Barrier Function & Biomechanical Properties of

the Skin

Maha Adel Shaheen, MDProfessor of Dermatology & Venereology

Ain Shams University

Skin Structure

1- Epidermis - Stratum Corneum

- Viable Epidermis

← BMZ →

2- Dermis

3- Hypodermis (Subcutaneous fat)

Viable Epidermis

• Basal Layer

stratum germinativum

• Spinous Layer intercellular bridges (desmosomes)

• Granular Layer

(KHG – Odland bodies)

Stratum Corneum

• 15-20 layers of terminally differentiated keratinocytes.

• Dead non-nucleated thin flat cells (squames) (corneocytes).

• Held together by lipids and desmosomes.

• Function: Epidermal Barrier

Epidermal Barrier(Brick and Mortar Wall)

• Site: lower stratum corneum.

• Function: protection from water loss & noxious physical, mechanical & chemical insults.

• Structure:1- Corneocytes (hard

building blocks).2- Intercorneocyte lipids

(space filling mortar).

Corneocytes1- KIF cytoskeletonTightly bundled keratin intermediate filaments aligned ≈ to the skin

surface.

2- Cornified cell envelope (CE)

• Uniform band located beneath the KC

plasma membrane.

• Formed of cross linked specific structural proteins.

Keratin Intermediate Filaments

- Rope-like fibers extending

from nucleus periphery.

- Mechanical support.

- Tissue specific expression

of heterodimers

(K5/K14 - K1/K10)

Structure of Intermediate Filaments

• Two dimers of cytokeratin group into a keratin tetramer by anti-parallel binding.

• This cytokeratin tetramer is considered to be the main building block of the cytokeratin chain.

• By head-to-tail linking of the cytokeratin tetramers, the protofilaments are originated, which in turn intertwine in pairs to form protofibrils.

• Four protofibrils give place to one cytokeratin filament.

Organization of KIF (Bundling) in Epidermal KC

Desmosomes(Desmosome - Tonofilament Complexes)

CE Proteins• Involucrin • Loricrin• Keratolinin• pro (Filaggrin)• Desmosomal proteins: - desmoplakin - envoplakin - .............

Inter-corneocyte Lipids (mortar)

• Keratinization specific multilamellar lipid sheets in-between corneocytes

• Formed in the granular cell layer Odland (lamellar) bodies

- Ceramides- Cholesterol & esters- Free fatty acids- phospholipids

Defects of Skin Barrier(Broken Bricks - Weak Mortar)

1- Atopic Dermatitis

2- Psoriasis

3- Lamellar Ichthyosis

4- Netherton Syndrome

5- Contact Dermatitis

Basement Membrane Zone( BMZ )

• Histopathological BMZ (PAS +ve)

• Ultrastructural BMZ

• Molecular BMZ

Basement Membrane Zone

Skin BMZ

BMZ - Hemidesmosome

Human skin basement membrane as a target of autoimmune diseases

Diseases chch by autoantibodies directed against hemidesmosome

1- Bullous pemphigoid

2- Linear IgA bullous dermatosis

Diseases chch by autoantibodies directed against lower lamina lucida

1- Cicatricial pemphigoid with autoantibodies to bullous pemphigoid antigen

2- Anti-laminin cicatricial pemphigoid

3- Anti-p105 pemphigoid

Diseases chch by autoantibodies directed against sub-lamina densa

1- Epidermolysis bullosa acquisita

2- Bullous SLE

Molecular Basis of Inherited Skin Diseases

• Epidermolysis bullosa (EB)

EB Simplex ----- K5 & K14

EB Junctional ----- Laminin

EB Dystrophic ----- Collagen VII• Ichthyoses

Ichthyosis Vulgaris ---- Profilaggrin

XLRI ------- Steroid sulfatase

BIE ------ K1 & K10• Palmoplantar Keratodermas• Ectodermal Dysplasias

Sites of Skin Cleavage in Different EB Syndromes

Extracellular Matrix

• Any material produced by cells & secreted into the surrounding medium.

• ECM is produced by cells & influences the behavior of cells.

3 major components

1- Fibrous elements (collagen, elastin, reticulin)

2- Link proteins (fibronectin, laminins,…)

3- Space-filling molecules ( GAGs)

Extracellular Matrix

Extracellular Matrix

Fibrillar Matrix (structural proteins)

• Collagen - Elastin - Reticulin

Extrafibrillar Matrix

• Glycosaminoglycans (GAGs)

• Proteoglycans

• Hyaluronic acid

Glycoproteins (adhesive function)

• Laminins, fibronectin, vitronectin .…..

ECM FunctionA- Structural Function:

• Skin elasticity, resilience, tautness.

• Strong adherence between epidermis and dermis by BMZ anchoring complexes -------> resistance against external sheering forces.

B- Regulation of cellular functions:

• Cell adhesion, migration, division, signaling, apoptosis …..

