Giles Kisby
GE Y1 Dermatology
Dermatology:
Spring Term:
LECTURES:
10/01/14: Introduction:
Los (from booklet):
1
Explain the concept of the skin as a single organ of the body with its complex intra-relationships
with other organ systems of the body.
2 Describe the basic anatomical structure of the skin and the intra-relationships between
the epidermis, dermis and subcutis.
3 Describe the structure of the epidermis and associated adnexal structures its foetal
development and regulation of growth.
4 Outline the mechanisms by which the integrity of the dermoepidermal junction is
maintained and the results of failures of these mechanisms.
5 Describe the migrant cell populations within the epidermis and detail their origins.
6 Describe the structure of the dermis including the vascular and nerve supply to the skin,
the development of the dermis, regulation of collagen formation and events that occur
in senescence.
7 Describe skin pigmentation, the development, function and control of melanocytes and
the principals of immediate and delayed tanning.
8 Describe the development and maturation of acquired melanocytic naevi and the
features of carcinogenic change within these lesions.
9 Describe the development of the hair follicle, its anatomy and regulation of growth
through life including the effect of sex hormones and age on hair growth.
10 Describe the principles of barrier function of the skin and its role in controlling
percutaneous water loss and absorption and defence against microbial invasion.
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11 Explain the control of body temperature and the role of the cutaneous vasculature in
maintaining body temperature.
12 Explain the importance of the skin as an immunological organ and describe the role of
individual cell types in the cutaneous immune system.
13 Explain the mechanism of skin wound healing
14 Describe the consequence of skin organ failure and give examples of the impact of this
on the body and other organ systems.
Notes:
Introduction to the Skin: Tony Chu
Epidermis  dermis  adipose layer
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Basic Structure of the Skin
o The skin has 3 components:
 Outer stratified squamous epithelium - epidermis
 Structural dermis
 Deep subcutaneous adipose layer
o The components are intimately linked with cross talk between the layers and
migration of various cell types between the layers
o The skin is a dynamic not static organ
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Function of the Skin
o Barrier function - prevents fluid loss from the body, protection against toxic and
infectious agents, radiation etc
o Temperature control
o Peripheral outpost of the immune system
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Skin disease
o Skin is intimately linked to other organ systems of the body
o Diseases of other organs will affect the skin - yellow skin of jaundice of liver disease
o Skin signs may be the first evidence of systemic disease
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Additional tests are used to confirm the diagnosis:
o Biopsy and histology/immunohistochemistry
o Skin scrapings for fungus; swabs for infection
o Gene rearrangement studies for malignancies
o Patch testing for allergy
10/01/14: Structure of the epidermis and adnexal structures
Notes:
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Layers of the epidermis
o Basal cell layer (stratum basale)
o Spinous layer (stratum spinosum)
o Granular cell layer (stratum granulosum)
o Cornified layer (stratum corneum)
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THE BASAL LAYER
o 1 – 3 layers of cuboidal cells
o Main proliferative component of epidermis
o Large oval nuclei
 Because function is to divide
o Small basophilic cytoplasm
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o
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 Because not very metabolically active
Factors that stimulate proliferation :
 EGF, TGFα, IL-1, IL-6, GM-CSF
 These factors are produced by keratinocytes, Langerhans cells, dermal
lymphocytes
Factors that inhibit proliferation :
 TFG β, IFN α and γ, TNF α
 Prevent excessive proliferation
CYTOSKELETON OF MAMMALIAN CELLS
o Microfilaments
 Actin
 7 nm in diameter: smallest
o Microtubules
 Tubulin + Tau
 20 – 25 nm in diameter: biggest
o Intermediate filaments
 Six types
 Diameter: 7 – 10 nm: intermediate size
 Vimentin (mesenchymal cells)
 Glial fibrillary acidic protein (glial cells)
 Neurofilaments (neurons)
 Desmin (muscle)
 Lamins A, B and C (nuclear matrix)
 Keratins (all epithelial cells)
 THE KERATINS
o 20 members, between 40 – 70 kD
o Each member a product of a different gene
o Divided into 2 groups: acidic and basic
o Basic keratins: 1 to 8 (12q11 - q13)
o Acidic keratins: 9 to 19 (17q12 – q21)
o [“ie opposite to pH order”]
 THE KERATINS
o Keratin filament is formed by assembling one acidic and one
basic keratin type in pairs
o Different pairs are expressed at different levels of the
epidermis
o Basal layer: K5 + K14
o Spinous layer: K1 + K10
 FILAGGRIN [“filament aggregation (of ketatin filaments)”]
o Cationic protein in the stratum corneum (26 – 48 kD)
o Profilaggrin: precursor inside keratohyalin granules (500 kD)
o Forms dense aggregates of keratin filaments
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

CORNIFIED ENVELOPE
o 15-nm thick envelope underneath the plasma membrane of
keratinocytes
o Includes involucrin, loricrin, keratolinin, pancornulins,
cornifin and cystein-rich envelope protein
o Molecules are cross-linked with transglutaminases
o Keratins become crosslinked to the cornified cell envelope
STRATUM CORNEUM
o Major responsible for barrier function of the skin
o Epidermis is, in large part, devoted to its production
o Results from a sequence of events including:
 Synthesis and assembly of keratins
 Addition of filaggrin
 Synthesis and assembly of the cornified envelope
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During cornification, the process whereby living keratinocytes are transformed into nonliving corneocytes, the cell membrane is replaced by a layer of ceramides which become
covalently linked to an envelope of structural proteins (the cornified envelope)
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Pemphigus vulgaris
o Commonest form of pemphigus
o Only affects stratified epithelium
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IMMIGRANT CELLS TO THE EPIDERMIS
o Langerhans cells
 Are dendritic cells
o Melanocytes
o Merkel cells
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Sweat glands
o Eccrine glands
 Present all over except lips, nailbed, glans, foreskin and labia minora
 Most numerous: palms, plantar and axillae
 Derive from buds from epidermis
 One layer of cuboidal cells
 Positioned at dermo-adipose junction
 Surrounded by myo-epithelial cells
 Clear cells: contain glycogen.
