Anatomy, Histology and

Physiology of the skin,

mucous membranes
& Keratinization.
Dr. ADIL HAMID HASSAN
BASHIR, MD
DERMATOLOGIST.
orcid-org/0000-0003-4232-3601
researchgate.net
• Skin is the largest organ in human body.
• It has a surface area 1.5-2 m square.
• Weight about 15% of total body weight.
• It measures a body mass 3.6 Kg.
• Skin receives a blood flow 462ml/min.
• Arterio-venous O2 difference 25ml/L.
• O2 consumption 12ml/min.
• It has a resistance 11.7 R units (Absolute).
• The integument is composed of the skin,
which covers the entire body, in addition to
accessory organs derived from skin. The
accessory organs include the nails, hair,
and glands of various kinds.
• The skin is considered the largest organ of
the body and has many different functions.
• Skin serves many important functions:
(1) It is an impervious barrier that excludes harmful
substances and prevents desiccation;
(2) it plays an important role in the regulation of body
temperature;
(3) it readily repairs itself;
(4) it receives sensory stimuli (touch, pressure,
temperature, and pain);
(5) sweat glands excrete waste products;
(6) lacrimal glands produce an isotonic saline bathing
solution for the eyes;
(7) sebaceous and ceruminous glands secrete sebum
and cerumen ("wax"), respectively; and
(8) mammary glands secrete milk.
• The skin is divided into two main regions, the
epidermis, and the dermis, each providing a
distinct role in the overall function of the skin.
The dermis is attached to an underlying
hypodermis, also called subcutaneous
connective tissue, which stores adipose tissue
and is recognized as the superficial fascia of
gross anatomy.
• The epidermis is the most superficial layer of
the skin and provides the first barrier of
protection from the invasion of foreign
substances into the body. The principal cell of
the epidermis is called a keratinocyte.
 Cell kinetics
• Are complicated in the epidermis by the
balance between growth with differentiation and
cell death.
• A major concept is that of turnover time, which
is the amount of time for the whole cell
population to replace itself (regeneration time or
replacement time).
• The cell cycle or intermitotic time (Tc)
represents the interval between two successive
mitoses (M).
 Epidermal differentiation and keratin gene
expression
• The epidermis of the skin is a stratified
squamous epithelium, which plays an important
protective role. It manifests this role by building
an extensive cytoskeletal architecture, the
unique feature of which is the presence of
keratin filaments. There are two major pairs
of keratins in the epidermis: one pair is
expressed in dividing cells and the other
expressed in terminally differentiating cells.
As such, keratins provide useful biochemical
markers to explore the molecular mechanisms
underlying the balance between growth and
differentiation in the epidermis
 Epidermal differentiation and keratin gene
expression.
• Epidermis, a continuously self-renewing and
differentiating organ, produces a protective
stratum corneum that shields us from external
chemical, physical and microbial threats.
Epidermal differentiation is a multi-step process
regulated by influences, some unknown, others
insufficiently explored. Detachment of
keratinocytes from the basement membrane is
one such pro-differentiation stimulus.
 The regulation of epidermal differentiation
• In skin development, several signaling
pathways such as Hedgehog, Wnt and
Transforming Growth Factor- β (TGF-β) have
been implicated.
• Three main classes of transcription factors,
AP1, AP2 and Sp1,appear to be relevant.
• Regulation of the Nuclear transcription Factor
NF-κB also appears to be significant in the
process of terminal differentiation in epidermis.
• Terminal differentiation is also influenced by Retinoids
that act at the mRNA level to inhibit aspects of
differentiation and to promote proliferation.
 Growth stimulatory signals
family
• Epidermal Growth Factor (EGF) Stimulates
cell proliferation and differentiation in a wide
range of tissues.
• TGF-α, Synthesized by epidermal keratinocytes
and stimulates keratinocyte growth.
• interleukin-1 (IL-1), IL-6 and Granulocyte–
Macrophage Colony-Stimulating Factor (GM-
CSF) can also stimulate growth.
• Paracrine factors stimulate keratinocyte
growth.
 Growth inhibitors for keratinocytes
• Epidermal growth is under the influence of a
negative-feedback mechanism.
• TGF-β present in normal cells and malignant
cell lines, stimulates fibroblast growth and
increases fibrosis, but inhibits growth of
keratinocytes.
• Interferon-α (IFN-α) and IFN-γ have cytostatic