Collagen

Collagen Triple Helix

Collagen Molecule

• A triple helix of three extended protein chains wrapped around one another.

• Numerous rod like collagen molecules cross-link together to form un - extendable collagen fibrils.

• Collagen fibrils are striped because of the regular repeating arrangement of the collagen molecules within the fibril.

Collagen Basic Structure

Procollagen Molecule

Collagens(26 types – 44 genes)

Skin Collagens• Collagen I, II, III

• Collagen IV (BM collagen)

• Collagen VII (Anchoring fibrils)

Elastin molecule uncoils when the fiber is stretched and spontaneously recoils when the stretching force is relaxed

Extrafibrillar Matrix

• Glycosaminoglycans (GAGs)

Large polysaccharide chains made up of repeating disaccharide units that are negatively charged and hold a large amount of water compared to other ECM molecules

• Proteoglycans

Protein and polysaccharide complexes

Extrafibrillar Matrix

Mechanical Skin Properties

Tension: taut - tense - stretched firmly - not slack - resists deforming forces.

Elasticity: recoils or springs back to its original length or shape after being stretched or squeezed.

Resilience: springy- adaptive - readily recovering from shock.

Tensile Strength: the degree to which it can be elongated before it tears.

Mechanical Skin Properties

Cytoskeleton Supports the cell and gives it its shape

Glycosaminoglycans( GAGs) & Proteoglycans Viscoelastic properties & resistance to compression

Collagen fibers Tensile strength (resistance to breaking or tearing)

Elastic fibers Tension, resilience, elasticity

Abnormalities of Dermal Fibrous & Elastic Tissue

Ehlers-Danlos Syndrome (EDS)Skin Hyperelasticity

EDS Joint Hypermobility1. More than 10º hyperextension of

the elbows.

2. Passively touch the forearm with the thumb, while flexing the wrist.

3. Passive extension of the fingers or a 90º or more extension of the fifth finger (Gorling’s sign). This is used as a “Screen Test”.

4. Knees hyperextension greater than or equal to 10º.

5. Touching the floor with the palms of the hands when reaching down without bending the knees. This is possible as a result of the hypermobility of the hips, and not of the spine as it is commonly believed.

EDS Joint Hypermobility

Cutis LaxaHyperextensible non elastic skin

Pseudoxanthoma Elasticum (PXE)

PXECalcium salts deposited on abnormal elastic fibers

Solar or Senile Elastosis Favre-Racouchot Syndrome

Abnormalities of Dermal Extrafibrillar Matrix

Cutaneous Mucinoses

A heterogeneous group of conditions caused by dermal fibroblasts producing abnormally large amounts of glycosaminoglycans → focal or diffuse dermal deposition.

H&E: bluish, feathery material H&E: bluish, feathery material between collagen bundlesbetween collagen bundles

Mucin Stains

• Colloidal Iron

• Alcian Blue

• Toluidine Blue

• Incubation of tissue in hyaluronidase eliminates the staining, confirming the presence of mucin

Lichen myxedematosus - Papular mucinosis - Scleromyxedema

The etiology is unknown. The disease is commonly associated with plasma cell dyscrasia.

The basic defect ≈ a fibroblast disorder → increased mucin deposition in the skin.

Most patients have a monoclonal paraprotein band, usually IgG type.

The association between this paraprotein and the mucin deposition is not clear, and the protein does not directly stimulate fibroblast proliferation.

Why Shar Pei Dogs Have So Many Wrinkles

• The genetic alteration in this breed multiplies the activity of an enzyme responsible for an excessive production of hyaluronic acid which gathers under the skin and produces wrinkles.

• Understanding this molecular mechanism will be used to learn more about human disorders such as mucinosis and to gain more knowledge on the ageing process.

Mucopolysaccharidoses• A group of metabolic disorders caused by the absence or

malfunctioning of lysosomal enzymes needed to break down glycosaminoglycans.

• Patients either do not produce enough of one of the 11 enzymes required to break down these sugar chains into simpler molecules, or they produce enzymes that do not work properly.

• Over time, these GAGs collect in the cells, blood and connective tissues.

• The result is permanent, progressive cellular damage which affects appearance, physical abilities, organ and system functioning, and, in most cases, mental development.

Lipoid Proteinosis

• Skin scarring, beaded eyelid papules, laryngeal infiltration → hoarseness, Infiltrates in the tongue and its frenulum limit lingual movements and cause speech difficulties.

• PAS positive hyaline material in the skin, upper aerodigestive tract & internal organs.

• Mutations in the extracellular matrix protein 1 gene (q21) .

• ECM1 = glycoprotein that binds to perlecan, the major heparan sulphate proteoglycan of the BM, as well as to fibrillar proteins (“biological glue” in the dermis, helping to regulate basement membrane and interstitial collagen fibril macro-assembly ).