Pathophysiology of atopic dermatitis: Clinical implications

Jihyun Kim, M.D., Ph.D.,1–3 Byung Eui Kim, M.D., Ph.D.,2 and Donald Y. M. Leung, M.D., Ph.D.2

ABSTRACT
Atopic dermatitis (AD) is the most common chronic inflammatory skin disease. Genetic predisposition, epidermal barrier
disruption, and dysregulation of the immune system are some of the critical components of AD. An impaired skin barrier may
be the initial step in the development of the atopic march as well as AD, which leads to further skin inflammation and allergic
sensitization. Type 2 cytokines as well as interleukin 17 and interleukin 22 contribute to skin barrier dysfunction and the
development of AD. New insights into the pathophysiology of AD have focused on epidermal lipid profiles, neuroimmune
interactions, and microbial dysbiosis. Newer therapeutic strategies focus on improving skin barrier function and targeting
polarized immune pathways found in AD. Further understanding of AD pathophysiology will allow us to achieve a more
precision medicine approach to the prevention and the treatment of AD.
(Allergy Asthma Proc 40:84 –92, 2019; doi: 10.2500/aap.2019.40.4202)

dermal barrier.13–16 Recently, new insights into the

A topic dermatitis (AD) is the most common chronic
inflammatory skin disease.1 The U.S. prevalence
of AD was reported to be 11.3–12.7% and 6.9 –7.6% in
pathophysiology of the development of AD focused on
an important role of abnormalities in epidermal lipid
children and in adults, respectively.2 The Hanifin and layer as well as neuroimmune interactions and micro-
Rajka criteria and the American Academy of Derma- bial dysbiosis.17–20 These factors have been used to
tology Consensus Criteria are useful diagnostic tools develop novel therapeutic and preventative strategies
based on features of AD.3,4 AD severity can be assessed of AD. This review addressed recent insights into the
by using validated methods such as Scoring Atopic pathophysiologic mechanism of AD and the clinical
Dermatitis or the Eczema Area and Severity Index.5 application of these factors for improved treatment and
Although the pathophysiology of AD is not com- prevention of AD. This work was supported by Na-
pletely understood, numerous studies demonstrated tional Institutes of Health (grant AR41256). J. Kim and
that skin barrier dysfunction and immune dysregula- B. Eui Kim contributed equally to the article.
tion contribute to the pathobiology of AD.6 – 8 The epi-
dermis plays a crucial role as a physical and functional
barrier, and skin barrier defects are the most significant GENETICS
pathologic findings in AD skin.1,9,10 Filaggrin (FLG), The filaggrin (FLG) gene is located on chromosome
transglutaminases, keratins, and intercellular proteins 1q2, and encodes FLG (filaggrin protein), which is a ma-
are key proteins responsible for epidermal function. jor structural protein in the stratum corneum (SC).21 Pro-
Defects in these proteins facilitate allergen and micro- FLG polymers are proteolytically cleaved and dephos-
bial penetration into the skin.9 –11 phorylated into FLG monomers, which are associated
Skin barrier dysfunction has been considered to be with the aggregation of keratin filaments and the for-
the first step in the development of atopic march as mation of SC.13 The generation of FLG degradation
well as AD.7,12 However, it is also now evident that products, urocanic acid and pyrrolidine carboxylic
immune dysregulation, including the activation of type acid, contributes to SC hydration and acidic pH of
2 immune responses, results in impairment of the epi- skin.14 It is well known that FLG null mutations impair
skin barrier function and increase the risk of AD.21,22
FLG mutations, particularly homozygous mutations,
From the 1Department of Pediatrics, Samsung Medical Center, Sungkyunkwan Uni-
are associated with an increased risk of severe AD with
versity School of Medicine, Seoul, Korea, 2Department of Pediatrics, National Jewish
Health, Denver, Colorado, and 3Environmental Health Center for Atopic Diseases, earlier onset, longer persistence, and skin infec-
Samsung Medical Center, Seoul, Korea tions.8,22,23 Approximately 10% of European popula-
This work was supported by NIH grant AR41256. This study was also supported by
tions are heterozygous carriers of FLG mutations,
Ministry of Environment, Republic of Korea.
Presented at the Eastern Allergy Conference, June 2, 2018, Palm Beach Florida which results in a 50% reduction in expressed pro-
D.Y.M. Leung has consulted for Regeneron, Sanofi, Novartis and Genzyme. The tein.22 However, the pathophysiology of AD goes far
remaining authors have no conflicts of interest to declare pertaining to this article
beyond FLG mutations. For example, Japanese and
No external funding sources reported
Address correspondence to Donald Y.M. Leung, M.D., Department of Pediatrics, Korean patients have a lower frequency of FLG muta-
National Jewish Health, 1400 Jackson St, Denver, CO, 80206 tions than do patients in Western populations.13,24 Fur-
E-mail address: [email protected]
thermore, ⬃40% of subjects with FLG-null alleles do
Copyright © 2019, OceanSide Publications, Inc., U.S.A.
not show characteristics of AD, and most of the pa-

