ETAS_01 basic

Basic Science and Structure of Skin 1

1 Basic Science and Structure of Skin

Kelley Redbord, MD

Peter Schalock, MD

Bruce E. Strober, MD, PhD

C o n t e n t s

1.1 Epidermis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

1.2 Dermis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

1.3 Antigens Implicated in Autoimmune Diseases and Other Annoying Factoids . . . . . . . . . . . . . . . . . . .17

1.4 Wound Healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

1.5 Maturational . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

1.6 Hair Follicle Biology . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

1.7 Sebaceous Glands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

1.8 Eccrine Glands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

1.9 Apocrine Glands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

1.10 Nails. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

1.11 Nerves and Receptors of the Skin . . . . . . . . . . . . . . 26

1.12 Immunofluorescence Patterns - Direct . . . . . . . . . . 27

1.13 Connective Tissue Diseases . . . . . . . . . . . . . . . . . . . . 28

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1.1 EPIDERMISEpidermis

• Compliledofthefollowingcells:– Keratrocytes - 80%– Melanocytes-baselayer– Langerhanscellssuprabasal2-8%– Merkelcellsbasallayer

Keratinocyte• Ectodermalderivation• 80%oftotalpopulationofepidermis• 30differentkeratins:20epithelialand10nailkeratins->40–70kD– Bindtoeachotherintherodregion

• Acidickeratins:K9–K20,chromosome17• Basickeratins:K1–8,chromosome12• IntermediateFilaments(seealsoBullousandVesicularDermatoseschapter)– TypeI=acidickeratins9–20,chromosome17– TypeII=basickeratins1–8,chromosome12– TypeIII=vimentin,glialfibrillaryacidicprotein(GFAP),desmin,peripherin– TypeIV=neurofilaments– TypeV=nuclearlamins– TypeVI=nestin

• Keratinocytesareabletorelease,respondto,andproduceTNF-alpha.Causesincreaseddifferentiation(Bikle,1991)

Table1–1.KeratinExpressionPatterns

Type II Type I Location Hereditary Disease Association

1 Suprabasalkeratinocytes IchthyosishystrixofCurth-Macklin

Diffusenon-epidermolyticPPK(Unna-Thost)

1 10 Suprabasalkeratinocytes Bullouscongenitalichthyosiformerythroderma,EHK(corrugatedscale)

1 9 Palmoplantarsuprabasalarkeratinocytes

EpidermolyticPPK,diffusenonepidermolyticPPK

2e 10 Upperspinousandgranularlayers IchthyosisbullosaofSiemens(milderEHK)

3 12 Cornea Meesmann’scornealdystrophy

4 13 Mucosalepithelium Whitespongenevus(Cannon)-buccal

5 14 Basalkeratinocytes Epidermolysisbullosasimplex

1.)DowlingMeara(headortailofcentralroddomain)

2.)Koebner(segment1aor2bofroddomain)

3.)WeberCockayne(nonhelicalparts)

5 15 Mucosalbasallayer

6a 16 Outerrootsheath,hyperproliferativekeratinocytes

PachyonychiacongenitaJadassohnLewandowskytypeI,focalnonepidermolyticPPK

6b 17 Nailbed PachyonychiacongenitatypeII,steatocystomamultiplex(Jackson-Lawler)

uTIPa�Acidicandbasickeratinsareco-expressedinorderto

formfilamentousstructure-"obligateheteropolymers”

4 2011/2012DermatologyIn-ReviewlCommittedtoYourFuture

Type II Type I Location Hereditary Disease Association

8 18 Simpleepithelium Cryptogeniccirrhosis

hHb1

b6

Hairfollicle Monilethrix

19 Bulgecells&simpleepithelium Paget's=ck7,ck20

20 Merkelcellcarcinoma

1 16 NonepidermolyticPPK

17 SteatocystomaMultiplex

5 EBSMottledpigmentation(nonhelicalV1 domain)

14 EBSCAutosomalrecessive

Stratum Germinativum (Basale)Basalcellscontainornithinedecarboxylase(markerforproliferativeactivity)Stimulatedby:trauma,UV,EGF,estrogens,β agonists,tumorpromotersInhibitedby:proteindeprivationinpsoriaticskin(byretinoidsandsteroids)• Thebasallayer• K5andK14expressed-defectiveinepidermolysis bullosasimplex

• K19foundinbasalcellsattransitionalboundaries betweendifferenttypesofepithelia

• Microfilaments(actin,myosin,andalpha-actinin)assistinupwardmovementofcellsastheydifferentiate

• Integrinsregulateadhesionandinitiationofdifferentiation• Notallbasalcellshavepotentialtodivide• Stemcellsgiverisetotransientamplifyingcells• Oncebasalcellleavesbasallayerinhumans,normaltransittimetostratumcorneumisatleast14days,andtransitthroughstratumcorneumtodesquamationrequires14days,28daystotal

Stratum Spinosum• Roundernucleus,moreflattenedappearance• Containlamellargranules• K5/K14stillpresent,butnotmadedenovointhislayer• NewsynthesisofK1/K10->keratinization-specifickeratins,characteristicofepidermis,markersofterminaldifferentiation

• Inpsoriasis,actinickeratoses,andwoundhealingsuprabasalkeratinocytesdownregulateK1/K10andmakeK6/K16(mRNAalwayspresentforK6/K16,butonlytranslatedduringproliferation)

• Hyperproliferativestatesk6,k16,ki-67,α3β,integrin• Desmosomesform“spines,”calcium-dependentstructuresthatpromoteadhesion• Desmosomalplaque:Sixpolypeptides,plakoglobin,desmoplakinsIandII,keratocalmin,desmoyokin,demoyokin,andband6protein(seeTable1.2forlistingofdesmosomalproteinsandassociateddiseases)

uTIPa Keratin filaments in basal cells insert into

desmosomes and hemidesmosomes

Table1–1.KeratinExpressionPatterns(cont.)


Table1-2.DesmosomalProteins Protein Location Disease Association(s)

Plakoglobin Plaque NaxossyndromeDesmoplakinI/II Plaque CarvajalsyndromeKeratocalmin Plaque NonedescribedtodateDesmoyokin Plaque Nonedescribedtodateband6protein Plaque Ectodermaldysplasia/skinfragilitysyndromePlakophilin Plaque Ectodermaldysplasia/skinfragilitysyndromeEnvoplakin Plaque ParaneoplasticPemphigus(210kDantigen)Desmocalmin Plaque NonedescribedtodateDesmogleinI Transmembrane ADStriatePPK/PemphigusfoliaceusDesmogleinIII Transmembrane PemphigusvulgarisDesmocollinI Transmembrane SubcornealPustularDermatosisDesmocollinIII Transmembrane Nonedescribedtodate

• Transmembranecadherinsprovideadhesiveproperties-containdesmogleinIandIII,intracellulardomainslinkwithintermediatefilament cytoskeleton

• Gapjunctionsmoreabundantinstratumspinosumcomparedtostratumbasale– Communicationbetweencells– Moredifferentiatedkeratinocyteshavemoreabundantgapjunctions(fewinbasalcelllayer)

• Lamellar granules—Atypeofmembraneboundintracellularstructure,0.2–0.3micrometersindiameter;alysosomewithsecretoryfunc-tion.Theyarelamellatedbodies,containingceramide,arefoundintracellularlyinupperlevelkeratinocytes;theydischarge.Ceramideisthemajorlipidforbarrierfunctionoftheskin– Firstappearinstratumspinosum,butprimaryactivityinstratumcorneum– Dischargetheircontentsintotheextracellularspaceatthejunctionofthegranularandhornylayers,establishingabarriertowaterloss,and,withfilaggrin,mediatestratumcorneumadhesion

– Deliverlipidprecursorsintointercellularspace:glycoproteins,glycolipids,phospholipids,freesterols,andglucosylceramides(predominantlipidofstratumcorneum)

– Commonlyusedsynonymis“Odlandbodies”– Flegel’s disease—Decreasedlamellargranules– Harlequin ichthyosis—Lamellargranulesuniformlyabnormalorabsent.Defect in ABCA12 at2q34(alsodefectiveinlamellarichthyosistypeII)

