Epidermal kinetics

1. Epidermal kinetics Dr. Rohit K r.Singh P.G.Resident Skin centre(BH)

2. EPIDERMIS Structure and ultrastructure Stratified squamous Epithelium 95% cells are Keratinocytes SC SL SG SS SG DERMIS

3. EPIDERMOPOIESIS Epidermopoiesis Epidermal dynamics Epidermal kinetics

4. EPIDERMAL DYNAMICS Epidermal proliferative unit( EPU) Consists of Single Stem cell Transit amplifying cells Terminally differentiated cells (post mitotic cells)

5. EPIDERMAL KINETICS Turn over time Cell cycle Growth fraction

6. Mitotic index Is the fraction of basal cells that is in mitotic phase at any time. Labelling index Fraction of basal cells in DNA synthesis

7. Turnover time of the germinative epithelium Epidermal turnover time ( transit time= 14 days ) The time taken for a cell to pass from basal layer to the surface of the skin next 14 days Subsequent desquamation

8. Normal vs psoriatic cell cycle time Labelling Index( %) S phase hr G2 Phase hr M Phase hr G1 Phase hr TOTAL TIME DURATION(hr ) NORMAL EPIDERMIS 5.2 8.5 6 - 8 1 146 163 PSORIATIC EPIDERMIS 22.7 8.5 4 0.3 25 37.5

9. TURN OVERTIME TIME NORMAL (DAYS) PSORIATIC (DAYS) VIABLE- EPIDERMIS GERMINATIVE TRANSIT IN VIABLE EPITHELIUM 12 -19 26 - 42 1.5 4 – 6 STRATUM CORNEUM 14 2 TOTAL EPIDERMIS 52 - 75 8 - 10

10. Psoriasis Cells in Go /G1 Stage Enter the cell cycle

11. Regulation of epidermopoiesis Stimulatory factors Human epidermal growth factor(EGF) Transforming growth factor(TGF alpha) Amphiregulin IL-1,IL-2,GM-CSF Basic FGF Keratinocyte growth factor(KGF) Vitamin A Androgens

12. Inhibitory factors IFN alpha IFN gamma TNF alpha High calcium level Adrenaline Glucocorticoids

13. EPIDERMAL DIFFERENTIATION 8 % of the basal cells -(K-1/K10) undergo differentiation. Orchestrated expression of keratins and subunits of cornified envelope. Terminal differentiation ( keratinization ): Change in keratin expression . Formation of corneocyte .

14. TERMINAL DIFFERENTIATION 1.Formation of keratin 2.Keratin filaments aggregate into bundles with the help of filaggrin . 3.Cornified envelope .

15. 4.Changes in expression of Intracellular lipid Membrane glycoproteins Growth factor receptors Adhesion protein Blood group antigens Desmosomes .

16. KERATINOCYTES Any one of the cells in the skin that synthesize keratin. Contains actin , tubulin , intermediate filaments. Keratin is one of the 6 types of intermediate filaments.

17. KERATIN (CYTOKERATINS ) 54 functional keratin genes . Two gene family :- type 1(basic) type 2(acidic) Retinoic acid , growth factors ,hormones regulate keratin gene expression.

18. Type 1 keratins K9,K10 Epidermis( suprabasal ) K12 Cornea K13 Oral mucosa K14,K15 Complex epithelia K16,K17 Epithelial appendages K18 Simple epithelia K19 Broad distribution K20 Gut epithelium K23 pancreas K24 unknown K25-28,31-38,39,40 Hair shafts

19. Type 2 keratins K1,K2 Epidermis ( suprabasal ) K3 Cornea K4 Oral mucosa K5 Complex epithelia(basal layer) K6a,K6b Epithelial appendages K6c Skin K7,K8 Simple epithelia K71 – 74,75 Hair follicles H76 Oral mucosa K77 Sweat gland ducts K78 tongue

20. DIFFERENTIATING EPIDERMAL KERATINOCYTES Basal layer as proliferative cells express K-5 and K-14 The process of differentiation starts with the K – 10/K-1 expression (in TA cells ) K-2 is expressed at later stages of differentiation( granular layer )

21. Psoriasis Wound healing Altered epidermal differentiation Synthesis of suprabasal K-6 and K-16

22. BASIC K ACIDIC K TISSUE EXPRESSION DISEASE ASSOCITION 1 10 Suprabasal keratinocytes Bullous congenital icthyosiformis erythroderma ; Diffuse non epidermolytic PPK 1 9 Suprabasal keratinocytes ( palmo -plantar skin) Epidermolytic PPK 2 10 Upper spinous , granular Icthyosiform bullosa of siemens 3 12 cornea Meesmann’s corneal dystrophy 4 13 Mucosal epithelium White sponge nevus 5 14 Basal keratinocytes Epidermolytic bullosa complex 6a 16 Outer root sheath,hyperproliferative , palmo -plantar keratinocytes Paronychia congenita type 1 ; Focal non- epiderdermolytic PPK 6b 17 Nail bed ,epidermal appendages Paronychia congenita type II, Steatocystoma multiplex 8 18 Simple epithelium Cryptogenic cirrhosis

23. Keratohyaline granules Keratinocytes of stratum granulosum . Disappear in cornified squames . They contain granules rich in histidine . Keratin filament are aggregate into bundles by the action of the histidine rich basic protein callled filaggrin .

