1
Q
What are the three main structural layers of the skin and the general characteristic of each?
A
- Stratum Corneum (the dead keratinaceaous protective layer and main interface with outside world, often considered part of epidermis)
- Epidermis (main role is to replace SC)
- Dermis (the thickest structural layer composed mostly of collagen and elastin)
2
Q
Describe the dermal-epidermal junction.
A
- Separates the dermis and epidermis
- Contains hemidesmosomes, and anchoring fibrils that attach dermis to epidermis
3
Q
What are the two parts of the dermis?
A
Papillary
Reticular
4
Q
What are Type I and III collagen and where is each found?
A
- fibrous collagen
- Type I is thick/dense and makes up 80-85% collagen in dermis (mostly in reticular layer)
- Type III is thin and delicate, makes up the papillary layer, and helps attach dermis to epidermis
5
Q
What are the main characteristics of the epidermis?
A
- contains living epidermal layer and SC
- keratinocyte is main living cell
- morphologically divided into 5 layers
- main function is to replenish the SC
6
Q
What are the 5 layers of the epidermis? (and their other names)
A
From base upwards:
- Basal Cell Layer/Stratum Basale/Stratum Germinativum
- Prickle Layer/Stratum Spinosum/Malphigian Layer
- Granular Layer/Stratum Granulosum
- Clear Layer/Stratum Lucidum
- Horny Layer/Stratum Corneum
7
Q
What are the 4 specialized cells in the epidermis and their functions?
A
- keratinocytes(living cells)
- melanocytes (synthesize melanin/pigment)
- Langherhans cells (immune protection)
- Merkel Cells - sensory role
8
Q
What are the characteristics of the melanocytes?
A
- large, round cells with finger-like projections (dendrites) that reach out to keratinocytes
- found in the basal layer
- produce dark pigment granules (melanosomes) containing melanin that releases into kertinocyte and clusters around the nucleus
9
Q
What 3 factors influence the color of skin?
A
- melanocytes (melanin)
- hemoglobin
- carotenes
10
Q
What are the characteristics of the Merkel Cells?
A
- located in basal layer
- play a role in mechanical sensation
11
Q
Keratinocyte defects lead to… (4 things)
A
- abnormal growth/death
- flaking
- erythema
- thickening or skin
12
Q
What is the cell cycle/transit time of the keratinocytes?
A
- Stratum Corneum = 14 days
- Epidermis/SC = 28 days
- Psoriatic epidermal = 5 days
13
Q
What is keratinocyte proliferation and differentiation?
A
- Process by which keratinocytes multiply and divide.
- Regulated growth and death
- Process by which skin produces the superficial barrier to protect this organ
14
Q
What are the characteristics of the stratum basal?
A
- mitotically active keratinocytes
- orginate from a distinct number of stem cells that adhere to basement membrane
- only layer that has capacity for DNA synthesis
15
Q
What are the characteristics of the stratum spinosum?
A
- keratinocytes begin process of differentiation
- Lamellar granules become present (contain lipid precursors like loricrin and involucrin that later becomes part of cornified envelope in granular layer)
16
Q
How do cells in the stratum spinosum get their prickly shape?
A
- Cells in this layer are cuboidal, many-sided, or flattened keratinocytes containing bundles of filaments (tonofiliment bundles/tonofibrils)
- The ends of the filaments are gathered at the desmosomes located at the lip of each spiny projection, giving the cells their prickly look.
17
Q
What are the characteristics of the stratum granulosum?
A
- 1=5 layers of flattened cells
- final tailoring of protein synthesis
- profillagrin stored in keratohyalin granules produced (further modified to filaggrin)
- lamellar granules fuse with plasma membrane
- last stage of metabolic activity
18
Q
What is filaggrin?
A
Histidine and arginine-rich protein that helps stack the keratin filaments in the SC (precursor is profilaggrin)
19
Q
What happens when lamellar granules fuse with the plasma membrane in the stratum granulosum layer?
A
- Lipids released into intercellular space along with metabolic enzymes that modify lipids
- This process produces the protective lipids of the horny layer (SC)
20
Q
What happens as cells become permeable to calcium in the stratum granulosum?
A
Transglutiminase is activated and lysine cross-links produce the cornified envelope
21
Q
What are the characteristics of the stratum lucidum?
A
- Visible only in the thickest skin
- Thin layer of translucent flattened cells
- the cells have no nuclei
- cytoplasm filled with filaments
22
Q
What are the characteristics of the stratum corneum?
A
- uppermost layer
- thickest in palms/soles (glaborous skin)
- consists of approx. 15-20 layers of corneocytes
23
Q
What are corneocytes?
A
- Flat squames surrounded by multilamellar lipid layers
- contains no cell organelles or nuclei
24
Q
What are the types of keratin in the basal, spinous, and cornified layer?
A
- Basal = K14, K5
- Spinous = K1, K10
- Cornified = K1, K10
25
What is the function of the stratum corneum?
