Transcript 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:
–
–
–
–
–
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 2435 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
Physical injury
Reiss et al.; J. Exp. Med. 2001
Homey et al.; Nat. Med. 2002
Soumelis et al.; Nat. Immunol. 2002
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