopic der- LE, McLean WH, et al. Skin barrier dysfunction measured by tran-
matitis via the regulation of immune response. Korean J Physiol sepidermal water loss at 2 days and 2 months predates and pre-
Pharmacol 2017;21:335-43. dicts atopic dermatitis at 1 year. J Allergy Clin Immunol 2015;135:
113. Notay M, Foolad N, Vaughn AR, Sivamani RK. Probiotics, prebiot- 930-935.e1.
ics, and synbiotics for the treatment and prevention of adult der- 121. Kim J, Kim BE, Lee J, Han Y, Jun HY, Kim H, et al. Epidermal thymic
matological diseases. Am J Clin Dermatol 2017;18:721-32. stromal lymphopoietin predicts the development of atopic derma-
114. Simpson EL, Bieber T, Guttman-Yassky E, Beck LA, Blauvelt A, titis during infancy. J Allergy Clin Immunol 2016;137:1282-1285.e4.
Cork MJ, et al. Two phase 3 trials of dupilumab versus placebo in