Cutaneous Immunology

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Cutaneous Immunology

  1. 1. CUTANEOUS IMMUNOLOGY นพ . สุรสฤษดิ์ ขาวละออ 9/9/2009
  2. 2. CONTENTS <ul><li>Normal skin structure </li></ul><ul><li>Cutaneous immunology </li></ul><ul><ul><li>-innate immunity </li></ul></ul><ul><ul><li>-IL-1 </li></ul></ul><ul><ul><li>-complement activation </li></ul></ul><ul><ul><li>-PRRs </li></ul></ul><ul><ul><li>-Langerhans’ cell & dermal DC </li></ul></ul><ul><ul><li>-acquired immunity </li></ul></ul><ul><ul><li>-role of T & B cell </li></ul></ul>
  3. 3. NORMAL SKIN STRUCTURE <ul><li>Three functional layers </li></ul><ul><li>-epidermis 150 µm </li></ul><ul><li> thick </li></ul><ul><li>-horny layer </li></ul><ul><li>-clear layer </li></ul><ul><li>-granular layer </li></ul><ul><li>-basal layer </li></ul><ul><li>-basal membrane </li></ul><ul><li>-dermis or corium </li></ul><ul><li>2,800 µm thick </li></ul><ul><li>-subcutis </li></ul><ul><li>(hypodermis ) </li></ul>
  4. 4. NORMAL SKIN STRUCTURE <ul><li>1 Epidermis </li></ul><ul><li>2 Dermis </li></ul><ul><li>3 Subcutis </li></ul><ul><li>4 Hair follicle </li></ul><ul><li>5 Sebaceous gland </li></ul><ul><li>6 Sweat gland </li></ul>
  5. 5. NORMAL SKIN STRUCTURE <ul><li>1 Horny layer </li></ul><ul><li>(stratum corneum) </li></ul><ul><li>2 Clear layer </li></ul><ul><li> (stratum lucidum) </li></ul><ul><li>3 Granular layer </li></ul><ul><li>(stratum granulosum) </li></ul><ul><li>4 Prickle-cell layer </li></ul><ul><li> (stratum spinosum) </li></ul><ul><li>5 Basal layer </li></ul><ul><li> (stratum basale) </li></ul><ul><li>6 Basal membrane </li></ul>
  6. 6. NORMAL SKIN STRUCTURE
  7. 7. NORMAL SKIN STRUCTURE <ul><li>Dendritic cells in cutaneous immunity </li></ul><ul><li>The Langerhans’ cells(epidermal DC) </li></ul><ul><li>-LC arise in BM </li></ul><ul><li>-controversy about whether LC </li></ul><ul><li> descended from myeloid or lymphoid </li></ul><ul><li> progenitor but evidence suggest </li></ul><ul><li> myeloid origin </li></ul>Carole L. Berger.IJBCB 2006;38:1632-1636
  8. 8. NORMAL SKIN STRUCTURE <ul><li>The Langerhans’ cells(cont.) </li></ul><ul><li>-can differentiate from monocytes or </li></ul><ul><li> CD34 precursors(CD34=precursors of </li></ul><ul><li> hemopoietic cells/endothelium in high </li></ul><ul><li> endothelial venules) </li></ul><ul><li>-mediators of LC differentiation from </li></ul><ul><li> peripheral monocytes include TGF- β , </li></ul><ul><li> GM-CSF, IL-4 and Notch ligand δ -1 </li></ul>Carole L. Berger.IJBCB 2006;38:1632-1636
  9. 9. NORMAL SKIN STRUCTURE <ul><li>The Langerhans’ cells(cont.) </li></ul><ul><li>-keratinocyte secrete TGF- β , GM-CSF </li></ul><ul><li> and δ -1 </li></ul><ul><li>- LC express CCR6 Rc for MIP-3 α </li></ul><ul><li> (CCL20) by keratinocytes </li></ul><ul><li>- LC that endocytosed Ag and be </li></ul><ul><li> activated by inducible innate response </li></ul><ul><li> may directly present Ag to skin-resident </li></ul><ul><li> memory T cells or exit skin via lymph </li></ul><ul><li> vessels </li></ul>N Franklin. Middleton’s allergy 7th edition 2009
  10. 10. NORMAL SKIN STRUCTURE <ul><li>The Langerhans’ cells(cont.) </li></ul><ul><li>- in LN  LC process and present Ag </li></ul><ul><li> peptide to naïve T cells initial step to </li></ul><ul><li> develop acquired immunity </li></ul><ul><li>- LC can induce tolerance to self-Ag if </li></ul><ul><li> take up apoptotic material through </li></ul><ul><li> stimulation of T-regulatory cells which </li></ul><ul><li> inhibit immune responses </li></ul>Carole L. Berger.IJBCB 2006;38:1632-1636
