PigmentationPigmentation

Normal skin color is dependent onNormal skin color is dependent on : :

--HemoglobinHemoglobin

--CarotenoidsCarotenoids

-Melanin pigment (the major color -Melanin pigment (the major color

determinant).determinant).

Types of skin pigmentationTypes of skin pigmentation

11..Constitutive skin colorConstitutive skin color

genetically determinedgenetically determined

22..Facultative Facultative skin colorskin color

from sun exposurefrom sun exposure..

Classification of sun-reactive skin typesClassification of sun-reactive skin types..

Skin typeSkin typeSun sensitivitySun sensitivityPigmentary Pigmentary responseresponse

IIVery sensitive,always Very sensitive,always burn easilyburn easily

Little or no tanLittle or no tan

IIIIVery sensitive,always Very sensitive,always burnburn

Minimal tanMinimal tan

IIIIIISenstive ,burn Senstive ,burn moderatelymoderately

Tan gradually(light Tan gradually(light brownbrown))

IVIVModerately sensitive, Moderately sensitive, burn minimallyburn minimally

Tan easily(brownTan easily(brown))

VVMinimally sensitive,rarely Minimally sensitive,rarely burnburn

Tan darkly(dark Tan darkly(dark brown)brown)

VIVIInsensitive ,never burnInsensitive ,never burnDeeply Deeply pigmented(black)pigmented(black)

The melanocytesThe melanocytescells dedicated for the production of melanincells dedicated for the production of melanin

EmbryologyEmbryology a. a. Originally, melanocytes are derived from the Originally, melanocytes are derived from the

neural crest.neural crest. Melanocytes appear in the Melanocytes appear in the epidermis by the 8epidermis by the 8thth week of gestation, and week of gestation, and by the 10by the 10thth week, these cells contain week, these cells contain melanosomesmelanosomes showing early melanization. showing early melanization.

b. The neural crest cells destined to become b. The neural crest cells destined to become

melanocytes migrate, proliferate, melanocytes migrate, proliferate,

differentiate, and populate the skin, inner ear, differentiate, and populate the skin, inner ear,

choroid and part of the iris.choroid and part of the iris.

-The c-kit-The c-kit is a receptor (tyrosine kinase is a receptor (tyrosine kinase

receptor family).receptor family).

-Its activation by -Its activation by stem cell factor(SCF)stem cell factor(SCF) results results

in stimulation of multiple intracellular in stimulation of multiple intracellular

signaling cascade, which signaling cascade, which modulates survival modulates survival

and proliferation of melanocytes.and proliferation of melanocytes.

-The signals that induce formation of the -The signals that induce formation of the

neural crest include members of neural crest include members of fibroblast fibroblast

growth factor(FGF)growth factor(FGF)..

-These factors activate specific cell surface -These factors activate specific cell surface

receptors, initiating intracellular signaling receptors, initiating intracellular signaling

cascades.cascades.

Structure of melanocytesStructure of melanocytes--Melanocytes are dendritic cells which have Melanocytes are dendritic cells which have

neither tonofilaments, nor desmosomesneither tonofilaments, nor desmosomes..

-By Hx/E-By Hx/E:: they appear with small dark they appear with small dark

nucleus with clear cytoplasmnucleus with clear cytoplasm

-By Fontana Masson stain-By Fontana Masson stain:: they stain black they stain black

DistributionDistribution-Melanocytes form a network of dendritic -Melanocytes form a network of dendritic

cells in the basal layer of the cells in the basal layer of the epidermisepidermis

-They are also found in the -They are also found in the dermis, external dermis, external

hair root sheath, in the bulb of hair hair root sheath, in the bulb of hair

follicles, eye, around blood vessels, and follicles, eye, around blood vessels, and

peripheral nervesperipheral nerves

CaucasoidCaucasoid

))whitewhite((

NegroidNegroid

))blackblack((

))11((Density of Density of melanocytes in a melanocytes in a

particular skin particular skin sitesite::

Constant(same)Constant(same)Constant(same)Constant(same)

))22((MelanosomesMelanosomes::

))aa((sizesize::

))bb((distributiondistribution::

--SmallSmall

Melanosomes are Melanosomes are packaged ipackaged in n membrane bound membrane bound complexes within complexes within

the keratinocytethe keratinocyte . .

--LargerLarger

Melanosomes are Melanosomes are iindividually ndividually dispersed within dispersed within the cytoplasm of the cytoplasm of

keratinocytekeratinocyte . .

CaucasoidCaucasoid

))whitewhite((

NegroidNegroid

))blackblack((

●●Melanosomes Melanosomes showshow::

))melaninmelanin((

● ●MMelanin elanin pigmentpigment

●●Degradative Degradative changes even in changes even in the basal layer of the basal layer of

the epidermisthe epidermis

●●Concentrated in Concentrated in the the centercenter around around the nucleusthe nucleus

●●Are Intact to up Are Intact to up to the level of to the level of

stratum corneumstratum corneum

●●Spread in the Spread in the branchesbranches ..

