16.3 Skin & Appendages: Epidermis, Junctions, Dermis, Subcutaneous Tissue, Fascia, Nerves, Vessels, Lymphatics, Hair, Nails & Glands

Why this area matters

The TOS lists:

• the layers of the skin (epidermis, dermis);
• subcutaneous tissue;
• skin ligaments;
• deep fascia;
• nerve innervation and blood vessels;
• lymphatic vessels;
• the skin appendages (hairs, nails, sweat glands, sebaceous glands, arrector pili muscles).

Skin anatomy explains burn depth and healing, how surgical scars form, blistering diseases, skin infections and skin cancer.

Integumentary Microarchitecture & Cutaneous Adnexa

The skin consists of the stratified squamous epidermis derived from surface ectoderm, and the underlying fibroelastic dermis derived from mesoderm.

The Five Epidermal Strata (Deep to Superficial)

1. Stratum Basale (Stratum Germinativum): A single layer of cuboidal to low columnar mitotically active stem cells resting on the basement membrane via hemidesmosomes; connected laterally by desmosomes; rich in cytokeratins 5 and 14; houses melanocytes and Merkel cells.
2. Stratum Spinosum (Prickle Cell Layer): Multiple cell layers of polyhedral keratinocytes synthesizing cytokeratins 1 and 10; during histological preparation, cell shrinkage leaves prominent spines representing desmosomal junctions attached to intracellular tonofilament bundles; houses dendritic Langerhans cells.
3. Stratum Granulosum: Three to five layers of flattened keratinocytes containing intensely basophilic, non-membrane-bound keratohyalin granules (composed of profilaggrin and loricrin) and membrane-bound lamellar bodies (Odland bodies) that exocytose a hydrophobic, lipid-rich ceramide envelope into the intercellular space to create the epidermal water barrier.
4. Stratum Lucidum: A thin, homogeneous, translucent layer of flattened, eosinophilic keratinocytes lacking nuclei and cytoplasmic organelles; filled with the keratin intermediate eleidin; present exclusively in thick, hairless skin (palms of the hands and soles of the feet).
5. Stratum Corneum: The most superficial protective layer, comprising 15 to 30 layers of dead, anucleate, flattened cornified squames (corneocytes) completely filled with cross-linked keratin filaments embedded in a lipid matrix; continuously shed via desquamation through proteolytic cleavage of corneodesmosomes by kallikrein-related peptidases.

Specialized Non-Keratinocyte Epidermal Cells

• Melanocytes: Derived from the embryonic neural crest; migrate into the stratum basale; possess dendritic processes extending into the stratum spinosum. Synthesize the pigment melanin from tyrosine via the copper-dependent enzyme tyrosinase within specialized organelles called melanosomes. Melanosomes are transferred to neighboring basal keratinocytes via cytocrine secretion, positioning supranuclearly as "parasols" to shield nuclear DNA from ultraviolet radiation. In albinism, melanocyte cell numbers are normal, but tyrosinase activity is absent or severely deficient.
• Langerhans Cells: Bone marrow-derived dendritic antigen-presenting cells residing primarily in the stratum spinosum; express surface MHC class II molecules, CD1a, and langerin (CD207); uptake and process cutaneous antigens before migrating to regional lymph nodes; characterized ultrastructurally by pathognomonic rod- or tennis racket-shaped Birbeck granules containing langerin.
• Merkel Cells: Neuroendocrine mechanoreceptors located in the stratum basale; intimately associated with expanded terminal discs of myelinated sensory afferents (Merkel discs); function as slow-adapting Type I mechanoreceptors mediating fine touch, shapes, and edge perception; neuroendocrine granules contain chromogranin and synaptophysin (malignant transformation produces aggressive Merkel cell carcinoma).

