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ACVD Exam > Keratinization and Cornification (including diseases) > Flashcards

Keratinization and Cornification (including diseases) Flashcards

1
Q

Describe keratinization

A

Process of cytodiferentiation that the keratinocyte undergoes when proceeding from their post germinative state (stratum basale) to the finally differentiated, hardened cells of the stratum corneum

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2
Q

Describe the mammalian cytoskeleton

A
  • Primary regulator of cell shape due to its intrinsic mechanical properties allowing it to resist deformation as well as provide contractility
  • Generates forces on the surface of the cell to influence cell morphology
  • Comprised of actin filaments, intermediate filaments, and microtubules
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3
Q

Describe actin filaments

A

Also called microfilaments
7 nm in diameter

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4
Q

Describe intermediate filaments

A

Provide the scaffold
Keratins 7-12 nm diameter
Span the cytoplasm and attach at desmosomes

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5
Q

Describe microtubules

A

A and B tubulin
20 nm in diameter

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6
Q

Describe the size, charge, and solubility of keratins

A
  • Heterogenous in size (40 to 70 kDa)
  • Heterogenous in charge (4.7 to 8.4 pI)
  • All of them are insoluble
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7
Q

How many functional genes for keratins have been identified in humans?

A

54 (28 Type I and 26 Type II)

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8
Q

How well are keratins conserved in mammals?

A

Nearly perfectly

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9
Q

Where can you find high numbers of keratins?

A

Most surface exposed squamous epithelium

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10
Q

Describe the rim and spoke hypothesis

A

Keratins make a pan-cytoplasmic network from the nucleus surface to the periphery of the cytoplasm where they are membrane anchored at the sire of cell-matrix and cell-cell adhesion (ex. hemidesmosomes and desmosomes)

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11
Q

Where are keratins concentrated in polarized epithelial cells?

A

They are asymmetrically organized with keratins concentrated at the cytoplasmic periphery at the apical pole

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12
Q

Describe Type I keratins

A
  • Slightly smaller and more acidic than Type II
  • K9-19 in the epidermis
  • HA 1-8 in hair follicles/nails
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13
Q

Describe Type II keratins

A
  • Slightly larger and more basic/neutral than Type I
  • K1-8 in the epidermis
  • Hb 1-6 in the hair follicle/nail
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14
Q

What is the ratio of Type I to Type II keratins in mature intermediate filaments?

A

1:1 molar ratio so most Type I and Type II keratin genes are regulated in a pairwise, tissue type-related, and differentiation related fashion

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15
Q

Elaborate on the nomeclature of keratins (old vs new)

A
  • Original naming scheme from 1982 and listed keratins 1-19, Ha, and Hb keratins
  • Now there is a new scheme for humans that divides the genes into three categories (numbers go much higher and divide out non-human ones)
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16
Q

Where is the mutation in curly coat/sphynx/Devon rexes?

A

Keratin 71

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17
Q

What are keratin 71 mutations associated with?

A

Wavy/curly/wooly phenotype in dogs, cats, and humans

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18
Q

What are keratin 74 mutations associated with?

A

Wavy/curly/wooly phenotype in humans

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19
Q

What are keratin 25 mutations associated with?

A

Wavy/curly/wooly phenotype in horses, humans, and mice

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20
Q

What are keratin 27 mutations associated with?

A

Wavy/curly/wooly phenotype in cattle and mice

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21
Q

What are the primary keratins associated with the stratum basale?

A

K5/K14 (also K1/K6 in dogs)

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22
Q

Describe the structure of keratin (singular, not yet an intermediate filament)

A
  • Central alpha-helical rod domain
  • Amino (N)-terminal head and carboxy (C)-terminal tail that exhibit “glycine loops”
  • Head and tail are cystine rich and protease accessible to allow for interactions
  • Some middle parts of the rod section are glycine and proline rich for flexibility
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23
Q

Describe the formation of an intermediate filament aka polymerization

A
  • A type I and type II keratin combine to form parallel dimers (“coiled-coil”)
  • Two of these combine to form staggered, antiparallel tetramers (“protofibril”)
  • Two protofibrils combine (stacking end to end) to form a protofilament
  • Four protofilaments form a grouping that is crossed linked by disulfide bonds and is called a keratin intermediate filament
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24
Q

What is filaggrin?

