Anatomy and Physiology of the skin Flashcards
What are the 4 main types of cell junctions in the skin?
Desmosomes/hemidesmosomes, adherens junctions, tight junctions, gap junctions
What do desmosomes attach to connect cells?
They anchor/attach to keratins
What proteins make up the desmosomes and which ones are cytoplasmic and which ones are transmembrane?
Cytoplasmic: desmoplakin, plakophilin, plakoglobin
Transmembrane: desmocollin 1/2/3, and desmoglein 1/3
What do adherens junctions attach/secure to?
Actin filaments
What ion is required for desmocollin, desmoglein and other cadherins need to function?
Calcium
What proteins make up the adherens junction? Which are cytoplasmic and which are transmembrane?
Cytoplasmic: alpha-catenin, beta-catenin, plakoglobin
Transmembrane: Cadherins (E and P)
What protein make up tight junctions?
Claudins and occludins
In what layers are tight junctions and what is their purpose?
They are a tight seal against water LOSS and they are in the granular cell layer
What are the gap junctions made up of?
Connexons (6 connexons make up a junction)
What keratins are produced in the basal layer?
5/14
What enzyme is upregulated in the epidermis during states of proliferation and what medication inhibits it?
Ornithine decarboxylase is expressed more during hyperproliferative states.
-It is inhibited by corticosteroids, retinoids, and vitamin D3
Why are multiple pilomatrixomas associated with myotonic muscular dystrophy, Rubenstein-Taybi, and gardner syndrome?
Pilomatricomas are associated with disruptions in beta-catenin signaling, these are all associated with issues in beta-catenin.
Note also associated with sarcoid and turner syndrome
What is the transit time from the basal layer to the stratum corneum? What about to complete sluffing/desquamation?
14 days for the basal layer to stratum corneum, 14 days in the stratum corner, so 28 days from basal layer to desquamation
What types of keratins are produced in the stratum spinosum?
Keratins 1/10
What causes the terminal keratinocyte differentiation in the stratum spinosum and where does this occur?
Increased intracellular calcium in the suprabasal epidermis
What are Odland bodies and where are they produced?
These are lamellar granules w/ lysoome-like properties that are made in the spinous layer
What is the primary component of Odland bodies?
Ceramide (which is the most important lipid in barrier function)
-Also contain glycoproteins, glycolipids, and phospholipids
What are Odlund bodies in terms of organelles and where do they exert their effect?
Specialized lysosomes, their action is exerted in the stratum corneum
-Products are released in the junction between the stratum granulosum and statum corneum
What do ceramides help form?
The cornified cell envelope –> replaces the cell membrane eventually
What two diseases are caused by decreased lamellar granules?
Flegel’s disease and Harlequin ichthyosis
What are contained within the keratohyalin granules in the granule cell layer?
Profilaggrin, loricrin, keratin intermediate filaments, and involucrin
In what layer does the production of the cornified cell envelope mostly take place?
In the granular cell layer
What is the most abundant component of the cornified cell envelope?
Loricrin
What are the first early components of the cornified cell envelope and where do they form?
Envoplakin, periplakin and involucrin create scaffolding along the inner cell membrane (the inner cell membrane ultimately get’s replaced by ceramides from lamellar granules)
What is the function of loricrin in the cornified cell envelope?
It cross-links and reinforces the cornified cell envelope. It first appears in the granular cell layer
What enzyme actually performs the cross-linking of loricrin?
Transglutaminase-1 and it performs this cross-linking via gamma-glutamyl lysine isopeptide bonds
What makes up the outer layer of the cornified cell envelope?
The outer surface of the cornified envelope is made of lipids (primarily ceramide)
What is the most abundant amino acid in collagen?
Glycine
What is the pattern of amino acids in collagen?
Overall you get 3 chains of amino acids in a triple helix
-The overall structure is Glycine -AAx-AAy-Glycine. So glycine appears at every third spot, the other ones vary depending on the type of collagen
What is the most prevalent collagen in adult skin?
Collagen I, 80% of total collagen in adult dermis
What is the most prevalent collagen in fetal skin?
Collagen III, This makes up 10% of the collagen in the skin for adults. It is also present in the Gi-tract, heart, and blood vessels
What is the main purpose of collagen IV?