Cutaneous Adnexal Glands

• Eccrine Sweat Glands: Simple coiled tubular glands distributed across virtually the entire body surface; discharge directly onto the epidermal surface via merocrine exocytosis (no cellular loss); produce a hypotonic watery secretion for evaporative thermoregulation; uniquely innervated by sympathetic postganglionic cholinergic fibers releasing acetylcholine onto muscarinic $M_3$ receptors.
• Apocrine Sweat Glands: Coiled tubular glands with wide lumina restricted to the axillae, areolae, and anogenital region; empty into hair follicles; secrete a viscous, protein- and lipid-rich fluid via decapitation secretion; odorless upon release but degraded by skin commensal microflora into body odor; become functional at puberty; innervated by sympathetic adrenergic fibers.
• Sebaceous Glands: Simple branched acinar glands associated with hair follicles (pilosebaceous units); produce an oily lipid mixture (sebum) via holocrine secretion (the entire secretory cell ruptures and dies to release its contents); androgen-sensitive; plugging and Cutibacterium acnes proliferation drive acne vulgaris.

Intercellular Junctional Complexes & Autoimmune Bullous Dermatoses

Epithelial cohesion and selective permeability depend on lateral junctional complexes (junctional triad or terminal bar on light microscopy) organized in a strict apical-to-basal sequence:

1. Zonula Occludens (Tight Junction):

   • Located at the most apical position along the lateral cell membrane.
   • Formed by transmembrane anastomosing strands of claudins and occludins interacting with neighboring cells and linked to the actin cytoskeleton via zonula occludens proteins (ZO-1, ZO-2, ZO-3).
   • Establishes the paracellular diffusion barrier (gate function) and segregates apical from basolateral membrane proteins (fence function). Enteropathogens like Clostridium perfringens enterotoxin target claudins to dismantle tight junctions, causing secretory diarrhea.

2. Zonula Adherens (Adherens Junction):

   • Located immediately basal to the zonula occludens.
   • Mediates calcium-dependent intercellular adhesion via transmembrane E-cadherin glycoproteins.
   • The cytoplasmic tails of E-cadherin bind $\beta$-catenin and $\alpha$-catenin, which anchor the complex to the intracellular actin microfilament web. Loss of E-cadherin expression is a hallmark of epithelial-mesenchymal transition (EMT) and invasive adenocarcinoma metastasis (e.g., diffuse gastric carcinoma / signet ring cell carcinoma).

3. Macula Adherens (Desmosome):

   • Spot-weld mechanical anchoring junctions scattered along the lateral plasma membrane.
   • Transmembrane cadherins desmoglein (DSG1, DSG3) and desmocollin bridge the extracellular space, binding to cytoplasmic plaque proteins (plakoglobin, desmoplakin), which in turn anchor to intermediate filaments (cytokeratins / tonofilaments).
   • Imparts immense mechanical tensile strength across epithelial sheets.

4. Hemidesmosome:

   • Located exclusively along the basal plasma membrane, anchoring the epithelial cell to the underlying basal lamina.
   • Transmembrane $\alpha_6\beta_4$ integrin heterodimers and collagen XVII (BP180 / BPAG2) bind extracellularly to laminin-332 within the lamina lucida, while the intracellular plaque protein BP230 (dystonin / BPAG1) and plectin connect to cytokeratin intermediate filaments.

5. Gap Junction (Nexus):

   • Direct intercellular communication conduits formed by hexameric assemblies of connexin proteins termed connexons.
   • Aligned connexons form a central $1.5\text{ nm}$ hydrophilic pore allowing direct passage of inorganic ions ($Na^+$, $K^+$, $Ca^{2+}$), second messengers ($cAMP$, $IP_3$), and metabolites ($< 1.2\text{ kDa}$) between adjacent cells.
   • Essential for electrical coupling in cardiac intercalated discs and visceral unitary smooth muscle. Mutations in GJB2 (encoding connexin-26) cause congenital autosomal recessive sensorineural deafness.