 Produce the salt + water
 Dark cells: contain acid GAGs
 Ducts: absorb salt- sweat is hypotonic
 Function of glands:
 Sweat
 Drug uptake
 Wound healing role
 Main function of sweat:
 Evaporative cooling
 Cholinergic nerves of SNS discharge Ach on the surface of clear cells
 Thermal and emotional factors
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Apocrine glands
 Only in certain areas:
 Axillae, anogenital area, ceruminous glands, Moll glands
 Not true sweat glands, but scent glands
 Give BO
 Regress with age
 Originate from hair buds (rather than from epidermis)
 Surrounded by myo-epithelial cells
 Acini much larger than eccrine
 Acini in subcutaneous fat
 Enlarge under hormonal influences
 PAS+ columnar cells
 “Apocrine” secretion
 = Decapitation secretion
o Elements of membrane are part of the secretions
 Milky, odorless, viscous
 Stored for intermittent release
 Bacterial action breaks down secretion and produces short-chained
fatty acids that smell of b.o.
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SEBACEOUS GLANDS
o Holocrine
 Holocrine secretions are produced in the cytoplasm of the cell and released
by the rupture of the plasma membrane, which destroys the cell and results
in the secretion of the product into the lumen.
o Present on all skin except palms, soles, dorsal feet [ie matches where hair is found
due to gland association with hair follicle]
o Usually associated with hair, except on areolae, labia minora, foreskin, vermillion
borders of lips.
o Originate from hair
o Outer layer of cuboidal undifferentiated cells
o Progressively accumulate intracytoplasmic lipid
o Cells desintegrate and fall into the duct
o Sebum: triglycerides, waxes, cholesterol and squalenes.
o Secretion depends on adrenal and gonadal androgens
o Prominent at birth
o Inconspicuous during childhood
o Size and activity increases in puberty
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10/01/14: Dermis and dermoepidermal junction: Tony Chu
Notes:
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Dermis
o
o
o
o
Supporting ‘foundation’ for the epidermis
Comparatively non-cellular connective tissue
Contributes 15-20% of the total weight of the body
Varies in thickness in different locations – 5mm on back, 1mm on eyelids depending on the necessary tensile strength
Dermis
o Consists of supporting matrix or ground substance with protein fibres:
 Collagen
 Elastic fibres
o Cellular Elements
 Fibroblasts, mast cells, histiocytes, Langerhans cells, lymphocytes,
eosinophils
o Embedded in the dermis are:
 Nerves
 Blood vessels
 Lymph vessels
 Muscles
 Pilosebaceous/apocrine units
 Eccrine sweat units
o Adventitial Dermis
 Thin zone just under the epidermis (papillary dermis) and dermis around
adnexal structures
 Thin haphazardly arranged collagen fibrils
 Delicate branching elastic fibres
 Numerous fibroblasts
 Abundant ground substance
 Highly developed microcirculation
o Reticular Dermis
 Bulk of the dermis from papillary dermis to subcutaneous fat
 Irregularly arrayed coarse elastic fibres
 Thick collagen bundles arranged parallel to the skin surface
 Fewer fibroblasts and blood vessels than adventitial dermis
 Less ground substance than adventitial dermis
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Collagen
o Most abundant protein of the body
o 70% dry weight and up to 30% of the volume of the dermis
o High tensile strength
o A 1mm diameter collagen fibre can sustain 40kg weight
o Collagen
o 20 or more different proteins now identified
o Characteristic regular cross banding seen particularly in collagen types I, II and III
o Skin collagens:
 Fibrillar collagens -type I, III
 Basement membrane collagens, IV, VII, XVII (BPAG2)
 Non-fibrillar, non-basement membrane collagens – XVI
o Fibillar Collagen
 Type I – course fibres found in reticular dermis
 deep
 Type III – fine loosely arranged fibres of the adventitial dermis
 Superficial
o Fibrillar Collagen Formation
 Collagen is produced by fibroblasts
 Intracellularly, procollagen chains form perfect triple helical a chains
 In the extracellular space triple helices self assemble into irregular
overlapping staggered fibres
 Hydroxylation of proline of procollagen is the rate limiting step in collagen
synthesis
 Hydroxyproline stabilises the conformation of the triple helix
 Cross-linking of collagen molecules to form microfibrils and fibres is
mediated by lysyl oxidase
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Elastic Fibres
o Produced by fibroblasts
o <1% dry weight of dermis
o Highly branched structures
o Central core of elastin with peripheral microfibrils – fibrillin 1 and 2, MAGP-1, -2, -3
o Important property allowing return of skin to original shape following deforming
forces
o Naturally present in contracted form
o Capable of extension to twice resting length
o Absent from scars and striae - stretch marks
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Ground Substance
o Produced by fibroblasts
o Amorphic extracellular material
o Enmeshes fibrillar and cellular compartment of skin
o Consists of water, electrolytes, plasma proteins and mucopolysaccharides
o 0.2% dry weight of skin but most of the volume of the dermis
o Mucopolysaccharides
 In dermis:
 Hyaluronic acid
 Dermatan sulphate
 Chondroitin-6-sulphate
 Heparan sulphate
o Function
 Salt and water balance – binds large amounts of sodium and water
 Support for other components of dermis – due to high viscosity
 Regulates connective tissue metabolism by promoting cell growth, migration
and differentiation
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Fibroblasts
o Most numerous cell in connective tissue
o Highly metabolic cell
o Produce ground substance, collagen and elastin
o Most numerous in the papillary dermis
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Mast Cells
o Bone marrow derived
o Found close to blood vessels, nerves and appendages
o Most numerous in subpapillary dermis 7000/mm3 of normal skin
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o
o
o
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Ovoid or spindle shaped
Contain numerous round cytoplasmic granules
Reservoir of preformed inflammatory mediators
Rapidly synthesize other mediators on activation
Dermoepidermal Junction
o One of the largest epithelial-mesenchymal junctions
o Key role in epidermal cell anchorage, adhesion, migration and differentiation
o Serves as a barrier and filter
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Bullous Pemphigoid
o Problem with:
 230 kDa BP Antigen
 Bullous Pemphigoid Antigen and/or type XVII collagen
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Epidermolysis Bullosa (junctional)
o Problem with Type XVII collagen leads to upward displacement of lamina lucida
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Epidermolysis Bullosa (dystrophic)
o Problem with Type VII collagen leads to upward displacement of Lamina Lucida and
Lamina Densa
o Problem is below basal lamina so extensive scarring results