  11. 11. NORMAL SKIN STRUCTURE <ul><li>Dermal dendritic cells </li></ul><ul><li>two types of DDC </li></ul><ul><li>1.interstitial DDC </li></ul><ul><li>-dermis compose of extracellular matrix </li></ul><ul><li> (ECM) and contain fibroblasts,DC,M Ø, </li></ul><ul><li> infiltrating T lymphocytes </li></ul><ul><li>-dermal DC present in ECM & also </li></ul><ul><li> called type-I dendrocytes </li></ul>J.Valladeau.Seminars in Immunology 2005;17:273-283
  12. 12. NORMAL SKIN STRUCTURE <ul><li>Dermal dendritic cells(cont.) </li></ul><ul><li>-expression MHC class II, scavengerRc </li></ul><ul><li> (CD36), coagulation factor XIIIa </li></ul><ul><li> these 3 markers can find in MØ </li></ul><ul><li>- expression of lectin DC-SIGN/CD209 </li></ul><ul><li> distinguishes DDC from other dermal </li></ul><ul><li> cellular populations </li></ul>J.Valladeau.Seminars in Immunology 2005;17:273-283
  13. 13. NORMAL SKIN STRUCTURE <ul><li>Dermal dendritic cells(cont.) </li></ul><ul><li>2.plasmacytoid DC </li></ul><ul><li>-pDC lymphoid origin </li></ul><ul><li>-natural IFN-  /  -producing cells </li></ul><ul><li>-present in skin in atopic dermatitis, </li></ul><ul><li> contact dermatitis, psoriasis, SLE </li></ul><ul><li>-immature pDC also described in situ in </li></ul><ul><li> primary melanoma </li></ul><ul><li>- normal skin  very low frequency </li></ul>J.Valladeau.Seminars in Immunology 2005;17:273-283
  14. 14. NORMAL SKIN STRUCTURE <ul><li>Dermal dendritic cells(cont.) </li></ul><ul><li> plasmacytoid DC(cont.) </li></ul><ul><li>-more sensitive than myeloid skin DC </li></ul><ul><li> to danger signals  produce typeI-IFN </li></ul><ul><li> via TLRs </li></ul><ul><li>-little is know about pDC trafficking in </li></ul><ul><li> vivo </li></ul>J.Valladeau.Seminars in Immunology 2005;17:273-283
  15. 15. NORMAL SKIN STRUCTURE <ul><li>Dermal dendritic cells(cont.) </li></ul><ul><li> plasmacytoid DC(cont.) </li></ul><ul><li>-mechanism for recruitment into skin </li></ul><ul><li>1.1.pDC express CCR6(Rc of CCL20 that </li></ul><ul><li>responsible for homing of LC to skin </li></ul><ul><li>1.2.pDC express CXCR3 whose ligrands </li></ul><ul><li>highly expressed in inflammatory skin </li></ul><ul><li>1.3.pDC express ChemR23 binds chemerin </li></ul><ul><li>expressed on dermal inflamed vessels </li></ul>J.Valladeau.Seminars in Immunology 2005;17:273-283
  16. 16. NORMAL SKIN STRUCTURE <ul><li>Migration of cutaneous DCs </li></ul><ul><li>1.TNF-  & IL-1 induce migration of </li></ul><ul><li> LC out of epidermis </li></ul><ul><li>2.CCR6 control migration from </li></ul><ul><li> blood/dermis to epidermis </li></ul><ul><li>3.CCR7 control migration from </li></ul><ul><li> epidermis to regional lymphatics </li></ul><ul><li> (CCR7=Rc of SLC) </li></ul>J.Valladeau.Seminars in Immunology 2005;17:273-283
  17. 17. NORMAL SKIN STRUCTURE <ul><li>Migration of cutaneous DCs(cont.) </li></ul><ul><li>4.trafficking is controlled at level of cell </li></ul><ul><li> adhesion </li></ul><ul><li>-LC down-regulate some adhesion </li></ul><ul><li> molecules to exis epidermis and </li></ul><ul><li> up-regulate other to migrate across </li></ul><ul><li> dermal ECM & home to T cell area </li></ul><ul><li> of region lymphoid tissue </li></ul>J.Valladeau.Seminars in Immunology 2005;17:273-283
  18. 18. NORMAL SKIN STRUCTURE <ul><li>Migration of cutaneous DCs(cont.) </li></ul><ul><li>-key role of CD44 &  6 integrins in </li></ul><ul><li> LC migration was demonstrate </li></ul><ul><li>-down-regulation of E-cadherin also </li></ul><ul><li> key event in LC migration </li></ul><ul><li> 5.expression of matrix metalloproteinases-9 </li></ul><ul><li> & -2 (MMP) are necessary both for </li></ul><ul><li> migration of LC & DDC </li></ul>J.Valladeau.Seminars in Immunology 2005;17:273-283
  19. 19. NORMAL SKIN STRUCTURE <ul><li>-cutaneous DC Ag presentation involve </li></ul><ul><li> interaction of </li></ul><ul><li>-MHC class II-antigenic pepetide </li></ul><ul><li>-MHC class I-antigenic peptide </li></ul><ul><li>-via CD1 molecules(non-peptide </li></ul><ul><li> microbial antigen presented) </li></ul>N Franklin. Middleton’s allergy 7th edition 2009
