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Atopic dermatitis: mechanism of disease

  1. 1. Atopic Dermatitis : Mechanism of disease 20/7/2012 Suparat Sirivimonpan,MD.
  2. 2. Introduction • 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 893-1999
  3. 3. 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 NJEM 2008;358:1483-94 NJEM 2008;358:1483-94
  4. 4. 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
  5. 5. 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 Adv Immunol.2009;102;135-226
  6. 6. Pathophysiology of AD • Genetics • Barrier function of the skin • Immunopathologic mechanism • Autoimmunity NJEM 2008;358:1483-94
  7. 7. 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 Adv Immunol.2009;102;135-226 NJEM 2008;358:1483-94
  8. 8. 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
  9. 9. 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 Adv Immunol.2009;102;135-226
  10. 10. N Engl J Med 2011;365:1315-27.
  11. 11. • 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
  12. 12. Br J Dermatol2011;165:106–114
  13. 13. • 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
  14. 14. • 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
  15. 15. 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 Adv Immunol.2009;102;135-226
  16. 16. Genes involved in skin barrier function SCCE (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 Adv Immunol.2009;102;135-226
  17. 17. 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 Adv Immunol.2009;102;135-226
  18. 18. Genes involved in the immune response Chromosome 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;135-226 J Allergy Clin Immunol 2006;118:24-34
  19. 19. Genes involved in the immune response Chromosome 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 Adv Immunol.2009;102;135-226
  20. 20. 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
  21. 21. J Allergy Clin Immunol 2006;118:24-34
  22. 22. Barrier function of the skin • Physical barrier • Innate immune system NJEM 2008;358:1483-94
  23. 23. 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 J Clin Invest.2006;116:1150-58 Adv Immunol.2009;102;135-226
  24. 24. • 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 epidermis Adv Immunol.2009;102;135-226
  25. 25. Trends Mol Med.2008;14:20-7
  26. 26. 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;135-226 2 N Engl J Med 2011;365:1315-27.
  27. 27. Profilaggrin • histidine-rich and glutamine-rich proteins • modulate pH of the stratum corneum • promote the retention of moisture • possibly exert antimicrobial activity against staphylococcus N Engl J Med 2011;365:1315-27.
  28. 28. N Engl J Med 2011;365:1315-27.
  29. 29. Physical barrier proteases, 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) Adv Immunol.2009;102;135-226
  30. 30. 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 NJEM 2008;358:1483-94
  31. 31. Innate immune system • protect skin against infection ▫ Pathogen associated molecular pattern (PAMP) molecules VS Pattern recognition receptors (PRRs) ▫ Antimicrobial peptides (AMPs) Adv Immunol.2009;102;135-226
  32. 32. 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 NJEM 2008;358:1483-94 Adv Immunol.2009;102;135-226
  33. 33. 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 Adv Immunol.2009;102;135-226
  34. 34. 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) NJEM 2008;358:1483-94
  35. 35. 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 NJEM 2008;358:1483-94
  36. 36. Immunopathologic mechanisms • neuropeptide-induced, irritation-induced, or pruritus-induced scratching, which releases proinflammatory cytokines from keratinocytes NJEM 2008;358:1483-94
  37. 37. NJEM 2008;358:1483-94
  38. 38. Key cell in AD • T lymphocytes • Dendritic cells (DCs) • Keratinocytes • Mast cells • Eosinophils J Allergy Clin Immunol -
  39. 39. 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 Adv Immunol.2009;102;135-226
  40. 40. 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 J Allergy Clin Immunol 2006;117:418-25
  41. 41. J. Clin. Invest.2004;113:651–657
  42. 42. • 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 Mark Boguniewicz, Donald Leung.Middleton’s Allergy 7’th edition 083-1099 -
  43. 43. 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
  44. 44. 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 Adv Immunol.2009;102;135-226
  45. 45. T lymphocyte : T reg T 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 J Allergy Clin Immunol 2006;117:418-25 • Staphylococcal superantigens subvert Treg cell function ▫ > 90% of patients have S. aureus colonization ▫ enhanced effector T cell activation  skin inflammation Adv Immunol.2009;102;135-226
  46. 46. 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 Adv Immunol.2009;102;135-226 Allergy 2010; 65: 712–721
  47. 47. 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 Adv Immunol.2009;102;135-226
  48. 48. 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 Adv Immunol.2009;102;135-226 NJEM 2008;358:1483-94
  49. 49. 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 Adv Immunol.2009;102;135-226
  50. 50. 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 J Allergy Clin Immunol 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
  51. 51. 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 Adv Immunol.2009;102;135-226
  52. 52. 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 Adv Immunol.2009;102;135-226
  53. 53. 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
  54. 54. 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 J Allergy Clin Immunol - Adv Immunol.2009;102;135-226
  55. 55. 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 J Allergy Clin Immunol - Adv Immunol.2009;102;135-226
  56. 56. 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 Adv Immunol.2009;102;135-226
  57. 57. 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 Adv Immunol.2009;102;135-226
  58. 58. J. Clin. Invest.2004;113:651–657
  59. 59. 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
  60. 60. 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 NJEM 2008;358:1483-94
  61. 61. Gene–Gene and Gene–Environment Interactions in the Natural History of Atopic Dermatitis NJEM 2008;358:1483-94
  62. 62. Thank you for your attention…

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