A
  • Filament aggregating protein
  • Cationic
  • Histidine rich
  • Interacts with intermediate filaments but not other components of the cytoskeleton
  • Organizes keratin intermediate filaments into tight bundles
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25
Q

What is profilaggrin?

A
  • The precursor to filaggrin
  • Giant, heavily phosphorylated, and insoluble
  • Main constituent of keratohyalin granules
  • Has filaggrin repeats flanked by two truncated filaggrin repeats by a C-terminal and an N-terminal (that has two Ca2+ binding motifs)
  • Synthesis starts in stratum spinosum shortly after expression of K1 and K10 start
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26
Q

What is filaggrin degraded into?

A

Degraded in the stratum corneum by caspase-14 –> hygroscopic free amino acids –> natural moisturizing factors pyrrolidone carboxylic acid (PCA = moisture) and urocanic acid (UCA = photoprotection)

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27
Q

Which keratin regulates protein synthesis and cell size in wound-proximal keratinocytes?

A

K17

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28
Q

Which keratins are primary present in the suprabasal layers?

A

K1/K10 (dogs also have K4, K15/16)
- keratin intermediate filaments are organized with more bundling when these appear

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29
Q
A

Structure of keratin

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30
Q

Think about the structure of keratin intermediate filaments

A
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31
Q

What is the cubic rod-packing and membrane templating model?

A
  • Disputes keratin self-assembly
  • Proposes membrane template organizes keratin assembly
  • Explains strength and water-holding capacity of epidermis
  • Explains findings with cryotransmission electron microscopy on fully-hydrated epidermis
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32
Q

Which Type II keratin is expressed at later stages of differentiation (ie. starting in the granular layer)?

A

K2e (and K11?)

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33
Q

Which keratins are normally restricted to wound repair but may be upregulated in psoriasis and other hyperplastic disorders?

A

K6a, K6b, K16, and/or K17

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34
Q

Which keratin is present in the stress bearing ridges of the palm/sole and provides a more resilient cytoskeleton?

A

Type I K9

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35
Q

Which keratins have more pliability than K1, K9, and K10; function as a hinge; and are found in the secondary ridges of the human palm/sole?

A

K6a, K16, and K17

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36
Q

What are the functions of filaggrin?

A

Aligns KIFs and flattens corneocyte
Contributes to hydration once degraded to NMF

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37
Q

What are the epithelial keratins/genes in the new human nomenclature?

A
  • Type I is 9-28
  • Type II is 1-8 and 71-80
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38
Q

What are the hair keratins/genes in the human nomenclature?

A
  • Type I is 31-40
  • Type II is 81-86
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39
Q

What are the keratin pseudogenes in the new nomenclature?

A
  • Type I is 221+
    -Type II is 121-220
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40
Q

What is the structure of keratin proteins?

A

Central alpha-helical rod domain
Amino (N)-terminal head and carboxy (C)-terminal tail that exhibit “glycine loops”

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40
Q

What are the non-human epithelial and hair genes in the new nomenclature?

A
  • Type I 41-70
  • Type II which is 87-120
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41
Q

What is the classic model of keratin filament assembly?

A

Type I and II keratins→
Staggered, antiparallel heterodimers x 2→
Tetramers end to end→
Protofilaments x 2→
Protofibrils x 4→
KIF

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42
Q

How many protofilaments go into a KIF?

A

8

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43
Q

How are keratins cross-linked?

A

Disulfide bonds
(also bundled by filaggrin)

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44
Q

Where is profilaggrin made?

A

In the stratum spinosum after starting production of K1/K10

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45
Q

How many filaggrin repeats does profilaggrin have in dogs?

