1 - SKIN: BASIC STRUCTURE AND FUNCTION Flashcards
Skin is composed of three layers:
the epidermis, dermis, and subcutaneous fat (panniculus)
The outermost layer, the epidermis, is composed of viable keratinocytes covered by a layer of keratin, the stratum corneum. The principal component of the dermis is the fibrillar structural protein collagen. The dermis lies on the panniculus, which is composed of lobules of lipocytes separated by collagenous septa that contain the neurovascular bundles.
The epidermis is thickest where? What is the measurement?
Palms and soles
1.5 mm
The dermis is thickest where? what is the measurement?
Back
30 - 40x as thick as the overlying epidermis
During the first weeks of life, the fetus is covered by a layer of nonkeratinizing cuboidal cells called the
Periderm
The adult epidermis is composed of three basic cell types:
Keratnocytes, melanocytes and langerhans cells
An additional cell, the ______\_ , can be found in the basal layer of the palms and soles, oral and genital mucosa, nail bed, and follicular infundibula.
Merkel cells
Merkel cells contain intracytoplasmic dense-core neurosecretorylike granules and, through their association with neurites, act as slow-adapting touch receptors. They have direct connections with adjacent keratinocytes by ________ and contain a paranuclear whorl of intermediate keratin filaments.
Desmosomes
Both polyclonal keratin immunostains and monoclonal immunostaining for keratin 20 stain this whorl of keratin filaments in a characteristic _______
Paranuclear dot pattern
Merkel cells also label for neuroendocrine markers such as
Chromogranin and synaptophysin
_______ are of ectodermal origin and have the specialized function of producing keratin, a complex filamentous protein that not only forms the surface coat (stratum corneum) of the epidermis but also is the structural protein of hair and nails.
Keratinocytes
Mutations in the genes for _____ are associated with epidermolysis bullosa simplex
Keratins 5 and 14
mutations are associated with epidermolytic hyperkeratosis.
Keratin 1 and 10
The epidermis can be divided into ____
- the innermost basal layer (stratum germinativum),
- the malpighian or prickle layer (stratum spinosum),
- the granular layer (stratum granulosum),
- the horny layer (stratum corneum)
- On the palms and soles, a pale clear to pink layer, the stratum lucidum, is noted just above the granular layer
When the skin in other sites is scratched or rubbed, the _____ thicken, a _______ forms, and the ______ becomes thick and compact.
malpighian and granular layers thicken
stratum lucidum forms
stratum corneum becomes thick and compact.
regulate epidermal differentiation
Histones
suppresses expression of profilaggrin
Histone deacetylation
Sites rich in stem cells include
deepest portions of the rete, especially on palmoplantar skin, as well as the hair bulge
Stem cells divide infrequently in normal skin, but in cell culture they form active, growing colonies. They can be identified by their high expression of
Ξ²1-integrins and lack of terminal differentiation markers
Stem cells can also be identified by their low levels of
desmosomal proteins, such as desmoglein 3
Abnormal keratinization can manifest as
- parakeratosis (retained nuclei),
- as corps ronds (round, clear to pink, abnormally keratinized cells), or
- as grains (elongated, basophilic, abnormally keratinized cells).
During keratinization, the keratinocyte first passes through a what phases on its way to becoming a horn cell.
synthetic and then a degradative phase
Identify the phase of keratinization.
within its cytoplasm the keratinocyte accumulates intermediate filaments composed of a fibrous protein, keratin, arranged in an Ξ±-helical coiled pattern. These tonofilaments are fashioned into bundles, which converge on and terminate at the plasma membrane, where they end in specialized attachment plates called desmosomes.
synthetic phase
characterized by the disappearance of cell organelles and the consolidation of all contents into a mixture of filaments and amorphous cell envelopes.
degradative phase of keratinization
programmed process of maturation resulting in death of the cell
terminal differentiation
Terminal differentiation is also seen in the involuting stage of keratoacanthomas, where the initial phase of proliferation gives way to terminal keratinization and involution.
Degradation of the mitochondrial network within keratinocytes occurs with ____
aging
Oxidation injury to keratinocytes occurs with environmental exposure and thermal burns, and can be partially prevented by ______
vitamin C in the form of L-ascorbic acid
appears in hematoxylin and eosin (H&E)βstained sections as scattered brightred cells, some of which may contain small, black pyknotic nuclei. These cells are present at various levels of the epidermis, because this form of cell death does not represent part of the normal process of maturation.
Premature programmed cell death, or apoptosis
Widespread apoptosis is noted in the
verrucous phase of incontinentia pigmenti.