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Summary of Skin Diseases:
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10/01/14: Organisation of the skin immune system: Tony Chu
Notes:
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Skin Immune System
o Key Players:
 Keratinocyte
 Langerhans cell
 T cell
 Monocyte/Macrophage
 Endothelial cell
 Mast cell
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Keratinocytes:
o Major factories for the production of cytokines
o Phagocytic
o Can be induced to express MHC Class II antigen
o Express Toll like receptors
o Produce antimicrobial peptides
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o
o
o
o
o
o
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Produce Pro-inflammatory cytokines
BUT also produce down-regulatory cytokines
 IL1Ra
 IL10
 a-MSH
 CXCL10
 PGE2
Produce Growth Factors
 GM-CSF – moncytes/macrophages
 IL7 – B cells
 IL15 – T cells
 SCF – Mast cells
 VEGF – blood vessels
Produce Chemoattractant Cytokines
 IL1 – neutrophils and macrophages
 CCL27 – T cells
 CCL5 – eosinophils and memory T cells
 CXCL10 – T cells
 Mig – T cells
 IP9 – T cells
 CCL20 – Langerhans cells
Keratinocytes can be induced to express MHC Class II antigen by g interferon
 Class II expression is a cardinal feature of antigen presenting cells
 Keratinocytes lack co-stimulatory molecules
 Do NOT show antigen presentation
Toll like receptors respond to highly conserved motifs on micro-organisms
 Keratinocytes express TLRs: TLR1, TLR2, TLR4 and TLR5
Antimicrobial Peptides
 Keratinocytes will produce the cathelicidin peptide LL-37 under
inflammatory conditions
 Keratinocytes produce human b defensins 1, 2 and 3
Langerhans cell
o Dendritic antigen presenting cell of the skin
o Migrant from bone marrow precursor
o Renewed from bone marrow precursors but also locally self replicating
o Represent 2% of the epidermal cell population
o Express a unique combination of surface antigens
 HLA-DR (vs prots), CD1a ( vs lipids) (important in lipid antigen presentation
to immune system), Langerin (vs carbs)
o Stimulated to mature by GM-CSF, TNFa, IL4 and TGFb
o In CFS-1 and TGFb1 knock-out mice, no epidermal Langerhans cells are present
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o
o
o
o
o
o
o
o
o
o
Possess a unique intracytoplasmic organelle the Birbeck granule
 Trilaminate structure with and extended terminal end look rather like a
tennis racket
 Initially thought to be a viral inclusion, now considered important in
endocytosis
Langerin is a lectin present on the surface of the Langerhans cells but also found
within the Birbeck granule
 Birbeck granule = tennis racket shaped:
Precursors able to home to the skin via the CLA receptor which uses E-selectin on
endothelial cells as a ligand
Cells express CCR6 receptor for CCL20 produced by keratinocytes
Held in the epidermis by adhesion molecule E-cadherin
Reside in the suprabasalar area of the epidermis
Dendritic but unlike other DCs they are flattened and extend along a horizontal
plane
Dendrites cover over 25% of the skin surface making them a very efficient network
for capturing and recognising antigens in the epidermis
Following stimulation, cells change their chemokine receptor to CCR7, lose Ecadherin and migrate out of the epidermis to the dermal lymphatics
Cells up-regulate CD80 and CD86 and migrate to the para-cortical zone of lymph
nodes to interact with CD4+ T cells
Langerhans cells start to apoptose when they leave the epidermis: do not recycle
back to the epidermis
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Monocyte/Macrophages
o Arise from myeloid precursors in the bone marrow
o Circulate as monocytes – 2 to 10% of blood leukocytes
o Migrate into various tissues including the skin where they activate as macrophages
o Express Toll like receptors
o Phagocytic
o Produce a large range of pro-inflammatory cytokines and growth factors
o Produce down-regulatory cytokines to regulate immune responses
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Endothelial cells
o Prevent clotting under normal circumstances
o Allow cells to adhere and migrate through them – E-selectin
o Express receptors for a number of cytokines
o Produce a number of cytokines including basic fibroblast growth factor
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T Cell
o
o
o
o
T cells that go to the skin express the skin homing antigen CLA
In the steady state the main T cell that circulates through the epidermis is the CD8+
T cell
In inflammatory skin conditions, the major T cell population is the CD4+ helper T cell
– interaction with Langerhans cells
T cells can recycle though the skin
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Mast Cells
o Important effector cells in allergic disease
o 10,000/mm3 are found in the skin near blood vessels, hair follicles, and sweat glands
o Activation is mainly during Type I IgE mediated hypersensitivity
o Mast cells express TLR 2, 4, 6, 8
o Express C3a and C5a receptors
10/01/14: Pigmentation of the skin
Notes:
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MELANOCYTES
o Derived from neural crest cells
o Network in basal and suprabasal position
o Epidermal melanin unit = 1 melanocyte for 36 keratinocytes
 Melaninocyte injects the pigment to the keratinocytes: the latter hold most
of the melanin but do not make the melanosome organelles from which it is
dervied
o Divide under stimuli
o Produce and transfer melanosomes
 A melanosome is an organelle found in animal cells, and is the cellular site of
synthesis, storage and transport of melanin
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MELANIN
o Eumelanin
 Black, insoluble
o Phaeomelanin
 Red. Human red hair. Feathers of red hens
o Both
 Derived from tyrosine by tyrosinase
 Share initial steps of synthesis
o SYNTHESIS OF EUMELANIN:
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SYNTHESIS OF PHAEOMELANIN:
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Use sunscreen every day to prevent aging effects
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FUNCTIONS OF MELANIN
o Avoids damage to DNA of keratinocytes
o Decreases cutaneous carcinogenesis
o Eliminates genetically damaged cells
o Prevents ageing of the skin
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TANNING
o Immediate
 Oxidation of pre-formed melanin
 UVA
o Delayed
 Proliferation of melanocytes
 ↑ tyrosinase activity
 ↑ transfer of melanosomes
 UVB
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SKIN PHOTOTYPES
o Phototype Sun sensitivity
o
I
Burns easily
o
II
Always burns
o
III
Burns moderately
o
IV
Burns minimally
o
V
Rarely burns
o
VI
Never burns
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Inducible skin colour
Never tans: red hair
Minimal tan: caucasian no tan
Tans gradually (light brown): Caucasian tan
Tans easily (brown): mediteranian
Always tans (dark brown): mexico
Always tans (black): African [intrinsic SPF8]
RACIAL DIFFERENCES IN MELANOCYTIC FUNCTION
o Caucasians
 = number of melanocytes