– X-linked ichthyosis—Steroidsulfatasemissinginlamellargranules.Increasedlevelsofthebetafractionofcholesterolsulfatecanbeidentifiedbyserumlipoproteinelectrophoresis.Prenatal diagnosis can be accomplished by measurement of decreased estrogen levels and the presence of nonhydrolyzed sulfated steroids in maternal urine

uTIPa Lamellar granules deliver lipid precursors into

intercellular space: glycoproteins, glycolipids, phospholipids, free sterols, and glucosylceramides

uTIPa�Disease relating to gap junctions:

26 Vohwinkel’s syndrome, KID syndrome, PPK with deafness

30.3 & 31 erythrokeratoderma variabilis

30 hidrotic ectodermal dysplasia


Stratum Granulosum• Keratohyalingranulescontainprofilaggrin(Fgranules)andloricrin(Lgranulescontain

loricrinatperipheryandhelpformcornifiedcellenvelope)• K1modifiedtoK2,andK10toK11byproteolysisandphosphorylation

• Cornified cell envelope (CE):Proteinssynthesizedinspinous/granularlayers– Durable,protein/lipidpolymerformedwithindifferentiatingkeratinocytes– Eventuallyexistsoutsideofcornifiedcells– Componentsinclude:• Envoplakin – Homologoustodesmoplakin.MaylinktheCEtodesmosomesandtokeratinfilaments

• Involucrin – Cross-linkedbytransglutaminaseingranularlayertoaninsolublecellboundary• Loricrin – Inupperspinouslayerandthroughoutthestratumgranulosum – 75%ofCE’smass(majorproteincomponentofCE) – Vohwinkelsyndromevariantassociated –Filamentaggregatingactivity –InPsoriasis:iloricrin, hinvolucrin,ifilaggrin

• Filaggrin(histadinerich)FilamentAggregatingActivity-defectcausesIchthyosisvulgaris– Profilaggrinconvertedtomonomericfilaggrinsubunitswhengranularlayertransformedtocornifiedlayer;a calcium-dependentprocess

– Thoughttopromoteaggregationanddisulfidebondingofkeratinfilamentsincornifiedcell(likeaglue)

– Degradedintourocanicacidandpyrrolidonecarboxylicacid;bothhydratestratumcorneumandblockUVradiation

– Storedinkitgranule

• Transglutaminase:3versionsthatfunctionincrosslinking the CE (calcium-dependent pro-cess).Formsgamma-glutamyl-lysine isodipeptidebondsintheCE,mostprominentlywithinvolucrin

– TG-1(typeK)-keratinocytetransglutaminase,membraneassociated,defectcauseslamel-larichthyosistypeI(TGM1gene)

– TG-2(typeC)-fetalepidermisandbasallayerofadultepidermis,soluble– TG-3-presentinhairfolliclesanddifferentiatedepidermalcells,soluble.Presentinsublaminadensa-antigenfordermatitis herpetiformis. 77kDa

• Programmeddestructionofgranularcell-lossofnucleus,yetretentionofkeratinfilamentsandfilaggrinmatrix– Destructioninvolvesapoptosistransitioncells(“T”cells)

Stratum Corneum• TransitionfromStratumGranulosumaccompaniedbylossof45–86%indryweight• Providesmechanicalprotection,barriertowaterlossandbarrierpreventingpermeationofenvironmentalsolublesubstances

uTIP Basal layer k5, 14 Keratin filaments

Spinous layer k1, 10 Lamellar granules

(k6, 16 in psoriasis)

Granular layer k2, 11 Keratohyalin granules


Figure 1-1. Skin Adhesion Molecules with Corresponding Diseases

• NormalSCcellshavenonuclei;maypersistinincompletelykeratinizedcells(parakeratosis)• Bricks-Corneocytes;Mortar-extracellularlipidmatrix(fromloricrin)/lamellarlipidbarrier

Epidermal Differentiation• Triggeredbycalcium• CE:1.)crossedlinkedenvoplakin,periplakin,involvingalonginnescellmembrane,2.)lamellargranule6extrusionintoextracellularspace3.)loricrincrosslinksenvelope 4.)keratinandfilaggrincrosslink


Table1-3.EpidermolysisBullosa

Condition Defect

EBS K5,K14,plectin

EBS–herpetiformis(DowlingMeara) K5,K14(headortailofcentralroddomain)

EBS–WeberCockayne(palms/soles) K5,K14(nonhelicalparts)

EBS–Koebner K5,K14(segment1aor2bofroddomain)

EBS–musculardystrophy Plectin

JEB–lethal, Herlitz Laminin5(LAMB3gene)

JEB–pyloric atresia Alpha-6-Beta-4 integrin

DominantDEB(CockayneTouraine,hyperplastic,AlbopapuloidPasini)-atrophicwhitescars

CollagenVII(Col7A1)

RDEBHallopeau-Siemens CollagenVII(Col7A1)

Bart’ssyndrome CollagenVII

EBacquisita CollagenVII

EBS-mottledpigmentation K5(nonhelicalVIdomain)

EBS-AR K14

Basement Membrane Zone(RefertoFigure1-2)• Siteofinteractionbetweenepidermisanddermis• Threelayers– 1.)Laminalucida,2.)Laminadensa,3.)Sub-laminadensa

• Hemidesmosomaladhesioncomplex:1.)hemidesmosomalplaque,2.)anchoringfilaments,and 3.)anchoringfibrils

• Knowtheelectronmicroscopypictureofthebasementmembranezone.

Figure 1-2. Dermal-Epidermal Junction Components


Lamina LucidaHemidesmosome• Attachmentcomplexforbasalkeratinocytesandextracellularmatrix• Electron-densedomainontheventralsurfaceofbasalkeratinocytes-bridgecytoskeletonandcutaneousbasementmembrane

• Proteins:– BPAg1—230kDprotein(desmoplakin)• Intracellularatattachmentplaque• Memberoftheplakinfamilyandhomologoustodesmoplakin• Attachesintermediatefilaments(keratins)tohemidesmosomalplaque• BelongstothegenefamilyincludingdesmoplakinI

– BPAg2—180KDprotein(collagenXVII)• Transmembraneprotein• InteractswithBPAg1,beta-4integrin,andplectinintracellularly

• ItsNC16Adomain(target of autoantibodies in bullous pem-phigoid)interactswithalpha-6integrinextracellularly

• Alsointeractswithlaminin5extracellularly

• Twoforms:full-lengthtransmembraneandsoluble120kDaectodomainthatisshedfromcellsurface

• Integrins:Transmembraneproteins– alpha-6-beta-4integrinfoundatsiteswherekeratinintermediatefilamentsattach– Expressionlimitedtobasallayerofepidermis– Coordinateslinkagebetweenintermediatefilamentsandextracellularmatrixofthebasementmembrane

– Beta-4membraneproximaldomaininteractswithplectinanditsdistaldomaininteractswithBP180;absenceofbeta-4preventshemidesmosomalassembly

– Extracellularalpha-6domainbindslaminin5– Defectinbeta-4seenincicatricial pemphigoid with ocular involvement only– Defectsinalpha-6-beta-4resultsinJEB with pyloric atresia

• Plectin:Memberoftheplakinfamily– Linksintermediatefilamentstotheplasmamembraneandcrosslinksvarioushemidesmosomalproteins

– Mutationsresultinepidermolysis bullosa simplex with muscular dystrophy

Anchoring Filaments• Laminin5andBP180aremajorcomponents• Laminins– Glycoproteinswithatleast14membersofthefamily– Cross-shapedassemblyofthreeclassesofpolypeptides– Spanfromplasmamembraneofbasalkeratinocytestolaminadensa– Twomajorroles:1.)structuralnetworkinbasementmembranetowhichotherproteinsattach;2.)signaling

uTIPa�Disease Associations (see chapter 12 for more details)

