Structure and Function of Skin

1. Structure and Function of Skin Erik Austin, D.O., M.P.H.

3. Epidermis ~ continually renewing stratified squamous epithelium that keratinizes and gives rise to cutaneous appendages • Epidermis is 0.4mm thick (eyelid) to 1.5mm thick (palm/sole)

4. Epidermal Cell Types • Keratinocytes ~ • 80% of cells in epidermis • Provide physical protection and immunologic defense • Ectodermal origin • Mitotically active • 4 layers: basalis, spinosum, granulosum, and corneum

5. Keratins ~ • Filament proteins expressed by keratinocytes • Classified as: • Type I = acidic (K9-20, 40-56.5kD, chromosome 17) • Type II = basic/neutral (K1-8, 52-67kD, chromosome 12) • Specific keratin pairs are synthesized in distinct epidermal cell layers ~ K5/K14: basal, K1/K10: spinous/granular • K6/K16: expressed in hyperproliferative states

6. K1/K10 mutation = epidermolytic hyperkeratosis • K5/K14 mutation = epidermolysis bullosa

8. Epidermal Anatomy • Basal ~ anchor epidermis and dermis; divides and renews outer layers of skin • Epidermal germinative cells divide q 19 days • Total epidermal renewal time = 45 days • Basal cells are columnar and attach to the BM via hemidesmosomes • BASAL LAYER ~ EXPRESS K5/K14

9. Hemidesmosomes are protein and are composed of the following: • BPAG1 (230kd), BPAG2 (180kd), plectin, and integrin a6B4 • STEM CELLS (regenerating cells) are located in basal layer (in the HAIR BULGE)

10. Spinosum ~ • Spines = bridges = desmosomes • SPINOSUM LAYER ~ EXPRESS K1/K10 • Lamellar granules = lysosomes • Hyperproliferative states lead to increased K6/K16 production, with decreased K1/K10 • Desmosomes: desmoplakin 1 & 2, envoplakin and periplakin • Desmosome components: desmoglein 1 & 3, plakoglobin, plakophilin, desmocollin I & II, keratocalmin

11. Keratocalmin is a calmodulin binding protein • Desmosomal components are the targets of autoantibodies and bacterial toxins • Gap Junctions/Connexins provide pores

12. Granulosum ~ • Contain keratohyaline and trichohyaline granules • Keratohyaline granules are composed of profilaggrin, keratins, and loricrin • Profilaggrin forms fillagrin = filament aggregation protein • Lamellar bodies (Odland bodies): discharge lipid components and provide cohesion

13. Cornified envelope ~ involucrin, loricrin, keratolinin, cornifin and envoplakin ~ encoded on chromosome 1q21 • Cells loose cytoplasm and release calcium which activates transglutaminase which catalyzes cross-linking of the cornified envelope (note: transglutaminase 1 is mutated in lamellar ichthyosis) • Keratin filaments are 63-67kd

14. Corneum ~ • Cells contain keratin and filaggrin • Lamellar granules produce ceramides, fatty acids, and cholesterol • Parakeratosis = incompletely keratinized cells with retained nuclei

15. Growth factors regulate epidermal growth: • Transforming Growth Factor alpha: made by keratinocytes in epidermis • Keratinocyte Growth Factor: made in dermis • TGF-B: made by keratinocytes; promotes differentiation • Platelet Derived Growth Factor: made in epidermis; acts on melanocytes • Basic Fibroblast Growth Factor: made in epidermis; induces melanocyte growth • Tumor Necrosis Factor alpha: cytokine involved with inflammation

16. Other Epidermal Cells • Melanocytes ~ • Dendritic pigment synthesizing cells derived from neural crest and are found in basal layer • Life cycle depends on tyrosine kinase receptor c-kit and its stem cell • Melanocytes contain melanosomes which produce melanin • Melanocytes stain for DOPA and silver stains • Markers: S100, Vimentin, HMB-45, MART 1

18. Epidermal melanin unit: one melanocyte + many keratinocytes • Skin color is determined by the NUMBER, SIZE, AND DISTRIBUTION OF MELANOSOMES, MELANOSOMES, MELANOSOMES!!! • UV light makes melanocytes and melanosomes larger • Brown/Black pigment = eumelanin/elliptical melanosomes • Yellow/Red pigment = pheomelanin/round melanosomes

19. Merkel cells ~ • Probably, touch receptors • Originate from neural crest at 11-12 weeks • Normal Merkel cells are S100+ • Merkel tumor cells are S100- • Cytokeratin 20 is the marker of choice

20. Langerhans cells ~ • Antigen presenting cells (present to T cells) • Bone-marrow derived (mesoderm origin) • Contain Birbeck granules (tennis racquet) • Markers: membrane-bound ATPase, CD1a

22. Epidermal Appendages • Eccrine glands ~ • Regulate temperature by excreting sweat • Watery (merocrine) secretion • Everywhere except: vermilion border of lips, nail bed, labia minora, glans penis and inner prepuce • Markers: Succinicdehydrase, Amelophosphorylase, Leucine aminopeptidase (think: SAL)