 ↓ melanin production by tyrosinase
 Small melanosomes
 Lighter melanosomes
 Fewer melanosomes
 Clustered melanosomes
o Afro-caribbeans
 = number of melanocytes
 ↑ melanin production by tyrosinase
 Large melanosomes
 Dense melanosomes
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

Numerous melanosomes
Singly-distributed
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EFFECTS OF THE SUN ON THE SKIN
o Dermal elastosis  ageing
o Decrease in the number of Langerhans cells
 Ie immunosuppression by sun
 Eg eczema or psoriasis  recommend sun exposure
 Eg can cause cold sore flare-ups
o Mutations in keratinocytes  cancer
o Production of free radicals
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Photoageing vs intrinsic ageing:
o 10% intrinsic ageing
 ↓1% collagen synthesis per year of adult life
 Fewer fibroblasts
 Decreased number of blood vessels
 Fewer epidermal layers
o 90% photoageing
 Limbs: thin skin; easily bruised or torn
 Solar lentigos
 Wrinkles
 Thin epidermis
 Solar elastosis
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Photodamage
o Thinning of the epidermis
o Flattening of the rete ridges
o Solar elastosis
o Decrease in number of blood vessels
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PENETRATION OF UVR
o UVA: 320 < λ < 400 nm: ageing of the skin. Penetrates glass.
o UVB: 290 < λ < 320 nm : burns, tumours. Blocked by glass.
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Xeroderma Pigmentosa:
o Can be caused by a range of mutations:
 defect in nucleotide excision repair (NER) enzymes
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10/01/14: Blood vessels and nerves
Los (from booklet):
Objectives
Blood Vessels
Cellular Structure
Anatomical Distribution
Function
Nerves
Efferent Nerves
Afferent Nerves
Sensory Pathway
Notes:
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Blood Vessels – role?:
o Contains the blood
 Together with the heart make up Cardiovascular system
o Regulates blood flow
 Thermoregulation
 Conduction/convection/radiation
o Selectively permeable membrane
 Nutritive structures
 O2, CO2, N2
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Cappilaries and venules:
o Capillaries are composed of specific cell types, they are lined by endothelium and
surroundied by pericytes which have limited contractile function. These pericytes do
not completely cover the circumference and are often multilayered on the venous
side and provide a seal for the vessel. Importantly, capillaries lack smooth muscle.
o They are surrounded by a membrane of type iv collagen and laminin.
o Veil cells seen here are unusual, their function is unknown but they are found
surrounding blood vessels in the skin.
o Capillaries drain into venules whose basic structure is similar but their lumen is
much larger and there is a thin endothelial cell lining.
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Vascular plexus:
o In the skin, blood vessels form layers of decreasing diameter. In the low dermis /
subcutis fat layer are venules and arterioles known as the deep plexus tributaries
supply deep structures such as hair, sweat gland
o Intricate connections to network called the superficial plexus As you ascend –
vessels are getting smaller
o Superficial plexus – in the superficial papillary dermis these supply the capillary
loops which supply the epidermis. In some areas these papillary loops are more
developed such as the face which explains why when men cut themselves shaving
they bleed for quite some time.
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Blood flow regulation:
o In the deep plexus there are precapillary sphincters which decrease the diameter of
the communicating vessels and thereby reduce blood flow. They are under the
influence of the autonomic nervous system
o Variations in surrounding temperature can have dramatic effects on blood flow
o In hot environments, dilatation of these sphincters results in educed peripheral
resistance and increased flow
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Blood Flow – Arteriovenous Anasatomosis
o Only present at specific sites exposed to maximal cooling
 In some areas of the body there are direct communications between the
arteries and veins known as anastamosis.
 This are primarily in the hands, feet and earlobes
o AV Anastamoses have strong muscular coats innervated by adrenergic
vasosconstrictors
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o
In extreme cold constriction of anastamoses results in significant reudction in
cutaneous blood flow
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Weibel-Palade Body
o Secretory granules in vascular endothelial cells
o Formed from trans Golgi network
o Round/ovoid shape with tubular inclusions
o Release vWF and P Selectin in response to injury
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Function – Cell Trafficking
o Normal skin has very few lymphocytes
o Inflammation and infection require recruitment of circulating lymphocytes
 Initial step requires adhesion to vascular endothelium
 Cellular adhesion molecules (CAM’s) upregulated
 ICAMs VCAMs
 Selectins are expressed – weak adhesion molecules
 P selectin (adherence)
 E selectin (cell arrest at that position)
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Functions – Response to Injury and Angiogenesis
o Following injury, thromboxanes and prostaglandins cause spasm 
vasoconstriction
o 20 mins later histamine induced dilatation and increased porosity erythema
swelling and inflammatory cell influx
o Angiopoietins released from pericytes in response to trauma:
 Angiopoietins
 Ang-1/2 ligand
 Tie-1/2 receptor
 VEGF
o angiogenesis
o Stem cells of Endothelial cells from uninjured blood vessels are chemotactically
recruited resulting in neovascularisation.
o Pathology of Angiogenesis: Psoriasis and Cancer
 Growth factors are secreted in some inflammatory skin conditions
 Causes the erythema, the histopathology of psoriasis is characterised by
increased vessels
 Cancer can’t grow greater than 0.5 cm3 volume without hijacking
angiogenesis
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Afferent Nerves
o Transmit numerous sensory modalities
 Temperature, touch, vibration, pressure, itch and pain
o Secrete neuropeptides
 Substance P [“powder”], nerve growth factor  itching
 Substance P is released from the terminals of specific sensory nerves, it is
found in the brain and spinal cord, and is associated with inflammatory
processes and pain.
o Defined by the nature of the distal sensory organ of the nerve:
o
Free Nerve Endings
 Derived from non-myelinated fibres
 Located in superficial dermis and epidermis
 Polymodal
 Touch
 Pain (nociceptors)
 Pressure
 Temperature
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


o
Hair follicles are surrounded by fine nerve filaments
Detail:
 Most common form of nerve and most are in the skin
 Non-myelinated fibers are seen in the superficial dermis and in the
overlying epidermis (may abut on to Merkel cells).