It is also a prominent finding in catagen hairs, where apoptosis results in the involution of the inferior segment of the hair follicle.
appear in the intercellular space (separates plasma membranes of adjacent cells), primarily at the interface between the granular and cornified cell layers.
Lamellar granules (Odland bodies or membrane-coating granules)
Lamellar granules contribute to skin cohesion and impermeability.
Conditions such as ______ and ______demonstrate abnormal lamellar granules.
lamellar ichthyosis and Flegel hyperkeratosis
contribute a water-barrier function to skin and are typically found in topical products meant to restore the epidermal barrier.
Glycolipids such as ceramides
Lamellar bodies form abnormally in the absence of
critical ceramides such as glucosylceramide, or there is disproportion of critical lipids.
Desmosomal adhesion depends on
cadherins, including the calcium-dependent desmogleins and desmocollins.
Antibodies to these molecules result in immunobullous diseases, but desmogleins function not only in adhesion but also in differentiation. The binding of the desmoglein 1 cytoplasmic tail to the scaffoldingprotein Erbin downregulates the Ras-Raf pathway to promote stratification and differentiation of keratinocytes in the epidermis.
Keratinocytes of the granular zone contain, in addition to the keratin filament system, keratohyaline granules, composed of amorphous particulate material of high
ulfur-protein content.
This material is a precursor to filaggrin, so named because it is thought to be responsible for keratin filament aggregation
profilaggrin
Conversion to filaggrin takes place in the ______, and this forms the electron-dense interfilamentous protein matrix of mature epidermal keratin.
granular layer
a serine protease secreted from lamellar granules, appears to function in profilaggrin cleavage
Kallikrein-related peptidase 5
hygroscopic, and repeated cycles of hydration and dehydration contribute to normal desquamation of the stratum corneum.
Keratohyalin
characterized by a diminished or absent granular layer, contributing to the retention hyperkeratosis noted in this disorder.
Ichthyosis vulgaris
results in the formation of soft, flexible keratin.
Keratohyalin
Keratin that forms in the absence of k tohyaline granules is typically
hard and rigid.
Hair fibers and nails are composed of hard keratin.
______ secrete a wide array of cytokines and inflammatory mediators, including tumor necrosis factorβalpha (TNF-Ξ±). They also can express molecules on their surface, such as ntercellular adhesion molecule 1 (ICAM-1) and major histocompatibility complex (MHC) class II molecules, suggesting that keratinocytes actively respond to immune effector signals.
Keratinocytes
During wound healing, epithelial cell migration occurs before dermal remodeling. Tight junction proteins _____ and _____ are critical for effective migration.
claudin-1 and occludin
Downregulation of claudin-1 expression results in
delayed migration and reduced epithelial proliferation.
downregulation impairs wound healing when cells are also subjected to mechanical stress
occludin
Wound healing occurs best in a _____ environment but can be impaired by excessive maceration.
moist
Melanocytes are derived from
neural crest
Melanocytes can be found as early as what AOG within the fetal epidermis?
8th week
In normal, sun protected trunk epidermis, melanocytes reside in the basal layer at a frequency of
about 1 in every 10 basal keratinocytes
in heavily sun-damaged facial skin, Mart-1 immunostaining can demonstrate ratios of melanocytes to basal keratinocytes that approach
1 : 1
Recognition of the variation in melanocyte/keratinocyte ratio is critical in the interpretation of biopsies of suspected lentigo maligna (malignant melanoma in situ) on sun-damaged skin.
What determine differences in skin color?
the number, size, and distribution of the melanosomes or pigment granules within keratinocytes.
Racial differences in skin color are not caused by differences in the number of melanocytes
Chronic sun exposure can stimulate melanocytes to produce ______, thereby making the distribution of melanosomes within keratinocytes resemble the pattern seen in dark-skinned individuals.
larger melanosomes
Pale skin has fewer melanosomes, and these are smaller and packaged within membranebound complexes. Dark skin has more melanosomes, and these tend to be larger and singly dispersed.
How does melanocyte appear in histologic sections of skin routinely stained by H&E?
cell with ample amphophilic cytoplasm or as a clear cell in the basal layer of the epidermis.
The apparent halo is an artifact formed during fixation of the specimen. This occurs because the melanocyte, lacking tonofilaments, cannot form desmosomal attachments with keratinocytes.
Keratinocytes also frequently demonstrate clear spaces but can be differentiated from melanocytes because they
demonstrate cell-cell junctions and a layer of cytoplasm peripheral to the clear space.