The SC functions as a barrier to permeability by controlling the loss of valuable fluid and the penetration of noxious foreign materials and radiation
26
How much water does a person with normal barrier function lose?
approx. 5 grams/hour through each square meter of skin
27
What amino acids are present in keratins?
aspartic acid
glutamic acid
glycine
(little proline)
28
How do keratins form a coiled-coil structure?
- Two alpha-helices coil around one another and the heptad repeat structure is important to this formation.
- Heptad repeat unit ABCDEFG where A d are hydrophobic and E and G have oppositely charged side chains
29
What is the hierarchy of the filament structure?
2 alpha helices --> coiled coil
2 coiled coils --> protofilament
2 protofilaments --> protofibril
4 protofibrils --> intermediate filament
30
What is the second function of filaggrin?
After the keratin is aggregated, the arginine of filaggrin is converted to the uncharged side chain, citrulline. This causes filaggrin to dissociate from the keratin and then be digested to amino acids by enzymes in the lower SC. These amino acids form part of the Natural Moisturizing Factor (NMF)
31
Where is involucrin synthesized and what is its function?
- Involucrin is syntehsized in the stratum spinosum and cross-linked in the stratum granulosum by the transglutiminase enzyme that makes it highly stable.
- It provides structural support to the cell, thereby allowing the cell is resist invasion by micro-organisms
32
What is loricrin?
The sulfur-rich fraction of keratohyalin protein. It interacts with involucrin to form the protein part of the SC cell envelope
33
What is the function of transglutaminase?
enzyme that cross-links loricrin and involucrin
34
What is the cornified cell envelope?
- forms around the corneocyte
- provides structure and protection of the corneocyte
- comprised of epidermal proteins - transglutaminase, loricrin and involucrin
- surrounded by covalently bound lipid layer - ceramide and fatty acid
35
What are the 4 key regulatory mechanisms for maintaining keratinocyte proliferation and differentiation?
- nuclear hormone receptors
- calcium second messenger signaling
- immunomodulatoary regulation
- cytokines and growth factors
36
What are the 8 potential targets based on symptoms of aberrant barrier? (vicious cycle of cutaneous inflammation)
- flaking
- skin thickening
- neutrophils/eosinophils
- keratinocytes
- T cells
- Lipid barrier
- itch
- infalmmation
37
What are the 3 research strategies for the cutaneous inflammatory diseases? (Atopic dermatitis, psorasis)
- keratinocytes
- inflammatory mediators
- immune dysfunction
38
What are the 4 extracellular signaling mechanisms of the response to injury?
- ions (calcium, potassium)
- cytokines (TNF-a, IL-1a, IL-2, etc)
- growth factors (TGF-B, TGF-a, EGF, etc)
- nuclear receptors (PPAR, Retinoid, Vitamin D)
39
Explain the general calcium second messenger signaling. Keratinocytes grown in high/low do what?
- There is a calcium gradient in the epidermis, low in the basal proliferating layer and higher in the superficial layers
- Keratinocytes grown in low calcium proliferate
- keratinocytes grown in high calcium differentiate
40
Explain the mechanism by which calcium regulates keratinocyte differentiation (model)?
1. Membrane-bound G-protein-coupled calcium sensing receptor leads to activation of phospholipase C when activated by external calcium
2. This produces two important second messengers from hydrolysis of PIP2
3. The two important messengers are DAG and IP3
4. IP3 stimulates the release of calcium from endoplasmic reticulum and increases intracellular free calcium concentration
5. The increase in DAG and Ca activates protein kinase C (PKC)
6. PKC induces AP-1 transcription factors to upregulate the expression of the genes encoding the differentiation specific proteins such as involucrin, TG, and loricrin involved in cornified envelope formation
41
What are two other ways to stimulate and increase the expression of calcium: to ultimately upregulate the transcription of involucrin, TG, and loricrin by mechanisms other than through AP1?
- Increase in the internal calcium may also stimulate the influx of calcium through calcium channels and prolong the signal
- Vitamin D increases the expression of CaR and PLC, enhancing the cellular response to calcium
42
Inflammatory processes are characterized by... (two things)
- erythema
| - swelling
43
define angiogenesis
multiplying, leaky blood vessels
44
Disruption of barrier with irritants like surfactants elicit production of what two specific cytokines in the first phase? How do they act?
TNF - alpha
IL-1 alpha
act by binding to specific receptors on the cell membrane
45
What is the immunomodulatory cytokine action in skin?
- Antigen presenting cell binds to the T cell in skin
- T cell interacting with antigen is either Th-1 or Th-2 depnding on the disease/irritant mechanism
- Th cells release cytokines assoc. with the disease state that act on mast cells or recruit appropriate white blood cells
46
What 3 cytokines do Th1 release?
IL-2
IFN-gamma
TNF
47
What 4 cytokines do Th2 release?
IL-4
IL-5
IL-10
IL-13
48
What do the white blood cells/T cells do to help control the chronic disease state?
Move into the skin & start to multiply. They secrete inflammatory mediators which help to control the chronic disease state.