effects on keratinocytes.
• Apoptosis programmed cell death.
•
 Differentiation
Terminal differentiation of the epidermis in vivo
• As the epidermal keratinocytes move through
the epidermis after losing their attachment to
the basal lamina, they undergo the complex
process of terminal differentiation to produce
the stratum corneum. stratum spinosum have
lost this ability to divide, and are inevitably
committed to differentiation, stratum corneum
cells (squames or corneocytes) have lost their
nuclei and other recognizable organelles, and
comprise 65% insoluble cysteine-rich,
disulphide cross-linked, fibrous proteins or
keratins.
• keratin filaments aggregate into bundles
through the action of the histidine-rich basic
protein filaggrin is the process of
keratinization, epidermal differentiation
involves the synthesis of a highly insoluble
cornified envelope whose cross-linking is
catalysed by a keratinocyte specific
transglutaminase from a precursor protein
called involucrin, intercellular adhesion
proteins (integrins), cell-matrix adhesion
proteins and blood-group antigens.
Terminal differentiation is also influenced by several other
factors including expression of desmosome proteins and
signaling pathways such as Notch or phosphatidylinositol 3
kinase, extracellular matrix protein 1 (ECM1) , vitamin D
receptors, FGF10, cyclo-oxygenase enzymes, calcium-sensing
receptors, sodium channels and small heat shock protein.
Keratin biochemistry, synthesis and changes in epidermis.
• Simple epithelia are characterized by the keratin pair
K8/K18, and the stratified squamous epithelia by
K5/K14.
• In skin, suprabasal keratins K1/K10 are characteristic
of epidermal differentiation. In the stratum
granulosum, release of filaggrin from the
keratohyalin granules forms macrofibres.
• K19 is expressed in basal keratinocytes of the
hair-follicle bulge region at the site of
pluripotential stem cells. K9 and K2e
expression are site restricted in skin: K9 to
palmoplantar epidermis and K2e to superficial
interfollicular epidermis.
• epidermal hyperproliferation, as in wound
healing and psoriasis, expression of suprabasal
keratins K6/ K16/K17 is rapidly induced
suprabasally, probably due to previous
expression of their mRNAs with
posttranscriptional regulation.
 Hair and nail differentiation
• The pilosebaceous units develop from epidermal down
growths under the influence of specific mesenchymal cell
condensations between the 10th and 14th week estimated
gestational age. They have complex groups of specialized cell
layers with distinctive pathways of differentiation.
• There are four classes of pilosebaceous unit: terminal on the
scalp and beard; apopilosebaceous in axilla and groin; vellus
on the majority of skin; and sebaceous on the chest, back and
face. The dermal papilla is located at the base of the hair follicle
with a rich ECM. Around the papilla are germinative (matrix)
cells that have a very high rate of division, and give rise to
spindle-shaped central cortex cells of the hair fiber, and the
single outer layer of flattened overlapping cuticle cells.
• The epidermis is 0.8 to 1.4 mm in thickness,
devoid of blood vessels but is nourished by
diffusion from capillaries in the underlying dermis
and subdivided into five layers or strata,
the stratum germinativum (SG)-basale,
the stratum spinosum(SS)-Prickle cell layer, the
stratum granulosum (SGR)-granular layer,
the stratum lucidum and the stratum corneum
(SC) in which a keratinocyte gradually migrates to
the surface and is sloughed off in a process called
desquamation.
• The strata basale and spinosum are also referred
to as the Malpighian layer.
• Three additional cell types are found in the
epidermis: (1) melanocytes, (2) Langerhans cells,
and (3) Merkel's cells.
 Stratum germinativum, basale,
Malpighian.
• The stratum germinatum (SG) provides the
germinal (proliferative) cells necessary for the
regeneration of the layers of the epidermis,
constitute a single layer of columnar or cuboidal
cells in contact with the basement membrane
and connective tissue of the dermis. After a
mitotic division a newly formed cell will undergo
a progressive maturation called keratinization
(differentiation) as it migrates to the surface.
 Stratum Spinosum, prickle cell
layer.
• The cells that divide in the stratum
germinativum soon begin to differentiate
into polyhedral cells, accumulate many
desmosomes on their outer surface which
provide the characteristic “prickles” of the
stratum spinosum (SS), which is often
called the prickle-cell layer.
 Stratum granulosum