The melanocyte is a dendritic cell. Its dendrites extend for long distances within the epidermis, and any one melanocyte is therefore in contact with a great number of keratinocytes; together they form the so-called
epidermal melanin unit
Melanosomes are synthesized in the Golgi zone of the cell and pass through a series of stages in which the enzyme ______ acts on melanin precursors to produce the densely pigmented granules.
tyrosinase
Melanocytes in red-haired individuals tend to be rounder and to produce more
pheomelanin
important in the regulation of melanin production
melanocortin 1 receptor (MC1R)
Loss-of-function mutations in the MC1R gene bring about a change from
eumelanin to pheomelanin production
whereas activating gene mutations can enhance eumelanin synthesis.
Eumelanin production is optimal at what pH
6.8
changes in cellular pH also result in alterations of melanin production and the eumelanin/pheomelanin ratio.
AKA whitening of the skin
leukoderma
In vitiligo, the affected skin becomes white because of
destruction of melanocytes.
differentiate vitiligo from albinism
In vitiligo, the affected skin becomes white because of destruction of melanocytes.
In albinism, the number of melanocytes is normal, but they are unable to synthesize fully pigmented melanosomes because of defects in the enzymatic formation of melanin.
results from a localized increase in production of pigment by a near-normal number of melanocytes.
freckle
demonstrate basilar hyperpigmentation and prominent melanin within the stratum corneum.
Black βsunburnβ or βink spotβ lentigines
benign proliferations of melanocytes
Nevi
malignant proliferations of melanocytes.
Melanomas
Langerhans cells are normally found scattered among keratinocytes of the
stratum spinosum.
The highest density of Langerhans cells in the oral mucosa occurs in the ______, and the lowest density is in the ________, suggesting he latter is a relatively immunologically βprivilegedβ site.
vestibular region (highest)
sublingual region (lowest)
At the light microscopic level, Langerhans cells are difficult to detect in routinely stained sections. However, they appear as dendritic cells in sections impregnated with _______, a stain specific for Langerhans cells.
gold chloride
They can also be stained with CD1Ξ± or S-100 immunostains.
Ultrastructurally, langerhans cells are characterized by a folded nucleus and distinct intracytoplasmic organelles called
Birbeck granules
In their fully developed form, the organelles are rod shaped with a vacuole at one end, resembling a tennis racquet. The vacuole is an artifact of processing.
The junction of the epidermis and dermis is formed by the
basement membrane zone (BMZ).
basement membrane zone (BMZ) is composed of 4 elements namely,
- the plasma membranes of the basal cells with the specialized attachment plates (hemidesmosomes);
- an electronlucent zone called the lamina lucida;
- the lamina densa (basal lamina);
- and the fibrous components associated with the basal lamina, including anchoring fibrils, dermal microfibrils, and collagen fibers.
What type of collagen is the major component of the basal lamina
Type IV collagen
What type of collagen is the major component of anchoring fibrils.
Type VII collagen
The two major hemidesmosomal proteins are
BP230 (bullous pemphigoid antigen 1) and BP180 (bullous pemphigoid antigen 2, type XVII collagen)
What constitute the skin adnexa
Eccrine and apocrine glands, ducts, and pilosebaceous units
Embryologically, they originate as downgrowths from the epidermis and are therefore ectodermal in origin.
Abnormalities in this pathway contribute to the formation of pilar tumors and basal cell carcinoma.
Hedgehog signaling
In the absence of hedgehog signaling, embryonic hair germs may develop instead into modified sweat gland or mammary epithelium.
The intraepidermal spiral duct, which opens directly onto the skin surface, is called the
acrosyringium
It is derived from dermal duct cells through mitosis and upward migration. The acrosyringium is composed of small polygonal cells with a central round nucleus surrounded by ample pink cytoplasm
What are the 2 types of the secretory cells of the sweat glands?
- large, pale, glycogen-rich cells and
- smaller, darker-staining cells.
Type of secretory cells of the sweat glands which are thought to initiate the formation of sweat.
pale glycogen-rich cells
Type of secretory cells of the sweat glands which may function similar to cells of the dermal duct, which actively reabsorb sodium, thereby modifying sweat from a basically isotonic to a hypotonic solution by the time it reaches the skin surface.
smaller, darker-staining cells.
develop as outgrowths not of the surface epidermis, but of the infundibular or upper portion of the hair follicle.
Apocrine units
What makes apocrine sweat odoriferous?
Apocrine sweat is odorless until it reaches the skin surface, where it is altered by bacteria, which makes it odoriferous.
Where are apocrine units found?
Although occasionally found in an ectopic location, apocrine units of the human body are generally confined to the following sites: axillae, areolae, anogenital region, external auditory canal (ceruminous glands), and eyelids (glands of Moll).