  20. 20. NORMAL SKIN STRUCTURE <ul><li>Epidermis lymphocyte </li></ul><ul><li>-about 1% in epidermis </li></ul><ul><li>-close proximity to basement membrane </li></ul><ul><li>-majority of T cells are memory cell </li></ul><ul><li> (CD45RO + ) most express CD8 receptor </li></ul><ul><li>-50% of epidermal T cell express CLA </li></ul><ul><li> (cutaneous lymphocyte Ag) : </li></ul><ul><li> Sialyl Lewis-X glycoprotein serve as </li></ul><ul><li> ligand to endothelial cell adhesin </li></ul><ul><li> (E-selectin) </li></ul>B.Spellberg.Life Sciences 2000;67:477-502
  21. 21. NORMAL SKIN STRUCTURE <ul><li> Epidermis lymphocyte(cont.) </li></ul><ul><li>-T cell do not enter epidermis by </li></ul><ul><li> random migration, rather epidermal </li></ul><ul><li> T cells are special population of </li></ul><ul><li> memory cells, which have specific set </li></ul><ul><li> of instruction to selectively home to </li></ul><ul><li> epidermis </li></ul><ul><li>-human αβ -T cell : γδ -T cell = 10:1 </li></ul>B.Spellberg.Life Sciences 2000;67:477-502
  22. 22. NORMAL SKIN STRUCTURE <ul><li>Nerve </li></ul><ul><li>- numerous free nerve endings, consist </li></ul><ul><li> of dendrite branching of slow </li></ul><ul><li> conducting nerve fibers </li></ul><ul><li>-afferent sensory, unmyelinated, </li></ul><ul><li> terminate at epidermal surface of </li></ul><ul><li> basement membrane </li></ul>B.Spellberg.Life Sciences 2000;67:477-502
  23. 23. NORMAL SKIN STRUCTURE <ul><li>Nerve(cont.) </li></ul><ul><li>-nerve ending can be found between </li></ul><ul><li> keratinocytes through Stratum </li></ul><ul><li> Granulosum </li></ul><ul><li>- able to elaborate neuropeptides which </li></ul><ul><li> modulate local immunologic function </li></ul>B.Spellberg.Life Sciences 2000;67:477-502
  24. 24. INNATE IMMUNITY <ul><li> keratinocyte express epidermal </li></ul><ul><li> growth factors : amphiregulin </li></ul><ul><li>-induce inflammatory-immune </li></ul><ul><li> reaction </li></ul><ul><li>-recent finding expression amphiregulin </li></ul><ul><li> by Th2 important mechanism to clear </li></ul><ul><li> intestinal helminth infestation through </li></ul><ul><li> epithelial shedding </li></ul>N Franklin. Middleton’s allergy 7th edition 2009
  25. 25. INNATE IMMUNITY <ul><li> epidermal γδ -T cells , like B cell, capable </li></ul><ul><li> directly binding to small phospate </li></ul><ul><li> containing Ag with their receptors </li></ul><ul><li>-do not require Ag presentation in context </li></ul><ul><li> of MHC or CD1 </li></ul><ul><li>-serve as primitive, immediate response </li></ul><ul><li> element, recognizing conserved </li></ul><ul><li> phosphoprotein or phospholipid Ag of </li></ul><ul><li> microbes & necrotic human tissues </li></ul>B.Spellberg.Life Sciences 2000;67:477-502
  26. 26. NORMAL SKIN STRUCTURE B.Spellberg.Life Sciences 2000;67:477-502
  27. 27. CUTANEOUS IMMUNOLOGY <ul><li>Innate immunity </li></ul><ul><li>- first-line defense mechanism </li></ul><ul><li>-two separate categories </li></ul><ul><li>-constitutive innate immunity </li></ul><ul><li>-anatomic barrier -physiologic barrier </li></ul>N Franklin. Middleton’s allergy 7th edition 2009
  28. 28. CUTANEOUS IMMUNOLOGY <ul><li>-inducible innate immunity </li></ul><ul><li>-acute inflammation </li></ul><ul><li>-cellular infiltration </li></ul><ul><li>-both do not demonstrates acquired </li></ul><ul><li> specificity or memory for invading </li></ul><ul><li> pathogen </li></ul>N Franklin. Middleton’s allergy 7th edition 2009