 Hair follicles have fine nerve filaments running parallel to and
encircling the follicles; mediating touch sensation.
 Primary a pain receptor
 Free nerve endings can detect temperature, mechanical stimuli
(touch, pressure, stretch) or pain (nociception). Thus, different free
nerve endings work as thermoreceptors, cutaneous
mechanoreceptors and nociceptors. In other words, they express
polymodality.
The majority of Aδ (A delta) fibers (group III) and C (group IV) fibers end as
free nerve endings.
Corpuscvular
 Meissner’s Corpuscule
 Texture receptors
 Glabrous skin (hairless)
 Thick lamellated capsule
 20-40 um diameter
 150 um length
 Detail:
o Sit on the papillary ridges of the dermis . Seen in higher
concentration in non hair bearing skin but concentrated in
areas especially sensitive to light touch, such as the
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o
o

fingertips, palms, soles lips, tongue, face and the male and
female prepuce.
They are primarily located just beneath the epidermis within
the dermal papillae
respond to texture and slow vibrations
Pacinian Corpuscule
 Encapsulated receptors
 Ovoid structure
 1mm
 Lamellated cross section – onion like 
 A single myelinated sensory axon at its core
 Movement and vibration
 Detail:
o Loss of vibration early in diabetics due to damage to this
pathway
o Similar to meissners but larger and fewer of them
o They detect gross pressure changes
o Also particularly good at deeper sustained touch and
detecting vibration
o They have a large receptive field, more sensitive in the
centre
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
Merkel Cell
 Merkel “Touch Spot”
 Composed of a number of Merkel cells borne on branches of a
myelinated axon
 Merkel cells contain a lobulated nucleus and characterisitc granules
 Embedded in basal layer of epidermis – connects with desmosomes
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-
Sensory Modalities
-
Adaptation
o In response to sustained stimulus
 Tickle and Itch
o Mild stimulation of pain nerve endings
 Group C unmyelinated nerve fibres
 Itch excites the scratch reflex
 Physiology of sensory receptors
Superficial Sensations
o Pain, Temp, Crude touch
 1st order neuron in posterior root ganglion
 Ascends in posterior horn (Lissauers tract)
 2nd order Crosses in anterior commissure near central canal and ascends
lateral spinothalamic tract
 Terminates in thalamus
 3rd order neuron terminates in sensory area of cerebral cortex
o 2. Deep sensations and fine touch
 1st order neuron – posterior root ganglion
 Directly ascends posterior column (Gracile and Cuneate tracts) ending in
medulla
 2nd order neuron - cross to opposite side and ascends to thalamus
 3rd order neurone present in thalamus passes up to internal capsule and
sensory area of cerebral cortex
-
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Function of the Skin: Tony Chu
-
Function of the skin
o Organ of sexual attraction and social interaction
o Barrier to loss or absorption of fluid and molecules
o Barrier to infection
o Protection against ultraviolet and other radiations
o Temperature control
o Reaction to infection, cancer and foreign substances
-
Organ of sexual attraction and social interaction
o Social and sexual interaction
o Skin and hair are important in sexual display
o Skin and hair are important in exerting social status
o Quality of Life Issues
 Dermatological conditions are visible and may have profound impact on
quality of life
 Facial dermatoses may result in loss of confidence, reclusiveness, depression
and social isolation
 Scaly skin conditions may make staying overnight difficult
 Skin loss onto the bedding
 Itching may result in bleeding onto clothes and bedding
 Blood marks on bedding
o Skin and employment
 Patients with acne were found to have a 50% greater unemployment rate
than age matched individuals without acne
 Patients with significant acne cannot join the armed forces
o Social Stigma
 In certain countries, vitiligo, where the skin develops white patches, is a
major social stigma
 Kaposi Sarcoma is a very visible sign of AIDS and can lead to patients being
ostracised by areas of society
-
Barrier to loss or absorption of fluid and molecules
o Skin limits water loss from the body
o Regulates penetration of water and other chemicals into the body
 Barrier to absorption of most substances
 Permits selective entry of some
o Most barrier function resides in the epidermis within the stratum corneum
 Lipid barrier important
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o
o
o
o
Keratinocytes synthesise fibrous proteins of keratin and histidine rich proteins –
keratohyalin and filaggrin
Odland bodies develop in keratinocytes close to the Golgi apparatus and migrate to
the cell periphery
Within Odland bodies uni-laminar liposomes rich in sphingolipids and neutral lipids
become arranged in disc form
In the stratum granulosum, Odland bodies fuse with the cell membrane and the
contents are discharged [lipid lamellae ejected and will form continuous barrier
around the body]
 After discharge from the granules the discs become arranged parallel to the
cell membrane and fuse to produce uninterrupted sheets consisting of two
lipid bilayers in close apposition
 These intercellular lamellae are the main barrier to trans-epidermal water
loss and prevent absorption of water through the skin
 Ceremides are essential in the formation of the bilamelar lipid membrane
 Ceremides contain essential fatty acids and deficiencies of these, especially
linoleic acid results in poor barrier function
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o
Eczema:
 In atopic eczema there is an enzyme deficiency of δ6-desaturase which
results in poor incorporation of linoleic acid into ceramides
 Patients have dry skin with poor barrier function
 Dry skin is irritable and adds to the itch of the eczema
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o
Percutaneous Absorption
 Skin is slightly permeable to water
 Permeability increases with lipid solubility
 Drugs that penetrate the skin are generally soluble in lipids or contained in a
lipid containing medium
 Topical therapy
 To the skin for skin disease
o Available in vehicles that allow good penetration into the
skin
 To the skin for diseases of other organs
o Becoming more important in conventional and in genetic
treatment
o Important pharmacologically in delivering drugs to organs
other than the skin
 Patches for nicotine
 Patches for hormone replacement therapy
 Topical non-steroidal anti-inflammatory agents in
arthropathies
 Nitroglycerine for coronary insufficiency
 Certain areas show increased absorption:
o Scrotum
o Face
o Forehead
o Dorsum of hands
 Through the stratum corneum- principle pathway
 Through pilosebaceous apparatus or sweat ducts – minor role providing
rapid route of entry for ions, polyfunctional polar compounds and very large
molecules
 Absorption is through the corneocytes rather than between them
 In infant and old skin absorption is greater due to the reduced thickness of
the skin
 In disease skin where barrier function is lost, absorption is greater