A

4

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46
Q

How many filaggrin repeats does profilaggrin have in humans?

A

10-12

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47
Q

How many filaggrin repeats does profilaggrin have in mice?

A

12-20

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48
Q

What happens to filaggrin in the stratum granulosum?

A

Profilaggrin is released from keratohyalin granules –>
Profilaggrin cleaved into filaggrin units –>
Filaggrin bundles KIFs into tight arrangement

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49
Q

What happens to filaggrin in the stratum corneum?

A

it is enzymatically degraded into NMFs

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50
Q

What do SASPase and Prss8 do?

A

Degrade profilaggrin to filaggrin molecules

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51
Q

What does peptidylarginine deiminase do?

A

Takes filaggrin off of KIFs

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52
Q

What happens in SG1?

A

Keratin intermediate filament assembly
Cornified cell envelope construction
Lamellar body exocytosis and creation of corneocyte lipid envelope and intercellular lipid lamellae

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53
Q

What do the linker domains in the keratin rod region have that helps to confer flexibility?

A

increased amounts of glycine and proline

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54
Q

What part of the structure of K5 and K14 have been found to have mutations that are linked to EBS?

A

linker domains (specifically L12 - very middle) in the rod

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55
Q

How do acidic keratins differ from others?

A

Don’t have the H2 region in their tail

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56
Q

How do the “head” and “tail” of hair and claw/nail keratins differ from others?

A

Are cysteine rich so that they can have more disulfide bonds for stability

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57
Q

What parts of the keratin structure are most important for protein interactions?

A

Head and tail

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58
Q

What happens if there is a mutation in the “tail” of K1?

A

Keratin doesn’t bundle or retract the cytoskeleton from the nucleus

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59
Q

What happens to non-paired keratins?

A

They degrade quickly

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60
Q

What keratins are expressed in the basal layer?

A

K5/14

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61
Q

What keratins are expressed in the spinous layer?

A

K1/10
Has low amount of K6/16 unless there is a wound or inflammation

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62
Q

What is cornification?

A

The process by which keratinocytes undergo terminal differentiation
- Nucleus and cytoplasmic organelles are hydrolyzed
- Marked reduction of cytosolic water
- Flattened shape

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63
Q

What is the cornified envelope?

A

Proteinaceous wrapper over a dense core of keratin

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64
Q

What is the cornecyte lipid envelope?

A

Overlying monolayer of ceramides

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65
Q

What is filaggrin degraded into?

A

Natural moiusturizing factor
Free amino acids (glutamine, arginine, histidine)
Urocanic acid - UV protection
Pyrrolidonecaroboxylic acid (moisturizing factor)
Lactic acid, citrate, urea

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66
Q

What keratins are in the stratum basale?

A

K5 and K14 (humans and dogs)
K1 and 6 in dogs

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67
Q

What is the epidermal proliferative unit?

A

10 basal cells: 1 stem cell surrounded by rapidly proliferating transit amplifying cells

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68
Q

What makes up the “spines” of the stratum spinosum

A

Desmosomes

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69
Q

What keratins are expressed in the stratum spinosum

A

K1 and 10
K4 and K15/16

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70
Q

What proteins do the cells of the spinous layer produce

A

Involucrin and (pro)fillagrin
+ form lamellar bodies which contain lipids, proteins and enzymes

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71
Q

What layers is the stratum granulosum split into?

A

SG1
SG2 - tight junctions seal intercellular spaces
SG3

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72
Q

At what layer do tight junctions seal intracellular spaces?

A

Stratum granulosum SG2

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73
Q

Where in the epidermis would you find keratohyalin granules?

A

Stratum granulosum

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74
Q

What are keratohyalin granules

A

These basophilic granules are accumulations of the synthesized proteins, primarily profilaggrin, loricrin and keratin filaments, needed for the construction of the stratum corneum.