BPAg1/BPAg2-NC16A bullous pemphigoid

BPAg2 lichen planus pemphigoides

portion of BPAg2 linear IgA disease

BPAg2-NC16A herpes gestationis

BPAg2 C terminal domain cicatricial pemphigoid


– Moleculesthatinteractwithotherproteins(suchasintegrins)totransmitmorphogeneticinformationtothecell’sinterior

– Laminin5(majorcomponentofanchoringfilaments;alsocalledepiligrin)andlaminin6isoformsare

foundintheDEjunctionofhumanskinandmucousmembranes• Uncein– 19DEJ1-Ag– Associatedwithanchoringfilaments

• Fibronectin– Centralfunctioninwoundhealing– Secretedbymyofibroblasts->stimulatedbyEGFandthrombin– AllowsfibroblaststoadheretoECM,provides“scaffolding”forcollagenfibrils(Bolognia)andassistsinwoundcontraction

• Nidogen– Alsocalledentactin– Dumbbell-shaped– Bindstolaminin1

Lamina DensaType IV Collagen• Functionsinstructuralsupportandconfersflexibilitytobasementmembrane• Highlycross-linked,formingalattice• Primarycomponentofanchoringplaques

Heparan Sulfate Proteoglycan• Negativelycharged,thusisapermeabilitybarrier

Sublamina DensaType VII Collagen• Targetedauto-antigeninepidermolysisbullosaacquisitaandbullouslupuserythematosus• Mutatedindystrophicepidermolysisbullosa• Primaryconstituentofanchoringfibrils• Homotrimericprotein

Anchoring Plaques• ComposedoftypeIVcollagen• PointofattachmentforanchoringfibrilscomposedoftypeVIIcollagen(from“above”)andcollagensIandIIIfromthedermis“below”

Melanocytes• Dendriticcellderived from neural crest• Foundinmultipletissues:epidermis,hairmatrix,retinalpigmentepithelium,ear(striavascu-laris),leptomeninges,andmucousmembranes

Skin Melanocytes• Inskin,localizedtobasallayerofepidermis• Functionsinclude:melaninproduction(melanogenesis),arborizewithprocessesthatcon-tactkeratinocytes(epidermalmelaninunit=approximately36keratinocytesincontactwithonemelanocyte),andtransferpigmenttokeratinocytes


• Keratinocytescanproducebothgrowthandinhibitorfactorsformelanocytes– Growth—beta-FGFandTGF-alpha– Inhibitory—IL-1,IL-6,TGF-beta

• Beabletorecognizeamelanocyteonelectronmicroscopy

Melanin Synthesis• Tyrosine->DOPA->DOPAquinone,bothstepscatalyzedbytyrosinase,acoppercontainingenzyme

• DOPAquinoneconvertedtopheomelaninoreumelanin• Tyrosinehydroxylaseisnotexpressedinmelanocytes (onlyinneurons)

• Melaninabsorbsandscattersultravioletradiation(280-400nm),andthusprotectsfromUV-inducedDNAmutations

Melanosomes• Containmelanin• Relatedtolysosomes:positionedaftertheGolgiapparatusinthesecretorypathway• Ellipticalmelanosomessynthesizebrownorblackeumelanin;havelongitudinallyoriented,concentriclamellae

• Spheroidmelanosomesproduceyelloworredpheomelanin;havemicrovesicularinternal structure

• Melanintransferinvolvestheactivephagocytosisofthedendritictipsofmelanocytesbythekeratinocytesandhaircortexcells

• Melanindistributedpreferentiallytomorebasallylocatedkeratinocytes• Oculocutaneous albinism (OCA)– Defectinmelaninsynthesisdueto:• Tyrosinase(OCA1)(melanosomesarrestinstageIorII)• P-gene(OCA2)• TRP-1gene(OCA3)

Differences in Skin Color: More Darkly Pigmented Races Show• Agreaterproductionofmelanosomesinthemelanocytes• Individualmelanosomeswithahigherdegreeofmelanization• Largermelanosomes• Higherdegreeofdispersionofmelanosomesinthekeratinocytes• Aslowerrateofmelanosomedegradation

Hair Melanocytes• Melaninunitexistsinproximalanagenbulb:onemelanocyteandfivekeratinocytes• Follicularmelanogenesiscoupledtohairgrowthcycle:melanocyteproliferationoccursduringearlyperiodofanagen

• Hairfolliclecontainsmelanocyteprecursorsthatcanrepopulatetheinterfollicularepidermis• Grayingcausedbygradualdeclineinthenumberoffollicularmelanocytes;influencedbybothageandgenes

• MC1-Rgenemutationsassociatedwithredhair

uTIPa�Melanin has two forms:

• Eumelanin - brown-black, insoluble

• Pheomelanin - red-yellow, alkali-soluble, sulfur-containing

a�Both types of melanin made from tyrosine via action of the enzyme tyrosinase


Merkel Cells• Mechanoreceptorsatsitesofhightactilesensitivity• Locatedatthebasalleveloftheepidermis• KeratinocyticdeformationinducessecretionofchemokinesbyMerkelcells• Locationvaries:hair-bearingskinandglabrousskinofthedigitsandlips,oralcavity,and

ORShairfollicle

• Keratin20(ck20)isaspecificandreliablemarkerofMerkelcellsandperinucleardots• Makesynapticconnectionwithneurons(theMerkelcell-neuritecomplex);neurochemicaltransmissionoccursbetweenanactivatedMerkelcellanditsneuron

Langerhans Cells• Bone-derived,CD34+,antigen-processingandpresentingcellsofmonocyte/macrophagelineagemigratefrombonemarrowinembryonicdevelopmentandcontinuetorepopulateepidermisduringlifetime

• Foundintheskinandotherepithelialtissues:oralmucosa,esophagus,vagina• Alsofoundinlymphnodesanddermis• TwostagesintheLangerhanslifecycle:1.)Inepidermis,ingestandprocessantigens,areweakstimulatorsofT-cells2.)ActivatedLangerhanscellsthathavecontactedantigenandcanstronglystimulatenaïveT-cells

• OnceaLangerhanscellencountersandprocessesagivenantigenit“matures”andmigratestoalocallymphnode,whereitthenpresentstheantigentoanaïve(orresting)T-cell,activatingthatT-cell

• Centraltothepathogenicprocessesofatopicder-matitis,psoriasis,allergiccontactdermatitis,andinfectionssuchasLeishmaniasis

• Functionallyimpairedbyultravioletradiation.AfterUVradiation,Langerhanscellsareimpairedintheabilitytopresentantigenandaredepletedinnumber

• Locatedinalllayersofepidermis,butmostlyinsuprabasallayer• Adherestocellsbye-cadherin,produceIL-1• DiseaseprocessesinvolvingLangerhansCells(allS-100andCD1a+withBirbeckgranulesin

cytoplasm):– Letterer-Siwe disease– Hand-Schüller-Christian disease– Eosinophilic granuloma– Hashimoto-Pritzker disease– CanbeinfectedwithHIV– ProducesIL-I,expressesE-Cadherin(toadheretoKC)

• Stains(+)CD45(ICAorOKTG),ATPase(1stmarkertodevelop),S100,FcReceptor(+),C3,CD1a,actin,vimentin

• Kidneyshapednucleus,BirbeckgranulesonEM

uTIPa

The most important cells for recognition, uptake and processing of antigens in the skin and presenting these antigens to naïve T-cells

a Characteristic finding on electron microscopy - Birbeck granules- tennis racket shaped bodies in the cell. Be able to identify an electron micros-copy image of a Langerhans Cell


1.2 DERMISDermis

• Collagen,elasticfibers,Matrix,Cells(fibroblasts,monocytes,phagocytes,mastcells,dermaldendrocytes,glomuscells)

Collagen• Primarydermalconstituent75%ofdryweightofskin• Providestensilestrengthandelasticity• Adultdermis:typesI,III,andV;typeIaccountsfor85%ofcollagen;typeIIIaccountsfor10%;typeVaccountsfor5%

• Lysylhydroxylaseandprolinehydroxylasecrosslinkscol-lagen(desmosineresidues)-vitaminCrequiredcofactor(copperandVitaminB6also)forfunctionofenzyme-vitaminCdeficiency=Scurvy