84 March 2019, Vol. 40, No. 2

tients with AD and with FLG mutations eventually haust, cigarette smoke, and chemical irritants.13,42,43
outgrow the disease.25 When using skin tape samples, a Korean birth cohort
Polymorphisms of various immune pathway genes study showed elevated expression of TSLP in the skin
are associated with an increased risk of AD through of 2 month-old infants before the development of clin-
alternations in the T-helper (Th) type 2 signaling path- ical AD at 24 months of age.44
way.21,26 Upregulation of interleukin (IL) 4 and IL-13 Although blockade of type 2– driven inflammation
lowers FLG expression, which leads to skin barrier improves AD symptoms, the pathogenesis of AD is not
defects.27,28 A gain of functional polymorphisms of exclusively explained by Th2 immunity. In this regard,
type 2 cytokine receptors (IL-4R and IL-13R) are also IL-17 has been reported to reduce expression of FLG
implicated in AD pathogenesis.28,29 Other immune- and involucrin.45,46 More prominent Th17 activation
related genes that contribute to the development of AD was observed in blood and acute AD skin lesions in
include IL-31, IL-33, signal transducer and activator of Asian patients compared with European-American pa-
transcription (STAT) 6, thymic stromal lymphopoietin tients.47 In addition, AD is classified as the extrinsic
(TSLP) and its receptors (IL-7R and TSLPR), interferon and the intrinsic type, and production of IL-17 cytokine
regulatory factor 2, Toll-like receptor 2, and high-affin- is higher in intrinsic AD with normal immunoglobulin
ity IgE receptor (Fc␧RI) ␣ gene in specific popula- E levels than in extrinsic AD.48 IL-22 is also highly
tions.21,26,30 –33 Additionally, recent studies demon- upregulated in the skin of patients with AD and is
strated that vitamin D receptor polymorphisms and associated with skin barrier dysfunction and abnormal
cytochrome P450 family 27 subfamily A member 1 epidermal markers, such as keratin 6 and keratin
(CYP27A1) variant are associated with AD.34,35 CYP27A1 16.49 –51 In particular, transition to the chronic phase is
is known to be involved in the metabolism of vitamin D3, manifested by the start of Th1-cell activation as well as
which plays an essential role in immune modulation.34 the sustained activation of Th2 and Th22 cells (Fig.
Epigenetic mechanisms are heritable and can regu- 1).52,53 Of interest, tumor necrosis factor ␣ in combina-
late gene expression without changing the DNA se- tion with Th2 cytokines altered the expression of early
quence.13 There is increasing evidence that demon- and terminal differentiation products and reduced the
strates that environmental exposures induce epigenetic level of long-chain free fatty acids (FFA) and ester
changes and AD through DNA modification and mi- linked ␻-hydroxy (EO) ceramides.17,20
cro-RNA–mediated posttranscriptional regulation.26,36 Recent studies showed that skin-resident group 2
A recent study provided evidence for the importance innate lymphoid cells (ILC2) play a role in the patho-
of DNA methylation and showed the relationship be- genesis of AD. ILC2s were found to produce IL-5 and
tween umbilical cord blood methylation at 5⬘-C-phos- IL-13, which result in the development of an AD-like
phate-G-3⬘ sites of IL-4R and the development of AD at skin lesion.54,55 Similarly, human skin ILC2s are highly
1 year of age.37 DNA methylation in one adjacent CpG enriched in lesional skin of patients with AD and acti-
site of FLG was reported to have a significant interac- vated by the epithelial cell– derived cytokines such as
tion with FLG sequence variants and association with IL-25, IL-33, and/or TSLP.55,56 This leads to the pro-
the increased risk of eczema,38 whereas another study, duction of type 2 cytokines and skin allergic inflam-
which used buccal cells, could not show the relation- mation.55,56 In contrast, epidermal ILC2s are inhibited
ship between methylation of the FLG promoter and by E-cadherin, and its downregulation recent studies
gene expression and allergic diseases.39 Furthermore, showed that skin-resident.56
hypomethylation of TSLP and Fc␧RI ␥ promoters con-
tributes to gene overexpression in patients with AD.26
NEUROIMMUNOLOGIC MECHANISMS
A subset of sensory neurons that express histamine
IMMUNE DYSREGULATION H1 receptor and histamine H4 receptor is activated by
Previous studies showed that type 2 immune cyto- histamine, which can cause itch as well as allergic
kines, e.g., IL-4 and IL-13, play important roles in inflammation.57 H1 antihistamines have been widely
chemokine production, skin barrier dysfunction, sup- used for the treatment of itch due to urticaria, but its
pression of antimicrobial peptides (AMP), and allergic effects are limited in the treatment of chronic itch in
inflammation.15,40 Interestingly, IL-31 was reported to patients with AD. Recently, much interest has focused
enhance the release and production of brain-derived on the role of histamine-independent itch signaling
natriuretic peptide and to coordinate cytokine and pathways in which TSLP and type 2 cytokines, such as
chemokine release from skin cells, thereby inducing IL-4, IL-13, and IL-31, stimulate neurons expressing
itch in patients with AD.41 In addition, TSLP is highly transient receptor potential cation channel subfamily A
expressed in the epidermis of patients with AD, and its member 1 and afferent neurons via its receptors and
production is triggered by exposure to environmental Janus kinase (JAK) family, respectively.19 Of note,
factors such as allergens, microorganisms, diesel ex- IL-31 induces sensory nerve elongation and branching,

