INTRODUCTION:
The skin has a surface area of 2 sq.meter.
It accounts for 16-20% of the total body weight.
It is the largest organ of the body
It is composed of epidermis, dermis and the subcutaneous tissue (the hypodermis).
Full thickness skin is 1.5- 4mm.
Human skin is of 2 types --------- nonhairy (glabrous skin) and hairy skin.
The glabrous skin is marked by a series of ridges ad grooves with a configuration unique to each individual
------- known as dermatoglyphics.
THE EPIDERMIS:
It is made of stratified squamous epithelium.
It gives rise to derivative structures ( pilosebaceous units, nails and sweat glands) called appendages.
It is approximately 0.4-1.5 mm in thickness.
The keratinocytes and are organized into 4 layers
IMMIGRANT CELLS OF THE EPIDERMIS: They are melanocytes, langerhans cells, and merkel cells. Other cells
like the lymphocytes are extremely rare in normal skin.
The epidermis rests on and is attached to a basal lamina that saperates the epidermis and dermis
KERATINOCYTE: It is an ectodermally derived cell that constitutes 80% of the epidermis. All keratinocytes have
cytoplasmic keratin intermediate filaments and desmosomes.
Keratin filaments: They are a hallmark of keratinocytes and other epithelial cells. They are the cytoskeleton.
More than 30 different keratins are present ------- 20 epithelial and 10 hair keratins, all within the range of 40-
70kDa. The keratins are saperated into acidic (type I; cytokeratins K10 to K20) and basic to neutral (type II;
cytokeratins K1 to K9). Keratins are “obligate hetero polymers” meaning that a member of each family (acidic
and basic) must be coexpressed for a filament structure.
The end point of keratinization is a terminally differentiated, dead keratinocyte (corneocyte) that contains keratin
filaments, matrix proteins and protein reinforced plasma membrane with surface associated lipids.
BASAL LAYER
• Consists of 1-2 layers of cells.
• Contains mitotically active, columnar shaped keratinocytes.
• It has a large nucleus and organelles
• The K5 and K14 pair of keratins are expressed in the basal layer of the epidermis and other stratifying
epithelia.
• Other keratins like K15 and K19 are present in putative stem cells.
• Microfilaments and microtubules are other cytoskeletal elements present in basal cells.
• Some microfilaments maintain important links with the external environment via their association with
integrin receptors of the cell surface. Integrins are a large family of cell surface molecules involved in
cell- cell and cell – matrix interactions and INITIATION OF TERMINAL DIFFERENTIATION.
• Not all basal cells display equal proliferative properties. Based on cell kinetics, 3 populations coexist in
this layer ---- stem cells, transient amplifying cells and postmitotic cells.
• Stem cells are present in the bulge region of the hair follicle and also in the basal layer. These cells
happen to be clonogenic, progress rapidly through the S phase of the cell cycle and divide infrequently
during stable self renewal. However, under conditions requiring rapid proliferative activity ( wound
healing) or after exposure to exogenous growth factors ------- THE STEM CELLS UNDERGO RAPID
MULTIPLE CELL DIVISIONS.
• Transient amplifying cells are a subset of daughter cells produced by the stem cells. These transient
amplifying cells are NEEDED FOR STABLE SELF RENEWAL AND ARE THE MOST COMMON CELL TYPE OF
THE BASAL LAYER.
• The postmitotic cells arise from the TAC after they undergo several cell divisions. It is the post mitotic
cells that undergo terminal differentiation, detaching from the basal lamina and migrating superficially.
• Cell divisions in stratum corneum occur every 18-19 days.
• The normal transit time of a basal cell, from the time it detaches from the basal lamina to the time it
reaches the stratum corneum is at least 14 days. Transit through the stratum corneum and
desquamation require another 14 days.
SPINOUS LAYER
• It contains 8-10 layers of cells
• They are named for the spine like appearance of the cell margins in histologic sections. The spines are
the abundant desmosomes, calcium dependant cell surface modifications that promote adhesion of
epidermal cells and resistance to mechanical stresses.
• CELLS OF STRATUM SPINOSUM:
Polyhedral with a
Rounded nucleus
Cells of the upper spinous layers are larger; more flattened and contain organelles called
lamellar granules.