Along one side of the fetal follicle, what are the two buds formed?
- an upper bud develops into the sebaceous gland, and a
- lower bud becomes the attachment for the arrector pili muscle.
A third epithelial bud develops from the opposite side of the follicle above the level of the sebaceous gland anlage and gives rise to the apocrine gland.
The uppermost portion of the follicle, which extends from its surface opening to the entrance of the sebaceous duct, is called
infundibular segment
It resembles the surface epidermis and its keratinocytes may be of epidermal origin
The portion of the follicle between the sebaceous duct and the insertion of the arrector pili muscle
isthmus
The actual hair shaft, as well as an inner and an outer root sheath, is produced by
matrix portion of the hair bulb
The sheaths and contained hair form concentric cylindrical layers. The hair shaft and inner root sheath move together as the hair grows upward until the fully keratinized, inner root sheath sheds at the level of the isthmus. The epidermis of the upper part of the follicular canal is contiguous with the outer root sheath. The upper two portions of the follicle (infundibulum and isthmus) are permanent; the inferior segment is completely replaced with each new cycle of hair growth.
Active growth phase of the hair.
This phase lasts for how many years?
Anagen phase
3 - 5 years
Normally, about 85%β90% of all scalp hairs are in the anagen phase, a figure that decreases with age and decreases faster in individuals with male-pattern baldness (as length of anagen decreases dramatically). Scalp anagen hairs grow at a rate of about 0.37 mm/day.
Involution phase of the hair.
This lasts for how long?
Catagen phase
2 weeks
Resting phase of the hair.
This lasts for how long?
Telogen Phase
3 - 5 months
Shorter or longer
Most sites on the body have a much ______ anagen and much _____ telogen, resulting in shor hairs that stay in place for long periods without growing longer.
much shorter anagen and much longer telogen
Each hair follicle undergoes intermittent stages of activity and quiescence. Synchronous termination of anagen or telogen results in _____
telogen effluvium
Most commonly, telogen effluvium is the result of early release from anagen, such as that induced by a febrile illness, surgery, or weight loss.
Explain the pathophysiology of effluvium in pregnancy.
Pregnancy is typically accompanied by retention of an increased number of scalp hairs in anagen, as well as a prolongation of telogen. Soon after delivery, telogen loss can be detected as abnormally prolonged telogen hairs are released. At the same time, abnormally prolonged anagen hairs are converted synchronously to telogen. Between 3 and 5 months later, a more profound effluvium is noted.
Why do patients receiving chemotherapy often have hair loss?
Patients receiving chemotherapy often have hair loss because the drugs interfere with the mitotic activity of the hair matrix, leading to the formation of a tapered fracture. Only anagen hairs are affected, leaving a sparse coat of telogen hairs on the scalp As the matrix recovers, anagen hairs resume growth without having to cycle through catagen and telogen.
The growing anagen hair is characterized by
pigmented bulb and an inner root sheath
Histologically, catagen hairs are best identified by
presence of many apoptotic cells in the outer root sheath.
Describe telogen club hairs
Telogen club hairs have a nonpigmented bulb with a shaggy lower border.
The presence of bright-red trichilemmal keratin bordering the club hair results in a flamethrower-like appearance in vertical H&E sections. As the new anagen hair grows, the old telogen hair is shed.
Hair shape is at least partially controlled by what gene
trichohyalin gene
Hair color depends on what?
degree of melanization and d tion of melanosomes within the hair shaft.
Melanocytes of the hair bulb synthesize melanosomes and transfer them to the keratinocytes of the bulb matrix. Larger melanosomes are found in the hair of black persons; smaller melanosomes, which are aggregated within membrane-bound complexes, are found in the hair of white persons. Red hair is characterized by spherical melanosomes. Graying of hair results from a decreased number of melanocytes, which produces fewer melanosomes.
What causes the normal graying of the hair?
Repetitive oxidative stress causes apoptosis of hair follicle melanocytes, resulting in normal hair graying.
Premature graying is related to exhaustion of the melanocyte stem cell pool.
formed embryologically as an outgrowth from the upper portion of the hair follicle
Sebaceous glands
They are composed of lobules of pale-staining cells with abundant lipid droplets in their cytoplasm. At the periphery of the lobules, basaloid germinative cells are noted. These cells give rise to the lipid-filled pale cells, which are continuously being extruded through the short sebaceous duct into the infundibular portion of the hair follicle.
sebaceous glands are not found in?
Palms and soles
Sebaceous glands are always associated with hair follicles, except at what following sites?