Allergy and Asthma Proceedings 85

Figure 1. Effects of cytokines on epidermis in AD. Disrupted epidermal barrier and environmental triggers stimulate keratinocytes to release
IL-1␤, IL-25, IL-33, MDC, TARC, and TSLP, which activate dendritic cells and Langerhans cells. Activated dendritic cells stimulate Th2
cells to produce IL-4, IL-5, IL-13, IL-31, and IL-33, which leads to barrier dysfunction, decreased AMP production, impaired keratinocyte
differentiation, and itch symptoms. Chronic AD is characterized by recruitment of Th1, Th22, and Th17 subsets, which results in epidermal
thickening and abnormal keratinocyte proliferation. AD ⫽ atopic dermatitis; AMP ⫽ antimicrobial peptide; DC ⫽ dendric cell; IFN ⫽
interferon; IL ⫽ interleukin; KC ⫽ keratinocyte; LC ⫽ Langerhans cell; MDC ⫽ macrophage-derived chemokine; S100A ⫽ S100
calcium-binding protein A; Th ⫽ T-helper type; TARC ⫽ thymus and activation-regulated chemokine; TSLP ⫽ thymic stromal
lymphopoietin.

which supports its role that involves sensitivity to min- sponses (Table 1).9,10 FLG is highly downregulated in
imal stimuli and sustained itch in patients with AD.58 both lesional and nonlesional skin of patients with AD.65
In addition, the activation of STAT3 in the astrocytes of Recently, McAleer et al.66 demonstrated that FLG
the spinal dorsal horn has been reported to be involved breakdown products in the first year of life are lowest
in chronic pruritus via the generation of lipocalin-2.59 in the cheek compared with the elbow and the nasal
tip, and the slowest to achieve maturity levels, which
EPIDERMAL DYSFUNCTION supports the importance of FLG on the pathogenesis of
IL-4, IL-13, IL-31, IL-33, and high-mobility group box infantile AD. In that study, FLG processing enzymes
1 downregulate the production of epidermal barrier such as bleomycin hydrolase and calpain-1 were also
proteins, including FLG, keratins, loricrin, involucrin, increased at cheek skin by 1 month of age.64 This may
and cell adhesion molecules.14,15,60 – 62 A damaged epi- explain the predilection for AD at the cheeks initially in
dermal barrier not only leads to the development of early childhood. Epidermal FLG levels are also reduced
AD but also heightens sensitization to allergens and by environmental factors, including low humidity, sun-
contributes to the risk of Food allergy (FA) and airway burns, diesel exhaust particles, and skin irritants.67,68 In
hyperreactivity.7,12 Impairment of skin barrier function addition, loricrin and involucrin are downregulated by
at birth and at 2 months, as evaluated by transepider- overexpression of Th2 cytokines through a STAT6-
mal water loss (TEWL), can precede clinical AD by 12 dependent mechanism in AD skin.69 Corneodesmosin
months of age.63 Moreover, increased TEWL in the (CDSN) and tight junctions play a central role by sup-
early newborn period is associated with a higher inci- porting the adhesion between corneocytes and the in-
dence of FA at 2 years of age, which supports the tegrity of the skin barrier as an intercellular protein.9,70
concept of transcutaneous allergen sensitization.64 A recent study showed that CDSN was downregulated
Defects in epidermal barrier proteins, such as FLG, by IL-4, IL-13, IL-22, IL-25, and IL-31 in human kera-
transglutaminases, keratins, and intercellular proteins, fa- tinocytes, and the penetration of vaccinia virus was
cilitate dysregulated immune responses to external anti- enhanced in a CDSN-deficient skin model.69 In addi-
gens and drive skin and systemic inflammatory re- tion, claudin 1– deficient mice were reported to die

86 March 2019, Vol. 40, No. 2

Table 1 Epithelial skin dysfunction in atopic dermatitis
Epithelial Dysfunction Abnormalities Effects
Cornified envelope proteins Decreased expression of filaggrin, 2 Skin hydration
transglutaminases, keratins, 1 Skin pH
loricrin, involucrin, and 1 Penetration of allergens and microbes
intercellular proteins 1 Proinflammatory cytokines
2 Inflammatory threshold levels
Tight junctions Reduced claudins 2 Skin hydration
1 TEWL
1 Penetration of allergens and microbes
Antimicrobial peptides Decreased cathelicidin (LL-37) 1 Skin infections
and human ␤-defensins 1Cytokine production
Microbiome S. aureus colonization and 2 Expression of filaggrin, loricrin,
decreased bacterial diversity desmocollin1, and keratins
1 Proinflammatory cytokines
1Skin infections
Epidermal lipids Decreased long-chain free fatty 1 TEWL
acids and ceramides 1 S. aureus infections
2 ⫽ decreased; 1 ⫽ increased; TEWL ⫽ transepidermal water loss; S. aureus ⫽ Staphylococcus aureus.