This is the primary collagen in the lamina densa anchoring plaque. These interact with collagen I/III in the dermis.
What is the primary role of Type VII collagen?
These are anchoring fibers, these help anchor the lamina densa plaque made up of type IV collagen to the type I and III collagen in the dermis
What is the role of type XVII collagen?
BPAG-2 –>transmembrane protein in the basement membrane zone that connects the hemidesmosome to the lamina densa with the help of laminin 332
What is the stratum corner molecularly?
Mostly made of protein-rich corneocytes which have no nuclei; keratin filaments, attached to cornified envelope and are embedded in a lipid “mortar” that holds everything together
What are the differences between type I and type II keratins?
Type I: acidic, low MW, K9-28, 31-40, from chromosome 17
Type II: basic, high MW, K1-8, 81-86 (hair), come from chromosome 12
What is the functional unit of keratin?
Keratins are made up of heterodimers between type I and type II keratins and then form tetramers and ultimately filaments
What connects keratin to the plasma membrane?
Desmosomes
What signaling is required for melanocyte development and migration?
c-kit
What types of melanoma are associated with mutations in c-kit?
Acral and mucosal melanoma
What is the ratio of melanocytes to keratinocytes along the stratum basale in the 2D plane?
1:10 ratio
How many keratinocytes does one melanocyte interface with?
36
Where is melanin produced?
In the melanosome (lysosome-type organelles)
What element is required for melanin production?
Copper, melanin is made from tyrosine via a multistep process involving tyrosinase (copper-dependent enzyme)
What are the two end product types of melanin and what types of melanosomes produce them?
Pheomelanin (yellow/red) is made by round melanosomes and eumelanin (black/brown) is made by elliptical melanosomes
What are the differences in melanin which drive skin types?
There are no differences in melanocyte density across skin types. There are differences in melanosomes
-Melanosomes in darker skin people: larger, darker (have increased melanin), more stable, and are transferred individually
-Melanosomes in lighter skin types are smaller, lighter, less table, and clustered
What stimulates the production of melanin?
Melanocyte-stimulating hormone (MSH) and ACTH act on MC1-R on melanocytes
What is the phenotype of MC1-R mutations?
It increases the Pheomelanin:eumelanin ratio which leads to red hair/fair skin and increased risk of melanoma phenotype
What are the differences seen with melanin in early versus chronic tanning?
Immediate tanning is from the oxidation of existing melanin, and then delayed tanning requires new melanin synthesis
What results from mutations to the tyrosinase enzyme?
Oculocutaneous albinism
What are the two major types of cadherins in the skin?
There are two major groups:
- Classic (e/p/n)
- Desmosomal: desmoglein/desmocollin
These are all calcium-dependent
What molecules mediates the interaction between keratinocytes and Langerhans cells?
E-cadherin
What are the major immunohistochemical stains for Langerhans cells?
CD207 (langerin; most sensitive, specific for Birbeck granules); CD1a, S100, CD34, vimentin, and actin
What is the significance of CD34 staining in Langerhan’s cells?
This is a transmembrane glycoprotein which marks progenitor cells from the bone marrow like other monocytes/macrophages
Where are Langerhans cells mostly located?
Stratum spinosum
What happens to Langerhans cells after UV exposure?
They are downregulated in the skin after UV exposure so you get decreased immune surveillance
Where are Merkel cells located?
Slow-reacting mechanoreceptors located on the fingertips, lips, oral cavity, and hair follicle ORS
What skin layer are the Merkel cells found?
Stratum basale
What immunohistochemical stains are + in Merkel cells?
CK20 in a perinuclear dot pattern, and also + for neurofilaments, S100, synaptophysin, chromogranin A, vasoactive intestinal peptide, neuron-specific enolase, and calcitonin gene-related peptide
What components make up the hemidesmosome on the basal cell layer and what connects these to the dermis?
Keratin intermediate filaments (5/14) attach to plectin and BPAG1 (BP230) –>BPAG-2 and Alpha-6 Beta-4 integrin subunits attach to the type IV collagen of the lamina densa via the laminin 332 –>the type VII collagen connect the laminin 332 and type IV collagen of the lamina densa to the type I/III collagen in the dermis
What components make up the lamina lucida?
the transmembrane components of BPAG-2, alpha6beta4, and the extracellular component of laminin 332
What is the weakest part of the hemidesmosome?
