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