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Atopic Dermatitis : Mechanism of disease
20/7/2012
Suparat Sirivimonpan,MD.
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• AD is a chronic relapsing inflammatory skin disease
• More than 50% develop asthma
• 75% develop AR
• complex interrelationship of
▫ genetic, environmental, immunologic, and epidermal factors
Mark Boguniewicz, Donald Leung.Middleton’s Allergy 7’th edition 1893-1999
Introduction
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Epidemiology•Affects 15-30% of children, 2-10% of adult•45% begin within the first 6 mo•60% begin during the first yr•85% begin before 5 yrs
•Up to 70%: spontaneous remission before adolescence
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Acute AD• Intensely pruritic, erythematous papule associated with
excoriations, vesiculation, and serous exudate• Pathology : spongiosis (intercellular epidermal edema), superficial
epidermal hypertrophy and acantholysis
• marked infiltration of CD4 activated memory T cells, APCs, (LCs, inflammatory dendritic epidermal cells (IDECs), macrophages), and degranulated mast cell
Histology: Spongiotic area within the epidermis
Adv Immunol.2009;102;135-226
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Chronic AD• thickened plaques with increased lichenification • Pathology : marked epidermal hyperplasia, acanthosis • macrophage-dominated mononuclear cell infiltrate in dermis, and
perivascular accumulation of lymphocytes in smaller numbers than seen in acute AD
Hyperplastic of epidermis with hyperkeratosis
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Pathophysiology of AD
•Genetics •Barrier function of the skin• Immunopathologic mechanism•Autoimmunity
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Genetics of AD • atopic dermatitis–specific genes• related loci on chromosomes 3q21,1q21,16q,17q25, 20p,3p26• loci associated with psoriasis , two disease are rarely linked
genes expressed in skin play important role• do not overlap with allelic variants that are frequent in allergic
asthma
NJEM 2008;358:1483-94Adv Immunol.2009;102;135-
226
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Genetic of AD• two major groups of genes
• (1) genes involved in skin barrier function : FLG, SCCE, SPINK5
• (2) genes involved in the immune response
Adv Immunol.2009;102;135-226
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Genes involved in skin barrier function• strong genetic linkage to Chromosome 1q21 : human EDC
(epidermal differentiation complex )
• Mutations in the FLG (encode filaggrin) gene located on chromosome 1q21.3▫ identified in ichthyosis vulgaris, AD
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N Engl J Med 2011;365:1315-27.
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• 425 Singaporean Chinese patients• All patients : Dx by two paediatric dermatologists according to the U.K.
Working Party’s diagnostic criteria for AD• examined for palmar hyperlinearity and keratosis pilaris• AD severity was graded as mild, moderate or severe according to SCORAD• mean ± SD age was 10 ± 5.18 years (range 1–21) • 68% of patients were male
• Control : Genomic DNA from 440 Singaporean Chinese individuals was obtained from the Singapore Bio Bank
• Unknown IV ⁄AD status• mean ± SD age = 44 ± 14 years (range 1–80), 44.1 % males
Br J Dermatol2011;165:106–114
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Br J Dermatol2011;165:106–114
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• Irish AD cohort is slightly enriched for cases of severe AD (47.8%, defined by the Nottingham Eczema Severity Score) compared with the Singaporean Chinese cohort (39.5%) contributing factor
Br J Dermatol2011;165:106–114
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• palmar hyperlinearity : PPV 34.1% , NPV 85.5%• keratosis pilaris : PPV 31.6%, NPV 79.3%• indicates that patients with AD with the absence of palmar
hyperlinearity and ⁄or keratosis pilaris are unlikely to carry FLG-null mutations
Br J Dermatol2011;165:106–114
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FLG • Null mutations in the FLG gene are predisposing factor for
early-onset AD, which persists into adulthood
• FLG expression is also reduced in AD patients with no FLG mutations