The lamina lucida, this is where things get cleaved by salt-split skin and suction blisters
What are glomus cells and where are they located?
smooth muscle cells, they are derived from Sucquet-Hoyer canals. these are involved in shunting blood flow from arterioles to venules (bypassing capillaries)
-Located on the palms and soles mostly
What cells produce the extracellular matrix?
Fibroblasts
What are dermal dendritic cells?
Bone marrow-derived APC that resides in the dermis and is highly phagocytic
What is the extracellular matrix mostly made up of?
Collagens, elastins, fibrillins, fibulins, integrins, laminins, glycoproteins, and proteoglycans
What are the 3 main amino acids aside from glycine (most common) used in collagen?
Proline, hydroxyproline and hydroxylysine are common
What collagen is involved in new scars and keloids?
More type III collagen in scars and keloids
What enzyme is involved in cross-linking collagen and what vitamin is required?
Lysyl hydroxylase and proline hydroxylase catalyzes crosslinking of collagen
-Dependent on vitamin C
What effect do retinoids have on collagen?
Increases production
What signaling does elastic fibers modulate?
TGF-B and BMP
What proteins make up elastic fibers?
90% elastins and 10% fibrillan (surrounds the elastins).
What amino acids are most prominent in elastic fibers?
Desmosine and isodesmosine (these crosslink w/ fibrillin via lysyl oxidase, copper-dependent)
What enzyme catalyzes the crosslinking of elastic fibers and what element is required?
Lysyl oxidase (copper necessary for function)
What are the different fibers in the reticular dermis versus the DEJ in the papillary dermis?
Elaunin fibers run horizontally/parallel in the reticular dermis and the oxytalan fibers run up and down in the papillary dermis (“stand [=vertical] up-high [high in dermis] with OXYgen (OXYtalan))
What are the most important glycosaminoglycans in the dermis?
Hyaluronic acid, chondroitin sulfate, dermatan sulfate, and heparan sulfate
What breaks down GAG’s in the dermis?
lysosomal hydrolases
What are the two vascular plexuses in the skin?
Superficial (goes to vessels of the reticular dermis) and deep (goes to follicles and glands)
What is the primary mediator of vasculogenesis?
VEGF
What are the main histologic markers of lymphatic vessels?
Prox1, Podoplanin (D2-40), LYVE-1 and VEGFR-3
What are Krause end bulbs and where are they located?
Specialized corpuscular nerve endings on the genitals, perianal region, and vermillion lips
Where are Pacinian corpuscles located?
Deep dermis/fat, mechanoreceptor most concentrated on the palmoplantar skin, nipples, and genitals region
What is the mechanoreceptor most concentrated around fingernails?
Ruffini corpuscle (deep/fat). Slow adapting and senses sustained pressure
What components in the skin are under adrenergic control?
Vascular smooth muscle, apocrine glands and arrector pili contraction
What things are under cholinergic control in the skin?
Eccrine glands
What type of glands are eccrine glands?
Exocrine glands
Where do you not have eccrine glands?
external auditory canal, lips, glans penis, clitoris, and labia minora
Where do you have the highest concentration of sweat glands?
Palms and soles
What controls the eccrine glands and what type of signaling occur?
Controlled by the hypothalamus; innervated by postganglionic sympathetic fiber, which synapses with muscarinic acetylcholine receptors on the glands
What type of secretion do eccrine glands undergo?
Merocrine
What immunohistological stains are used for eccrine glands?
S100, keratin, CEA
Where are apocrine glands located?
anogenital skin, axillae, external ear canal, vermillion border, periumbilical region, eyelid margin, and breast
What is the secretory control of apocrine glands?
Glands are noninnervated, do have beta-adrenergic receptors (stimulated from circulating catecholamines)
What are the main components of the apocrine secretions?
Decapitation secretion: made up of cholesterol and cholesterol esters, triglycerides, squalene and fatty acids
What is lipofuscin?
Pigmented mixture of lipids and proteins –> responsible for the bromhidrosis (yellow-brown)
Where are the modified apocrine glands located that secrete onto the skin surface directly?
mammary glands on the breast, ceruminous glands on the external auditory canal, and Moll’s glands on the eyelids
What areas have the most sebaceous glands?