  29. 29. INNATE IMMUNITY <ul><li>1.cutaneous constitutive innate </li></ul><ul><li> immunity consist of </li></ul><ul><li>1.1.normal skin flora </li></ul><ul><li>1.2.cornified keratinocytes </li></ul><ul><li>1.3.antimicrobial polypeptides/lipids </li></ul><ul><li>1.4.low pH </li></ul><ul><li>1.5.normal body temperature </li></ul>N Franklin. Middleton’s allergy 7th edition 2009
  30. 30. INNATE IMMUNITY <ul><li>Normal flora of skin </li></ul><ul><li>-coryneforms and staphylococci </li></ul><ul><li>-mush lesser extent, fungi (primarily </li></ul><ul><li> Malassezia) </li></ul><ul><li>Compete with other pathogenic organisms </li></ul>N Franklin. Middleton’s allergy 7th edition 2009
  31. 31. INNATE IMMUNITY <ul><li>Cornified keratinocytes </li></ul><ul><li>-form impenetrable surface </li></ul><ul><li>-outward growth and shedding of </li></ul><ul><li> cornified keratinocytes  eliminate </li></ul><ul><li> superficially bound pathogens </li></ul><ul><li>-reduced water content & lipid layers of </li></ul><ul><li> stratum corneum reduce relative </li></ul><ul><li> humidity  bad environment </li></ul>N Franklin. Middleton’s allergy 7th edition 2009
  32. 32. INNATE IMMUNITY <ul><li>Antimicrobial polypeptides </li></ul><ul><li>-β-defensin-1 and -2, dermcidin, </li></ul><ul><li> iron-binding proteins, lysozyme, RNases, </li></ul><ul><li> DNases, and natural IgM on skin </li></ul><ul><li> from sweat and from keratinocytes </li></ul><ul><li>Reduce skin surface pH </li></ul><ul><li>-exhibit antibacterial activity </li></ul><ul><li>-lactic acid excreted in eccrine sweat </li></ul>N Franklin. Middleton’s allergy 7th edition 2009
  33. 33. INNATE IMMUNITY <ul><li>Normal body temperature </li></ul><ul><li>-inhibits growth of some pathogens </li></ul><ul><li>2.Inducible innate immunity </li></ul><ul><li>Acute inflammation </li></ul><ul><li>2.1.performed IL-1 α stored in cytoplasm </li></ul><ul><li> of keratinocyte,released from </li></ul><ul><li> itch/scratch </li></ul><ul><li>2.2.TNF- α </li></ul>N Franklin. Middleton’s allergy 7th edition 2009
  34. 34. INNATE IMMUNITY <ul><li>IL-1 </li></ul><ul><li>- 2 forms : α and β </li></ul><ul><li>-31 kDa molecules </li></ul><ul><li>-IL-1 β must be cleaved by ICE </li></ul><ul><li>(IL-1 β converting enzyme : caspase-1) </li></ul><ul><li>-produced by monocyte, MØ, langerhans </li></ul><ul><li> cells, dendritic cells </li></ul><ul><li>-IL-1 α biologically active predominates in </li></ul><ul><li> epithelial cells (keratinocytes, etc) </li></ul>Murphy JE. J Invest Dermatol 2000; 114:602-608
  35. 35. INNATE IMMUNITY <ul><li>-receptors </li></ul><ul><li>-IL-1R1 can bind both IL-1 α & IL-1 β </li></ul><ul><li>-IL-1ra(IL-1 receptor antagonist) </li></ul><ul><li> bind to this Rc but does not induce </li></ul><ul><li> signaling </li></ul><ul><li>-mice defcient in IL-1ra show </li></ul><ul><li> exaggerated & persistent </li></ul><ul><li> inflammatory responses </li></ul>Murphy JE. J Invest Dermatol 2000; 114:602-608
  36. 36. INNATE IMMUNITY <ul><li>-IL-1R2 </li></ul><ul><li>-short cytoplasmic domain </li></ul><ul><li>-bind IL-1 α & IL-1 β efficiently </li></ul><ul><li>-but not IL-1ra </li></ul><ul><li>-serves to inhibit IL-1 responses </li></ul><ul><li>-expression can be upregulated by </li></ul><ul><li> corticosteroids & IL-4 </li></ul>Murphy JE. J Invest Dermatol 2000; 114:602-608
  37. 37. INNATE IMMUNITY Murphy JE. J Invest Dermatol 2000; 114:602-608
  38. 38. INNATE IMMUNITY <ul><li>-important among this cascade of events is </li></ul><ul><li> induced expression inflammatory cytokine, </li></ul><ul><li> chemokine, mediators(eicosanoids, </li></ul><ul><li> histamine, neuropeptides, ROS) </li></ul><ul><li>-contribute to classic signs of acute </li></ul><ul><li> inflammation : redness, heat, swelling, pain </li></ul><ul><li> </li></ul>N Franklin. Middleton’s allergy 7th edition 2009