24. Membrane – coating granules Also called as lamellar granules or odland bodies . Found in spinosum and Granulosum layers of skin. Contains phospholipids, glycolipids and free sterols. Forming an important barrier to permeability .

25. CORNIFIED ENVELOPE Highly insoluble cell envelope. Present in stratum corneum . It’s development is triggered by intracellular calcium. Involucrin is main envelope precursor. Others include Loricin 6. Envoplakin Cornifine 7. Periplakin Pancornulin 8. 61KDa protein Elafin Keratolini

26. Transglutaminases cross-link plakins and involucrin . Other desmosomal proteins are also cross-linked ,forming a scaffold along the entire inner surface of the plasma membrane. High calcium level increases differentiation .

27. PROTEIN DISEASE ASSOCIATION CYSTATIN A Harlequin ichthyosis PROFILAGGRIN /FILAGGRIN Ichthyosis vulgaris Atopic dermatitis LORICIN Mutilating keratoderma with ichthyosis ; Progressive symmetric erythroderma

28. NORMAL HOMIEOSTASIS-EPIDERMIS 1.Mitotic rate of germinative cells 2.Generation time of epidermal cells 3.Desquamation rate of corneocytes

29. DISTURBANCE IN EPIDERMAL KINETICS 1. ACANTHOSIS Enhanced cell proliferation Enlargement of the germinative cell Increased mitotic rates Broadening of epidermis

30. Conditions showing Acanthosis :- Psoriasis Eczema Condyloma acuminatum

31. DISTURBANCE IN EPIDERMAL DIFFERENTIATION 2. PARAKERATOSIS Incomplete differentiation in post mitotic phase Faulty and accelerated cornification Retension of of pyknotic nuclei of epidermal cells Leads to gap between cells Loss of barrier function of the epidermis

32. HISTOLOGICAL FINDINDS IN PSORIASIS

33. Conditions associated with Parakeratosis Psoriasis Pellagra Epidermolytic hyperkeratosis Scurvy Note – it can be normally found in hard palate

34. 3 . DYSKERATOSIS Morphologic presentaion of apoptosis of keratinocytes Eosinophilic cytoplasm , pyknotic nucleus Cells are packed with keratin filaments Cell will tent to round up Loose it’s attachment with surrounding cells

35. Conditions showing dyskeratosis Darier disease Actinic keratosis Squamous cell carcinoma

36. CANCERS OF THE EPIDERMIS Squamous cell cancer Irregular masses of epidermal cells. Differentiation is in direction of keratinization Horn pearls – concentric layers of squamous cells with increasing keratinization at centre. Keratohyaline granules are sparse or absent.

37. Basal cell cancer Predominent basal cell type Keratotic basal cell carcinoma Parakeratotic cells Horn cysts – fully keratinized cells, represent attempt at hair shaft formation.

38. DRUGS ACTING ON EPIDERMAL CELL Retinoic acids Acts on retinoic acid receptors RAR and RXR CRABP II – in human epidermis Epidermal differentiation Increased in – Psoriasis Lamellar ichtyosis Darier’s disease PRP

39. CRABP II Retinoic acid Epidermal differentiation

40. Vitamin D analogues( calcitriol,calcipotriol ) Acts on vit D receptors on keratinocytes MOA- Regulate keratinocyte proliferation. Epidermal differentiation. Formation of cornified membrane.

41. Tazarotene Acts on retinoic acid receptors Modulate abnormal epidermal differentiation and proliferation. Upregulation of K-10 terminal differentiation.

42. Coal tar Inhibit DNA synthesis Atrophogenic effect

43. Salicylic acid > 3% keratolytic MOA – Dissolves the intercellular cement substance of the corneocytes .

44. REFERENCES 1) FITZPATRICK’S DERMATOLOGY IN GENERAL MEDICINE 2) ROOK’S TEXTBOOK OF DERMATOLOGY 3) IADVAL TEXTBOOK AND ATLAS OF DERMATOLOGY BY R.G AND AMEET VALIA 4) COLOUR ATLAS OF HISTOLOGY OF THE SKIN BY WALTER F.LEVER

45. Thank you