• TypeI&IIIaremajorinterstitialfiberformingcollagens

Table1–4.TypesofCollagenandTissueDistributionI(85%) MatureSkin,Bone,Tendon(exceptbonemarrow

andcartilage)COL1A1/2—Ehlers-Danlossyndrome(EDS)Arthrochalasiatype&OsteogenesisImperfecta

II Cartilage,Vitreous Relapsingpolychondritis

III(10%) FetalSkin,BloodVessels,Intestines Woundrepair,COL3A1—EDSVasculartype

IV BasementMembranes AlportandGoodpasturesyndrome

V(5%) Ubiquitous COL5A1/2—EDSClassicaltype

VI Aorta,Placenta Congenitalmusculardystrophywithoutskinfindings

VII AnchoringFibrils,Amnion Dystrophicepidermolysisbullosa(EB),bul-louslupus,cicatricialpemphigoid

VIII Cornea—Descemet’smembrane Cornealdystrophy

IX Cartilage Noassociatedskindisease

X Cartilage Noassociatedskindisease

XI Cartilage Noassociatedskindisease.Stickler&Marshallsyndromes(ophthalmicdisease)

XII Cartilage&fibroblasts Noassociatedskindisease

XIII Fibroblasts Noassociatedskindisease

XIV Skin,placenta,tendon,Cartilage,muscle Noassociatedskindisease

XV Placenta Noassociatedskindisease

XVI Placenta Noassociatedskindisease

XVII Anchoringfilaments JunctionalEB,generalizedatrophicbenignEB,bullouspemphigoid

XVIII Liver,kidney,placenta

XIX Rhabdomyosarcoma Rhabdomyosarcoma

uTIPa Composed of three chains that vary

according to collagen type. All have Gly-X-Y amino acid motif that repeats where X and Y are proline an hydroxy-proline


Collagen DiseasesEhlers-Danlos Syndromes• Excessivestretchabilityandfragilityoftheskinwithatendencytowardeasyscarformation (“fish-mouth”scars)

• Calcificationoftheskintoproducepseudotumors• SeeChapter3,Genodermatoses,fordescriptionoftypesRandom Associated Diseases:

• Osteogenesis ImperfectaabnormaltypeIcollagen• Homocystinuria:Abnormalcrosslinkingofcollagenbecauseofmutatedβcystathionesynthase

• Tenascin-X:AutosomalrecessivetypeEDSsimilartoClassictype.Associatedwithcollagenfibrillinogenesis

Elastic Fibers• 4%ofdryweightoftheskin• FormscomplexmeshworkextendingfromlaminadensaoftheDEJthroughthedermisandintothehypodermis

• Returnsskintonormalconfigurationafterbeingstretched• Elasticfibers:90%elastin,wrappedbyfibrillinmicrofibrils(mutatedinMarfan’s)• Desmosineandisodesmosinearetypicalaminoacidsfoundinelasticfibers,andcrosslinkfibrillinrequireslysyloxidase(copper-dependentprocess)

• Oxytalanfibers:containnoelastin;runperpendicularfromDEJwithinsuperficialpapillary dermis

• Elauninfibers:havelesselastinandmorefibrillin;runparallelinthinbandswithinthereticulardermis• Elasticfibersturnoverslowlyintheskinandaredamagedbyultravioletradiation

Elastin DiseasesCutis laxa• Fibulin5genedefect• Decreaseddesmosineandlysyloxidase• Fragmentationandlossofelasticfibers

Marfan’s Syndrome• DecreasedfibrillinI• Fragmentationofelasticfibers,especiallyaortic

Congenital Contractural Arachnodactyly• Mutationinfibrillin2

Pseudoxanthoma Elasticum• MDRP(multipledrugresistantprotein)• ABCC6genedefect—(adenosinetriphosphatebindingcassettesubfamilyCmember6)• Increasedglycosaminoglycansonelasticfibers• Calciumdeposition• Accumulationoffragmentedandcalcifiedelasticfibers

Buschke-Ollendorf Syndrome• LEMD3(a.k.a.MAN1)genedefect• Increaseddesmosine• Increasedamountofthickenedelasticfibers


Anetoderma• Decreaseddesmosine• Lossofandfragmentationofelasticfibers

Dermal Matrix Components• Proteoglycansandglycosaminoglycans→groundsubstancethatsurroundsthefibrousconstituentsofthedermis;0.2%ofdryweightofthedermis

• Proteoglycansconsistofa“coreprotein”withaglycosaminoglycansuchashyaluronicacidbindingtothecoreprotein;otherglycosaminoglycansincludedermatansulfate,heparansulfate,andchondroitinsulfate

•Canbindupto1000timestheirvolumeandregulatewater-bindingcapabilityofthedermis• Mucopolysaccharidosesrepresentgeneticstoragediseasesresultingfromabnormallyso-somalfunctionandsubsequentaccumulationofthesesubstances.→ Hurler’s(Alpha-L-iduronidase),Hunter’s(Iduronatesulfatase),forexample.SeeGenodermatosesChapterformoredetailontheseconditions

Papillary Dermis• Youngorhealthyskin:smalldiametercollagenfibrilsandoxytalanelasticfibers• Agingoractinicallydamagedskin:matureelasticfibersthatarelargeanddense• Highdensityoffibroblastcellsthatproliferaterapidly

Reticular Dermis• Largediametercollagenfiberswithmature,branchingelasticfibers• Elasticandcollagenbundlesincreaseinsizeprogressivelytowardthehypodermis

Cells of the DermisFibroblast• Derivedfrommesenchyme• Producesextracellularmatrixframework• Synthesizessolublemediatorsthatmayconstitutesignalingbetweenthedermisandepidermis• Woundhealing-producefibroplasiaandwoundcontraction(myofibroblasts)

Mononuclear Phagocytic Cells• Monocytes,macrophages,anddermaldendrocytesfrombonemarrow• AllphagocyticskinmacrophagesexpressCD11c,CD6;CR4(CD11c)=β2integrinthatbinds;

C3b+stimulatesphagocytosis• Macrophagefunctions– Phagocytic– ProcessingandpresentingantigenstonaïveT-cells– Microbiocidalthroughproductionandreleaseoflysozyme,peroxide,andsuperoxide– Tumoricidal– Secretory(cytokines,growthfactors,etc.)– Involvedincoagulation,atherogenesis,woundhealingandtissueremodeling– CD11a=LFA(bindsto(CAM-2)– CD11b=Mac-1onphagocytesbindstoLCAM


Mast CellsTable1–5.MastCells

Mast Cell Type Mediator Location

TType Tryptaseonly Boweandrespiratorymucosa

TCType TyprtaseandChymase Skin,GI,submucosa

CType Chymaseonly Skin,lymphnode

• Greatestdensityinthepapillarydermis,insheathsoftheappendages,andaroundbloodvesselsandnervesofthesubpapillaryplexus

• Diseases:Mastocytosis,solitarymastocytoma,diffuseerythrodermicmastocytosis,TMEP,UP• Derivedfrombonemarrow-residingCD34+stemcells

•Proliferationdependsonthec-kitreceptoranditsligandstem-cellfactor(SCF).Mutations in c-kit may result in mastocytosis or piebaldism

• StainCD34+,C-Kit,stemcellfactor(SCF),giemsa,teledyne,lederstain(naphtholchloroacetateesterase)• Producedandstoredinpreformedsecretorygranules-manyinflammatorymediatorssuchashistamine,heparin,tryptase,chymase,carboxypeptidase,neutrophilchemotacticfactor,andeosinophilicchemotacticfactorofanaphylaxis.ProduceIL-8(strongneutrophilchemo-tacticfactor)-ProducePqD2andtryptase

• Releasewithoutstoring-growthfactors,cytokines,andleukotrienesincludingprostaglandinD2• Preformedmediatorinmastcell-serineproteases(tryptase),heparin,histamine• Secretorygranulesarereleasedbyavarietyofstimuli,andprocess.Degranulationisidenticalregardlessofstimulus

• Degranulationproducesvascularsmoothmusclecontraction,increasesvascularpermeabil-ity,tissueedema,andtherecruitmentofinflammatorycells