  39. 39. INNATE IMMUNITY <ul><li> IL-1 α induce molecules of typical </li></ul><ul><li> cutaneous inflammatory response </li></ul><ul><li> include : TNF- α , IL-8(CXCL-8), </li></ul><ul><li> nitrous oxide synthase, </li></ul><ul><li> PG-producing cyclooxygenase, </li></ul><ul><li> postcapillary venule endothelial </li></ul><ul><li> cell expression of ICAM-1, </li></ul><ul><li> VCAM-1, E-seletin </li></ul>N Franklin. Middleton’s allergy 7th edition 2009
  40. 40. INNATE IMMUNITY <ul><li>-Moreover,IL-1 α & other induced </li></ul><ul><li> molecules activate most cell types of skin, </li></ul><ul><li> alerting and preparing them for further </li></ul><ul><li> host defense functions including cytokine </li></ul><ul><li> and chemokine secretion, wound repair, </li></ul><ul><li> release of antimicrobial products, </li></ul><ul><li> phagocytosis, initiation of acquired </li></ul><ul><li> immune responses </li></ul>N Franklin. Middleton’s allergy 7th edition 2009
  41. 41. INNATE IMMUNITY <ul><li>2.3.inducible pathogen-targeted soluble </li></ul><ul><li> molecules </li></ul><ul><li>-inducible antimicrobial polypeptides </li></ul><ul><li>-complement-activating a/o opsonin </li></ul><ul><li> proteins </li></ul><ul><li>-complement proteins </li></ul>N Franklin. Middleton’s allergy 7th edition 2009
  42. 42. INNATE IMMUNITY <ul><li>Inducible antimicrobial polypeptides </li></ul><ul><li>- β -defensin-2 and -3, cathelicidin LL-37 </li></ul><ul><li>-produced by keratinocytes </li></ul><ul><li>-IFN- α , IFN- β , IFN-k another class of </li></ul><ul><li> antimicrobial polypeptides </li></ul><ul><li>(IFN- α produced by plasmacytoid DC, </li></ul><ul><li> mononuclear phagocytes) </li></ul>N Franklin. Middleton’s allergy 7th edition 2009
  43. 43. INNATE IMMUNITY <ul><li>- IFN- β produced by many cell ; fibroblasts </li></ul><ul><li> sometimes called fibroblasts IFN) </li></ul><ul><li>-protective activities related to antiviral </li></ul><ul><li> effect on host cells rather than diract toxic </li></ul><ul><li> to pathogen </li></ul>N Franklin. Middleton’s allergy 7th edition 2009
  44. 44. INNATE IMMUNITY <ul><li>2.4.complement activating/opsonin molecules </li></ul><ul><li>-members of acute phase proteins </li></ul><ul><li> (C-reactive protein, serum amyloid </li></ul><ul><li> protein) </li></ul><ul><li>-members of collectin(mannan-binding </li></ul><ul><li> lectin) </li></ul><ul><li>-ficolin lectin families </li></ul><ul><li>-C3b fragment, natural IgM </li></ul>N Franklin. Middleton’s allergy 7th edition 2009
  45. 45. INNATE IMMUNITY <ul><li>2.4.complement activating/opsonin molecules </li></ul><ul><li>- acute phase protein produced by liver & </li></ul><ul><li> supply to skin via blood </li></ul><ul><li>-increase serum concentration in response </li></ul><ul><li> to IL-1, IL-6, TNF- α from activated MØ </li></ul><ul><li>- collectins & ficolins recognize </li></ul><ul><li> carbohydrates on bacteria, fungi, viruses </li></ul><ul><li> then mark them for destruction </li></ul>N Franklin. Middleton’s allergy 7th edition 2009
  46. 46. INNATE IMMUNITY <ul><li>- opsonin C3b target pathogen : phagocytosis </li></ul><ul><li>- C3a, C5a(anaphylatoxins) : keratinocyte </li></ul><ul><li> activating, chemoattractant, mast cell </li></ul><ul><li> degranulating functions) </li></ul><ul><li>- C5b, C6, C7, C8, C9 : MAC(lethal pore) </li></ul>N Franklin. Middleton’s allergy 7th edition 2009
  47. 47. INNATE IMMUNITY <ul><li>2.5.PRRs host molecules recognize </li></ul><ul><li>-PRRs host molecules recognize PAMPs </li></ul><ul><li>-PAMPs include </li></ul><ul><li>-unmethylated CpGs of bact. DNA </li></ul><ul><li>-dsRNA(e.g.influenza) </li></ul><ul><li>-mannans </li></ul><ul><li>-gram+ bact. lipoteichoic acids </li></ul><ul><li>-gram- bact. LPS </li></ul><ul><li>-bacterial peptidoglycan </li></ul>N Franklin. Middleton’s allergy 7th edition 2009