Comparative Pathology: Pemphigus Vulgaris vs. Bullous Pemphigoid

The dermis and skin ligaments

• The papillary dermis is thin, loose connective tissue in the dermal papillae. It contains capillary loops, Meissner corpuscles (light touch, rapidly adapting) and free nerve endings. Its ridges interlock with the epidermal rete ridges and form the fingerprints on the palms and soles.
• The reticular dermis is thick, dense irregular connective tissue (type I collagen and elastic fibers). It contains hair follicles, glands and Pacinian corpuscles (deep pressure and vibration). It gives skin its tensile strength.
• Cleavage (Langer) lines follow the main direction of dermal collagen bundles. Incisions parallel to them gape less and heal with narrower scars.
• Skin ligaments (retinacula cutis) are fibrous bands that tie the dermis to the deep fascia. They are dense in the palms and soles, which stops the skin sliding, and in the breast, where they form the suspensory ligaments.

Subcutaneous tissue and deep fascia

• Subcutaneous tissue (hypodermis, superficial fascia): fat and loose connective tissue containing cutaneous vessels, nerves and lymphatics. It insulates, stores energy and allows the skin to move. In the lower abdominal wall it has two layers: the fatty Camper's fascia and the membranous Scarpa's fascia.
• Deep fascia: dense connective tissue enclosing muscles. It forms intermuscular septa and osteofascial compartments. Because it does not stretch, swelling within a compartment raises pressure (compartment syndrome). Thickenings form retinacula at the wrist and ankle, the fascia lata of the thigh, and the plantar and palmar aponeuroses. Necrotizing fasciitis spreads rapidly along the fascial planes.

Cutaneous innervation, blood vessels and lymphatics

• Nerves:
  • Cutaneous branches of spinal nerves supply segmental dermatomes, for example T4 at the nipple, T10 at the umbilicus and L1 at the inguinal region.
  • Herpes zoster follows a single dermatome because the virus reactivates in one dorsal root ganglion.
  • Sympathetic fibers supply sweat glands, arrector pili and vessels.
  • Receptors include free nerve endings (pain, temperature), Meissner and Pacinian corpuscles, Merkel discs and Ruffini endings.
• Blood vessels: two plexuses, a deep (cutaneous) plexus at the junction of dermis and subcutis, and a superficial (subpapillary) plexus beneath the epidermis. The epidermis has no vessels and is nourished by diffusion. Arteriovenous shunts (glomus bodies) in the fingers help regulate temperature.
• Lymphatics: begin as blind capillaries in the papillary dermis and drain to the regional nodes. Blocked dermal lymphatics cause peau d'orange, and melanoma spreads early through them.

Hair and nails

• Hair grows from a follicle, an epidermal down-growth with a bulb and dermal papilla.
  • The arrector pili (smooth muscle, sympathetic) raises the hair ("goose flesh") and squeezes out sebum.
  • The growth cycle has three phases: anagen (growth, years on the scalp), catagen (involution, weeks) and telogen (rest, months).
  • Telogen effluvium is diffuse shedding after fever, childbirth or stress. Anagen effluvium follows chemotherapy.
• Nails are hard keratin plates made by the nail matrix. The lunula is the visible part of the matrix, and the nail bed lies beneath the plate.
  • Fingernails grow about 3 mm a month and toenails more slowly.
  • Clinical signs: koilonychia (iron deficiency), clubbing (chronic lung disease, cyanotic heart disease, endocarditis), splinter hemorrhages (endocarditis), Mees lines (arsenic), pitting (psoriasis).

Thick versus thin skin, burns and healing

Burn depth follows the layers:

• Superficial (first-degree): epidermis only.
• Superficial partial-thickness: into the papillary dermis. Blisters form, the burn is very painful, and it heals from adnexal stem cells within about 2 to 3 weeks.
• Deep partial-thickness: into the reticular dermis. Healing is slow and scarring likely.
• Full-thickness (third-degree): through the dermis. The burn is leathery and painless because the nerve endings are destroyed, and it needs grafting.

Because epidermal regeneration comes from hair follicles and sweat glands, deeper burns lose this source of cells.