• Responsibleforimmediate-typehypersensitivityreactionsandparticipateinchronicinflammatoryconditions

• Histologically:Roundorovalnucleusanddarkstaininggranules• Mastcellmediators:tryptase,chymase,cathepsinG,histamine,heparin,IL-4,IL-13,IL3,IL5,GMCSF,TNF-alpha,CCL3,leukotrienesC4D4EF,platletactivatingfactor

Mast Cell Mediators• Tryptase,chymase,cathepsina,histamine,heparin,IL-4,IL-V,IL3,IL5,GM-CSF,TNF-alpha,

CCL3,leukotrienesC4D4E,Plateletactivityfactor

Dermal Dendrocytes• Subsetofantigen-presentingcellsfunctionintheafferentlimboftheimmuneresponse• Derivedfrombonemarrow• Foundinpapillarydermisandupperreticulardermis• Highlyphagocytic,sameasmelanophagesinthedermisthatcontainingestedpigment• Likelythecelloforigininbenignproliferativetumorssuchasdermatofibromasorfibroxanthomas

Glomus Cells• DerivedfromSusquet-Hoyercanals• Vascularsmoothmusclecells• Allowtherapidshuntingofbloodfromthearteriolestovenules,bypassingcapillaries-occursprimarilyinpalmsandsoles

• Diseaseprocessesincludeglomustumorandglomangioma


1.3 ANTIGENS IMPLICATED IN AUTOIMMUNE DISEASES AND OTHER ANNOYING FACTOIDS

Paraneoplastic Pemphigus• Plectin(500kd)• DesmoplakinI(250kd),II(210kd)• BPAg1(230kd)• Envoplakin(210kd)• Periplakin(190kd)• Unknown170kdantigen• Dsg1,3(160kd,130kd)

Pemphigus Vulgaris• Desmoglein3(130kd),coprecipitateswithplakoglobin(85kd)

Pemphigus Foliaceus• Desmoglein1(160kd)

Linear IgA Disease• BPAg2(180kD)(CollagenXVII)-maybethe97kdfragment

Subcorneal Pustular Dermatosis (IgAPemphigus,Sneddon-WilkinsonDisease)• Desmocollin1(115and105kd)

Intraepidermal Neutrophilic IgA Dermatosis• Desmoglein3

Pemphigoid Gestationis• BPAg2(180kd)

Cicatricial Pemphigoid (MucousMembrane)• BPAg2(180kd)• Laminin5-antiepiligrinCP• Laminin6• β-4integrin-OcularCP• TypeVIIcollagen

The Plakin Family• Envoplakin(210kd)• Periplakin(190kd)• Desmoplakin(250kd)• BPAg1(230kd)• Plectin(500kd)

Table1–6.BlisteringD/OAntigen Inherited AI

K5,14 EBSDowlingMeara

Plectin EBS-MD PNP

BPAG2 GenerallyatrophicbenignEB EB,CP


Antigen Inherited AI

α6β4Integrin JEB=gatricatresia β4integrinocularCP

LamininV JEB CPwithmaln

CollagenVII DEBCollayenousdomain EBAnoncollagenousdomain

BullousLECollapsedomain

1.4 WOUND HEALINGInflammatory Stage

Clot Formation• Initialstepinwoundhealing• Provisionalmatrixforcellmigration• Functionsinhemostasis

Coagulation• Criticaleventisavailabilityofsurfacethatpromotesadsorptionandactivationofspecificcoagulationpro-enzymes

• Clotprovidesascaffoldingforrecruitmentofcellstoinjuredsite• Fibrin and fibronectinactasprovisionalmatrixforinfiltratingmonocytes,fibroblasts,andnewlyformedbloodvessels

• Clearanceofclotmatrixisasimportantasdeposition,andinadequateremovalofprovisionalmatrixmayleadtofibrosis;proteolyticenzymessuchasplasminogenandplasminarethemajorproteins

Platelets in Wound Healing(FirstResponse)• Aggregationandadhesionrequired• Releasemanymediators,includingADP,andclottingfactors• Fibrinclotandthrombinactasnidusforfurtheradhesionandaggregation• PlateletsreleasePDGF,EGF,fibronectin,andTGF-alphaand–betawhichpromotenewtissue

growth

Neutrophils in Wound Healing• Migratewithmonocytesconcurrently,butarrivefirstingreatnumbersbecauseoftheirabundanceincirculation

• ChemoattractantsforPMNs:Fibrinogen/fibrinsplitproducts,C5a,leukotrienes• Ifwoundcontaminationcontrolled,PMNmigrationceaseswithinafewdays,andPMN’sbecomeentrappedwithinthewoundclot,undergoapoptosisorphagocytosedbymacrophages

Monocytes in Wound Healing

• Macrophages are REQUIREDforwoundhealing-withoutmacrophages,thereisnohealing• Monocytechemoattractantsincludefragmentsofcollagen,elastin,andfibronectin• Macrophagesdebridetissuethroughphagocytosisanddigestionoforganisms,tissue

debris,andeffetePMN’s• Secretecollagenase• AdherencetomatrixstimulatesexpressionofcytokinesandgrowthfactorsFGF,IL-1,TGF-alpha,PDGF,andTGF-beta,thereforefacilitatingtransitionfrominflammationtorepair

• Proliferationphase:epithelizationgranulationcollagendeposit;Angiogenesis(stimulatedbyTNFα)

Table1–6.BlisteringD/O(cont.)


Epithelialization• Beginshoursafterinjury• Keratinocytesfromresidualepithelialstructuresleapfrogeachother• Woundepidermalcellshavelateralmobilitybyvirtueofdissolutionofintercellulardesmosomes• Cellsinalllayersofmigratingepidermiscontainkeratins5and14(usuallyonlyfoundinbasalepidermis)andkeratins6and16;thisphenotyperesemblesthatfoundinlesional

psoriaticskin• Onetotwodaysafterinjury,cellsatwoundmarginproliferate• Ifbasementmembranedestroyed,migrationoccursoverprovisionalmatrixofcollagentypeV,fibrin,fibronectin

• Migratingcellsbothtraverseoverwoundcoatedwithprovisionalmatrixandthroughwoundusinganarrayintegrinreceptorstoguidethepath

• Collagenaseisproducedtoassistinmigration• Migrationanddissectionresultsinescharsloughing• Migrationisaresultofacombinationofchemotacticfactors,directguidancebycontact,andlossofnearestneighbor,butnotbyproliferation

• Oncebasementmembraneproteinsreappear,epidermalcellsreverttotheirnormalphenotype• 1stdegreeburn-basementmembraneintact• 2nd/3rddegreeburn-basementmembranedestroyed

Granulation Tissue• Fourdaysafterinjury,granulationtissueforms• Composedofnewcapillaries,macrophages,fibroblastsandbloodvessels,whichmoveintowoundspaceasaunit

• Formationofgranulationtissuedependentonpresenceoffibronectin• Orderedsequenceofmatrixdeposition:fibronectin→collagenIII→collagenI• GranulationtissueprimarilycontainscollagentypeIII

1.5 MATURATIONAL

Fibroplasia and Wound Contraction• Fibroplasiaisgranulationtissuethatarisesfromfibroblasts,andisamixtureoffibroblastsandextracellularmatrix(ECM)

• Monocytes→macrophages→secretionofgrowthfactors(alsofromplatelets)→fibroblastproliferationandactivationoffibroplasia

• Oncemigratedintoawound,proteinsynthesisoccurstocreatetheECM/collagenmatrix• Woundcontractionensuesduringsecondweekofhealing→governedbywoundfibro-blasts’abilitytoactlikesmoothmusclecells(myofibroblasts),anchoredbycollagenbundles

• Largebundlesofactin-containingmicrofilamentsappearinthesefibroblasts• Fibroplasiainwoundrepairendswithapoptosisoffibroblastsatorarounddaytenofhealing• 30%ofnormalstrength

Neovascularization• Solublefactorsthatstimulateangiogenesis:VEGF,TGF,angiogenin,angiotropin,andothers• Angiogenesisoccursduringfirstweekofwoundrepair


