1 skin biology alain khaiat, ph.d. vice president r&d johnson & johnson asia pacific
TRANSCRIPT
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SKIN BIOLOGY
Alain KHAIAT, Ph.D.
Vice President R&D
Johnson & Johnson Asia Pacific
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CONTENTS
• Inflammation
• Pigmentation
• Skin Aging
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CONTENTS• Inflammation
– irritation– sensitization– biochemistry
• Pigmentation
• Skin Aging
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EPIDERMIS
The cells contained in the epidermis are:
• corneocytes
• keratinocytes
• Langerhans cells
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DEJ
It is the site of adhesion of epidermis to dermis, via:
• hemidesmosomes
• anchoring filaments (Kalinin)
• adhesive protein (Laminin)
• fibronectin
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DEJ
Hemidesmosome
Basal cell
Lamina lucidaAnchoring
filaments
Anchoring fibril
Lamina densa
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DERMIS
The dermis contains:
• fibrobalsts
• mast cells
• Langerhans cells
• lymphocytes and blood vessels
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The skin is the interface between the organism and its environment
Because it contains:– Langerhans cell– lymphocytes– blood vessels– masts cells
exogenous or endogenous stimuli will create inflammation processes
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INFLAMMATION
• Inflammation is the body’s general distress response to biological, physical or chemical causes of:– irritation– sensitization– photosensitization
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INFLAMMATION
• Clinically, inflammation has been defined through 4 signs:– erythema– edema– pain– heat
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IRRITATION
• Irritants are chemical, biological or physical agents which can produce inflammation
• Irritation can be either objective or subjective
• Objective irritation is characterized by the 4 signs mentioned. It is externally observable
• Subjective irritation is characterized by: stinging, burning or itching
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IRRITATION
• The result of insulting the skin is the release of histamine by the mast cells in the irritated area.
• Histamine is a potent vasodilator, it produces the visible erythema and increased vascular permeability (leaking of fluid = edema), allowing cells (PMN= polymorphonucleocytes) to migrate to the area
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SENSITIZATION
• Skin sensitization is the result of exposure to sensitizers or allergens
• Skin sensitization is a delayed type humoral immune response mediated by the T cell
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SKIN SENSITIZATION
• The sentitizing substance (hapten), combines with a protein in the skin to form the allergen
• The Langerhans cells in the stratum germinativum interacts with the allergen and migrates to the lymphoid gland
• It then “teaches” the T cells about the allergen
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SKIN SENSITIZATION
• Sensitized T cells migrate to the site and, on contacting the allergen, liberate cytokines
• these cytokines attract leukocytes to the site and appear to raise the temperature of the area
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AllergenLangehans cell
T cell Activated T cell
cytokine
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CYTOKINES
• Cytokines are essential transmitters of intercellular communication
• They have an inherent role in the regulation of responses of the immune system
• Each cytokine has multiple functions
• More than one cytokine may mediate the same, or very similar, function
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CYTOKINES
• They form part of a complex cellular signaling language
• They are proteins
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T CELL RESPONSE
• TYPE 1: cell mediated response, essentially to viruses, bacteria, protozoa, chemicals. Th1 response leads to secretion of:– IL2 IFN– TNF– IL12
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T CELL RESPONSE
• TYPE 2: humoral response following parasitic infection. Th2 releases:– IL4– IL5– IL6– IL10– IL13
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T CELL RESPONSE
• The type of response is function of genes and the environment.
GenesEnvironment
Th1 Th2
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T CELL RESPONSE
• Allergic contact dermatitis is in its early stages Th1 (IL2, IFN) becoming later Th2 (IL4). This explains why the reaction decreases
• Atopic dermatitis is a Th2: IL4, IL5, IL6, IL10, then IgE, mast cells growth, eosinophil infiltration
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UV B EFFECT
• UV B has been shown to suppress immune reaction (induction phase only)
• UV B stimulates synthesis and release of TNF- by keratinocytes which in turn modifies the behavior and morphology of Langerhans cells
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TWO MECHANISMS• Mast cells can respond directly to external trauma,
to antigen-IgE complexes on their surface or to mediators generated from complement (anaphylatoxins) by degranulating and releasing vaso active mediators: histamins
• Langerhans cells interact specifically with T-lymphocytes and keratinocytes to initiate host response to antigens
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BIOCHEMISTRY OF INFLAMMATION
• Phospholipids are the major raw material and starting point for the arachidonic acid pathway. Irritants increase the biosynthesis of phospholipids
• Arachidonic acid is resident to the cell membrane where it is the source of several major biochemical pathways
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Phospholipides
Arachidonic Acid
Prostaglandin G2
Prostaglandins (PGE2, PGF2, etc)
Leucotrienes
HydroperoxitetraenoicAcid (HETE)
Prostacyclin
Thromboxane
Prostaglandin H2
Cyclooxygenase
Phospholipase A2
12-Lipoxygenase
5-Lipoxygenase
SteroidsNSAIDEugenol
Acetylsalycilic acid
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ARACHIDONIC PATHWAY
• If arachidonic acid is acted upon by cyclo-oxygenase, prostaglandin G2 is generated. It is itself converted into thromboxane or prostacyclin or PGH2, the later then generating the other members of the PG family.