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Barrier to infection
o Protection against Micro-organisms and Destructive Chemicals
 Intact stratum corneum prevents invasion by microorganisms
 Sebum has anti-bacterial properties
 Glycophospholipids and free fatty acids are bacteriostatic
o Sebum
 Holocrine excretion produced by sebaceous glands
 Excreted into the hair follicle and gains access to the surface of the skin
 Sebaceous gland is active from 26 weeks gestation - sebum contributes to
the vernix caseosa on newborn babies
 Sebum excretion is mainly controlled by androgens:
 Maternal in the foetus
 Adrenal glands
 Ovaries in women
 Testes in men
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
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Minor role of ambient temperature
Function:
 In animals, important in coating and waterproofing hair and fur
 In man role is more speculative
 Possible role in reducing moisture loss but not a major part of
barrier function
 Lipids have antibacterial and anti-fungal properties
Protection against ultraviolet and other radiations
Temperature control
Reaction to infection, cancer and foreign substances
Immunology of the Skin: Tony Chu
-
Immunology of the Skin
o Innate immune response
o Acquired immunity
-
Innate Immune Response
o Skin barrier function keeps micro organisms out
o Sebum –
 Fatty acids and acid pH inhibit growth of micro organisms
o Sweat –
 lysozyme damages cell wall of bacteria (dermcidin constitutively produced
and has broad spectrum activity against Gram + and - bacteria and yeasts)
o General:
 Initial response to bacteria, fungi and viruses
 Broad spectrum
 Prevents infection
 Damages cell wall of micro-organism
 Removal by ingestion
o Epidermal cells [like those of gut]
 Toll-like receptor expression by epidermal cells
 Production of antimicrobial peptides by epidermal cells
o Toll-Like Receptors
 General:
 Cell surface pattern recognition receptors
 DNA encoded genes
 Recognise evolutionary conserved proteins within cell wall of
bacteria and fungi
 Activates cell to produce chemokines and cytokines
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

o
o
o
-
Transmembrane proteins
Cytoplasmic domain homologues similar to IL1R1
Respond to highly conserved motifs on different micro organisms –
Pathogen-associated molecular patterns (PAMPs)
 Ligand binding leads to stimulation of antimicrobial peptides as well
as induction of immune response genes through NF-kB activation
 Keratinocytes express TLR1, 2, (4) and 5
 TLR1, 2 and 5 are constitutively expressed
 TLR4 expression is controversial with some studies suggesting it is
not functionally active
 Langerhans cell express TLR2 and TLR4
 Targets:
 TLR2 – peptidoglycan from Gram + bacteria
 TLR4 – lipopolysaccharide from Gram – bacteria
 TLR5 – flagellin
 TLR2/1 heterodimer – triacylated lipoprotiens
Antimicrobial Peptides
 First line defence against infectious agents
 Multifactorial acting as natural antibiotics but also signalling activation of
host immune cells
 Cathelicidin and defensin gene families
 Directly kill Gram + and – bacterial, fungi and some viruses
 In resting conditions small amounts of AMP are produced in the skin at
potential sites of entry by bacteria – follicular openings, sweat ducts
 After injury or inflammation there is a rapid increase
Cathelicidins
 In humans restricted to a single gene
 Human cathelicidin – LL-37/hCAP18
 Broad spectrum antimicrobial activity
 Chemoattractant to neutrophils, macrophages mast cells and T cells
 Observed in human epidermal keratinocytes under inflammatory conditions
– psoriasis and contact dermatitis
Defensins
 3 families – a, b and o
 Only human b defensins have been identified in epidermis – HBD 1, 2 and 3
(2 and 3 upregulated in psoriasis)
 HBD have broad spectum antimicrobial activity
 HBD bind to CCR6 and are chemotactic for immature dendritic cells and
memory T cells
 HBD2 promotes histamine release and PGD2 production by mast cells
Acquired Immune Response
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o
o
o
Key players in the skin
 Keratinocyte
 Langerhans cell
 T cell
Keratinocyte
 Efficient factory constitutively secreting or induced to secrete a large
number of cytokines
 Can be induced to express HLA-DR
 Phagocytic
 HLA-DR expression
 Induced by IFNg
 In cell lines, IL8 can induce expression
 ICAM-1 expression
 Induced by IFNg and TNFa
 Antigen presentation
 HLA-DR induced
 IL1 production
 Phagocytic
 Unable to present antigen to T cells - ? Lack of CD80 and CD86 expression
 Studies suggest HLA-DR+ keratinocytes are able to induce tolerance in T cells
Langerhans cell
 Bone marrow derived from CD34+ and CLA+ precursor cell
 In vitro, GM-CSF, IL4 and TGFb can induce a LC phenotype
 Resident in the suprabasalar area of the epidermis
 Represent 2% of the epidermal cells
 Flattened dendrites extend horizontally covering 25% of the surface of the
skin but do not interconnect
 CD1a
 non-polymorphic , MHC class I like molecule – role in lipid
presentation to T cells
 Birbeck granules
 rod or racket shaped intracytoplasmic organelles implicated in the
endocytic pathway – express Lag antigen
 Langerin CD207
 mannose specific C type lectin expressed on the cytoplasmic
membrane and in the Birbeck granule
 In the skin in a resting state LC are immature
 Lack CD80 and CD86 expression
 Active in antigen processing – uptake by endocytosis and macropinocytosis
 Relatively poor stimulators of T cells (NB differences in murine and human
systems)
 Maturation
 Stimulated by:
o Bacterial and viral products
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





o Inflammatory cytokines
o Antigens
o UV radiation
o Heat shock protein
 Reduced antigen uptake
 Expression of co-stimulatory molecules
 Up-regulation of HLA-DR
 Down regulation of CD1a
 Migration
Cytokines involved in maturation include
 IL1b
 TNFa
 GM-CSF
 EGF
Cells lose E-cadherin expression
Express CCR7 directing migration towards draining lymph nodes
General:
 Immune surveillance in the skin
 Langerhans cells are central to sensitisation and elicitation phases of
contact allergic dermatitis
 Target for allogeneic skin graft rejection and target in graft verses
host disease
Langerhans cell and Cancer Surveillance
 Langerhans cells are sensitive to UV radiation with dose dependant
reduction in antigen presenting ability
 UV radiation is the major cause of skin cancer
 ? Developmentally, UV suppression of LC function reduces the risk
of autoimmune disease to UV generated neo-antigens in the skin
Contact Dermatitis
 Sensitisation phase:
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o

May take many years of skin contact to establish
sensitisation
o Antigen taken up by LC and taken to paracortical zone of
draining lymph node where it is presented to naïve T cells
 Elicitation phase
o Challenge by antigen results in presentation by LC to
memory T cells and a type 4 response
Graft Versus Host Disease
 Host dendritic cells expressing self proteins involved in maintenance
of tolerance
 Donor naïve T-cells are stimulated to mature by host dendritic cells.