• The stratum granulosum is composed of a layer

of three to five cells in thick skin and 2-3 in thin
skin that contains keratohyalin granules of
irregular shape that stain with basic dyes,
contain lipids, which along with the desmosomal
connections help to form a waterproof barrier
(lipid barrier) that functions to prevent fluid loss
from the body (Trans-epidermal water loss).
• The progressive maturation of a keratinocyte is
characterized by the accumulation of keratin,
called keratinization.
 Keratohyalin granules
• highly distinctive cellular inclusions in
differentiating epidermis forming the
characteristic granules of the stratum
granulosum. found in other cornifying epithelia,
such as palate and gingiva, but not in non-
cornified squamous epithelia. Filaggrin is
derived from a high-molecular-weight precursor
profilaggrin, which is insoluble, cannot
aggregate filaments and is highly
phosphorylated. The degradation of filaggrin
produces amino acids that help to retain
stratum corneum water.
 Stratum Lucidum

• The stratum lucidum consists of a tightly packed

layer of cells without nuclei containing a
refractile substance called eleidin. This layer is
strongly eosinophilic.
• Epidermis varies in thickness throughout the
body depending mainly on frictional forces and
is thickest on the palms of the hands and soles
of the feet. The stratum lucidum is normally only
well seen in thick epidermis and represents a
transition from the stratum granulosum to the
stratum corneum, and act as an immunological
layer.
 Stratum corneum

• The most superficial layer, the stratum corneum, is

composed of many dead cells without nuclei, which are
filled with keratin. As a cell accumulates keratinohyalin
granules, it is thought that rupture of lysosomal
membranes release lysosomal enzymes that eventually
cause cell death. The dead and dying cells filled with
mature keratin form the stratum corneum (SC)-fully
differentiated cell (corneocyte). The deeper cells of
the stratum corneum retain their desmosomal junctions,
but as they are pushed to the surface by newly forming
cells of the stratum germinativum (SG), the dead cells
gradually break apart and are lost, a process called
desquamation.
 The cornified envelope
• highly insoluble by the formation of glutamyl-
lysysl isodipeptide bonds between envelope
proteins, catalysed by transglutaminases.
• There are three distinct transglutaminases:
• TG1 (keratinocyte
transglutaminase),Involucrin
The dermo epidermal junction
• One of the largest epithelial-mesenchymal junctions in
the body. It forms extensive interface between the
dermis and epidermis.
• Have a key role in a wide range of epithelial
mesenchymal interactions including:
*Epidermal cell anchorage, adhesion, migration and
differentiation. Signaling between the extracellular matrix
and basal cells, and serves as a barrier and filter.
Basement membranes allow migrating cells to
pass under physiological conditions, but act as
barriers against tumor cell invasion and regulate
the passage of molecules based on their
electronic charge and molecular size.
It encompasses:
• The basal plasma membrane of keratinocytes.
Melanocytes, Merkel’s cells and
Hemidesmosomes.
Immediately beneath:
• Basement Membrane Zone (BMZ), 0.5-1.0mm-
thick, which consists of three layers:
• Lamina Lucida, Lamina Densa, and Sub Lamina
Densa (fibroreticularis).
• Lamina densa is observable as an
electron-dense layer.
• lamina lucida is proposed to be an artifact
resulting from rapid dehydration during tissue
processing.
• The skin BMZ can be divided into four
ultrastructurally distinct areas: the
hemidesmosome/upper lamina lucida, the lower
lamina lucida, the lamina densa, and the sub-
lamina densa. Well-characterized BMZ
components include the hemidesmosome/upper
lamina lucida-located bullous pemphigoid
antigens (BP230 and BP180), a6b4 integrin, and
plectin; the lower lamina lucida-located laminin-1,
laminin-5 (previously named kalinin, epiligrin,
nicein, BM600), laminin-6 (previously named k-
laminin), p105, and entactin/nidogen; the lamina
densa-located type IV collagen and perlecan; and
the sub-lamina densa-located type VII collagen
(epidermolysis bullosa acquisita antigen).
Mucosal BMZ also contain identical components
as skin BMZ.
• basement membranes, consists of a number of
collagenous and non-collagenous
macromolecules.
• Type IV collagen is the main structural
constituent of the basement membrane-
immunolocalized mainly to the lamina densa.
• The type IV collagen molecule is able to
interact with laminin, nidogen, heparan sulphate
proteoglycan (PG), BM-40/SPARC and β1
integrin. Immunolabelling of normal human skin
with an antitype IV collagen antibody.
• Type VII collagen was recognized that crystallites of
SLS collagen were similar to anchoring fibrils.
• The laminins an α chain, β chain, and γ chain.
laminins 1, 2, 5, 6 and 10 are known to occur in
epidermal basement membrane.
• Nidogen key stabilizer of basement membrane,
binding to type IV collagen, perlecan and
fibulins.
• Perlecan is the main PG of basement
membranes, binds to Nidogen, dystroglycan
and ECM1. Its functions include stabilization of
basement membrane and regulating basement
membrane synthesis and turnover.
 The hemidesmosome - anchoring filament-
anchoring fibril adhesion complex
• Hemidesmosomes are thought to form a
continuous link between the intracellular keratin
filament network and the extracellular
basement membrane.
• hemidesmosomes are important not only in
adhesion but also as a pathway for signal
transduction between the extracellular and
intracellular compartments.
• Major intracellular (plaque) components of the
hemidesmosome include the 230 kDa bullous
pemphigoid antigen (BP230 or BPAG1) and
plectin.
• basement membrane synthesis and turnover through
binding cytokines and growth factors. The major
component involved in adhesion between basal cells
and ECM.
• The α6β4 integrin and the 180-kDa bullous
pemphigoid antigen (BP180, BPAG2 or collagen type
XVII) are both transmembrane components of
hemidesmosomes.
• The anchoring filament associated proteins include
laminin 5, laminin 6, the extracellular segment of type
XVII collagen, the linear IgA antigen, LAD-1 (which
constitutes part of the extracellular domain of type
XVII collagen and the as yet unknown antigen
recognized by 19-DEJ-1 monoclonal antibody .
• Laminin 5 (previously known as nicein, kalinin
or epiligrin)
 Dermis (corium)