- tarsal plate of the eyelids (meibomian glands),
- buccal mucosa and vermilion border of the lip (Fordyce spots),
- prepuce and mucosa lateral to the penile frenulum (Tyson glands),
- labia minora, and
- female areola (Montgomery tubercles).
Fingernails grow an average of ___ mm/day, requiring about ____ months to replace a complete nail plate.
0.1 mm/day
4β6 months
The growth rate is much slower for toenails, with _____ months required to replace the great toenail
12β18 months
Brittle nails demonstrate what in electron microscopy?
Brittle nails demonstrate widening of the intercellular space between nail keratinocytes on electron microscopy.
The nail cuticle is formed by what?
keratinocytes of the proximal nailfold
The nail plate is formed by what
matrix keratinocytes
Endogenous pigments of the nail tend to follow the contour of the _____ (distal portion of matrix), whereas exogenous pigments tend to follow the contour of the _____.
lunula
cuticle
The dorsal nail plate is formed by what?
proximal matrix
the ventral nail plate is formed by what
distal matrix with some contribution from the nail bed.
The location of a melanocytic lesion within the matrix can be assessed by what
the presence of pigment within the dorsal or ventral nail plate.
The constituents of the dermis are ____ in origin except
mesodermal
nerves, which, as with melanocytes, derive from the neural crest.
give rise to dermatofibromas, angiofibromas, acquired digital fibrokeratomas, pleomorphic fibromas, and fibrous papules
Factor XIIIaβpositive dermal dendrocytes
principal component of the dermis
collagen
Collagen serves as the major structural protein for the entire body; it is found in tendons, ligaments, and the lining of bones, as well as in the dermis. Collagen represents 70% of the dry weight of skin.
synthesizes the procollagen molecule, a helical arrangement of specific polypeptide chains that are subsequently secreted by the cell and assembled into collagen fibrils
fibroblast
Collagen is rich in what amino acids
hydroxyproline, hydroxylysine, and glycine
major collagen component of the dermis.
Type I collagen
Collagen fibers are loosely arranged where?
papillary and adventitial (periadnexal) dermis.
What type of collagen is the major structural component of anchoring fibrils and is produced predominantly by _______
Type VII collagen
keratinocytes
Abnormalities in type VII collagen are seen in what disoerder
dystrophic epidermolysis bullosa
autoantibodies to Type VII collagen characterize what disease
acquired epidermolysis bullosa
Collagen fibers are continuously being degraded by proteolytic enzymes called _________ and replaced by newly synthesized fibers
βspare collagenasesβ
What amino acids are unique to elastic fibers
desmosine and isodesmosine
term generally used to refer to a clinically heterogeneous group of autoimmune diseases, including lupus erythematosus, scleroderma, and dermatomyositis
Connective tissue disease
Where are capillaries and postcapillary venule found in the skin?
The dermal vasculature consists principally of two intercommunicating plexuses. The subpapillary plexus, or upper horizontal network, contains the postcapillary venules and courses at the junction of the papillary and reticular dermis (Fig. 1.7). This plexus furnishes a rich supply of capillaries, end arterioles, and venules to the dermal papillae.
Smooth muscle occurs in the skin as what
arrectores pilorum (erectors of the hairs), as the tunica dartos (or dartos) of the scrotum, and in the areolas around the nipples
The arrectores pilorum are attached to the _____ below the sebaceous glands and, in contracting, pull the hair follicle upward, producing gooseflesh.
hair follicles
Striated (voluntary) muscle occurs in the skin of the neck as the platysma muscle and in the skin of the face as the muscles of expression. This complex network of striated muscle, fascia, and aponeuroses is known as
superficial muscular aponeurotic system (SMAS).
Mast cell granules stain metachromatically with _____ and ____ (in Giemsa stain) because of their h gh content of heparin.
toluidine blue and methylene blue
They also contain histamine, neutrophil chemotactic factor, eosinophil chemotactic factor of anaphylaxis, tryptase, kininogenase, and Ξ²-glucosaminidase. Slow-reacting substance of anaphylaxis (leukotrienes C4 and D4), leukotriene B4, plateletactivating factor, and prostaglandin D2 are formed only after IgE-mediated release of granules.
What disorder is characterized by mast cells accumulate in skin because of abnormal proliferation, migration, and failure of apoptosis
mastocytosis
Give some endocrine functions of the panniculus or subcutaneous tissue.
It is an important site of hormone conversion, such as that of androstenedione into estrone by aromatase. Leptin, a hormone produced in lipocytes, regulates body weight through the hypothalamus and influences how we react to flavors in food.