within 1 day of birth with wrinkled skin appearance sential because they are covalently bound to cornified-
and severe dehydration, which provides good evi- envelope proteins and cover the surface of each cor-
dence for the essential role of claudin for the skin neocyte.79 Th2 cytokines reduce levels of long-chain
barrier function.72 FFAs and EO ceramides with a STAT6-dependent
AMPs, including cathelicidin (LL-37) and human manner.17,18,20 The levels of long-chain ceramides were
␤-defensins, are produced by keratinocytes and play a decreased in patients with AD and who were colonized
pivotal role for host defense as well as control of host with S. aureus when compared with those who were
physiologic functions, such as inflammation and wound not colonized. TEWL was negatively correlated with
healing.73 AMP expressions are inhibited by Th2 cyto- levels of these ceramides.80
kines, which are highly produced in AD skin.74 The de-
creased expression of AMPs is associated with a higher MICROBIOME
predisposition to Staphylococcus aureus colonization, AD skin has decreased bacterial diversity associated
which can aggravate AD.75 It has been reported that with increased Staphylococcus, Corynebacterium, and
human ␤-defensins and LL-37 are chemoattractants for with reduced Streptococcus, Propionibacterium, Acineto-
T lymphocytes, monocytes, dendritic cells, and neutro- bacter, Corynebacterium, and Propionibacterium during
phils, and can induce cytokine production by mono- AD flares.81,82 Greater bacterial diversity with in-
cytes and epithelial cells.76,77 These immunomodula- creased abundance of Staphylococcus epidermidis and
tory properties of AMPs have important roles for host Streptococcus, Corynebacterium, and Propionibacterium
defense against infections through activation of im- species was observed after AD treatment and reduced
mune cells as well as their direct antimicrobial activity. eczema.82 Species-level investigation of AD has shown
a higher predominance of S. aureus in patients with
LIPIDS more-severe disease and an abundance of S. epidermidis
Lipids, such as ceramides, long-chain FFAs, and cho- in patients with less-severe disease.83 S. aureus colo-
lesterol, constitute the lipid matrix that is organized in nizes AD skin and has pivotal roles in the development
lamellar bodies and located between corneocytes.78 and exacerbation of AD.84 S. aureus can induce T-cell–
During epidermal differentiation, precursor lipids are independent B-cell expansion; upregulate proinflam-
stored in lamellar bodies within the upper cell layers of matory cytokines, such as TSLP, IL-4, IL-12, and IL-22;
the epidermis and extruded into the extracellular do- and stimulate mast cell degranulation, which results in
main.79 Subsequent enzymic processing produces the Th2 skewing and skin inflammation.85– 88
major lipid classes, which are necessary to maintain the A recent study demonstrated that epidermal thick-
integrity of the epidermal barrier. Altered lipid com- ening and expansion of cutaneous Th2 and Th17 cells
position is observed in lesional and nonlesional AD were induced when mice were exposed to S. aureus
skin.20 In particular, long-chain EO ceramides are es- isolates from patients with AD.83 Of note, methicillin-

