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Dermatology: Skin Anatomy and Function Notes

Carney complex and PRKAR1A mutation analysis

  • Also known as LAMB syndrome or NAME syndrome

  • Key features (autosomal dominant, PRKAR1A gene on 17q23-q24):

    • Skin and mucous membrane lentiginosis (ephelides)

    • Cardiac (atrial) and skin myxomas, schwannomas

    • Blue nevi

    • Endocrine hyperfunction

  • Gene: PRKAR1A; encodes the type 1A regulatory subunit of protein kinase A (PKA)

Skin as the largest organ: structure and roles

  • Largest organ covers about 2\,\mathrm{m}^2 and weighs a significant portion of body mass

  • Defensive roles: protection from chemical, physical, microbial factors (including UV-light and antigens/haptens)

  • Maintains homeostasis: water, electrolytes, macromolecules; thermoregulation

  • Additional roles: perception (sensation), calorie reserve, vitamin D synthesis, sexual and reproductive signaling, and psychological/emotional/social development

  • Skin contributes to overall health and disease prevention

Structure of the Epidermis: overview

  • Epidermal layers (from top to bottom):

    • Stratum corneum

    • Stratum lucidum (present in thick skin)

    • Stratum granulosum

    • Stratum spinosum

    • Stratum basale

  • The basement membrane separates epidermis from dermis

  • Dermis consists of papillary and reticular layers; subcutaneous tissue (hypodermis) lies beneath

  • Dermal-epidermal junction (DEJ) provides adhesion and barrier between layers

  • Hair follicles, sebaceous glands, and sweat glands are associated with dermal structures

  • Thick skin (hairless) vs. thin skin (hairy) differ in epidermal thickness and dermal plexus organization

Layer-by-layer details of the epidermis

  • Stratum basale (germinativum):

    • Proliferation of keratinocytes; contains basal cells and stem cells

    • Desmosomes and hemidesmosomes connect to basement membrane

  • Stratum spinosum: spinous (prickle) cells with desmosomes; strong cohesion

  • Stratum granulosum: keratinocyte granules; lamellar bodies secrete lipids; formation of the epidermal barrier

  • Stratum lucidum (only in thick skin): clear layer

  • Stratum corneum: dead, flattened corneocytes; cornified envelopes; keratinocyte shedding (desquamation)

Keratinocyte differentiation and cornification (epidermal maturation)

  • Keratinocyte differentiation sequence: basal cells → transit-amplifying cells → differentiating cells → mature corneocytes

  • Proliferation rate: approximately 1 division per 400 cells per cycle

  • Cornification process includes:

    • Formation of cornified envelopes

    • Lipid extrusion for barrier function

    • Expression of late differentiation markers (e.g., filaggrin, loricrin)

    • Reinforcement of cytoskeleton; exit from cell cycle; complete renewal by proliferation

  • Key structural proteins:

    • Basal layer keratins: K5, K14; basal cell markers; later keratin 15

    • Spinous/granular layers keratins: K1/K10; K2

    • Proteins involved in cornified envelope: loricrin, involucrin, trichohyalin; S100 proteins; small proline-rich proteins

  • Critical structures:

    • Desmosomes (cell–cell adhesion)

    • Cornodesmosomes and hemidesmosomes (cell–basement membrane adhesion)

Diseases related to keratinocyte proliferation and differentiation

  • Psoriasis: inflammatory proliferation of keratinocytes; rapid turnover; clinical features include scaling plaques

  • Ichthyosis vulgaris: retention and abnormal desquamation due to altered lipid barrier and keratinocyte maturation

  • Ichthyosis congenita: proliferative disorder of keratinocytes with increased maturation defects

  • Temporal scales mentioned: typical epidermal renewal time can be shortened or prolonged depending on condition

Tight junctions and epidermal barrier integrity

  • Tight junctions in the stratum granulosum contribute to the SC barrier

  • Key components: ZO-1 and associated tight junction proteins; barrier function can be visualized en face and side views

  • Tight junctions coordinate with antimicrobial peptides and chemical defense

  • Innate and adaptive immune system interplay: cytokines, T cells, mast cells, macrophages participate in barrier protection

Desmosomes and hemidesmosomes: adhesion scaffolds

  • Desmosomes connect keratinocytes (desmocollin, desmoglein; plakophilin; desmoplakin)

  • Hemidesmosomes anchor basal keratinocytes to the basement membrane (BPAG1/e, BP180 type XVII collagen, integrins)

  • Structural linkage to keratin intermediate filaments and basement membrane components (laminins, type IV collagen, nidogens)

  • Anchoring fibrils (type VII collagen) connect to the dermis

Keratinocyte adhesion defects: clinical genetics and autoimmune diseases

  • Epidermolysis bullosa (EB): genetic junctional and dystrophic forms; defective DEJ adhesion

  • Autoimmune diseases: Bullous pemphigoid (BP180, BP230 antibodies) and Epidermolysis bullosa acquisita (anti-collagen VII antibodies)