23. Apocrine glands ~ • Serve as scent glands (odorless, but bacterial action on the sweat produces odor) • Only in axilla, anogenital, external ear, eyelid, and breast • Markers: B-glucuronidase, Acid phosphatase, and NADPH (think: BAN deodorant)

24. Sebaceous glands ~ • Everywhere except palm/sole • Holocrine secretion • Under hormonal control (androgens) • Secrete TGs, phospholipids, cholesterol, waxes

26. Basement Membrane Zone • Composed of Hemidesmosome, BM, and Anchoring Fibrils • Lamina lucida is composed is composed of laminin, enactin/nidogen, and fibronectin • Anchoring filaments: associated with laminins 1, 5, 6, and uncein • Lamina densa: contains Type IV collagen • Sublamina densa: contains Anchoring Fibrils composed Type VII collagen

27. Dermis • Papillary and Reticular • Helps regulate epidermal growth • Dermal fibroblast and epidermis interaction involves integrins

28. Collagen ~ • Provides tensile strength • Type I: 85% of collagen in adult skin • Type II: found in cartilage • Type III: fetal skin • Type IV: BM collagen • Type V: vascular tissue • Type VII: component of Anchoring Fibrils

29. Elastin ~ • Consist of microfibrils and matrix elastin • Fibrillin is a component of microfibrils • Oxytalan are fibers that extend perpendicularly to DEJ • Elaunin are fibers that extend parallel to DEJ

30. Ground substance ~ • Consists of GAGs which produce proteoglycans • Sulfated acid mucopolysaccharides: dermatin, heparan, chondroitin, and sulfate • Nonsulfated: hyaluronic acid

31. Cells of dermis: • Fibroblasts • Myofibroblasts • Smooth muscle cells • Bone marrow derived cells: dendrocytes (APCs, Factor XIII), macrophages, mast cells

32. Cutaneous Vasculature • Blood supply of skin comes from subcutaneous muscular arteries • 3 plexi: subpapillary, perifollicular, and eccrine • Glomus: a special vascular structure in certain areas ~ nail bed, finger pad, volar hands/feet, ears, center of face

33. Nerves and Sensory Receptors of Skin • Both sensory and autonomic (primarily sympathetic) – autonomic fibers are unmyelinated • Sebaceous glands lack autonomic innervation • Sensory nerves are myelinated ~ modulate pain sensation • Meissner corpuscles ~ fine touch • Vater-Pacini corpuscles ~ pressure

34. Hair Follicle • Infundibulum: from the uppermost portion to the entrance of the sebaceous duct • Isthmus: the portion between the duct and the insertion of the erector pili muscle • Matrix: the lowermost part of the follicle and the hair bulb • The hair shaft, as well as the inner and outer root sheath, develop from the mitotically active undifferentiated cells of the matrix

36. The cross-sectional shape of the hair depends on the arrangement of cells in the bulb • Hair color depends on the distribution of melanosomes within the hair bulb • Black hair = Big melanosomes • Red hair = Round melanosomes • Gray hair = decreased melanocytes

37. Anagen (growth) ~ 3 years (90%) • Catagen (involution) ~ 3 weeks (1%) • Telogen (resting) ~ 3 months (10%) • Exogen (shedding) • Telogen = club shaped hairs (lose 50-150 per day) • 5 million follicles cover body at birth – no follicles form after birth, although the size of the follicle may change and is under the influence of androgens • Hair is composed of keratin • Three types: lanugo (fine), vellus, and terminal (coarse)

38. Follicular unit: composed of 2-4 hairs and are associated with a sebaceous gland, arrector pili muscle, and collagen • Average scalp density = 65-100 follicular units per cm squared

39. Nails • Four structures: • Proximal nail fold ~ extension of epidermis that adheres to nail plate (aka cuticle) • Nail matrix ~ produces the nail plate • Nail bed ~ distal end of matrix and continues to Hyponychium • Fingernails grow an average of 0.1 mm/day or 3mm/month; slower for toenails

40. CUTANEOUS SYMPTOMS, SIGNS, AND DIAGNOSIS

41. Pruritus • Carried from the skin by unmyelinated C fibers • Hepatobiliary diseases, especially biliary obstructive disease, severe renal insufficiency, iron-deficiency anemia, endocrine disorders, and internal malignancy (especially lymphoma) • Thyroid dysfunction • Less commonly parathyroid • DM • Is typically generalized when associated with renal failure (uremic pruritus) • Kyrle’s disease

42. Pruritus of live disease • Hepatitis C virus infection • Antidepressants, belladonna, alkaloids, opiates, and oral contraceptives may induce pruritus • Recreational drugs (amphetamines and cocaine)

43. Psychiatric disease • Most frequently anxiety/depression • Or obsessive compulsive disorder • Treat the underlying disorder

44. CUTANEOUS SIGNS

45. PRIMARY LESIONS Macules, patches, papules, plaques, nodules, tumors, wheals, vesicles, bullae, and pustules

46. Flat: Macule (<10mm)/Patch (>10mm)

47. Papule: raised (<10mm)

48. Nodules: raised (>10mm)

49. Tumors • Soft or firm freely moveable or fixed masses