due to local expression of Th2 cytokines IL-4 ,IL-13 : downregulate FLG expression in keratinocytes
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Genes involved in skin barrier functionSCCE (stratum corneum chymotryptic enzyme)• 19q13• play a central role in desquamation by cleaving proteins of
the SC
SPINK5 gene• 5q32• encodes LEKTI (lympho-epithelial kazal-type related
inhibitor) : regulates proteolysis in terminal keratinocyte differentiation
• Mutations in SPINK5 : Netherton’s syndrome▫ many features of AD including dermatitis, eosinophilia, and high IgE level
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Genes involved in skin barrier function• E420K single nucleotide polymorphism (SNP) variant in the
SPINK5 gene ▫ significant association with disease severity ▫ presence of food allergy in children with AD
• Other protease inhibitors with similar roles to SPINK5 are encoded by a cluster of genes on chromosome 20q12, : linked to AD
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Genes involved in the immune responseChromosome 5q31-33• cytokine genes cluster • Th2 : IL-4, IL-5, and IL-13• CD14 antigen • IL-12b subunit (IL-12 p40) (Th1 cytokines)
Chromosome 16q12 • SNPs within the a chain of the IL-4 receptor gene
Adv Immunol.2009;102;135-226J Allergy Clin Immunol
2006;118:24-34
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Genes involved in the immune responseChromosome 11q22.2–22.3• IL-18
Chromosome 1q31–32 • IL-10 gene , anti-inflammatory responses
Chromosome 11q13• FcƐRI gene• associate with AD and asthma
Chromosome 12q24• IL-31, associated with itching
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Genes involved in the immune response• Promoter region of lymphocyte- attracting chemokine
(17q)1
▫RANTES (17q11) (regulated on activation, normal T-cell expressed and secreted)
▫Eotaxin 1 (17q21.1-q21.2)
• Gain-of-function polymorphisms in the α subunit of IL-4 receptor (16q12) 2
• Polymorphisms of the gene encoding IL-18 (11q22) 2
1 J Allergy Clin Immunol 2006;118:24-34
2 NJEM 2008;358:1483-94
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J Allergy Clin Immunol 2006;118:24-34
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Barrier function of the skin
•Physical barrier•Innate immune system
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Barrier function of the skin
• Cornified envelop (CE) :several proteins▫ filaggrin, loricrin, trichohyalin, small
proline-rich proteins, involucrin and keratin intermediate filaments
▫ cross-linked extensively by transglutaminases
▫ epidermal differentiation complex (EDC)
▫ a cluster of genes on human chromosome 1q21
• SC lipid composition : ▫ ceramides (45–50% by
weight)▫ Cholesterol (25%)▫ free fatty acids (10–15%) ▫ less than 5% each of several
other lipids : most important = cholesterol sulfate
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• Profilaggrin : giant inactive precursor, highly phosphorylated polypeptide • main constituent of keratohyalin F granules : granular cell layer• profilaggrin is dephosphorylated and proteolytically cleaved by serine proteases, into
multiple filaggrin polypeptides• filaggrin binds to keratin in a structure aligned parallel to the outer surface of the
epidermisAdv Immunol.2009;102;135-226
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Trends Mol Med.2008;14:20-7
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Filaggrin• filaggrin peptides are further degraded into hydrophilic amino
acids, including urocanic acid, pyrrolidone carboxylic acid, and alanine 1
• Trans-urocanic acid : protection against ultraviolet radiation,modulates immune function 2
• Pyrrolidone carboxylic acid :derivative of glutamine 2
• Arginine residues in filaggrin are converted to citrulline proteolysis short peptides a pool of hygroscopic amino acids and derivatives : natural moisturizing factor (NMF) 2
▫ involves caspase 14 and other proteases
1 Adv Immunol.2009;102;135-2262 N Engl J Med 2011;365:1315-27.
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Profilaggrin• histidine-rich and glutamine-rich proteins• modulate pH of the stratum corneum• promote the retention of moisture• possibly exert antimicrobial activity against
staphylococcus
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N Engl J Med 2011;365:1315-27.
