/피부과

김 현 정 caspase@hanmail.et

Hyunjung Kim M.D, ph.D

Department of Dermatology , Atopy and Asthma center, Seoul Medical Center Research Institute

Seoul Medical Center, Seoul, Korea

Intrinsic AD Extrinsic AD

Incidence • Percentage of intrinsic AD in total AD: 20% in K

orea

• Female predominance (collectively 70–80%)

• More prevalent in children than adults

• 80% in Korea

Clinical features • Dennie-Morgan fold

• No ichthyosis vulgris or palmar hyperlinearity

• No non-specific hand or foot eczema

• Lower colonization of Staphylococcus aureus

• Relative late onset

• Milder severity

• personal or family history of atopy

• recurrent conjunctivitis

• palmar hyperlinearity

• keratosis pilaris

• pityriasis alba

• non-specific hand or foot eczema

• influence of emotional or environme

ntal factors

Skin barrier

function

• Normal barrier function

• No filaggrin mutation

• Increased TEWL and lower skin surf

ace hydration on both lesional and n

onleasional skin

Pruritus perception • Normal barrier function and sensory reactivity to

external pruritic stimuli

• No correlation with the skin surface

hydration and inversely with TEWL

Immunological

features

• Lower expression of IL-4, IL-5, and IL-13

• Higher expression of IFN-g

• High CCL17/TARC and CCL22/MDC

• High peripheral blood mononuclear cell expressi

on of CCL17 and CCL22

• Elevation of IL-5 , eosinophil counts

,eosinophil cationic protein levels

• Decreased capacity to produce IFN-

g and GM-CSF

• No difference in the promoted produ

ction of chemokines attractive to Th

2 cells

• No significant difference in the eleva

ted amounts of sCD23, sCD25, and s

CD30 between the two types

Contact allergens • High prevalence of metal allergy

Significantly low incidence of FLG mutations in IgE low group- IgE-low cases (10.5%) had mutations in FLG, whereas 8 of 18 IgE-high patients (44.4%)

Higher circulating Th1 cell frequency in the IgE-low group The percentage of IFN-g+ T cells was significantly higher in the IgE-low than IgE-high group There was no significant difference in the IL-4, IL-5 or IL-17-positive cell frequency between the two

types. Downregulation of B cell IgE production by IFN-g

Higher Blood levels of CCL17/TARC in the IgE-high AD groups SP levels were same level and correlated with the itch levels in both

groups This may imply that neurogenic inflammation is not a characteristic feature

of intrinsic AD

Kabashima-Kubo R, et al. J Dermatol Sci (2012) http://dx.doi.org/10.1016/j.jdermsci.2012.04.004

FILAGGRIN HAPLOINSUFFICIENCY Lack of filaggrin protein resulting from a heterozyous loss-of-function mutation Ichthyosis vulgaris keratosis pilaris Xerosis Palmoplantar hyperlinearity Atopic dermatitis

FLG-null mutations is that of early-onset, severe, and persistent disease and with the associated ‘‘extrinsic’’ features of raised total IgE and allergic sensitization

Mild–moderate eczema shows a lower odds ratio than moderate–severe eczema, and its association with FLGnull mutations may be significant only in individuals carrying two null mutations

FLG LOSS-OF-FUNCTION MUTATIONS SHOW POPULATION SPECIFICITY

Irvine AD et al. N Engl J Med 2011;365:1315-27

Filaggrin deficiency and possible mechanisms of disesase

Filaggrin haploinsufficiency and increased risk of several complex traits

Irvine AD et al. N Engl J Med 2011;365:1315-27

Br J Dermatol 2010; 163:1333-1336

Early onset, severe, persistent to adulthood, atopy march associated ‘‘extrinsic’’ features of raised total IgE and allergic sensitization

Filaggrin loss-of-function mutation in AD

Large Swedish prospective birth cohort (BAMSE) to investigate the association between FLG mutations and dry skin and eczema, divided into AE and non-AE, at age 8 years.

FLG mutations increase the risk for persistent dry skin, persistent eczema at age 8 years, without interactions between FLG mutations and siblings or cat in the household at birth.

• SC IL-1 levels were

increased in patients with

ADFLG; these levels were

inversely correlated with

NMF levels.

• NMF values were also

inversely correlated with

skin surface pH.

• Skin and keratinocytes

from Flgft/Flgft mice had

up regulated expression of

IL-1b and IL-1RA mRNA

J Allergy Clin Immunol 2012;129:1031-9

ENVIRONMENT

„Tissue-related“ genes

(FLG, LEKTI,….)

Allergens

Environmental factors

Impaired epidermal barrier

Sensitization to allergens

GENES

Receptors, cytokines, etc..

Scratching/Tissue dammage

autoallergic atopic

dermatitis

„Atopic“ genes (cytokines, innate,

receptors,…)

Staph. A.