• KERATIN PAIRS IN STRATUM SPINOSUM: Keratin filaments are present as usual. K5, K14 of the
basal cells are present but in addition a new pair K1/K10 also occurs in the spinous layers. This new
pair is characteristic of epidermal pattern of differentiation and thus referred to as differentiation or
keratinization specific keratins.
• In hyperproliferative states ( psoriasis, actinic keratoses), the sprabasal keratiocytes switch to an
alternative pathway of differentiation in which the synthesis of K1/K10 is down regulated and K6/K16 is
favored. Correlated with this change in keratin expression is a loss of normal phenotypic differentiation
in granular and cornified cell layer.
• DESMOSOMES: Within each cell is a desmosomal plaque associated with the internal surface of the
plasma membrane and is composed of 6 polypeptides ------- PLAKOGLOBIN, DESMOPLAKIN I & II,
KERATOCALMIN, DESMOYOKIN AND BAND 6 PROTEIN (plakophillin). Transmembrane glycoprotein of the
cadherin family provide the adhesive properties on the external surface or core of the desmosome.
These glycoproteins are ----- desmogleins 1 &3 and desmocollin I & II. The extracellular domains of
these proteins form part of the core. The intracellular domains insert into the plaque, linking then to
the KIF.
• GAP JUNCTIONS: gap junctions between keratinocytes are the sites of physiologic communication.
Gap junctions are more abundant in more differentiated keratinocytes. Communications with these
junctions are important in the regulation of cell metabolism, growth and differentiation.
• LAMELLAR GRANULES:
Deliver precursors of stratum corneum lipids into the intercellular space.
The granules are first evident in the cytoplasm of the upper statum spinosum.
Their primary site of action is the granular – cornified layer interface.
They are 0.2-0.3 micrometer in diameter, membrane bound, secretory organelles that contain
a series of alternating thick and thin lamellae.
They contain GLYCOPROTEINS, GLYCOLIPIDS, PHOSPHOLIPIDS, FREE STEROLS AND A NUMBER
OF ACID HYDROLASES INCLUDING LIPASES, PROTEASES, ACID PHOSPHATASE AND
GLYCOSIDASES. GLUCOSYLCERAMIDES, the precursors to ceramide and the dominant
component of the stratum corneum lipids, are found in the lamellar granules.
• Roles of lamellar granule in providing the epidermal lipids responsible for the barrier properties of the
stratum corneum, synthesis and storage of cholesterol and adhesion/ desquamation of cornified cells
have been hypothesized.
GRANULAR LAYER
• This layer consists of 2-5 cell layers
• KERATOHYALIN GRANULES: This is so called because of the presence of intracellular BASOPHILIC
keratohyaline granules. KERATOHYALIN GRANULES are composed primarily of an electron dense
protein, profillagrin. Loricin, a protein of the cornified cell envelope is also found in the granules.
• Profillagrin is a high molecular mass histidine rich phosphorylated intermediate filament associated
protein . it is made up of tandem repeats of filaggrin monomers joined by small linker peptides.
• Conversion of profilaggrin precursor to filaggrin subunits occurs stepwise during the transition of
granular cell to cornified cell by proteolysis and by dephosphorylation. Final proteolysis to free amino
acids occurs in the outer layers of the stratum corneum. This is important for the regulation of
epidermal osmolarity and flexibility.
• The function of filaggrin: In the stratum corneum it is thought to serve as a matrix protein and
promotes the aggregation and disulfide bonding of the KIF.
• Proteins of the CORNIFIED ENVELOPE constitute a significant fraction of protein in the granular cells
and are rendered insoluble by cross linking via disulfide bonds formed by TRANSGLUTAMINASES. The
components of CE are -------
Involucrin ------- it is an insoluble, cysteine rich protein, first synthesized in the cytoplasm of
spinous cells. It becomes cross linked by transglutaminases in the granular layer into an
insoluble cell boundary that is resistant to denaturing and reducing chemicals.
Keratolinin
Loricin ---- it is a highly insoluble, sulfer- and glycine/serine rich protein . it is a later
differentiation product and is the major CE protein comparising 75% of the total CE protein
mass. The cytoplasmic surface of the CE is composed primarily of loricin.
Small proline rich proteins ( cornifin, SPR 1 & SPR-2)
Serine proteinase inhibitor elafin
Filaggrin linker segment peptide.