N.BN.B..

● ● Chronic Chronic sunsun exposure (in white skin) exposure (in white skin) can stimulate the melanocytes to can stimulate the melanocytes to produce produce larger melanosomeslarger melanosomes, , thereby making the distribution of thereby making the distribution of melanosomes within keratinocytes melanosomes within keratinocytes resemble the pattern seen in resemble the pattern seen in dark dark skinned individuals.skinned individuals.

Melanocytes in the hair follicleMelanocytes in the hair follicle provide provide

melanin for hair shaft pigmentation.melanin for hair shaft pigmentation.

The hair shaft melanin resides in the The hair shaft melanin resides in the

proximal anagen bulb. proximal anagen bulb.

MelanosomeMelanosome

-Special cytoplasmic organelles, on which -Special cytoplasmic organelles, on which

melanin is formed by the action of the enzyme melanin is formed by the action of the enzyme

tyrosinase.tyrosinase.

-They are membrane-bound granules related to -They are membrane-bound granules related to

lysosomes (both organelles contain similar lysosomes (both organelles contain similar

marker proteins).marker proteins).

Epidermal melanin unitEpidermal melanin unitEach melanocyte is surrounded by a group of Each melanocyte is surrounded by a group of

keratinocytes with which it maintains functional keratinocytes with which it maintains functional contact (thought to number approximately contact (thought to number approximately 3636 per melanocyte), the whole being termed an per melanocyte), the whole being termed an epidermal melanin unit. epidermal melanin unit.

Melanin pigmentation in the skin involves Melanin pigmentation in the skin involves

1.1.ProductionProduction of melanosomes within of melanosomes within

melanocytes melanocytes (termed melanogenesis)(termed melanogenesis), ,

2.2.Distribution and transfer Distribution and transfer of these of these

melanosomes to surrounding epidermal melanosomes to surrounding epidermal

keratinocytes.keratinocytes...

The The tip of the dendrite tip of the dendrite of the melanocyte of the melanocyte

becomes becomes embedded in the cytoplasm of embedded in the cytoplasm of

the keratinocytethe keratinocyte . .

A package of A package of melanosomesmelanosomes is transferred to is transferred to

the keratinocyte, which acts the keratinocyte, which acts as a as a

phagocytephagocyte

The major events that govern The major events that govern melanocyte melanocyte distribution and function distribution and function in the skin in the skin

includeinclude::

1.Migration of early melanocyte 1.Migration of early melanocyte progenitors, i.e., progenitors, i.e., melanoblastsmelanoblasts, from , from the neural crest, proliferation and the neural crest, proliferation and localization in the skin.localization in the skin.

2.Activation of 2.Activation of specific cell surface specific cell surface receptorsreceptors that transmit that transmit environmental signals for survival, environmental signals for survival, proliferation and pigmentationproliferation and pigmentation..

3.The expression of 3.The expression of key enzymes key enzymes and and structural proteins responsible for structural proteins responsible for melanin synthesismelanin synthesis..

4.4.Transport of melanosomes to Transport of melanosomes to dendrites and their transfer to dendrites and their transfer to epidermal keratinocyteepidermal keratinocyte

MelaninMelanin --Melanin determines skin, hair and eye Melanin determines skin, hair and eye

pigmentation.pigmentation.

Major product of melanocytes and is the main Major product of melanocytes and is the main

determinant of differences in skin colordeterminant of differences in skin color..

Types of melanin pigmentsTypes of melanin pigmentsMelanin is synthesized in two main formsMelanin is synthesized in two main forms::

11..EumelaninsEumelanins::Is insoluble and it gives the Is insoluble and it gives the brownbrown or black color or black color

to the skin.to the skin.

22..PheomelaninsPheomelanins::Is alkaline-soluble, sulfur containing, and it gives Is alkaline-soluble, sulfur containing, and it gives

the the yellowyellow--redred color to hair. color to hair.

Melanin is a mixture of Melanin is a mixture of pheomelanin and eumelanin pheomelanin and eumelanin

monomers and the monomers and the ratioratio between between the two determines the final color the two determines the final color

of the skin and hair.of the skin and hair.

Synthesis of melaninSynthesis of melaninTyrosineTyrosine

Tyrosinase enzymeTyrosinase enzymeDopaDopa

DopaquinoneDopaquinone

Eumelanine pheomelanineEumelanine pheomelanine

• Inside melanosomes, by the action of Inside melanosomes, by the action of tyrosinasetyrosinase enzyme, tyrosine enzyme, tyrosine is oxidized is oxidized to to

• 3,4-dihydroxyphenylalanine 3,4-dihydroxyphenylalanine (dopa),(dopa),

• which is further which is further oxidized to dopaquinoneoxidized to dopaquinone..