 Donor T-cells mount an immune response against host.
 Cornea does not contain Langerhans cells so can be transplanted to
anyone
Thermoregulation: Dr S Punjabi
-
-
-
-
General:
o Almost all birds and mammals have a high temperature almost constant and
independent of that of the surrounding air. This is called homeothermy.
o Almost all other animals display a variation of body temperature, dependent on
their surroundings. This is called poikilothermy.
Core temperature
o Most body heat is generated in the deep organs( liver, brain, and heart, and in
contraction of skeletal muscles).
o 37°C (98-990 F) is essential for normal function.
o Normal mental functions are dramatically impaired outside the 35-40°C range.
o Skin plays a decisive role as both radiator and insulator.
Peripheral temperature
o The skin assists in homeostasis.
o It does this by reacting differently to hot and cold conditions so that the inner body
temperature remains constant.
o Vasodilation and sweating are the primary modes by which humans attempt to lose
excess body heat.
Variation:
o Temperature variations throughout the day by 1 degree or so peaking in the
afternoon 4pm ish as a result of circadian rhythm. Lowest point is 2nd half of sleep
cycle – nadir.
o Diurnal variation
o Age
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o
o
o
-
-
-
-
External temperature
Exercise
Ovulation
 Within 24 hours of ovulation, women experience an elevation of 0.15 - 0.45
°C (0.2 - 0.9 °F) due to the increased metabolic rate caused by sharply
elevated levels of progesterone.
Thermoreceptors (Heat and cold receptors)
o Anterior Hypothalamus
 -preoptic area
o Deep Organs
 -spinal cord
 -great veins
 -abdominal viscera
o Skin Temperature receptors:
 more cold ones than hot ones.
Hypothalamus – the thermostat
o Hypothalamic centre (preoptic area)
o sensors are set at critical temperatures(set points)
o More finely controlled than the thermoreceptors of the skin.(a fall as small as 0.30C
in the blood reaching the sensors, produces an effect similar to a drop of 100C on
skin).
o Helpful, as we live in environments with wide swings of temperature.
Heat loss:
o Radiation
 60%
o Evaporation
 25%
 Insensible water loss : Skin and lungs (15 calories/hr).
o Conduction
 12%
o Convection
 3%
Role of Skin in Thermoregulation
o If skin temperature is greater than that of the surroundings, the body can lose heat
by radiation and conduction.
o But if the temperature of the surroundings is greater than that of the skin, the body
actually gains heat by radiation and conduction.
o In such conditions, the only means by which the body can rid itself of heat is by
evaporation.
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Feedback loop:
-
Cooling
o Vasodilation
 Blood flow thro the skin is 10 to 20 times greater than that needed for
cutaneous metabolism. Approx 10% of cardiac output flows thro skin under
basal conditions.
o Sweating
 Eccrine sweat glands
 Several million over most skin surface.
 Under neurological control.
 Secretes an ultrafiltrate of plasma like fluid.
 Resorption of sodium by the duct to produce hypotonic sweat.
 Humidity affects thermoregulation by limiting sweat evaporation
and thus heat loss
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o
o
-
Decrease heat production
 inhibition of shivering and chemical thermogenesis.
Behaviour
 move, wear less clothes, drink cold drink
Warming
o (Reduce sweating)
o Vasoconstriction
o Piloerection
 Arrector Pili muscle
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o
o
o
-
Shiver
Chemical Thermogenesis
Behaviour
Determinants of body temperature
o Production of heat by metabolic processes
o Mechanisms for sensing changes (thermoreceptors)
o Mechanisms for control of blood flow through skin (warming or cooling)
o Mechanisms for exporting heat through lungs and skin
o Mechanisms for conserving body heat
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Fever
o
o
A temporary increase in the set point as a result of infection
Pyrogen production
 IL1 production by macrophages
 Prostaglandin production
 Reduced by Aspirin and Paracetamol
Anhidrotic ectodermal dysplasia
o X linked recessive genetic disorder : complete or near complete absence of sweat
glands.
o Hypotrichosis, hypohydrosis and abnormal teeth.
o All heat loss occurs through radiation.
o Evaporative cooling plays no role.
o Overheating and death from exercise.