• The dermis (D), 0.3 to 4.0 mm in thickness, assumes the

important functions of thermoregulation and supports the
vascular network to supply the avascular epidermis with
nutrients. The dermis is typically subdivided into two
zones, a papillary dermis includes the ridges and
papillae and a reticular layer. The dermis contains
mostly fibroblasts which are responsible for secreting
collagen, elastin and ground substance that give the
support and elasticity of the skin. Also present are
immune cells that are involved in defense against foreign
invaders passing through the epidermis.
 Papillary dermis

• The papillary layer includes the ridges and papillae,

which protrude between the epidermal pegs. The
papillae contain tactile corpuscles of Meissner's and
small blood vessels. The papillary dermis (PD) contains
vascular networks that have two important functions. The
first being to support the avascular epidermis with vital
nutrients and secondly to provide a network for
thermoregulation. The vasculature is organized so that
by increasing or decreasing blood flow, heat can either
be conserved or dissipated. The vasculature
interdigitates in areas called dermal papillae (DP). The
papillary dermis also contains the free sensory nerve
endings and structures called Meissner’s corpuscles in
highly sensitive areas.
 Reticular dermis

• The reticular layer of the dermis (RD) consists of

dense irregular connective tissue, which differs
from the papillary layer (PD), which is made up,
of mainly loose connective tissue (note the
difference in the number of cells). The reticular
layer of the dermis is important in giving the skin
it overall strength and elasticity, as well as
housing other important epithelial derived
structures such as glands and hair follicles.
Subcutaneous Layer (Panniculus
Adiposus)
• This layer, not part of the skin, is also called
superficial fascia and is a loose network of
connective tissue bundles and septa, which
blend indistinctly with the dermis. This
arrangement of the connective tissue of the
superficial fascia allows the movement of skin
except on the palm of the hand and sole of the
foot, where the skin is firmly anchored to deeper
structures. In most places, particularly the
abdominal wall, lobules of fat may be abundant;
the layer may then also be called the panniculus
adiposus.
 Skin Appendages
• The skin contains a variety of
appendages, mainly hair follicles (HF),
sweat glands , and sebaceous glands
(SG), which are all embrylogically
epidermal in origin.
• In most parts of the body, such as
abdominal skin, the keratin layer is thin. Thick
keratin is most prominent on the soles and
palms. In this abdominal skin, the basal layer of
epidermal cells has faint pigmentation, and the
basement membrane can be seen beneath the
basal layer. The difference between the thin,
outer papillary dermis and the broader, deeper
reticular dermis is subtle. A granular layer with
prominent keratohyaline granules is often not
distinct in normal skin, except where keratin is
present in large amounts.
• Melanocytes appear
within the basal layer as cells with clear cytoplas
m.
They exist in a ratio of 1-to-10 with the basal
keratinocytes, i.e., one melanocyte for every ten
basal cells (every 6). In the above diagrams, the
melanocytes are shown in light blue (for clarity);
under normal circumstances they are not
pigmented. Although melanocytes do produce
the brown pigment, melanin, they transfer it to
neighboring epidermal cells and do not normally
store it in visible amounts.
Histopathological keys
• Histopathological examination of a skin
biopsy taken from an appropriate lesion is
a great help in assisting the clinician to
come to a correct diagnosis, and therefore
come to a decision regarding management
of the patient.
1. Acanthosis:
Increase in number of cells in the Malpighian or prickle cell
layer of the epidermis.
Features may be seen:
-Naevoid conditions.
-Virally induced papillomas.