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75
Q

What is filaggrin

A

protein involved in the aggregation of keratin

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76
Q

What is loricrin

A

cysteine rich flexible protein that is made in the granular layer and is a key component of the corneocyte cornified envelope

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77
Q

What change triggers the assembly of the keratin intermediate filaments and construction of the cornified envelope?

A

Increased intracellular calcium

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78
Q

Where do the keratin intermediate filaments and cornified envelop develop in the epidermis?

A

Stratum granulosum

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79
Q

Where do epidermal lamellar bodies secrete their contents?

A

Extracellular spaces at SG1 and the apical surfaces of SG2 cells

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80
Q

What does the cornified cell envelope replace

A

Plasma membrane

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81
Q

What happens to the keratinocyte as it transitions from the stratum granulosum to the stratum corneum

A

1) Organelle activities cease
2) Cell Flattens with keratin intermediate filament bundling
3) Degradation of nucleus and organelles

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82
Q

What are corneocytes

A

Dead, flattened, terminally differentiated keratinocytes that have lost all nuclei and organelles

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83
Q

What makes up the CLE?

A

ceramides
free fatty acids
cholesterol

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84
Q

What are corneocytes

A

flattened, keratin-filled cells, lacking organelles and plasma membranes, that are coated with an insoluble proteinaceous layer known as the cornified cell envelope (CE).

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85
Q

What makes up the tripartite structure of keratin proteins?

A

α-helical rod domain
an amino-terminal head
a carboxy-terminal tail

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86
Q

What are features of Type 1 keratins?

A

acidic
smaller than type II
include K9-19 in the epidermis

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87
Q

What are features of Type 2 keratins?

A

basic
larger than type I
include K9-19

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88
Q

How many filaggrin monomers are present in dogs

A

4

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89
Q

Where does enzymatic cleavage of profilaggrin into filaggrin occur?

A

Transition of granular to cornified layer

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90
Q

What enzymes cleave filaggrin?

A

Caspase-14
Bleomycin hydrolase

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91
Q

What are the products of filaggrin degradation

A

Natural moisturizing factors:
- urocanic acid (photoprotection, hydration, antimicrobial)
- pyrrolidone carboxylic acid (hydration, antimicrobial)

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92
Q

Name the main components of the cornified cell envelope

A

Involucrin
Loricrin
Envoplakin
Periplakin
Small proline-rich peptides
(Also proteins like S100 and trichohyalin, cystatin, elafin and annexin)

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93
Q

What is necessary for transglutimase activity

A

Increase intracellular calcium

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94
Q

Where is TG1 located

A

Membrane

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95
Q

Where is TG3 located

A

Cytoplasm

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96
Q

Which protein is the major structural component of the CE

A

Loricrin (70% of mass) - cystine-rich highly flexible protein with glycine loops and is a fundamental promoter of terminal differentiation

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97
Q

What is the function of TG3

A

Crosslinking of loricrin and SPRs

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98
Q

What is the function of TG1?

A

Cross link oligomers to the developing CE

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99
Q

What is the corneocyte lipid envelope?

A

Hydrophobic intercellular ω-hydroxyceramides lipids that fill the spaces between the corneocytes

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100
Q

What are the major lipid classes of the stratum corneum extracellular lipid layer?

A

ceramides (50%)
free fatty acids (15%)
cholesterol (25%

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101
Q

What are ceramides?

A

amide-linked fatty acids attached to long chain amino alcohols called sphingoid bases

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102
Q

What are the contents of Lamellar bodies?

A

lipid precursors, including glucosylceramides, sphingomyelin, phospholipids, and cholesterol sulfate,

enzymes: β-glucocerebrosidase, acidic sphingomyelinase, phospholipase A2, and steroid sulfatase, respectively

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103
Q

From what is cholesterol synthesized?

A

Acetate - from lower epidermis

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104
Q

Which enzyme metabolizes cholesterol suphate to cholesterol?

A

Steroid sulphatase (contained within lamellar bodies)

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105
Q

What is the role of cholesterol sulfate?