Scalp, face, and upper anterior trunk
What things stimulate the maturation and secretion of sebaceous glands?
Pubertal androgens are the primary stimulus. Also, MSH, CRH, and substance P
What type of secretion occurs in sebaceous glands?
Holocrine secretion
What are the primary components of sebaceous gland secretions?
Triglycerides (#1, 50%), wax esters, squalene, >>choleserol, antimicrobial peptides, androgens and cytokines
Where are ectopic sebaceous glands located?
Meibomian glands on eyelid tarsal plate, Fordyce spots (vermillion lip/oral mucosa), Montgomery tubercles (areolae/nipples). Tysons glands (labia minora/prepuce), and zeis glands (eyelid margin, close to Moll’s gland)
What are the 3 types of hair?
Lanugo (fine hairs shed late in gestation), vellus (fine hairs over face, trunk, and extremities early in life), terminal (coarse, darker hairs of scalp, eyebrows, and eyelashes; post-pubertal androgens induce the switch to terminal)
Which hair colors have the highest density of hair follicles and which hair types have the least?
Blonde hairs tend to be the highest density and red hair tends to be the lowest
What are the follicular layers of the hair from outer to inner?
Glassy membrane, outer root sheath, inner root sheath (Henle’s layer, Huxley’s layer, and cuticle), and hair shaft (cuticle, cortex, and medulla)
Damage to what structure in the hair follicle leads to split ends?
The cuticle –> trichoptilosis (split-ends)
What is the dermal papilla?
Mesenchymal structure (from embryonic mesoderm), contains vasculature and contributes to the hair cycle regulation
What are the boundaries of the infundibulum of the hair follicle?
Opening of the skin down to where the sebaceous gland inserts
What are the boundaries of the isthmus of the hair follicle?
Region located between the opening of the sebaceous gland, down to the site of insertion of the arrector pili muscle
What type of cornification does the outer root sheet of the infundibulum have?
The outer root sheath shows similar morphology to the interfollicular epidermis (contains keratohyaline granules)
What type of cornification does the outer root sheath of the isthmus have?
Tricholemmal keratinization (No inner root sheath, this is shed before this point)
What are the boundaries of the lower hair follicle?
insertion of the arrector pili muscle down, this encapsulates the dermal papilla, has inner and outer root sheaths
What is the critical line of auber and where is it located?
This is the widest area of the lower root sheath, below this point is where all the mitotic activity is, above it there is no more mitotic activity
What is the function of the follicular dermal papilla?
Onion-shaped, fibroblast collection that has inductive and morphogenic properties. The volume of the dermal papilla determines the size of the hair bulb and thus hair shaft diameter.
What color does the inner root sheath stane and why?
Stains red and it is due to the presence of citrulline
Where is the inner root sheath located and what hairs is it not present in?
Not present in telogen hairs and it is only present below the isthmus (lower hair follicle)
Where are the pigment-producing cells located in the hair follicle?
Melanin producing cells are located up and around the upper one-third of the dermal papilla; they transfer melanosomes to the differentiating hair follicle keratinocytes in the precortical matrix. These go into apoptosis during each catagen phase and are regenerated from melanocyte stem cells in hair germ during anagen
What are the primary microflora of the pilosebaceous unit?
- Acroinfundibulum = pityrosporum ovale
- Mid infundibulum: s. epidermitis
- deep in the follicle: propaniobacterium
What is the exogen phase of hair growth?
The phase of active shedding of club hair between telogen and anagen (most people lose about 100 hairs/day)
What is the growth phase of hair and how long does it last?
Anagen: growth is 0.4mm per day or 1cm/month, lasts 2-6 years
What percentage of the scalp’s hairs are in anagen?
85-90%
At what stage does regression occur, what is regressing and how long does it occur?
Catagen: melanocytes in matrix apoptose; inner root sheath is lost in prep for telogen, lasts 2-3 weeks
What percentage of the hairs of the scalp are in catagen?
1-2%
What is the resting phase called and how long does it last?
Telogen, lasts 3 months
What percentage of the hairs on the scalp are in telogen?
10-15%
What is the ratio of melanocytes to keratinocytes in the hair unit?
1:5
it is key to note that pigment is only produced in the anagen phase
What determines how curly hair is?
The number of disulfide bonds via cysteine residues
when hair is straightened the goal is to break these bonds