-Chronic inflammatory conditions, for example Chronic
eczema, psoriasis.
- Pemphigus, Darier's disease.
-Malignant melanoma, Paget’s disease, Mycosis Fungoids
and Histiocytosis X.
*Pseudoacanthosis; increase thickness of the epidermis
due to enlarged keratinocytes.
*Pseudoepitheliomatous hyperplasia; reactive epidermal
proliferation
2. Acantholysis is the term used to describe loss of
cohesion between keratinocytes, due to breakdown of
intercellular bridges.
• Primary acantholysis:
• Pemphigus and its variants.
• Darier's disease.
• Transient and persistent acantholytic dermatosis.
• Warty dyskeratoma.
• Secondary acantholysis:
• Benign familial Pemphigus (Hailey-Hailey disease).
• Bullous impetigo.
• Viral disorders.
• Solar keratoses.
• Squamous cell carcinoma (some forms).
3. Dyskeratosis
• This term relates to some abnormality in
the process of epidermal cell
keratinization.
The process occurs in two main contexts:
• Firstly, in malignant and premalignant
epithelial lesions, such as
• Squamous cell carcinoma,
• Bowen's disease and
• Solar keratosis.
• Secondly, in various forms of acantholytic disorder such as
• Darier's disease.
In this condition, specific types of dyskeratotic cell include corps ronds
and grains.
• Benign familial Pemphigus (Hailey-Hailey disease).
• Transient and persistent acantholytic dermatosis.
• Warty dyskeratoma.
• Solitary dyskeratoma.
• Acantholytic dyskeratotic epidermal naevus
• (Grover’s disease)- focal Acantholytic dyskeratosis.
• Porokeratosis of Mantoux.
• Condylamata accuminata of uterine cervix.
• Chronic radiodermatitis.
• Graft Versus Host disease.
• Necrolytic migratory erythema with carcinoma of pancreas.
• Familial dyskeratotic comedones.
• Hereditary benign intraepidermal dyskeratosis
• (Witkop- Von Sallman syndrome)- focal Acantholytic dyskeratosis.
4. Grenz zone:
A zone of normal dermis between the epidermis and
pathological changes deeper in the dermis. This
comes from the German word for border.
• Lepromatous leprosy.
• Leukocytoclastic vasculitis.
• Early stage 1ry CTCL.
• Histiocytosis; Fat- storing hamartoma of dermal
dendrocytes.
• Melanocytic Naevi and Malignant Melanoma.
5. Hypergranulosis:
Increase in thickness of the granular layer of
the epidermis.
-Chronic lichenification, and lichen planus
(commonly).
6. Hyperkeratosis:
Increased thickness of the stratum corneum.
-Keratodermas.
-Icthyotic disorders.
-Chronic Discoid Lupus Erythematosus.
- Kyrle’s disease.
• 7. Necrolysis:
The separation of tissue constituents as a
consequence on cell death.
Epidermal changes of Necrolysis are seen in
various inflammatory reactions such as:
• Erythema multiforme, EM,
• Toxic epidermal Necrolysis, TEN and
• Necrolytic migratory erythema seen in
association with the glucagonoma
syndrome.
8. Papillomatosis:
Elongation upwards of the dermal papillae,
giving an accentuated and sometimes
irregular, undulating configuration to the
dermo-epidermal junction.
The feature is commonly seen in:
*Viral warts (Verrucae).
*Pemphigus vegetans.
9. Parakeratosis:
The retention of keratinocyte nuclei within the horny
cell layer,
it represents a:
• Disturbance of keratinization, and
• Is normally associated with an absence or
reduction in thickness of the granular cell layer.
• Closely associated either with:
* Increased epidermal cell turnover or
* with inflammatory changes in the epidermis itself.
It is commonly seen in:
-An earlier disturbance in the underlying
epidermis such as:
• Psoriasis,
• Subacute eczematous reactions, and
• Pityriasis lichenoides.
• -Dysplastic epithelial changes, such as:
*Actinic keratoses and
* Bowen's disease.
• 10. Spongiosis ( Intercellular edema):
-Widening of the intercellular spaces between
keratinocytes due to fluid accumulation.
*Acute and Subacute eczema (characteristically).
(1) Langerhans cells in the epidermis
(2)    Lymphocytes in the epidermis
(3)    Spongiosis
(4)    Hyperkeratosis & parakeratosis
(5)    Elongated rete ridges
(6)    Lymphocytes surrounding dermal vessels