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Skin as a protection against environmental threats

Skin as a protection against environmental threats. Antti Lauerma, M.D., Ph.D. Chief Medical Officer FIOH Dermatology Figures: copyright Blackwell (Rook, Textbook of Dermatology). SKIN AS ORGAN. Surface area 1.5 - 2 m2 Weight ~10% of body weight Purpose: To protect body against:

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Skin as a protection against environmental threats

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  1. Skin as a protection against environmental threats Antti Lauerma, M.D., Ph.D. Chief Medical Officer FIOH Dermatology Figures: copyright Blackwell (Rook, Textbook of Dermatology)

  2. SKIN AS ORGAN • Surface area 1.5 - 2 m2 • Weight ~10% of body weight • Purpose: To protect body against: • Mechanical stress • Physical damage • Pathogens • Foreign biologic material • Foreign nonbiologic material

  3. SKIN: THREE LEVELS OF PROTECTION • Mechanical barrier (stratum corneum) • Innate immunity • Acquired immunity

  4. STRATUM CORNEUM • The outer-most layer of skin • Approximately 10 cell layers thick • Consists of corneocytes and extracellular matrix • Protective layer against water loss from body

  5. STRATUM CORNEUM DAMAGE • EXOGENOUS DAMAGE • excess washing (toxic hand dermatitis) • ENDOGENOUS DAMAGE • inflammation • STRUCTURAL DAMAGE • atopic skin

  6. STRATUM CORNEUM REPAIR • Lipid synthesis in corneocytes • Lipid synthesis in keratinocytes • Basal keratinocyte proliferation

  7. STRATUM CORNEUM REPAIR (2) • Ointment/cream application • UV light therapy • Systemic retinoid use???

  8. Coombs-Gell I • Mast cells release histamine • Vasodilatation • Leakage of water to skin • Intense pruritus • 15 min - 2 hours (immediate hypersensitivity)

  9. Coombs-Gell II • Cytotoxic response • Macrophage-mediated killing of unfit cells • 24 hours • Erythema multiforme

  10. Coombs-Gell III • Antibody-antigen complexes • Complexes trapped at capillaries • Exanthema • 8-24 hours

  11. Coombs-Gell IV • APC presents antigen • T-cell mediated cellular inflammation • Allergic contact dermatitis • 24-48 hours (delayed hypersensitivity)

  12. INNATE IMMUNITY IN SKIN - START • Damage - danger signal • Preformed IL-1a released from KC • IL-1a stimulates KC to produce IL-1b, IL-6, TNFa and more IL-1a • TOLL receptors have same effect as IL-1a, sharing NF-kappa-beta signalling

  13. Arrival of Granulocytes • Larger vessel - lower speed • Attachment via P- and E-selectins • Movement to dermis through CXC -chemokine gradient • Proteases enable movement through ECM • Entrance to epidermis, movement through epidermis (”zipper movement”)

  14. Granulocytes in epidermis • Presence of IL-1, IL-6, TNF-a, GM-CSF, IFNg induce a respiratory burst in granulocytes • C3R, FCg receptors bind to microbes with opsonins (part of complement) to microbes • 1 bacteria/min, total over 50 bacteria per granulocyte

  15. Turn off the inflammation or call in the lymphocytes? • Keratinocytes produce IL-10, IL1ra, aMSH. • FB, MF, Lymphocytes produce TGF-beta: • IFN down • T cell anergy • Endoth. Cell Chk, adh mol down

  16. Turn off the inflammation or call in the lymphocytes? • Inflammation over 24-35 hours starts acquired immunity • Endothelial cells produce ICAM, VCAM • T cells adhere to endothelial cells and enter skin via chemokine (CC, not CXC) gradient

  17. Lymphocytes in the skin • Professional APC present antigen in the context of MHC II and B7.1/B7.2 to T cells. • (If keratinocytes present antigen, anergy results (no B 7.1/7.2)) • IFNg, IFNa, TNFa, and LPS, bacterial cell wall, CpG induce MF and DC to produce IL-12 • IL-12 favors Th1 response • Th1 T cells produce more IFNg that keeps up production of CC-chemokines

  18. What if ”danger” persists??? • Inflammatory area will be isolated from surrounding tissue • IL-4 and IL-10 induce giant cells from MF • TGF beta stimulates action of giant cells and FB • Granulomatous inflammation

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