o Heat loss may be increased by a simple measure.(exogenous spraying of water
frequently)
Hair and nails: Dr A Charakida
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Telogen Effluvium
o Premature termination of anogen  Telogen
o Diffuse Hair Loss
o Regrowth over 3-6 months if pregnancy related
-
Androgenic Alopecia [= male pattern baldness]
o Androgen Sensitive
 • 50% men over 50y
 • >80% men over 70y
 • Polygenic
 • Treat with –5α reductase inhibitors/minoxidil
o Hamilton-Norwood classification
o May occur in women : Ludwig scale
-
Autoimmune Alopecia Areata
o Immune privileged status of anagen hair breaks down
Infection/Inflammation
o Most common pathology of hair follicle
-
GE Y1 Dermatology
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Healing of skin wounds: Fernanda Teixeira
-
Healing: 2 types
o Regeneration
 (labile cells)
o Repair
 formation of fibrotic scar
-
processes:
o Epidermis:
 regenerates
o Dermis:
 repairs: scar will be left
 cleansing of all necrotic tissue
 demolition of the clot
 stimulation of blood vessels
 collagen synthesis
-
Acute inflammation [is necessary for healing]
o Vasodilatation
 (of arterioles)
 histamine
 prostaglandins
 hence NSAIDs give reduced removal of acid from stomach  ulcer
o Increased permeability
 (of post-capillary venules)
 histamine
 leukotrienes
-
Adhesion
o Expression of adhesion molecules
o Mediated by many molecules, including
 PAF (platelets, endothelium, macrophages)
 Leukotrienes
Emigration
o Neutrophils arrive first
o Attracted by chemotactic factors, as products of cell death
o Macrophages arrive later
o EXUDATE
Functions of the exudate
o Demolish dead cells
-
-
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o Demolish inflammatory debris
o Demolish old, damaged collagen
o Stimulate regeneration of epidermis
o Stimulate collagen deposition in the wounded dermis
Macrophagic growth factors
o Factories of growth factors
o Stimulate formation of granulation tissue
o IL-1
o PDGF
o TGF beta
o VEGF
Granulation tissue
o Very vascularised granular tissue
o Fills defect
o Formed by:
 Proliferated capillaries
 Increased intercellular matrix
 Collagen type III
Vascular proliferation
o VEGF
Maturation of granulation tissue
o Progressive decrease in number of capillaries
o Increased deposition of collagen
o Change from collagen III to collagen I
Mediators of epithelial proliferation
o Epidermal growth factor
o Produced in small amounts by normal epithelium
o Larger amounts by epithelium surrounded wound
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Healing by first intention
o Sutured wounds
o Borders approximated
o Smaller scar
Healing by second intention
o Used in infected wounds
o Good for concave areas
o Takes longer
o All healing processes are more voluminous in healing by second intention
Complications of healing
o Diabetes mellitus
 Non-enzymatic glycosylation: adhesion molecules of immune system etc
work less well due to the glycosylation
 Defective margination, phagocytosis
 Poor perfusion due to the microangiopathy
 Tendency for infection due to high sugar in blood
o Keloids
 Scars that are much bigger than the original insult
 Causes poorly understood
 ? TGF beta
o Dehiscence
 Caused by:
 Tension at closure  Poor circulation
 Infection
 Bleeding
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Why do fetuses heal without scarring?
o Sterile amniotic fluid
o Rapid epithelialization
o More HA
o Nonsulfated GAGs
o TGF 3 isoform
o More fibroblast migration
o High proportion PCIII
o No inflammatory effector cell
o Dry contaminated environment
o Slow epithelialization
o Less HA
o Sulfated GAGs
o TGF 1 isoform
o Slower fibroblast migration
o Low proportion PCIII
o Effector: macrophage
Failure of skin functions: F Teixeira
-
Twenty Nail Dystrophy
o Idiopathic nail dystrophy
o Appears in early childhood.
o Excessive ridging, with longitudinal striations and discolouration.
o The nails very slowly return to normality.
o This condition is not seen in adults.
-
Hypohidrotic ectodermal dysplasia
o Hypotrichosis
o Anodontia
o Hypohidrosis
o
o
o
o
Prominent supraorbital ridge
Thin lower face
Hypotrichosis
X-linked recessive or autosomal dominant (2q11-13)
o
o
o
Intermittent hyperpyrexia in infants
Decreased sweating
The mortality rate approaches 30%
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o
-
Recurrent high fever may also lead to seizures and neurological sequelae
(Oculocutaneous) Albinism
o Disruption of melanocyte migration
o Disruption of melanin synthesis (oculo- cutaneous albinism)
o Disruption of melanosome formation
o Disruption of transfer of melanosomes to keratinocytes
o
o
o
Four types, all autosomal recessive
 40% (type 1): mutations in tyrosinase gene
 50% (type 2): mutations in P gene (membrane transport)
 ”yellow albinos”
 Improved with age
Photophobia
White hair and skin [white hair gives reduced sun protection]
-
Vitiligo [dhtk details]
o Mutations in the NALP1 gene (17p13)
o Regulates inflammation and cell death
o NALP 1 expressed in T lymphocytes and Langerhans cells
o Products: Caspases 1 and 5, that activate IL 1- an inflammatory cytokine
-
Toxic epidermal necrolysis
o 95%- drug induced
o Fever, cough, sore throat, malaise
o Red macules- blisters - sheetlike epidemal detachment
o Mucosas first
o Cell-mediated cytotoxic reaction
o Target: epidermal cells
o Dead cells peel off
o Death rate: 30-40%
o Dehydration:
 >50% involvement: 4L
 made worse by g-i involvement
o Protein loss: (blister fluid: 40g/L protein)
o Heat loss
o Increased energy expenditure (200 g protein per day)- IL-1
o Renal tubular necrosis
o Bacterial sepsis: S.aureus, Gram - ; Hypothermia
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Epidemolysis bullosa
o Often get squamous cell carcinoma subsequently
-
Cancer and immunosuppression
o Immune system defends skin against cancer
 Hence if are immunocompromised must not expose self to sun
o CD8 lymphocytes destroy cancer cells, detected by changed surface antigens.
o Azathioprine sensitizes DNA to UVA.
o 6-thioguanine incorporates into the DNA of patient’s skin cells
o UVA transform thioguanine into guanine 6 sulfonate, which is mutagenic
The breakdown for the Support Systems exam is as follows:
30 SBAs
4 EMQs
2 SAQs
Mark Breakdown:
Alimentary – 11 marks
CVS – 17 marks [7 SBAs 1 SAQ]
Renal – 16 marks
Respiratory – 21 marks [1 SAQ…]
Skin - 5 marks
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