hyunjung kim m.d, ph.d 피부과 department of …department of dermatology , /피부과 김 현 정...
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/피부과
김 현 정 [email protected]
Hyunjung Kim M.D, ph.D
Department of Dermatology , Atopy and Asthma center, Seoul Medical Center Research Institute
Seoul Medical Center, Seoul, Korea
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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
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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
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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
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Irvine AD et al. N Engl J Med 2011;365:1315-27
Filaggrin deficiency and possible mechanisms of disesase
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Filaggrin haploinsufficiency and increased risk of several complex traits
Irvine AD et al. N Engl J Med 2011;365:1315-27
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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
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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.
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• 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
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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
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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)
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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.
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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
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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
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J Clin Cell Immunol. 2011 August 10; 2(3): . doi:10.4172/2155-9899.1000110
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Modified from Dr.Seung Hun Lee’s WDC 2012 presentation
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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
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J Clin Cell Immunol. 2011 August 10; 2(3): . doi:10.4172/2155-9899.1000110
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J Clin Cell Immunol. 2011 August 10; 2(3): . doi:10.4172/2155-9899.1000110
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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
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BJD 04-May-2012
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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
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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
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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.
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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
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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
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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
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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
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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
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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
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