• Thromboxane stimulates platelet aggregation and is a vasoconstrictor
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ARACHIDONIC ACID PATHWAY
• Prostacyclin inhibits platelet aggregation and vasoconstriction
• Prostaglandins are non protein chemical mediators: they are fatty acids
• 12-lipoxygenase transforms AA into HETE
• 5-lipoxygenase catalyses the production of the leukotriens (eicosanoid family)
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ANTI INFLAMMATORY TESTS
• Cytokines secretion by PBL (human peripheral blood lymphocytes) in culture following addition of a stimulant
• IL 6 release by human fibroblasts
• Contact hypersensitivity in mouse (ear edema), after application of Phorbol ester
• Ear edema in mouse following AA inflammation
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CONTENTS
• Inflammation
• Pigmentation– anomalies– melanogenesis
• Skin Aging
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PIGMENTATION
Skin color is the result of:
• nature of the melanin
• where the melanin is concentrated, i.e. quantity, type and distribution of melanosomes (epidermis or dermis)
• skin vascularisation
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PIGMENTATION ANOMALIES
1. Melanocytes proliferation is normal:
• Freckles: eumelanin zones on pheomelanin backgrounds (skin areas exposed to the sun)
• Chloasma: pregnancy mask: hypersecretion of melanin induced by hormonal factors and amplified by the sun
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PIGMENTATION ANOMALIES
• Diffuse brown melanosis: endocrine system disorders or nutritional anomalies
• Hypermelanosis can follow cutaneous inflammations: – pigmentation of scars, – caused by irritants combined with sun
(photosensitizers like bergamot oil)
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PIGMENTATION ANOMALIES
2. Melanocytes do not proliferate correctly
• Lentigines: can be hereditary, appear anywhere on the body
• Solar Lentigo: wider lesion than freckle, occurs after serious sunburn
• Senile Lentigo: generally on the back of the hand of older subjects, stimulated by solar exposure
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PIGMENTATION ANOMALIES
• Dubreuilh melanosis or malignant lentigo of the elderly: large pigmented multi colored stain, pre-cancerous
• Moles or Naevus: accumulation of melanocytes in epidermis and dermis
• Malignant melanomas: cancerous tumors. The first signs are degeneration of existing naevus or Dubreuilh melanosis
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PIGMENTATION
• All methods to reduce pigmentation on the market today have the objective to reduce melanogenesis
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MELANOGENESIS PATHWAYS
L-TYROSINE
TYROSINASE
3,4-DIHYDROXYPHENYLALANINE
TYROSINASE
DOPA QUINONE
GSH CYCLISATION
GSH-DOPA LEUCODOPACHROME
3-S-CYSTEINYL DOPA DOPACHROME
INTERMEDIATE PDTS 5,6 DIHYDROXYINDOLE
TRP2 TRP1
PHEOMELANIN QUINONE-IMINE
EUMELANIN
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MELANOGENESIS INHIBITION
• Inhibition of the production of active tyrosinase in the ribosomes: placental extract
• Inhibition of the transfer of tyrosinase to pre-melanosomes by interrupting glycosylation (tunicamycine, glucosamine)
• Elimination of inflammatory reactions (flavonoids, tannins, etc)
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MELANOGENESIS INHIBITION
• Inhibition of tyrosinase: Kojic acid, ascorbic acid, etc. EDTA or Phytic acid (since tyrosinase requires Cu++)
• Inhibition of the formation of eumelanin: by adding glutathion and glutathion reductase transforming GSSG into GSH, promote the formation of glutathion DOPA leading to pheomelanin
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PIGMENTATION
• Melanin is formed in the Melanocytes, where it is stored in the melanosomes
• Melanocytes extend arms to transfer melanosomes into the keratinocytes
• It is the keratinocytes charged with the melanosomes that constitute the dark spots on the skin
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Tyrosinase
Pigmentation Formation Mechanism
KERATINOCYTE(Epidermis)
MELANOCYTE(Basal Layer)
Tyrosine Melanin
Dermis
UVUVIrritation
Inflammatory Response
Hormone
3
12
Melanosome
FIBROBLAST
• Variety of Causes
• Variety of Responses
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Basic Structure of Skin
Stratum Corneum
Viable Epidermis
Basal Layer
Dermis
Keratinocyte
Melanocyte
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PIGMENTATION
• A novel approach has recently been published: blocking the transfer of melanosomes from the melanocyte to the keratinocytes
• Accumulation of charged melanosomes inhibits melanin synthesis
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SUGGESTED MECHANISM
1. Less TRP-1 is made tyrosinase not stable2. More TRP-2 is made shift to brownish melanins
Less eumelanin produced, lighter color
Less melanosometransfer
Melanosomes accumulate
Negativefeed-back
Depigmentation
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NOVEL MECHANISM
• Protease Activated Receptor (PAR-2) is expressed in keratinocytes. PAR-2 is activated by trypsin
• By inhibiting PAR-2, one probably blocks the keratinocyte-melanocyte interaction
• TRP1 (tyrosinase-related protein) decreases leading to less Eumelanin