Sensitization to self-proteins

Allergic Rhinitis Asthma

„IgE-associated“ atopic

dermatitis +/-

Ep

ige

ne

tic r

eg

ula

tio

n

The natural history of atopic dermatitis

Adapted from Bieber T., N Eng J Med, 2008, 358:1483-1494

„Non-IgE“ associated

Infantile eczema

Skin's barrier function has three elements: 1. Stratum corneum (air-liquid barrier) 2. Tight junctions (liquid-liquid barrier) 3. Langerhans cell network (immunological barrier)

障壁派 免疫派

SC barrier damages induce danger signals in the epidermis.

After SC barrier abrogation, protease-active allergens and uncontrolled intrinsic proteases, as well as bacterial molecules such as lipoteichoic acid of gram-positive bacteria, might agonize Par2 and TLRs on keratinocytes, respectively Keratinocytes then produce TNF-α, IL-1, and thymic stromal lymphopoietin (TSLP) in response to which LCs become activated .

Alternatively, protease-active allergens might directly obscure the TJ barrier and then penetrate the epidermis , where they directly or indirectly activate LCs.

Upon SC perturbation, dendrites of activated LCs penetrate the TJs to take up protease-active or -inactive antigens from the extra-TJ environment .

Such percutaneous sensitization and chronic allergen challenge via different routes, such as the lungs, nasal cavities, and intestinal tract, are speculated to manifest as the atopic march.

Primary barrier defects lead to the release of a number of epidermal derived mediators including ones that are considered pro-Th2 and pro-Th17.

Some of these cytokines are released in an autocrine manner through proteinase-activated receptor (PAR)-2 activation or by epithelial-derived ‘‘danger signals’’ that act on innate immune receptors expressed on keratinocytes.

The presumption is that barrier disruption comes in different flavors, each resulting in a specific adjuvant profile that would either favor a Th2, Th17, or another adaptive immune response to an antigen.

Endogenous danger-associated molecular patterns or alarmins, such as Hsp70, Hsp90, and IL-33, could activate innate receptors following epidermal injury

Several Th2 and Th17 products establish an autocrine feedback loop and further aggravate barrier disruption (e.g., secondary barrier defects). To date, this has been best characterized for Th2 cytokines

Th2

IL-4

LC Th

Ig E↑

IL-4,5,13

Inflammation

Skin Barrier Homeostasis

Filaggrin ,loricrineNHE1,involucrin

expressions

Desmoglein3 expressions

Antimicrobial peptides

expressions

Ceramide synthesis

IL31,IL20,24, IL25, IL22

J Clin Cell Immunol. 2011 August 10; 2(3): . doi:10.4172/2155-9899.1000110

Modified from Dr.Seung Hun Lee’s WDC 2012 presentation

Trigger factors such as allergens, bacteria, mechanical injury, and exogenous proteases induce the release of IL-33, IL-25, and thymic stromal lymphopoietin (TSLP) from keratinocytes.

IL-33, alone or in combination with other cytokines and chemokines, activates mast cells, dendritic cells, and (potentially) lymphocytes of innate lineage in inflamed skin.

Activation of mast cells regulates the function of dendritic cells, eosinophils, T cells, and nerves (not shown) via release of cytokines, chemokines, growth factors, proteases, and leukotrienes, for example.

Via the IL-33–induced release of IL-25 and IL-18, dendritic cells regulate the function of T helper type 2 (Th2) cells and B cells (early) and (probably later) Th1 cells.

Via IL-33 induction, innate lymphoid cells (ILCs) regulate Th2-driven immune responses in various organs. The role of these potentially important cells in Th2 regulation has not been verified in skin. ILCs have been described to be important in the early stage of immune signaling and probably enhance the Th2 immune response pathway in the skin. The arrows illustrate the interaction among the various immune cells and their cell-specific secretion products involved in inflammatory skin diseases, including atopic dermatitis.

Thus, IL-33 may be involved in orchestrating early inflammatory responses in the onset and perpetuation of atopic dermatitis

Potential role of IL-33 and ST2 (suppression of tumorigenicity 2) in skin inflammation and pathophysiology of atopic dermatitis

J Clin Cell Immunol. 2011 August 10; 2(3): . doi:10.4172/2155-9899.1000110

J Clin Cell Immunol. 2011 August 10; 2(3): . doi:10.4172/2155-9899.1000110

produced primarily by Th2 cells

mast cells secrete IL-31 and other pruritogenic mediators upon stimulation with human b-defensins and cathelicidin

Signals through the IL-31 receptor a (IL-31RA)/ oncostatin M receptor b (OSMRb) heterodimeric complex, which activates the Janus kinase (JAK)-signal transducer and activator of transcription (STAT), mitogen-activated protein kinase, and phosphoinositide-3-kinase (PI3K) signaling pathways

Dendritic Cells Activated by IFN-g/STAT1 Express IL-31 Receptor and Release Proinflammatory Mediators upon IL-31 Treatment

The Journal of Immunology, 2012, 188: 5319–5326

Pruritogenic cytokines in transgenic murine model and AD pt.