  48. 48. INNATE IMMUNITY <ul><li>2.5.PRRs host molecules recognize(cont.) </li></ul><ul><li>-N-terminal formyl-methionine </li></ul><ul><li>-parasitic phosphoglycans </li></ul><ul><li>-fungal glucans/zymosan </li></ul><ul><li>- M Ø & DC ,activated during cutaneous </li></ul><ul><li> inflammatory response, first phagocytic </li></ul><ul><li> host cells utilizing their cell-surface PRRs </li></ul>N Franklin. Middleton’s allergy 7th edition 2009
  49. 49. INNATE IMMUNITY <ul><li>-inflammation-ass increase chemotactic </li></ul><ul><li> factors (chemokines) , produced by </li></ul><ul><li> keratinocytes stimulated via their TLRs </li></ul><ul><li> and postcapillary venule endothelial cell </li></ul><ul><li> adhesion molecules (P- & E-selectin, </li></ul><ul><li> ICAM-1, VCAM-1) synergiscally mediate </li></ul><ul><li> integrin-dependent extravasation of </li></ul><ul><li> PRR-expressing leukocytes </li></ul>N Franklin. Middleton’s allergy 7th edition 2009
  50. 50. INNATE IMMUNITY <ul><li>-cellular infiltration </li></ul><ul><li>- neutrophils earliest infiltrating </li></ul><ul><li> leukocytes(due to neutrophil </li></ul><ul><li> active CXC : IL-8) </li></ul><ul><li>-later, monocyte begin extravasate </li></ul><ul><li> into inflam. site </li></ul><ul><li>- assist in phagocytosis & </li></ul><ul><li> intracellular destruction of </li></ul><ul><li> pathogen with lysozyme, defesins, ROI </li></ul>N Franklin. Middleton’s allergy 7th edition 2009
  51. 51. INNATE IMMUNITY <ul><li>- eosinophil less phagocytic than </li></ul><ul><li> neutrophil, produce ROS at plasma </li></ul><ul><li> membrane surface, not intracellularly </li></ul><ul><li>  readily degranulate & deposit toxic </li></ul><ul><li> cationic proteins onto surface of </li></ul><ul><li> parasites </li></ul><ul><li>-furthermore : basophils, blood Dc, </li></ul><ul><li> mast cell, T cells, B cell, NK-T cell, </li></ul><ul><li> NK cells </li></ul>N Franklin. Middleton’s allergy 7th edition 2009
  52. 52. INNATE IMMUNITY <ul><li>-local defenses are quickly augmented by </li></ul><ul><li> recruitment of dermal M Ø , just beneath </li></ul><ul><li> basement membrane </li></ul><ul><li>-lymphocyte-/keratinocyte-derived IFN & </li></ul><ul><li> growth factors across basement membrane </li></ul><ul><li> initiates priming MØ to produce IL-12 </li></ul>B.Spellberg.Life Sciences 2000;67:477-502
  53. 53. INNATE IMMUNITY <ul><li>-epidermal-derived cytokine & Ag stimuli </li></ul><ul><li>  MØ mobilize their cytoskeletons to </li></ul><ul><li> become mobile & secrete metalloproteinases </li></ul><ul><li> and degradative enzymes  allow them to </li></ul><ul><li> slice through collagen and other structural </li></ul><ul><li> components of basement membrane  cross </li></ul><ul><li> into epidermis </li></ul>B.Spellberg.Life Sciences 2000;67:477-502
  54. 54. INNATE IMMUNITY <ul><li>- M Ø use ligands expressed on activated </li></ul><ul><li> keratinocytes, such as E-cadherin/ICAM-1, </li></ul><ul><li> to pull themselves through epidermis and </li></ul><ul><li> crawl to danger site by following chemokine </li></ul><ul><li> gradient to its source </li></ul>B.Spellberg.Life Sciences 2000;67:477-502
  55. 55. INNATE IMMUNITY B.Spellberg.Life Sciences 2000;67:477-502
  56. 56. INNATE IMMUNITY B.Spellberg.Life Sciences 2000;67:477-502
  57. 57. ACQUIRED IMMUNITY <ul><li>-inflammation state that continues beyond </li></ul><ul><li> 24-36 hr induces onset of adaptive immunity </li></ul><ul><li>-IFN- γ in epidermis stimulates leukocytes, </li></ul><ul><li> fibroblasts to express CC chemokines, </li></ul><ul><li> particular MCP-1, MIP-1, RANTES </li></ul><ul><li> while suppress production of CXC </li></ul><ul><li> chemokines such as IL-8 </li></ul>B.Spellberg.Life Sciences 2000;67:477-502