Allergy and Asthma Proceedings 87

resistant S. aureus colonization on AD skin is associated larized immune pathways have been newly developed
with lower microbial diversity and a more profound for patients with moderate-to-severe AD. Although
reduction in the composition of commensal bacteria, omalizumab did not show beneficial effects to treat
such as Streptococcus and Propionibacterium, than meth- AD,103,104 dupilumab, a humanized monoclonal antibody
icillin-sensitive S. aureus colonization.89 It is presumed (mAb) to block IL-4 and IL-13, has been approved by
that the differences and shifts in skin microbiome ac- the Food and Drug Administration.105,106 Clinical effi-
cording to AD status are associated with the produc- cacy of dupilumab occurred without significant safety
tion of bacteriocins and AMPs from commensal bacte- concerns in adult patients with AD.105,106 Clinical trials
ria.90,91 In addition, a recent study showed a positive are also underway with dupilumab in pediatric pop-
correlation between the abundance of propionibacteria ulations (NCT02407756, NCT02612454, NCT03054428,
and corynebacteria on epidermis and long-chain un- NCT03346434, NCT03345914). Because the upregula-
saturated FFAs, such as FA20:1, FA20:2, FA22:1, and tion of Th17 and Th22 cytokines have been identified in
FA24:1.92 These findings highlight the importance of patients with AD, the blockade of these pathways is
the balance between S. aureus and commensal bacteria. being investigated by using secukinumab and a human
Patients with AD have significantly lower numbers monoclonal antibody against interleukin-22 (ILV-094;
of intestinal commensal Bifidobacterium and higher NCT02594098, NCT01941537). Moreover, Guttman-
numbers of Staphylococcus than healthy control sub- Yassky et al.107 reported that an anti-IL-22 mAb (fez-
jects.93 Overgrowth of pathogenic bacteria, such as akinumab) showed clinical improvement in patients
Escherichia coli and Clostridium difficile, is postulated as with severe AD.107
being associated with a decrease in beneficial bacteria, A recent study also showed clear trends of therapeu-
reduced induction of regulatory T (Treg) cells, loss of tic effects of ustekinumab, which is an IL-12/IL-23p40
immune tolerance, and increased intestinal permeabil- antagonist, to suppress Th1, Th17, and Th22 immune
ity.94,95 These observations support the hypothesis that activation in adults with moderate-to-severe AD.108
specific microbial composition in the gut prevented However, there was no significant difference between
Th2-shifted immunity and stimulated regulatory im- treatment and placebo groups in that study.108 Another
munity, producing regulatory dendritic cells and Treg Japanese study also did not demonstrate meaningful
cells.96,97 However, further studies are necessary to efficacy of ustekinumab on AD,109 although it is known
elucidate how dysbiosis affects epidermal barrier func- to be effective for psoriasis.110 Nemolizumab (anti–IL-
tion and the development of AD. 31R mAb), lebrikizumab (anti–IL-13 mAb), and traloki-
numab (anti–IL-13 mAb) revealed promising results.106
Other biologic agents, such as Bristol-Myers Squibb-
CLINICAL APPLICATION 981164 (anti–IL-31 mAb), Tezepelumab (anti–TSLP
Frequent application of appropriate moisturizers, mAb), and MK-8226 (anti-TSLP receptor mAb), are
such as physiologic lipid mixtures and ceramide-dom- studied and may offer a range of new therapeutic
inant lipid, is known to help reduce TEWL, enhance options of AD. In addition, topical tofacitinib (JAK1/