• From dopaquinone, the From dopaquinone, the eumelanin and eumelanin and pheomelanin pathways diverge. pheomelanin pathways diverge.

Control of PigmentationControl of Pigmentation

11--Genetic ControlGenetic Control: :

Cutaneous pigmentation is under complex genetic Cutaneous pigmentation is under complex genetic control > 150 alleles over 90 loci → Regulatecontrol > 150 alleles over 90 loci → Regulate

[ [G.F , Enzymes , Structural proteinG.F , Enzymes , Structural protein] ] 22--Intracellular signal transduction pathwaysIntracellular signal transduction pathways..

33--Functional regulationFunctional regulation:: through epidermal melanin unitthrough epidermal melanin unit: :

● ●Development of melanocyte unitDevelopment of melanocyte unit. . ●●Meloncyte-keratinocyte interactionMeloncyte-keratinocyte interaction. .

●●Melanin transfer to keratinocyteMelanin transfer to keratinocyte. .

44--Hormonal RegulationHormonal Regulation. . A- StimulatorsA- Stimulators. .

1-1-MSH/ACTH/ Melanocortin receptor MSH/ACTH/ Melanocortin receptor ●●MSH secreted by the middle lobe ofMSH secreted by the middle lobe of

the anterior pituitary .the anterior pituitary .

● ● Structurally ,MSH peptides ( that Structurally ,MSH peptides ( that include include αα-MSH , ß-MSH , and -MSH , ß-MSH , and γγ-MSH -MSH peptides) have peptides) have common amino acid common amino acid sequencesequence with ACTH with ACTH ..

MSH & ACTHMSH & ACTH

+ +

MCR ( Melanocortin receptor )MCR ( Melanocortin receptor )

↓ ↓

↑ ↑ cAMP →↑Tyrosinase enzymecAMP →↑Tyrosinase enzyme. .

e.g. In Addison's disease →↑ACTHe.g. In Addison's disease →↑ACTH

↑→ ↑→ Pigmentation Pigmentation especially in sun exposed areaespecially in sun exposed area. .

2-2-Beta-Endorphin & opioid receptorsBeta-Endorphin & opioid receptors→ → Melanocyte, proliferation and Melanocyte, proliferation and differentiation differentiation 3-3-EndothelinsEndothelins & their & their receptors→Tyrosinase Enzymereceptors→Tyrosinase Enzyme

4-4-HistamineHistamine & its receptors . & its receptors .

5-5-EicosanoidsEicosanoids & their receptors & their receptors. .

66--CatecholaminesCatecholamines & their receptors & their receptors. .

77 - -Vitamin Vitamin DD & its Receptors & its Receptors..

88--EstrogensEstrogens & their Receptors & their Receptors

e.g.↑pigmentation in Melasma “ e.g.↑pigmentation in Melasma “ chloasma “Melanogenesischloasma “Melanogenesis

99--AndrogensAndrogens & their Receptors & their Receptors . .

B-InhibitorsB-Inhibitors

1-1-Serotonin Serotonin & its receptors →Apoptosis & its receptors →Apoptosis of melanocytes .of melanocytes .

2-2-MelatoninMelatonin & its receptors & its receptors →Melanosomes aggregation around →Melanosomes aggregation around the nucleus . the nucleus .

3-3-DopamineDopamine & its receptors →Inhibit & its receptors →Inhibit hair follicular melanogenesis .hair follicular melanogenesis .

. .

4-4-AcetylcholineAcetylcholine & its receptors : & its receptors : →inhibit melanogenesis .→inhibit melanogenesis .

5-Cytokines , Growth Factors 5-Cytokines , Growth Factors , & their , & their receptors: IL-1,IL-6, & IFN- receptors: IL-1,IL-6, & IFN- αα and and γγ and their receptors.and their receptors.

6-Vitamin E6-Vitamin E → potent inhibitors of → potent inhibitors of melanogensismelanogensis

C-MiscellaneousC-Miscellaneous

11--GlucocorticoidsGlucocorticoids & their receptors & their receptors. . → → both ↑ or ↓ melanin synthesis has both ↑ or ↓ melanin synthesis has

been reported after glucocorticoid been reported after glucocorticoid treatmenttreatment. .

22--Retinoic acid & its receptorRetinoic acid & its receptor ..→ → Inhibit melanocyte proliferationInhibit melanocyte proliferation ,however,however,,

↑ ↑tyrosinase activity in white skin but tyrosinase activity in white skin but not in blacknot in black . .

Functions of melaninFunctions of melanin

Melanin provides the following functionsMelanin provides the following functions

--ProtectionProtection of tissues, particularly the lower layers of tissues, particularly the lower layers

of the skin against ultraviolet rays (UVR)of the skin against ultraviolet rays (UVR)

--Provides the Provides the gross coloration gross coloration of the skinof the skin

. .