  • Pemphigus: autoimmune anti-desmosomal proteins (e.g., anti-Dsg1, anti-Dsg3)

  • Impetigo contagiosa: bacterial infection causing superficial blisters; can be complicated by autoimmune phenomena in some contexts

  • Inheritance patterns: EB often autosomal dominant or recessive depending on subtype; pemphigus is autoimmune rather than hereditary in most cases

Dermo-epidermal junction (DEJ): structure and components

  • DEJ includes:

    • Keratin filaments anchoring to inner plaque

    • Hemidesmosome–plaque complexes linking to basement membrane

    • Laminins (511/322) and type IV collagen forming the lamina densa and lamina lucida

    • Type VII collagen forming anchoring fibrils connecting to the dermis

    • BP180 (collagen XVII) and BP230 as key adhesion molecules

  • DEJ integrity is essential for mechanical stability and barrier function

Lipids of the epidermis: bricks and mortar model

  • Bricks: keratinocytes

  • Mortar: lipids

  • Epidermal lipids composition (approximate):

    • Cholesterol: 15{-}20 ext{%}

    • Ceramide: 40{-}50 ext{%}

    • Free fatty acids: 20 ext{%}

  • Lipid barrier disruption leads to irritant eczema; proper lipid balance is essential for barrier function

Epidermal lipids and skincare approaches

  • Common moisturizers and skincare lines emphasize ceramides and barrier repair

  • Examples mentioned (brands and formulations): Cetaphil, RESTORADERM, CeraVe, Eucerin, etc. with ceramide-rich products and non-drying formulas

  • Skincare aims to restore and maintain the barrier, provide controlled release of active ingredients, and be fragrance-free when possible

  • Practical guidance: select products that support barrier function for dry, itchy skin and for pediatric use

    • Study: use an emoliant for baby between 18-24 months can prevent atopic dermatitis

Filaggrin mutations and atopic disease predisposition

  • FLG (filaggrin) mutations are common and predispose to atopic dermatitis and asthma

  • Key references cited: JID 2007; McLean et al., Nat Genet 2006

  • Implication: barrier dysfunction due to filaggrin deficiency contributes to disease susceptibility and severity

Stratum granulosum–stratum corneum life cycle and filaggrin biology

  • Filaggrin cycle and hydration maintenance: hydration of stratum corneum is critical

  • Filaggrin processing yields natural moisturizing factors (NMFs): free amino acids, pyrrolidone carboxylic acid, urocanic acid

  • Profilaggrin → filaggrin during keratinocyte maturation; keratin fibril aggregation and keratin intermediate filament organization

  • Atopic dermatitis is associated with filaggrin defects due to impaired barrier and hydration

Other cells of the epidermis

  • Langerhans cells: antigen-presenting dendritic cells in epidermis; discovery in 1868 by Paul Langerhans

  • Merkel cells: tactile/discriminative touch receptors

  • Free nerve endings: contribute to sensation (including itch)

Melanocytes and melanin production

  • Melanocyte located in epidermal melanin unit; derived from neural crest

  • Tyrosinase catalyzes tyrosine → DOPA → Dopaquinone; melanin types include eumelanin and pheomelanin

  • Melanocyte–keratinocyte interaction regulates pigment distribution; melanin packaged into melanosomes and transferred to keratinocytes

  • Regulation of melanogenesis involves multiple signaling pathways including MC1R, α-MSH, POMC, cAMP, PKA, MITF, and various cytokines (IL-1, endothelin-1, bFGF, SCF)

  • Genes encoding melanogenic proteins also contribute to pigmentation patterns and responses

Vitiligo: loss of melanocytes

  • Types: segmental and non-segmental (non-segmental typically >2-3% body surface area; segmental usually <2-3% BSA)

  • Notable reference: Taieb, Picardo, NEJM 2009

The role of melanocytes in melanoma

  • Melanocytes and their biology are central to melanoma development; refer to dermatology resources for details

  • Langerhans cells are involved in skin immunity and can be contrasted with melanoma risk areas

Langerhans cells and histiocytosis

  • Langerhans cells: antigen-presenting cells in the epidermis

  • Langerhans cell histiocytosis is a disease involving Langerhans cell proliferation

  • BRAF

  • can also involve other organs, like the lungs

The structure of the dermis

  • Dermis consists of two layers: papillary dermis (superficial) and reticular dermis (deeper)

  • The extracellular matrix includes:

    • Collagen fibers (mainly type I/III)

    • Elastic fibers

    • Glycosaminoglycans (GAGs)

  • Dermis contains epithelial cell components, mesenchymal cells, endothelial cells, and interstitial matrix; basement membrane separates dermis from epidermis

  • Adhesive junctions (hemidesmosomes, focal adhesions) connect dermis to epidermis

Papillary and reticular dermis; dermal-epidermal interface

  • Papillary dermis: loose connective tissue with dermal papillae interdigitating with the epidermis; contains capillary loops