A

Inhibits serine proteases (kallikreins) involved in desquamation

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106
Q

Which enzymes control desquamation?

A

Kallikreins (serine proteases)
Cathepsins (cysteine proteases)

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107
Q

What are desmosomes?

A

Specialized keratinocyte junctions that link KIFs to sites of intercellular adhesion, tethering adjacent cells and providing structural strength for the epidermis

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108
Q

What are the three families of proteins that comprise desmosomes?

A

❖ Cadherins – Transmembrane molecules that form a calcium-dependent adhesive interface between neighboring keratinocytes
❖ Armadillo protein family – Bind to the cytoplasmic portions of the cadherins
❖ Plakin protein family - Binds KIFs to armadillo family proteins

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109
Q

What molecules are contained within corneodesmosomes?

A

desmoglein 1
desmocollin 1
corneodesmosin (CDSN)

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110
Q

Which molecules contain corneodesmosin?

A

Keratins
Loricrin
Corneodemsosomes

CDSN forms structural motifs called “glycine loops” which have been suggested to mediate reversible and adjustable intermolecular adhesion by acting like Velcro.

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111
Q

Where are tight junctions located

A

SG2

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112
Q

What are tight junctions made up of?

A

claudins
occludins
junctional adhesion molecules (JAMs)
zonula occludens (ZO) proteins.

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113
Q

What are claudins?

A

Primary transmebrane molecules that function as a zip lock to seal the intercellular barrier, and claudins 1, 4, and 7 are expressed in the epidermis.

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114
Q

What is desquamation?

A

process by which corneocytes are shed from the epidermal surface

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115
Q

Which enzymes mediate desquamation?

A

Promoters:
kallikreins (KLK, a family of serine proteases)
cathepsins (cysteine proteases)

Inhibitors:
KLK inhibitors LEKTI (lymphoepithelial Kazal-type-related inhibitor, encoded by SPINK5 gene)
cholesterol sulfate

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116
Q

At what layer is the concentration of Ca2+ highest in the epidermis

A

Stratum granulosum (low in basal and spinous layers and decreases again in stratum corneum)

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117
Q

What processes are controlled by high intracellular calcium?

A

lamellar body secretion
transglutaminase activity
cleavage of profilaggrin to filaggrin

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118
Q

What are the barrier effects of filaggrin mutations?

A
  • decreased corneocyte osmolytes
  • decreased organic acids (UA, PCA)
  • decreased corneocyte hydration
  • increased water loss
  • increased pH
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119
Q

Which cytokines down regulate filaggrin expression?

A

Th2 cytokines

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120
Q

What happens to extracellular lipids in humans with AD?

A

Composition and architecture are disrupted
◦ Lamellar body secretion abnormal and some retained in corneocytes
◦ Reduction in
- Total lipids in stratum corneum
- Proportion of long chain ceramides
- Chain length of fatty acids in ceramides and free fatty acids

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121
Q

What happens to extracellular lipids in dogs with CAD?

A
  • Similar to humans
  • Decreased total lipids, fatty acids, and ceramides in AD
  • Abnormal, disorganized, and reduced intercellular lipid lamellae
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122
Q

What happens in the scaffolding stage (1st stage) of cornified envelope construction?

A

Envoplakin, periplakin, and involucrin move to cell membrane
Transglutaminases link involucrin to other proteins to form scaffold

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123
Q
A

Stage 1 of CE development, scaffolding

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124
Q

What happens in the lipid envelope stage (2nd stage) of cornified envelope construction?

A

Lamellar bodies fuse to cell membrane and secrete lipids and enzymes

125
Q
A

Stage 2 of CE development, lipid envelope

126
Q

What happens in the reinforcement stage (3rd stage) of cornified envelope construction?

A

-Loricrin comes in
- TG1 links loricrin to involucrin scaffold and involucrin to ω-hydroxyceramides to form CLE
- TG3 links loricrin to other cytoplasmic proteins

127
Q

What are transgluaminase enzymes?