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Physical barrierproteases, and protease inhibitors• Balance • Proteases, especially SC tryptic and chymotryptic enzymes :
desmosome breakdown and corneocyte desquamation
• skin proteases is controlled by protease inhibitors▫ SPINK5, a gene which encodes a putative serine protease
inhibitor, lymphoepithelial Kazal-type-related inhibitor (LEKTI)
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Physical barrier• Changes in pH • Changes in the cornified envelope proteins involucrin and
loricrin or lipid composition• Decrease in ceramide• Underlying inflammation can alter the expression of genes
such as FLG
increase in skin penetration of allergen and increased TEWL + pruritus inflammation and sensitization
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Innate immune system
•protect skin against infection▫Pathogen associated molecular pattern
(PAMP) molecules VS Pattern recognition receptors (PRRs)
▫Antimicrobial peptides (AMPs)
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PAMPs and PRRs• Toll-like receptors (TLRs) (TLR1-11) • 39 C-type lectins• nucleotide-binding oligomerization domain–like receptors• peptidoglycan-recognition proteins (PGRPs) (4)
• expressed on macrophages, DCs, PMNs, mucosal epithelial, and endothelial cells
Adv Immunol.2009;102;135-226
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Antimicrobial peptides (AMPs)
• expressed by keratinocytes and cells that form sebaceous and sweat glands, mast cells, circulating cells (PMNs,NK)
• Antimicrobial action against bacteria, viruses, and fungi
• 2 major classes ▫cathelicidins ▫defensins
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Innate immune system
• TH2 cytokine (prominent in AD) : IL-4, IL-13 down-regulates antimicrobial peptides in skin difficult to manage microbial infections
• Lesional and normal looking skin is extensively colonized by bacteria such as Staphylococcus aureus or fungi such as malassezia
• predisposed to eczema herpeticum and eczema vaccinatum (decrease cathelicidin potent antiviral activity)
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Immunopathologic mechanisms• Early-onset atopic dermatitis : absence of IgE-mediated
allergic sensitization• IgE mediated sensitization often occurs several weeks or
months after the lesions appear▫some children (mostly girls) —no IgE-mediated allergic
sensitization
• The initial mechanisms that induce skin inflammation in patients with atopic dermatitis are unknown
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Immunopathologic mechanisms• neuropeptide-induced, irritation-induced, or pruritus-induced
scratching, which releases proinflammatory cytokines from keratinocytes
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Key cell in AD
•T lymphocytes•Dendritic cells (DCs)•Keratinocytes•Mast cells•Eosinophils
J Allergy Clin Immunol 2006;118:152-69
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T lymphocyte• LCs and DCs present antigen to recirculating naive T cells• proliferation and differentiation into memory/effector cells that express skin
homing receptors such as ▫ cutaneous lymphocyte antigen (CLA)▫ CCR4, and CCR10
• Antigen-specific effector CD4 T cells leave LN into the circulation and re-enter the skin, via their skin specific receptors proliferate and secrete cytokine
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T lymphocyte• Skin homing cutaneous lymphocyte antigen (CLA +) T cell
▫ CLA : inducible carbohydrate modification of P-selectin glycoprotein ligand-1, memory T cells (absent on naïve)
▫ facilitates binding of T cells to E-selectin▫ distinct capacity to home to the skin through expression of
the skin-homing receptor CLA 90% of infiltrating T cells
▫ IL-4 and IL-13 like TH2 ▫ produce IL-31 Pruritus
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J. Clin. Invest.2004;113:651–657
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• Cytokines : ▫TNF-a and IL-1 ▫keratinocytes, mast cells, and DCs▫expression of vascular endothelial cell adhesion
molecules esp. VCAM-1, E-selectin, CD54
• Chemokines :▫Keratinocyte, LC▫RANTES, MCP-4, eotaxin : Eo, TH2 type lymphocyte ▫ IL-16 : CD4+ T cell▫CTACK/CCL27 : CTA+ T cell ▫CCL1, CCL18
• extravasation of inflammatory cells