  • Reticular dermis: dense irregular connective tissue with larger bundles of collagen and elastin; provides strength and elasticity

  • Rete subpapillare and rete cutaneum describe sub-epidermal connections

Dermal cells and extracellular matrix in aging

  • Key cells: fibroblasts, neutrophils, eosinophils, macrophages, mast cells, fat cells

  • Fibroblasts are central to wound healing, scar formation, and remodeling; NIH/3T3 is a model fibroblast line

  • Aging changes include reductions in collagen/elastin, glycosaminoglycans, and overall vascular density; decreased fibroblast activity and mast cell content contribute to aging skin

Aging and photoaging signs in skin

  • Epidermis: thinning, smoother DEJ, reduced melanocyte and Langerhans cell density

  • Dermis: decreased extracellular matrix, fewer fibroblasts, reduced capillary loops, fewer mast cells

  • Dermal matrix: changes in collagen and elastin leading to photoaging

Cutaneous vasculature: cutaneous plexuses

  • Superficial dermal plexus (closer to dermal papillae) and subcutaneous plexus (deeper in subcutis) supply blood to skin layers

Epidermal appendages

  • Sebaceous glands: holocrine glands; open into hair follicle; sebostasis and seborrhea may be discussed in clinical context

  • Eccrine sweat glands: heat/thermoregulation; widely distributed

  • Apocrine glands: associated with hair follicles; functional in specific body areas

Nerve endings and sensation in the skin

  • Meissner corpuscles (light touch)

  • Krause (cold), Ruffini (warm) corpuscles

  • Mechanoreceptors for pressure, vibration, and touch

  • C fibers associated with nociception and itch

Functions of the skin

  • Mechanical barrier and protection against environment

  • Sensory function

  • Thermoregulation

  • Light protection (UV) and chemical barrier

  • Absorption (limited)

  • Vitamin D synthesis

  • Immunological function: Skin Immune System (SIS)

Skin immune protection: innate and adaptive immunity

  • Innate immunity: keratinocytes, Langerhans cells, PMN leukocytes, NK-T cells

  • Adaptive immunity: T cells and B cells; antigen presentation and cytokine signaling

  • CD14-related innate pathways; TLR signaling (TLR4 with LPS, TLR2 with bacterial components)

  • MyD88, NF-kB, IRAK pathways; cytokine cascades and development of cell-mediated and humoral responses

Skin microbiome and ecology

  • Microbiome distribution differs by skin site (moist, dry, sebaceous)

  • Moist sites: Corynebacteriaceae, Proteobacteria, Staphylococcaceae, Micrococcaceae, other Firmicutes

  • Dry sites: Proteobacteria, Bacteroidetes, Corynebacteriaceae, other Firmicutes

  • Sebaceous sites: Corynebacteriaceae, Cutibacteriaceae, other Actinobacteria; Staphylococcaceae and other Firmicutes

  • Microbiome contributes to barrier function and immune education

Infliximab (Remicade) therapy in dermatology

  • Overview slide references: before treatment and after 3 months of Remicade therapy

  • Infliximab is an anti-TNF-α biologic used in inflammatory dermatoses (e.g., psoriasis, psoriatic arthritis, etc.); monitoring for infection risk and adverse effects is essential

Key takeaways and connections

  • The skin is a complex organ integrating barrier protection, immunity, sensation, and endocrine interactions

  • The DEJ and epidermal lipids are critical for barrier integrity; defects lead to blistering diseases and eczema

  • Genetic and autoimmune diseases affecting keratinocytes, DEJ components, and pigmentation thresholds illustrate the interconnectedness of dermatology with systemic health

  • Understanding the epidermal lifecycle aids in diagnosing diseases like psoriasis, ichthyoses, and atopic dermatitis

  • Skin aging involves both epidermal thinning and dermal matrix degradation, with photoaging accelerating these processes

  • The skin microbiome plays a significant role in barrier function and immune modulation; dysbiosis can influence disease risk and severity

References and suggested further reading

  • Taieb, Picardo NEJM 2009 – Vitiligo segmental vs non-segmental classifications and prevalence

  • McLean et al., Nat Genet 2006 – FLG mutations and atopic dermatitis risk

  • Dermal resources (e.g., www.dermall.hu) for additional diagrams and structural details

Quick recap of formulas and key numbers

  • Epidermal surface area: 2 \,\mathrm{m}^2

  • Skin mass percentage: 15\% of body weight

  • Skin turnover/debris: 3.0\times10^4\text{ to }4.0\times10^4\text{ cells/min}

  • Lifespan of lei: aging begins around age 20\,

  • Lipid composition ranges: \text{Cholesterol } 15{-}20\% , \text{Ceramide } 40{-}50\%, \text{Free fatty acids } 20\%

  • Filaggrin cycle products include pyrrolidone carboxylic acid and urocanic acid as natural moisturizing factors

  • Melanogenesis signaling involves MC1R, \alpha\text{–MSH}, \text{POMC}, \text{cAMP}, \text{PKA}, \text{MITF} and related kinases