  58. 58. ACQUIRED IMMUNITY <ul><li>-MIP-1 α : CCL20;induce chemotaxis of </li></ul><ul><li> neutrophil and lymphocytes </li></ul><ul><li>-MCP-1 : chemotactic for monocytes </li></ul><ul><li> & lymphocytes </li></ul><ul><li>-RANRES : selectively pro-inflammatory </li></ul><ul><li> Th1 lymphocytes, not </li></ul><ul><li> inflammatory-suppressive </li></ul><ul><li> Th2 cells </li></ul>B.Spellberg.Life Sciences 2000;67:477-502
  59. 59. ACQUIRED IMMUNITY <ul><li>-Th1 have RANTES Rc : CCR5 </li></ul><ul><li>-Th1 produce IFN- γ which drive RANTES </li></ul><ul><li> production by lymphocytes and MØ  </li></ul><ul><li> selectively summon additional Th1 cells </li></ul><ul><li> to area of danger </li></ul>B.Spellberg.Life Sciences 2000;67:477-502
  60. 60. ACQUIRED IMMUNITY <ul><li>- endothelial cell adhesins critical to </li></ul><ul><li> selection of leukocyte extravasation </li></ul><ul><li>- several hour after stimulation  lower </li></ul><ul><li> their expression of E-selectin(CD62E), </li></ul><ul><li> upregulate their ICAM-1 expression, </li></ul><ul><li> begin express VCAM  diminish neutrophil </li></ul><ul><li> across vascular lumen  L & Mo are </li></ul><ul><li> recruited into area </li></ul>B.Spellberg.Life Sciences 2000;67:477-502
  61. 61. ACQUIRED IMMUNITY <ul><li>-exposure to IFN- γ  endothelium express </li></ul><ul><li> MHC class II </li></ul><ul><li> then presence of IFN- γ , microvascular </li></ul><ul><li> endothelial cells capable acting as </li></ul><ul><li> professional APC to circulating T cells </li></ul>B.Spellberg.Life Sciences 2000;67:477-502
  62. 62. ACQUIRED IMMUNITY <ul><li>-keratinocytes unable to express sufficient </li></ul><ul><li> costimulatory molecules to drive T cell </li></ul><ul><li> activation  result in T cell anergy/deletion </li></ul><ul><li>-keratinocytes able to abort adaptive </li></ul><ul><li> response by competing with phagocytes </li></ul><ul><li> for presentation of Ag to T cells </li></ul>B.Spellberg.Life Sciences 2000;67:477-502
  63. 63. ACQUIRED IMMUNITY <ul><li>-In presence in skin of IFN- γ , IFN- α , </li></ul><ul><li> TNF- α , microbial particles </li></ul><ul><li> (LPS, gram+ cell wall fractions, prokaryotic </li></ul><ul><li> DNA)  induces M Ø & DC produce IL-12 </li></ul><ul><li>-IL-12 induces newly activated T cell to Th1 </li></ul>B.Spellberg.Life Sciences 2000;67:477-502
  64. 64. ACQUIRED IMMUNITY <ul><li> -if stimulus initiating danger response is </li></ul><ul><li> too bulky(hyphal fungi, helminths, large </li></ul><ul><li> foreign bodies,etc)  leukocytes initiate </li></ul><ul><li> “ frutrated phagocyte complex ” this </li></ul><ul><li> induce production of IL-10 prefentially </li></ul><ul><li> over IL-12  favoring antibody-based Th2 </li></ul>B.Spellberg.Life Sciences 2000;67:477-502
  65. 65. ACQUIRED IMMUNITY <ul><li>-antibody production stimulated by Th2 </li></ul><ul><li> response  allow leukocytes to damage </li></ul><ul><li> large organisms via ADCC </li></ul><ul><li>-eosinophil, neutrophil, NK, monocyte/M Ø </li></ul><ul><li> able to use this mechanism </li></ul>B.Spellberg.Life Sciences 2000;67:477-502
  66. 66. ACQUIRED IMMUNITY <ul><li>- B cell other key cell for acquired immunity </li></ul><ul><li>-B cell recognize relatively intact Ag </li></ul><ul><li> (contrast T cells) </li></ul><ul><li>-plasma cell, memory B cell development, </li></ul><ul><li> Ig class switching, somatic hypermutation </li></ul><ul><li> all occur in secondary lymphoid geminal </li></ul><ul><li> center of skin-draining LN </li></ul>N Franklin. Middleton’s allergy 7th edition 2009
  67. 67. ACQUIRED IMMUNITY <ul><li>-absence of cutaneous B cells suggests a </li></ul><ul><li> need for Ag that enter skin to be </li></ul><ul><li> transported to B cell as opposed to B cell’s </li></ul><ul><li> migrating to Ag in skin(but mechanism of </li></ul><ul><li> B cell activation remains unclear) </li></ul><ul><li>-five classes of Ig have been detected in </li></ul><ul><li> normal human sweat </li></ul>N Franklin. Middleton’s allergy 7th edition 2009
