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Skin as a protection against environmental threats
Antti Lauerma, M.D., Ph.D.
Chief Medical Officer
FIOH DermatologyFigures: 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:– Mechanical stress– Physical damage– Pathogens– Foreign biologic material– Foreign nonbiologic material
SKIN: THREE LEVELS OF PROTECTION
• Mechanical barrier (stratum corneum)
• Innate immunity
• Acquired immunity
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
STRATUM CORNEUM DAMAGE
• EXOGENOUS DAMAGE– excess washing (toxic hand dermatitis)
• ENDOGENOUS DAMAGE– inflammation
• STRUCTURAL DAMAGE– atopic skin
STRATUM CORNEUM REPAIR
• Lipid synthesis in corneocytes
• Lipid synthesis in keratinocytes
• Basal keratinocyte proliferation
STRATUM CORNEUM REPAIR (2)
• Ointment/cream application
• UV light therapy
• Systemic retinoid use???
Coombs-Gell I
• Mast cells release histamine
• Vasodilatation• Leakage of water to
skin• Intense pruritus• 15 min - 2 hours
(immediate hypersensitivity)
Coombs-Gell II
• Cytotoxic response• Macrophage-mediated
killing of unfit cells• 24 hours• Erythema multiforme
Coombs-Gell III
• Antibody-antigen complexes
• Complexes trapped at capillaries
• Exanthema• 8-24 hours
Coombs-Gell IV
• APC presents antigen• T-cell mediated
cellular inflammation
• Allergic contact dermatitis
• 24-48 hours (delayed hypersensitivity)
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
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”)
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
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
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
Skin Immune System
Reiss et al. ; J. Exp. Med. 2001Homey et al.; Nat. Med. 2002Soumelis et al.; Nat. Immunol. 2002
Physical injury
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
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