Envoplakin --- links CE to the desmosomes and KF.
• Although the envelope precursors are first synthesized in the spinous and/or granular layers where
they can be recognized biochemically and immunohistochemically, the CE is evident morphologically
only in cornified cells.
• The calcium requiring transglutaminases are present in all stratified squamous epithelia and in hair
follicles. There are 3 transglutaminases in the epidermis.
TGase 1 (keratinocyte TGase) : Exists as membrane bound activated forms responsible for
most of the activity in differentiating keratinocytes. Some activity is present in the basal cells
but the enzyme activity is especially prevalent in the granular layer of the epidermis.
Mutations occur in lamellar ichthyosis.
TGase 2 is present in the fetal epidermis and in the basal layer of the adult. It appears to play
a role in apoptosis. It is similar to tissue transglutaminase. It is an autoantigen reacting in DH.
TGase 3 ( epidermal TGase) is expressed after early differentiation marker ( K1 & K10 ) and is
coincident with loricin and filaggrin.
• ACTION OF LAMELLAR GRANULES STARTS IN THE GRANULAR CORNEAL INTERFACE: The lamellar
granules act in the interface between the granular and cornified cell layers. In this position they
aggregate into clusters, fuse with the plasma membrane and release their contents into the
intercellular space. The extruded material is stacked into discs, similar to the internal organization of
the granule, and is rearranged in various stages, leading to the formation of sheets. The hydrolytic
enzymes are released with the lipids and are involved in the reorganization and the subsequent
assembly into intercellular lamellae. Thus the probarrier lipids (glycolipids, free sterols and
phospholipids) are converted to barrier lipids ( eg. sphingolipids that create a seal at the interface of
the stratum granulosum and stratum corneum.
• SELF DESTRUCTION OF CELLULAR ORGANELLES IN THIS LAYER: The granular layer also plays a role in
its own programmed destruction . the change involves the loss of nucleus and virtually all cell
components with the exception of the KERATIN FILAMENTS AND FILAGGRIN MATRIX. DNAase, RNAase,
acid hydrolases, esterases, phosphatases, proteases and plasminogen activator are implicated in the
destruction .
STRATUM CORNEUM
• This layer is composed of 20-25 layers of cells
• The stratum corneum barrier is formed by a two compartment system
• The flattened polyhedral horny cell is the largest cell of the epidermis. They contain keratins and
fillagrin.
• High molecular mass keratins stabilized by intermolecular disulfide bonds account for upto 80% of the
cornified cell.
• The remainder of the cell contains electron dense matrix material, probably filaggrin surrounding the
filaments.
• INTERCELLULAR LIPIDS: The lipid enrichment results from the deposition of lamellar body contents.
Three key lipid types ----- cholesterol, ceramides and FFA ---- form the lipid bilayers.
• Changes in the structure, composition and function of cornified cells accompany their movement
towards the outer surface of the skin. Cells of the lower SC , sometimes called the stratum
compactum, are thicker and have more densely packed organized parallel arrays of KF, a more fragile
cornified CE and modified desmosomes. They have less capacity for water binding than the mid and
upper regions. The outer SC cells called the stratum disjunctum are more prone to desquamation.
Cells in the mid SC have the highest concentration of free AA and therefore are able to bind water with
greater efficacy. The CE becomes rigid. The desmosomes undergo proteolytic degradation ------
shedding.
• LOST BARRIER: Lipid extraction and metabolic imbalances such as FA deficiency perturb the barrier
function as well as resulting in epidermal hyperproliferation, scaling and inflammation.
• MORPHOLOGY: Langerhans cells are pale staining with a convoluted nucleus. The cytoplasm of the
Langerhans cells as seen by EM contains dispersed VIMENTIN INTERMEDIATE FILAMENTS AND SMALL
ROD OR RACKET SHAPED STRUCTURES CALLED LANGERHANS CELL GRANULES OR BIRBECK
GRANULES. It is a cup shaped disc which forms when membrane bound antigen is internalized by
endocytosis. Phagolysosomes are common in the cytoplasm of the Langerhans cells
• DISTRIBUTION IN THE SKIN: They are distributed in the basal, spinous and granular layers showing
preference for suprabasal position
• BONE MARROW DERIVED: They migrate from the bone marrow to the circulation into the epidermis
early in embryonic development and continue to repopulate the epidermis throughout life.