  68. 68. ACQUIRED IMMUNITY <ul><li>-sIgA arise from secretory epithelia of </li></ul><ul><li> eccrine glands, sebum also contain IgA </li></ul><ul><li>-exact source of cutaneously secreted </li></ul><ul><li> Ig remains unresolved </li></ul><ul><li>-IgG1 & IgA capable to clear pathogenic </li></ul><ul><li> organisms from skin via Fc γ Rc-mediated </li></ul><ul><li> immune response(ADCC, complement </li></ul><ul><li> fixation) and sIgA-coating of bacteria </li></ul>N Franklin. Middleton’s allergy 7th edition 2009
  69. 69. ACQUIRED IMMUNITY <ul><li>-in human IgE & IgG4 produced by type 2 </li></ul><ul><li> cytokine (IL-4, IL-13) </li></ul><ul><li>-most antigen-specific IgE supplied via </li></ul><ul><li> blood(except respiratory mucosa , local </li></ul><ul><li> IgE production appear posible) </li></ul><ul><li>-IgE can bind to Fc ε RI-bearing cells(LC, </li></ul><ul><li> mast cell, infiltrating basophils)  contribute </li></ul><ul><li> to various allergic skin dz </li></ul>N Franklin. Middleton’s allergy 7th edition 2009
  70. 70. ACQUIRED IMMUNITY <ul><li>-Ab specific for Fc ε RI may contribute to </li></ul><ul><li> cutaneous dz such as urticaria, Ab against </li></ul><ul><li> desmosomal and hemidesmosomal protein </li></ul><ul><li> provoke immunobullous dz </li></ul>N Franklin. Middleton’s allergy 7th edition 2009
  71. 71. ACQUIRED IMMUNITY <ul><li>-impact of innate to acquired immunity </li></ul><ul><li>-chemotactic activity of β -defesin-2 </li></ul><ul><li> & C5a for DC a/o T cells </li></ul><ul><li>-tissue injury danger signals or </li></ul><ul><li> engagement of PRRs (LPS Rc, </li></ul><ul><li> mannose binding Rc, TLRs, CD1a) </li></ul><ul><li> expressed on cutaneous APC such as </li></ul><ul><li> Langerhans’ cells, dermal DC, MØ </li></ul>N Franklin. Middleton’s allergy 7th edition 2009
  72. 72. ACQUIRED IMMUNITY <ul><li> increase co-stimulatory molecule </li></ul><ul><li> expression (CD80 & CD86) & modulate </li></ul><ul><li>cytokine expression patterns </li></ul><ul><li>-LPS bind to cell surface CD14 of M Ø </li></ul><ul><li> induces IL-12  favor Th1 development </li></ul><ul><li>-mast cell-produced cytokines such as IL-4, </li></ul><ul><li> histamine, keratinocyte-derived thymic </li></ul><ul><li> stromal lymphopoietin(TSLP)  acquire </li></ul><ul><li> immune response Th2 profile </li></ul>N Franklin. Middleton’s allergy 7th edition 2009
  73. 73. ACQUIRED IMMUNITY B.Spellberg.Life Sciences 2000;67:477-502
  74. 74. ACQUIRED IMMUNITY B.Spellberg.Life Sciences 2000;67:477-502
  75. 75. SUMMARY N Franklin. Middleton’s allergy 7th edition 2009
  76. 76. TAKE HOME MESSAGE <ul><li>-Various constitutive and inducible </li></ul><ul><li> innate immune mechanisms function in </li></ul><ul><li> skin to fight infection and to direct </li></ul><ul><li> acquired immunity – these include </li></ul><ul><li> keratinocyte– derived molecules such </li></ul><ul><li> as IL-1, antimicrobial pe ptides    </li></ul><ul><li>-Immune functions attributed to </li></ul><ul><li> cutaneous mast cells and dendritic </li></ul><ul><li> cells (DCs) </li></ul>
  77. 77. TAKE HOME MESSAGE <ul><li>-Langerhans' cells, dermal DCs, and </li></ul><ul><li> DCs infiltrating during inflammatory </li></ul><ul><li> disease are increasing in number and </li></ul><ul><li> being redefined -Skin homing of memory, effector, </li></ul><ul><li> and regulatory T-cell subtypes is </li></ul><ul><li> programmed by skin-derived DCs </li></ul><ul><li> and prominently directed by CLA,other </li></ul><ul><li> types of chemokines </li></ul>

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