J Allergy Clin Immunol 2006;118:152-69Mark Boguniewicz, Donald Leung.Middleton’s Allergy 7’th edition 1083-1099
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Predominant TH2 profile • TLSP : keratinocyte , LC
• TH1 cells : high IFN-ɣ–producing increased apoptosis both TH1 and TH2 (TH1 > TH2 cells)
• Increased expression of Fas, Fas-ligand, tumor necrosis factor receptor-II, and caspase activation was detected on TH1 cells
• IFN-ɣ keratinocyte apoptosis
J Allergy Clin Immunol 2008;121:652-8
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T lymphocyte• more chronic : expression of IFN-ɣ, IL-12, GM-CSF • The mechanism : switch from Th2 to Th1 type
▫ is not well understood▫ IDEC (Inflammatory dendritic epidermal cells) : IL12,18▫ could be related to microbial products TLR2 is important
for Th1 response to cutaneously introduced antigen
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T lymphocyte : T regT regulatory (CD4+CD25+FOXP3) • Immunosuppressive function • Inhibit development of both TH1 and TH2 responses• Increased in peripheral blood with normal immunosuppressive
activity• decreased in lesion
• Staphylococcal superantigens subvert Treg cell function▫ > 90% of patients have S. aureus colonization▫ enhanced effector T cell activation skin inflammation
J Allergy Clin Immunol 2006;117:418-25
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IL-31
• cutaneous and peripheral blood CLA+ T cells : source• correlation between IL-31 serum levels with the severity of AD
• staphylococcal enterotoxin rapidly induces IL-31 expression in lymphocytes,monocytes and macrophages (but not on dendritic) infection lead to exacerbation of pruritus
• IL-31 induces expression of the inflammatory T cell attracting chemokines CCL17/TARC and CCL22/MDC (keratinocytes)
• IL-31 enhanced secretion of IL-1, IL-6 and IL-18 and up-regulated CD86 expression
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Allergy 2010; 65: 712–721
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T lymphocyte : Th17 cell• markedly in acute than chronic AD lesions • number of Th17 cells is increased in the peripheral blood of AD • IL-17 serum levels are elevated
• IL-17 stimulates keratinocytes to produce GM-CSF, TNF-a, IL-8, CXCL10, and vascular endothelial growth factor (VEGF), and HBD-2
• produce IL-22• marked synergistic effect between IL-17 and IL-22 was
observed on IL-8 and AMP production
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Dendritic Cells• 2 myeloid dendritic cells (high-density display of FcεRI)
▫ Langerhans’ cells : normal skin▫ Inflammatory dendritic epidermal cells(IDEC) : only in
inflamed skin• Epidermal dendritic cells bear IgE and express its high-affinity
receptor(FcεRI)
• In skin lesions, dendritic cells of the plasmacytoid lineage (potent antiviral activity IFN-α production) are almost absent viral infection
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Keratinocyte• cutaneous immune responses • production of proinflammatory cytokines, chemokines, AMPs
activation and recruitment of DCs, T cells, other leukocyte amplify and maintain skin inflammation
• Itch induced scratching :release of proinflammatory cytokines and chemokines
• Atopic keratinocyte-derived GM-CSF : proliferation and differentiation of peripheral blood monocytes into mature DCs in presence of IL-4
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Keratinocyte• IL-1 and IL-18
▫ inactive precursors in keratinocytes▫ converted to active forms by CASP1 enzyme after
stimulation by danger signals▫ amount of active IL-18 in serum increases with
exacerbation of their disease
• TSLP ▫ Microbial products, physical injury, or inflammatory
cytokines, including proinflammatory (TNF-α and IL-1α) and Th2 (IL-4 or IL-13) cytokines induce TSLP
▫ polarizes human DCs to skew the T cell response to Th2 Adv Immunol.2009;102;135-226
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Keratinocyte• activated skin-infiltrating T cell can upregulate Fas
expression on keratinocytes keratinocyte apoptosis spongiosis (key pathogenic event in AD)
• overexpress numerous chemokines activation and recruitment▫CCL20/MIP-3α, CCL27, CCL17/TARC, CCL22/MDC
- attract DCs and T cells▫CCL20/MIP-3α - recruitment of CCR6-expressing
immature DCs and memory/effector T
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Keratinocyte• Keratinocyte-derived AMPs (antimicrobial peptide) : innate