• Angiogenesisinitiatedbyplasmaleak,releaseofFGF,andsubsequentactivationofcollage-nasetobreakdownthebasementmembraneonwhichtheendothelialcellsrest

• Theendothelialcellsprojectpseudopodsthroughthebasementmembraneandsubse-quentlymigrateintotheconnectivetissuespace

Tissue Remodeling• Endothelialcellsarefirsttoapoptose,thenmyofibroblasts,andmacrophages,leavingan

acellularscar• Progressionofeventsovertime:earlyformationoftypesI,III,andVcollagen,collagenbundlesgrowinsize• Increasingwoundtensilestrength,andproteoglycansaredepositedincreasingwoundresilienceto• Deformation• Fibrin:Firstextracellularmatrixtobedeposited;foreffectivehemostasis,interactionmustoccurwithplatelets(viaGPIIb-IIIaintegrin);fibroblastsrequirefibronectinformigrationintoafibrinclot

• Fibronectin:circulatesinbloodandbindsfibrin• Hyaluronan(hyaluronicacid):linearpolymer(memberofglycosaminoglycans);majorcom-ponentofearlygranulationtissue;producedbyfibroblasts

Strength of Scar• 5%atoneweek• 20%atthreeweeks• 70%atoneyear

1.6 HAIR FOLLICLE BIOLOGYEmbryology

• Firstprimordialhairfolliclesformatnineweeksgestationoneyebrows,upperlip,andchin• Remainingfolliclesdevelopatfourtofivemonthsinacephaladtocaudaldirection• Newfolliclescannotdevelopinadultskin• Ectodermalorigin,hairpapilla-mesoderm

Follicular Morphogenesis• Exchangeofsignalsbetweenepithelialandmesenchymalcells• Pregermstage:focalcrowdingofepidermalbasalnucleimatchbyaclusterofmesenchy-malcellsbeneaththebasementmembrane

• Crowdingofbasalkeratinocytescausesaslightbudonundersideofepidermis—termedthefolliclegermorprimitivehairgerm

• Folliclepeg:Resultoftheelongationoffolliclegermintoacordofepidermalcellsthatgrowsintodermisperpendiculartoskinsurface

• Tipoftheepithelialcordbecomesmatrixportionofthebulb• Outgrowthsofcellsfromtheouterrootsheathgiverisetothepresumptivesebaceousgland(uppermost)andthebulge(lowermost)—theinsertionsiteofthearrectorpilimuscle

• Dermalpapilla:Deepestportionofthebulboushairpegthatformsaninvaginationsur-roundingthebulkoftheunderlyingmesenchymalcells


• Matrixkeratinocytes:AbovetheBMoverlyingthedermalpapilla—giverisetohairshaftandinnerrootsheath;melanocytesresponsibleforthepigmentationofthehairdispersedamongthesematrixcells

• Outerrootsheath:Mostperipheralepithelialcellsofthefollicle;mostlikelynotformedfrommatrixcells

Hair Follicle Organization• Outerrootsheath(trichilemmalkeratin):mostperipheralofcellularcomponents• Innerrootsheath:Threecompartments,stainsredbecausecitrulline1.)Henle’slayer-keratinizesfirst2.)Huxley’slayer3.)Cuticle

• Hairshaft:Threecompartments1.)Cuticle2.)Cortex—formsbulkofhair3.)Medulla—central

• CriticallineofAuber:Widestdiameterofthebulb;bulkofmitoticactivitythatgivesrisetothehairandtheinnerrootsheathoccursbelowthislevel

The Hair CycleAnagen• 84%,3-4years• Follicletraversesentireepidermis• Matrixkeratinocytesinthebulbregionproliferaterapidly;thesecellsarepluripotentcellscapableofdifferentiatingintocuticle,cortexandmedullaofhairshaft

• Dividedintosixsubstages(ItoVI):thefirstfivecalledcollectivelyproanagen—definedbyprogressivelyhigherlevelsofnewhairtippositionwithinthefollicle;the6thstage,metana-gendefinedbyemergenceofhairshaftabovetheskinsurface

• Endofanagen:apoptosis• Scalp:Lasts2to6years• Leg:19–26weeks• Arm:6–12weeks• Mustache:4–14weeks

Anagen Effluvium• Frequentlyseenfollowingadministrationofcancerchemotherapeuticagents

• Stimulusinducestheabruptcessationofmitoticactivityinrapidlydividinghairmatrixcells;hairshaftthinsandthenbreaksatskinsurface

• Occurswithindaystoweeksofthestimulus• EntirelyreversiblewithcessationofdrugtherapyCauses• Antimetabolites• Alkylatingagents• Mitoticinhibitors• Thallium• Boron• Examples:doxorubicin,thenitrosureas,andcyclophosphamide

>Nokeratohyalingranules

uTIPa Inside to outside. Cuticle - IRS - Huxley-Henle - ORS - glassy/vitreous


Catagen• 2%,clubends,3weeks• Scalphairsshowgradualthinningandlighteningofthepigmentatthebaseofthehairshaft• Melanocytesinthematrixceaseproducingmelanin,andundergoapoptosis• Involutionlower2/3rdsbykeratinocyteapoptosis• Matrixkeratinocytesabruptlyceaseproliferating,undergoterminaldifferentiation• Atendofcatagen,thefollicularpapillacomestorestatthebottomofthepermanentportionofthehairfollicle

Telogen• ~14%,duration3months• Hairhasclub-shapedproximalend,andistypically

shedfromthefollicle• Theinnerrootsheathistotallyabsentfromthetelogenfollicle• Hairgrowthoccursina“wavepattern”inhumansinutero,withthefirsttelogenenterednearthetimeofbirthwithsheddingtwotothreemonthslater

• Mosaicgrowthpresentbyendoffirstpostnatalyear

Molecules Important for Transition from Anagen to Telogen•FGF5:Mutleadtoangoraphenotype;hairis30-50%longerthannormal

•Hairless:Mutcausesatrichia•VitDreceptor:Atrichia

Molecules Important for Transition Telogen to Anagen•Sonichedgehog(SHH)•Pathced(receptorforSHH)•Beta-catenin

Molecules Controlling Size of Follicle•SHH,beta-catenin,noggin,BMP,FGFs,TGFb,laminin10

Telogen Effluvium• Thesefactorspushthefolliclefromanagentocatagenandtelogen• Thereisnodisease,andnoinflammationDrugsImplicated• Amphetamines• Aminosalicylicacid• Angiotensin-convertingenzymeinhibitors• Anticoagulants• Beta-blockers• Bromocriptine• Carbamazepine• Cimetidine• Danazol• Etretinate• Interferon

uTIPa�Early and excessive loss of club hairs from

the normal resting follicles in the scalp

• Physicalstresssuchas:surgery,anemia, traction or systemic illness

• Psychologicalstress

• Endocrinecausessuchas:hypoorhyperthy-roidism or peri-/postmenopausal states

• Nutritionaldeficiencies:biotin,iron,protein (Kwashiorkor),zinc,essentialfattyacidor calorie deficiency (marasmus or starvation diets)

• HypervitaminosisA

• Parturition

• Fever

• Drugs


• Lithium• L-dopa• Oralcontraceptives• Valproicacid

Clinical• Diffuseloss• Onlyrarelyinvolvesgreaterthan50%ofthescalp• Pulltestabnormal:Pull40hairsandmorethan6pulledoutisabnormal(only10–15%intelogen)-makecertainpatienthasn’tshampooedthatday

• Totalnumberofhairsonscalp:100,000with100–150normallylostonadailybasis;telogeneffluviumresultsin150–400lostperday

• Inmany,nospecificcauseidentified• Mostcasesstopspontaneouslywithinafewmonthsandhairregrows.Takes6–12monthsforhairdensitytoreturntonormal

Therapy• Nospecifictherapy

Factoids• Atanyonetime,85%ofhumanscalphairinanagen,14%intelogen,1%incatagen• Glassymembranecanbeseenasthehairfollicleresorbsincatagen(remnantsofbasementmembrane)• Hairsgrow0.4mmperday• Hairfolliclesinscalp:100,000inbrown/blackhair,with10%moreinblondes,and10%lessinredheads