• ANTIGEN PRESENTING CELLS OF THE SKIN: They are antigen processing and presenting cells that are
involved in a variety of T cell responses.
• They are implicated in the pathologic mechanisms underlying ALLERGIC CONTACT DERMATITIS,
CUTANEOUS LEISHMANIASIS AND HIV INFECTION.
• They are reduced in the epidermis of patients with certain skin diseases like psoriasis, sarcoidosis.
• OTHER AREAS WHERE LANGERHANS CELLS ARE FOUND: It is found in the other squamous epithelia
including the oral cavity, esophagus, and vagina and also in lymphoid organs such as the spleen,
thymus and lymph nodes. It is also present in the dermis.
The dermis varies in thickness from 1mm in the eyelids to 5 mm on the back. The dermis forms the main bulk
of the skin.
It consists of
• A supporting matrix,
• Several protein fibres like the collagen, elastin and
• A number of cells like the fibroblasts, macrophages and mast cells.
• Vessels,
• Lymphatics and
• Sensory and motor nerve endings.
The superficial one tenth part of the dermis is called the papillary dermis and the lower nine tenth part is
called the reticular dermis. The papillary dermis and the periadnexal dermis together are also called the
adventitial dermis. Unlike the epidermis no differentiation occurs in the dermis but the matrix and the
connective tissue undergo restructuring and remodeling in response to external stimuli.
The dermis
• Provides pliability, elasticity and tensile strength.
• It protects the body from mechanical injury,
• Binds water,
• Aids in thermal regulation and
• Includes receptors of sensory stimuli.
• The dermis interacts with the epidermis in maintaining the properties of both the tissue and
collaborates during morphogenesis of the DEJ and epidermal appendages (teeth, pilosebaceous units
and sweat glands) and interacts in the repairing and remodeling the skin as wounds are healed.
The dermis is organized into papillary and reticular dermis; the distinction of the two zones is based largely on
their difference in connective tissue organization, cell density, and nerve and vascular patterns.
Mast cells originate in the bone marrow from CD34+ stem cells. Differentiation towards mast
cells occurs in the tissues under the influence of other cells and ECM matrix.
Like basophils they contain metachromatic granules and have IgE antibodies on their surface.
Differentiation towards mast cells occurs in the tissues under the influence of other cells and
ECM matrix.
Mast cells produce many mediators. Some of them are preformed and stored ----
• Histamine,
• Heparin,
• Tryptase,
• Chymase,
• Carboxypeptidase,
• Neutrophillic cationic factor and
• Eosinophilic cationic factor.
The mast cells synthesize and release other substance without storage -------
• Growth factors,
• Cytokines ( IL-1,3,4,5,GM-CSF,TNF-α),
• Leukotreins and
• PAFs.
• Lysosomal granules ----- Acid hydrolases that degrade GAGs, PGs, and complex glycolipids
intracellularly. These take part in the repair process and degradation of foreign material.
The Dermal Dendrocyte:
It is a stellate, dendritic or sometimes spindle shaped
It is a highly phagocytic cell in the dermis of the normal skin.
They are APCs.
They originate in the bone marrow.
They are particularly abundant in the papillary dermis and upper reticular dermis frequently in
the proximity of vessels of the subpapillary plexus.
Dermal dendrocytes are also present around the vessels in the reticular dermis and in the
subcutaneous tissue.
Sympathetic autonomic fibres: Sympathetic fibres are codistributed with the sensory nerves in
the dermis until they branch to innervate the sweat glands, vascular smooth muscle, the
arrector pili muscle of the hair follicles and the sebaceous glands.
The skin is innervated by the large myelinated cutaneous branches of the musculocutaneous nerves that
arise segmentally from the spinal nerves. Small branches that enter the deep dermis are surrounded by the
epineural sheath. Perineural sheath cover the fibre bundles and endoneural sheath cover individual fibres
respectively.
The pattern of nerve fibres of the skin is similar to the vascular pattern.
The sensory nerves, in general, supply the skin segmentally (dermatomes), but the boundaries are imprecise
and there is overlapping innervation to any given area. Autonomic innervation does not follow exactly the
same pattern because the post ganglionic fibres distributed in the skin originate in the sympathetic chain
ganglia where pre ganglionic fibres of several spinal nerves synapse.