▫ β-defensins (HBD-2 and HBD-3), and cathelicidin, hCAP18/ LL-37
• Expression of HBD-2, HBD-3, and hCAP18/LL-37 is significantly decreased in acute and chronic AD skin lesions compared to psoriasis skin lesions
• IL-13 and IL-4 inhibit production of HBD-3 by keratinocytes• Th2 cytokine may suppress innate immune response against
bacterial and viral pathogens
• Decreased AMPs in AD skin may contribute to its susceptibility to infections
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Mast cell • early stage AD : normal numbers but undergo degranulation in the
affected skin• late stage AD : increased number, but without degranulation
• Mast cell-derived histamine, mast cell proteinases enzymes tryptase and chymase (MCC), and other inflammatory mediators pruritus and inflammation
• Histamine upregulates production• inflammatory cytokines by keratinocytes• Increased proteinase activity skin barrier defect
Adv Immunol.2009;102;135-226
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Eosinophil• common findings in AD
▫ Peripheral blood eosinophilia▫ elevated serum levels of eosinophil granule proteins,
basic proteins eosinophil cationic protein (ECP), eosinophil-derived neurotoxin (EDN) major basic protein (MBP)
• correlate with disease activity• increased expression : eosinophil chemotactic factor
CCL11/eotaxin and of IL-5 and IL-5Rα in acute and chronic skin lesions , blood in AD patients
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J Allergy Clin Immunol 2006;118:152-69
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Eosinophil
• Eosinophils are recruited and activated by IL-5 and IL-13
inflammation and tissue damage
• Inhibition of eosinophil apoptosis in AD : IL-5 ,GM-CSF
• Eosinophils : switching TH1 response by IL-12
• more pronounced in chronic AD
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NK cell • release of perforin and granzyme • Release proinflammatory cytokines such as IFN-g, TNF-a,
GM-CSF, IL-5, and IL-8 recruitment of other innate immune cells
• Circulating CD56+CD16+ NK cells are reduced but increases in lesional skin with severity of disease
• NK : functionally defective in AD ▫ MHC-nonrestricted cytotoxicity against standard NK-
sensitive target cells▫ reduced release of IFN-ɣ
• Decreased NK activity skin infection
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PMNs• lack of detectable PMNs in skin lesion• PMN chemotactic defect
▫ found to correlate with markers of AD disease severity, serum IgE levels, and skin bacterial infection
• PMN functions are impaired especially during infectious period ▫ impaired phagocytosis, reduced capacity to produce reactive oxygen
species, impaired release of β-glucuronidase, defective leukotriene B4 production and release
▫ absent deposition of extracellular PMN granule proteins (lactoferrin and PMN elastase)
• contribute to the susceptibility of AD skin to infection
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J. Clin. Invest.2004;113:651–657
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Autoimmunity in Atopic Dermatitis• In addition to IgE antibodies against food and aeroallergens• Serum from patients with severe atopic dermatitis contain IgE
antibodies against proteins from keratinocytes and endothelial cells ▫ manganese superoxide dismutase▫ calcium-binding proteins
• serum levels of these IgE autoantibodies correlate with disease severity
• Scratching probably releases intracellular proteins from keratinocytes
• These proteins could be molecular mimics of microbial structures induce IgE autoantibodies
NJEM 2008;358:1483-94
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Autoimmunity in Atopic Dermatitis• 25% of adults AD : IgE antibodies against self-proteins• these patients, early-onset atopic dermatitis, intense pruritus,
recurrent bacterial skin infections, and high serum IgE levels are hallmarks of disease
• IgE antibodies against self-proteins can be detected in patients with atopic dermatitis as early as 1 year of age
• IgE antibodies against autoantigens in skin can perpetuate the allergic inflammation
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Gene–Gene and Gene–Environment Interactions in the Natural History of Atopic Dermatitis
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Thank you for your attention…