Structure of Hair• Non-livingbiologicfibers• Cortexcontainsthebulkofthehairkeratins• Keratinsareintermediatefilamentsinwhich400–500aaresiduesofindividualchainsarrangedinsequencescontainingheptadrepeats;pairtogethertoformcoiledcoils

• Otherproteins:thekeratin-associatedproteins(KAPs):1)highsulfurproteinrichincysteineand2)highglycine/tyrosine-containingproteins

• Disulfidebondingcontributestothephysicalpropertiesofthefiberandthesebondsarebrokenduringhairstylingandreformedwhenthedesiredchangeaccomplished

• Cuticlemaintainstheintegrityofthefiber.Ifdamagedbyphysicalorchemicalmeans,thefiberismorelikelytobreak—trichoptilosis(“splitends”)

Hair Pigmentation• Haircolordeterminedbymelanocytes,andhairispigmentedonlywhenitgrows—melano-cyticactivityoffollicularmelanocytescoupledtoanagenstage

• Haircolor:melanocytesinmatrixclosetopapilla• Melaninformationabsentthroughtelogenandcatagen• Melanocyteslocatedinmatrixareaoffollicle,abovethefollicularpapilla,producethepigment• Eumelaninisthepigmentofbrown/blackhairsandpheomelaninisthepigmentinred/

blondhairs• Intensityofcolorproportionaltotheamountofpigment,andabsenceofpigmentproduceswhitehair;markedlyreducedpigmentproducesgrayhair


Types of Hair• Lanugo:Soft,finehairthatcoversmuchofthefetusandusuallyshedbeforebirth• Vellusscalphair:Lengthslessthan1cm• Indeterminatescalp:Approximately1cm• Terminalscalp:Longerthan1cm• Eyelashandeyebrowhairsareconsideredterminal

Bulge-Activation Hypothesis• Thefollicularepithelialstemcellslocatedinthebulgeregionoftheouterrootsheathunder-gotransientproliferationduringearlyanagen,producingthetransientamplifying(TA)cells.TAcellsrapidlyproliferate,migratedownward,andeventuallybecomematrixkeratino-cytes.BecauseTAcellshavealimitedproliferativecapacity,theyexhausttheirproliferativereserveandundergoterminaldifferentiation(catagen)

Defects of Hair Shaft•Monilethrix:MuthairkeratinhHb6;alternatingthickandthinareas,beadedhair•Netherton’ssyndrome:Trichorhexisinvaginatum(bamboohair);mutinserine-proteaseinhibitor

•Piliannulati:Bandedhair•Menkesdisease:Twistedhair(pilitorti);defincoppertransporter•Uncombablehairsyndrome:Triangle-shapedhair•Hereditarymucoepithelialdysplasia:Redgums,KP,episodichairloss•Nanossyndrome:Mutinplakoglobin;woolyhairhyperkeratotisofpalmsandsoles,cardiacarrhythmia

1.7 SEBACEOUS GLANDS• Enlargeatpubertyinresponsetoincreasedandrogens• Oftenconsistsofseverallobulesthatemptyintoasebaceousduct• Holocrineglands/secretion• Foundinassociationwithhairstructures,butthereisnorelationshipbetweenthesizeofthesebaceousglandandthesizeoftheassociatedhair

• Underandrogenichormonalcontrolnotneutralcontrol

• Freesebaceousglandsnotassociatedwithhairsarefoundinspecificlocations– Nippleandareola→ Montgomery’sareolartubercles– Fordyce’scondition→freesebaceousglandsonvermillionborderofthelipsandonthebuccalmucosa

– Meibomianglands→locateddeepontheeyelids,usuallyembeddedintarsalplate,aremodifiedsebaceousglands.Formsthemostexterior(lipid)layerofthetearfilm,preventingevaporation.Inflammation=chalazion.Emptiestomucosa

– GlandsofZeis→locatedonsuperficialeyelidmargin.Alsocontributestoexteriortearfilmlayer.Inflammation=hordeolum.Emptytoskin

– GlandsofMollapocrineglandsonlidmargin– Tyson’sglands→freesebaceousglandslocatedonthegenitalia

• Foundeverywhereontheskinexceptthepalmsandsoles(prepuce)


Sebum Components: Epidermis:

Glycerides 57.5% 65%

Waxesters 26% 0

Squalene 12% 0

Cholesterolesters 3% 15%

Cholesterol 1.5% 20%

• Rateofsebumproction1mg/10cm2 • Thermoregulatoryrole• Humansebumdifferentfromotherlipidsbywakesters

1.8 ECCRINE GLANDS• Thermoregulatory• Postganglionicsympatheticfibers• Composedofthreesegments:intraepidermalduct(acrosyringium),theintradermalduct,andthesecretoryportion• Basalcoilexistseitherinthelowerportionofthedermisorattheborderofthedermisandthesubcutaneousfat

• S100,CEA,keratinpositive• Presenteverywhereontheskin,butabsentinmodifiedskinthatlackscutaneousappend-ages:Vermillionborderofthelips,nailbeds,labiaminora,glanspenis,clitoris,extauditorycanal

• Sweatformedintwosteps:secretionofprimaryfluid,isotonicNaClconcentrations;thenreabsorptionofNaClbytheduct.SweatingratemostimportantdeterminantofNaClcon-centrationinfinalsweatfluid.Othercomponents:lactate,urea,ammonia,aminoacids,pro-teinsandproteases

• Oneoffewfetalstructuresthatdoesnotdevelopcraniocaudal(develop1stonpalmsandsoles4thmonth,body5thmonth).Fullyformedatbirthnotfullyfunctional

• Longthinductopentoskin

1.9 APOCRINE GLANDS• Innervatedbysympatheticfibers• Developfrommantleofhairfollicle.1stseenweek24onscalp• Tubularglandsthatdemonstratedecapitationsecretion;partofcellpinchedoffduring

secretoryprocess• Likeeccrineglands,composedofthreesegments:intraepidermalduct,intradermalduct,andthesecretoryportion

• Ductofapocrineglandusuallyleadstoapilosebaceousfollicleaboveentranceoftheseba-ceous duct

• Apocrineglandsfoundinaxillae,anogenitalregion,externalearcanal(ceruminousglands),intheeyelids(Moll’sglands),andinthebreast(mammaryglands)

• Functionbeginsatpuberty.Unclearrole-?olfactorycommunication• Secretioninresponsetoemotivestimuli—throughactionofepinephrine/norepinephrine.Denervationdoesnotabolishthisresponse,thoughapocrinesweatingrequiresintactnervesupply

uTIPa�Cholinergic stimulation regulates activity

(thus, efficacy of botulinum toxin)

Table1-7.SebumandEpidermalComponents


• Initialsecretionisodorless,andodorderivedfromC6–C11acids-themostabundantis3-methyl-2-hexenoicacid

• Stain+keratin,S100,CEA,lysozyme• Shortthickductopensintofollicularcanal;decapitationsecret– Disease:Foxfordycedisease(occlusionofapocrineducts);chromhidrosis-pigmentedsweatduetolipofuscincontext

1.10 NAILS• (seeChapteronDisordersoftheHairandNails)

1.11 NERVES AND RECEPTORS OF THE SKIN• Sensorynervefibersmayexistalone(freenerveendings)orinconjunctionwithspecializedreceptorsoftouch,pain,temperature,itch,andmechanicalstimuli

• Receptorsespeciallydenseinhairlessareas• Aftersweatglands(cholinergicforeccrine;adrenergicforapocrine-aftervascularsmoothmuscle(adrenergic→ vasoconstriction)afterhairfollicles(adrenergic→ contracting)