skin hydration, decrease bacterial colonization, and im- JAK 3 inhibitor) and oral baricitinib (JAK1/ JAK2 in-
prove skin barrier function, which leads to decreased hibitor) were reported to have reduced skin inflamma-
need for topical corticosteroid.1,98,99 Petrolatum appli- tion and pruritus in patients with AD.111,112
cation has been reported to upregulate AMPs; induce Although topical and systemic antibiotics have been
key barrier differentiation markers, e.g., FLG; and re- used to eradicate bacteria from AD skin, long-term use
duces T-cell infiltration in AD skin.98 Of note, regular has limitations due to the induction of resistant micro-
application of emollients has been reported to reduce organisms and the negative impact on host commensal
the risk of AD development as a primary prevention bacteria. Recent studies reported that a bleach bath is
strategy in infants at high risk.100,101 In addition, a effective for the restoration of skin microbiome and the
recent study demonstrated that topical application of a treatment of AD.113,114 However, a recent meta-analy-
liver X receptor agonist (VTP-38543) improved epider- sis did not show its additional benefits compared with
mal differentiation and lipids in patients with mild-to- water bath alone.115 Interestingly, Nakatsuji et al.116
moderate AD.102 found targeted autologous skin microbiome transplan-
Topical calcineurin inhibitors, such as tacrolimus and tation of S. hominis and S. epidermidis decreased S.
pimecrolimus, inhibit calcineurin-dependent T-cell acti- aureus from AD skin. Another recent study showed
vation, which leads to downregulation of proinflamma- that the topical transplantation with Roseomonas mucosa
tory cytokines.99 Systemic immunosuppressants, includ- improved AD severity and reduced Staphylococcus au-
ing cyclosporine, methotrexate, and azathioprine, are reus colonization.117
used in patients with severe and difficult-to-treat symp- Recent studies demonstrated that appropriate probi-
toms.99 However, these drugs have limitations and ad- otics are beneficial in the prevention and treatment of
verse reactions. Therefore, various biologics to target po- AD through the modulation of host immune re-

88 March 2019, Vol. 40, No. 2

Figure 2. Prevention and treatment of AD. Skin barrier defects are the initial steps in the development of AD. Moisturizer prevents skin
barrier defects and inhibits Staphylococcus aureus colonization in the skin. Oral probiotics may prevent the development of AD and correct
gut microbial dysbiosis. Various biologics, e.g., dupilumab, target immune dysregulation. Antibiotics, bleach batch, and skin microbiome
transplantation inhibit S. aureus colonization and improve cutaneous dysbiosis. AD ⫽ atopic dermatitis; Th ⫽ T helper.

sponses.96,118,119 However, there have still been contro- us to achieve a precision medicine approach to the
versies regarding these clinical effects of probiotics in prevention and the treatment of AD.
patients with AD, which might be due to a difference
in the strains of probiotics and the characteristics of the ACKNOWLEDGMENTS
host. It is noteworthy that the response to probiotics is We thank Samsung Medical Information and Media Services,
greater in patients with an immunologically active Samsung Medical Center for the preparation of figures for this
state characterized by high total immunoglobulin E article.
levels and increased expression of transforming growth
factor ␤ and Treg cells.96 Analysis of these emerging data REFERENCES
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