IL-31 receptor expression is higher in the dorsal root ganglia of the sensory neurons

role for IL-31 in regulation of scratching behavior in AD

BJD 04-May-2012

Correlation of IL-31 with SCORAD score and Th2 cytokines including IL-4 and IL- 13 in children with extrinsic atopic dermatitis

In murine model, IL31 levels correlate wit h scratching behavior. But , in this human study icorrelated with sleepness

There was no correlation of IL-31 with pruritus, total IgE Ab, and ECP levels, whereas ECP levels significantly correlated with the SCORAD score in children with extrinsic atopic dermatitis

IL-31 interferes with keratinocyte proliferation.

IL-31 inhibits keratinocyte differentiation.

The expression of filaggrin, a protein essential for skin barrier function, is reduced by IL-31.

A cooperative effect of IL-31 and mutations in the gene encoding filaggrin on the AD phenotype is proposed

J Allergy Clin Immunol 2012;129:426-33

Interleukin-17A, interleukin-17F, interleukin-21 and interleukin-22

important in the regulation of innate immunity particularly in neutrophil recruitment, and have more recently been implicated in allergic disorders such as HIES

higher in acute AD skin lesions, compared to chronic lesion or normal skin

In vitro treatment of keratinocytes with IL-17 induced expression of several anti-microbial peptides including β- defensin

IL-17 expression is induced following OVA sensitization in the absence of the Th2 cytokines IL-4 and IL-13

Since the filaggrin mutant mice showed a baseline Th17 profile, and a mixed Th1, Th2, Th17 profile following cutaneous ovalbumin challenge , the precise role of Th17 cells, and the relationship with barrier defects and Th2 cells merits additional exploration.

produced by TH17, TH1, natural killer, or natural killer T cells

CD4+ or CD8+ T cells producing IL-22 alone (T22) infiltrate into chronic AD lesions(higher expression in AD than in psoriatic lesions)

Remodeling and wound healing

Induction of epidermal hyperplasia-> likely to contribute to the epidermal acanthosis seen in the chronic stage

Induced by the staphylococcal enterotoxin B(SEB) and alph toxin

Induces proliferation and suppresses terminal differentiation of keratinocytes

IL-22 and oncostatin M may enhance hBD-2 production via STAT3 in keratinocytes, while hBD-2 may enhance IL-22 and oncostatin M production in T cells.

Immunobiology 217 (2012) 436– 445

Mol Cell Biochem (2011) 353:41–46

Drive Th17 cell differentiation

Detected in acute lesion of AD

Critical regulator of the processes that lead to sensitization and allergic inflammation of the skin

Journal of Dermatological Science 60 (2010) 61–66

Th9 cells producing IL-9 and IL-10

important stimulus for tissue infiltration by mast cells, eosinophils,etc

particular gene (rs31563 (-4091G⁄A) SNP) was associated with the AD phenotype in Korea group

Serum Interleukin-9 Levels Are Associated With Clinical Severity in Children With Atopic Dermatitis

Gene-expression of IL-9 and IL-9 receptor is significantly increased in lesional skin areas of atopic dermatitis (AD)

IL-9 stimulates VEGF production in human mast cells

Pediatric Dermatology 1–4, 2012

J Dermatol Sci 2011; 62:16–21

PLoS ONE 7(3): e33271

Summary of target cells & pathways for individualized therapeutic approaches

Anti-IL17 Blocking

IL-21/IL21R

Specific Immunoth

erapy

Anti-CD20 Anti-IgE

VitD

Pimecrolimus Bcl-3 siRNA

Anti-IL-22 Anti-IL-9

Blocking H4R Blocking

IL-31/IL-31R

We also replicated association with the FLG locus and with two recently identified association signals at 11q13.5 (rs7927894; P = 0.008) and 20q13.33 (rs6010620; P = 0.002).

Our results underline the importance of both epidermal barrier function and immune dysregulation in atopic dermatitis pathogenesis.

Nature Genetics VOLUME 44 | NUMBER 2 | FEBRUARY 2012

ENVIRONMENT

„Tissue-related“ genes

(FLG, LEKTI,….)

Allergens

Environmental factors

Impaired epidermal barrier

Sensitization to allergens

GENES

Receptors, cytokines, etc..

Scratching/Tissue dammage

autoallergic atopic

dermatitis

„Atopic“ genes (cytokines, innate,

receptors,…)

Staph. A.

Sensitization to self-proteins

Allergic Rhinitis Asthma

„IgE-associated“ atopic

dermatitis +/-

Ep

ige

ne

tic r

eg

ula

tio

n

The natural history of atopic dermatitis

Adapted from Bieber T., N Eng J Med, 2008, 358:1483-1494

„Non-IgE“ associated

Infantile eczema