• Innervationoftheskinderivedfromthemusculocutaneousbranchesofthespinalnerves• Sensorynervesareroughlydistributedindermatomes,butoverlapoccurs• ItchistransmittedviaafferentfibersoftheA-deltaandC-polymodalnociceptorclass• Adrenergicinnervationcontrolsvasoconstriction,apocrinesecretion,andcontractionof

arrectorpilimuscles• Eccrinesweatingisunderthecontrolofcholinergicnerves• Sebaceousglandsarenotunderneuralcontrol,andonlyrespondtochemicalstimulisuch

ashormones

Free Nerve Endings• Mostwidespreadandimportanttype• Penicillate fibersfoundsubepidermallyinhair-bearingskin:detecttouch,pain,temperature,anditch;functioninfinediscriminationinthenon-hairy,ridgedareasofskin

• Papillary nerve endingsarefoundattheorificeofthehairfollicleandparticularlysensitivetocold

• FreenerveendingsalsopenetratetheepidermistocontactMerkelcells

Corpuscular Receptors• Containacapsuleandinnercore,andcontainbothneuralandnonneuralconstituents• Meissner’s corpuscle: Ovoid,elongatedmechanoreceptorlocatedinthedermalpapillaeofdigitalskin;detecttouchandlightpressure

• Pacinian (Vater-Pacini)corpuscle:Existsindeepdermisandwithinsubcutisinweight-bear-ingsitesofthebody;functionsasanadaptingmechanoreceptorthatrespondstovibra-tionalstimuli;perineuralcapsule

• Krause end bulbs:Mucocutaneousreceptorsfoundonglanspenis,clitoris,labiaminora,peri-analarea,andvermillionborderofthelips


1.12 IMMUNOFLUORESCENCE PATTERNS - DIRECT Immunofluorescence

Intercellular Space (ICS) Deposition• MajorityshowIgG→alltypesofpemphigus,exceptIgApemphigus• SimilarpatternseeninPV, PF,andtheirvariants(P. vegetans and P. erythematosus)• ComplementC3maybeseeninICS,too• IgA→IgApemphigus,targetproteinisdesmocollinI(115kd)• PositivepredictivevalueofDIFindiagnosisofpemphigusis100%,thenegativepredictivevalueis85%

Intercellular Space and BMZ Combination• Paraneoplastic pemphigus →antibodiestoBMZproteinsanddesmosomalproteins• Drug-inducedpemphigus→antibodiestodesmoglein1(2/3ofpatients)anddesmoglein3

(1/3ofpatients)

BMZ Deposition Alone• IgGand/orC3atBMZ→ bullous pemphigoid, mucosal pemphigoid, pemphigoid gestationis,

EBA, and bullous SLE• C3muchhigherintensitythanIgGfavorspemphigoidgroupofdiseases• IgGmuchhigherintensitythanC3favorsEBAandbullousSLE• DifferentiationbetweenBPandPGisnotpossibleusingeitherhistologyorIF• MultipledepositsattheBMZfavorsbullousSLEandEBAoverthepemphigoidgroup• UsefulfordifferentiatingbetweenbullousSLEandEBAbasedonunderlyingdiagnosisofSLEbyclinicalandserologiccriteria

• LineardepositionofIgAatBMZ→LinearIgAbullousdermatosisorchronicbullousdiseaseofchildhood

DIF Using Salt-split Specimens• 1molarNaClsplitsBMZatlowerlaminalucida• DifferentiatesBPfromEBA:Pemphigoiddepositsseenatepidermalsideofsplit;EBAandbullousSLEshowdepositsatdermalside

• Anti-epiligrinpemphigoid→dermalstaining

Mucosal Disease• Seenwithmucosalpemphigoid,EBA,cicatricialpemphigoid,andlinearIgAdisease• MucosalLPshowscytoidbodieswiththickbandoffibrinogen• IgGandC3depositinmucosalpemphigoidandantiepiligrindisease

Blood Vessel Deposition• PCT,pseudoporphyria,andEPP→homogeneousdepositsofmultipleimmunoreactantswithinsuperficialdermalbloodvesselwalls,inadditiontoBMZdeposition

• IgGandIgAmostcommon

Papillary Dermal Deposition• Dermatitisherpetiformis→IgAandC3inpapillarydermisandalongtheBMZ• DH:IgAdepositionin100%ofpatientswhenbiopsytakenfromnormal-appearingperilesionalskin

Indirect Immunofluorescence IgG Anti-intracellular Antibodies• Pemphigusvulgaris,pemphigusfoliaceus,paraneoplasticpemphigus,anddrug-induced

pemphigus


• Patientswithburns,penicillindrugeruptions,skingrafts,bullouspemphigoid,andmucosalpemphigoid

• Paraneoplasticpemphigus:ratbladderepithelium(75%sensitive,83%specific);stains desmosomesIgA Anti-intracellular Antibodies• IgApemphigus(50%ofpatients)

IgG Anti-BMZ Antibodies• 75%ofpatientswithBP• 50%ofpatientswithEBA

IgA Anti-BMZ Antibodies• AdultandchildhoodformsoflinearIgAdisease

Dermatitis Herpetiformis• Antiendomysial,antireticular,andantigliadinantibodies• Notdiagnostic

Bullous Pemphigoid vs EBA: IIF• Salt-splitskin-EBAshowsdermalstaining(collagenVII)• Pemphigoiddisordersshowepidermalanddermalstaining

Herpes Gestationis Factor• AmplifiedIIFprocedure• Positivein50%ofpatientswithHG

1.13 CONNECTIVE TISSUE DISEASES

Table1–8.DIFPatterninConnectiveTissueDisease

Disease Direct Immunofluorescence Pattern/Useful Info

DLE •ImmunedepositsalongtheDEjunction→IgGandIgM

•Cytoidbodies→degeneratedbasalkeratinocytesdroppedintothepapillary

dermis→IgMandIgA

•Patterns:shaggy,granular,linear

•Biopsytheoldest,untreatedlesiononnon-sun-exposedskin

SCLE •ImmunedepositsalongtheDEjunctionandbasalkeratinocytes→IgGandIgM

•Cytoidbodies→IgMandIgA

•Granularfluorescencethroughoutthecytoplasmandnucleusofbasalkeratinocytes(uniquetoSCLE)→reflectsbindingtoRoandLaantigens

MixedConnectiveTissueDisease

•Depositswithinepidermalcellnuclei(IgG)

•RarelyalongtheDEJ

Scleroderma,MorpheaandNeonatalLE

•DIFofnovalue

ErythemaMultiforme •DIFshowsimmunoglobulinwithinsuperficialvesselwalls,DEJ,andcytoidbodies

Dermatomyositis •PatternsimilartoLE,butintensityoffluorescencepatternisusuallylowerinDM

Vasculitis •DepositionofC3withinsuperficialbloodvesselwalls

•InHSP,IgAistheprimaryimmunoglobulin(75%ofpatients)


Disease Direct Immunofluorescence Pattern/Useful Info

LichenPlanus •DIFpositiveinvastmajority

•Depositionwithincytoidbodiesinsuperficialdermis→IgMandfibrinogen

•DEJdepositionisgranular

SLE •SerologymorereliablethanDIF

•DEJdeposition→lupusbandtest,lesionalandnonlesionalskin

•Cytoidbodies→IgMandIgA

•Immunedepositsmaybelocatedinsuperficialdermalbloodvesselwalls

similartovasculitis

•Epidermalkeratinocytenucleistaining,seeninpatientswithantibodiestoU1RNP

REFERENCES1. FreedbergIM,EisenAZ,WolffK,etal.,eds.Fitzpatrick’s Dermatology in General Medicine.6thed.NewYork

McGraw-Hill,HealthProfessionsDivision,2003.2. OdomRB,JamesWD,BergerTG.Andrew’s Diseases of the Skin: Clinical Dermatology9thed.Philadelphia:

WBSaundersCompany,2000.3. ElderDE,etal.eds.Lever’s Histopathology of the Skin.8thEd.:LippincottWilliams&Wilkens,1997.4. BikleDD,PillaiS,GeeE,HincenbergsM.Tumornecrosisfactor-alpharegulationof1,25-dihydroxyvitaminD

productionbyhumankeratinocytes.Endocrinology.1991Jul;129(1):33-8.5. Bolognia,J,etal.eds.Dermatology.1stEd.:Mosby,2003.

Table1–8.DIFPatterninConnectiveTissueDisease(cont.)


NOTES

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