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PIGMENTATION TESTING
• Tyrosinase activity in solution: mushroom, mouse or human tyrosinase are used with different results
• S91 melanoma cells in culture
• Keratinocytes-Melanocytes co culture
• Guinea pig ear: 15 days treatment
• Microswine spotted model: 6-8 weeks
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PIGMENTATION TESTING
• Human volunteers tests:– Chromameter® : L measure– Mexameter® : evaluation of melanin and
redness– Photography : visible, UV with data analysis
3 months minimum,
changes, so far, are not very significant against placebo
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CONTENTS• Inflammation
• Pigmentation
• Skin Aging– skin changes– biochemical changes
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MANIFESTATIONS OF SKIN AGING
• Epidermis :– reduction in cell renewal rate– thickening of stratum corneum
– decrease in barrier efficiency : increase in TEWL and hyperkeratosis
– ridges are flattened out and intercellular spaces enlarged
– pigmentation problems : actinic lentigines– decrease in skin immune system
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MANIFESTATIONS OF SKIN AGING
• Sebaceous glands :– reduction in sebum secretion (hormones
influenced)
• Sweat glands :– less active
• HLP film :– thinning of film means less protective barrier
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MANIFESTATION OF SKIN AGING
• Dermis :– destruction of collagen and elastin fibers
network– proteoglycans and glycoproteins are reduced– increase in elastin synthesis : elastosis
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PHOTOAGING
3 types of reactions to UV exposure:
• Free Radicals, essentially due to UVA
• Direct cell death, essentially due to UVB
• MMP Enzymes
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FREE RADICALS
Free radicals or ROS (reactive oxygen species) can lead to breakage of important molecules:
• DNA (mutations, renewal failure, cell death)
• collagen, elastin, GAG (skin firmness)
• lipids (membrane or structural)
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UV DAMAGE AND OXIDATIVE STRESS
DNA effectsDNA fragmentation
Matrix effectsMMP : TIMP ratio
Membrane effects:ROSLipids peroxidationHydroperoxides
Enzymatic systemsSODGlutathion peroxidaseHeme oxidase
UV damage
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DNA DAMAGE
• UVA acts through oxidative stress forming “reactive oxygen species” (ROS) that will damage the DNA and lead to cancer
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DNA DAMAGE
• UVB impact on DNA in the cell creating damages which may lead to cancer: non-melanoma skin cancer (NMSC)
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UVB DAMAGE
• Following structural changes in DNA, there is an altered expression of oncogenes and tumor suppression genes, such as p53
• NMSC show a high incidence of mutation in p53 gene
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p 53 GENE
Plays an important role in:– blocking the cell cycle after exposure to DNA-
damaging agents e.g. UV, in order to allow for repair before duplication
– or killing the cell to avoid multiplication of damaged cells (formation of sunburn cells)
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p 53 GENE
The induction of detectable levels of p53 in human epidermis after UV exposure is relevant to skin carcinogenesis
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Collagen & Photodamage
• Major structural component of ECM– 70% of the dry weight of skin
• Collagen degradation is believed to play a role in formation of wrinkles
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Collagen DegradationA balance between MMP:TIMP
MMP TIMP
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MMP ENZYMES
ROS MMP
COLLAGEN DEGRADATION
TIMP
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MMP ENZYMES
• Collagenases (1 to 4) are specific to various collagen,
• Gelatinases (A & B) are non specific
• Stromelysins (1-3) specific of fibronectin, laminin, collagen IV, etc.
• Elastase: elastin
• etc
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MEMBRANE EFFECTS
With age, reduction in membrane fluidity leading to less efficient exchanges:– intrinsic: reduction in the methylation of PE
into PC– extrinsic: lipid peroxides
Methyl donors will restore membrane fluidity
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ACTIVE PHOTOPROTECTION
ACTIVEPHOTOPROTECTION
Reduce matrixdegradation
Replenish antiox system
Inhibition of oxidative stress
Quench ROS
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Irradiation of Epidermal Equivalents with Solar Spectrum UV
MM & TIMP-1
Solar Simulator
Wavelength (nm)260 280 300 320 340 360 380 400 420
W/c
m2
10-11
10-10
10-9
10-8
10-7
10-6
10-5
10-4
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UV Irradiation of Epidermal Equivalents
• Markers of damage– MMP-1 induction– TIMP-1 induction, but to a lesser extent than
MMP-1– MMP:TIMP imbalance
• Protection provided by– Sunscreens– Anti-oxidants
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UV Irradiation of Epidermal Equivalents
• Model for assessing Photoprotective potential– Botanical ingredients– Fully formulated product
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THANK YOU