A

◦ Catalyze formation of N(ε)-(γ-glutamyl)-lysine isopeptide bonds
◦ Highly resistant to proteolytic enzymes
◦ Calcium dependent

128
Q
A

Stage 3 of CE development, reinforcement

129
Q

What happens in the mature corneocyte (final stage of development)?

A

CE replaces cell membrane with loricrin inside, involucrin outside
KIFs are linked to CE

130
Q
A

Mature corneocyte

131
Q

Put these in order from inside to outside in the mature corneocyte: involucrin, keratin, loricrin

A

keratin –> loricrin –> involucrin

132
Q

What is the “mortar” of the stratum corneum?

A

Composed of ceramides, free
fatty acids, and cholesterol
Extracellular lipid matrix
◦ Corneocyte lipid envelope (CLE)
◦ Intercellular lipid lamellae

133
Q

What happens in SG1?

A

Keratin intermediate filament assembly
Cornified cell envelope construction
Lamellar body exocytosis and creation of corneocyte
lipid envelope and intercellular lipid lamellae (at the SC interface)

134
Q

In which layer of the skin do lamellar bodies deliver lipid precursors and enzymes?

A

SG1
and stratum corneum interface

135
Q

What are the contents of lamellar bodies?

A

Lipid precursors
Enzymes
Lipid hydrolases
Steroid sulfatase
Kallikreins
Cathepsins
Corneodesmosin
Antimicrobial peptides

136
Q

What primarily makes up the corneocyte lipid envelope?

A

ω-hydroxyceramides

137
Q

What primarily makes up the intercellular lipid lamellae?

A

Ceramides, free fatty acids, and cholesterol

138
Q

What are the sphingoid bases?

A
  • phytosphingosine
  • sphingosine
  • dihydrosphingosine
    6-hydroxylsphingosine
139
Q

What are the features of the ω-hydroxyceramides that make up the corneocyte lipid envelope?

A

◦ Unique to stratum corneum
◦ Ultra long chain (ULC) fatty acids
◦ Linoleic acid (ω-6 EFA) is component
◦ Bonded to involucrin in CE

140
Q

What are the roles of the corneocyte lipid envelope?

A

Forms scaffold for intercellular lipid layers of stratum corneum
Key structure for skin barrier function and ichthyosis pathogenesis

141
Q

What links corneocytes to each other?

A

Corneodesmosomes

142
Q

How are corneodesmosomes different from desmosomes?

A

They have corneodesmosin
◦ Serine and glycine rich protein
◦ Forms glycine loops
◦ Secreted from lamellar bodies
◦ Attaches to desmoglea
◦ Key to stratum corneum cohesion

143
Q

What is desquamation?

A

Shedding of corneocytes
Regulated enzymatic cleavage of corneodesmosomes
Maintains epidermal homeostasis
Removes microorganisms, preventing colonization

144
Q

Where do the enzymes and inhibitors involved in desquamation come from?

A

Lamellar bodies

145
Q

What are the primary proteases involved in desquamation?

A

kallikreins (KLK 5, 7) and cathepsins

146
Q

What are the inhibitors involved in desquamation?

A

LEKTI (lymphoepithelial Kazal-typerelated inhibitor)
Encoded by SPINK5

147
Q

What is the role of pH in desquamation?

A

More desquamation at more acidic (low) pH
- LEKTI-1 binds strongly to KLK at neutral pH (deep stratum corneum)
- pH decreases in the superficial SC which releases KLK from LEKTI
- released KLK can now cause desquamation
pH normally drops more superficially in stratum corneum

148
Q

What is the genetic variant for ichthyosis in American bulldogs?

A

Autosomal recessive mutation in NIPAL-4 (ichthyin, involve in fatty acid synthesis, increases non-esterified free fatty acids –> creates cytotoxicity and damage to cell membranes)
CLE absent or attenuated
Appears before weaning
Generalized white scale, ventrally orientated erythema and adherent scale
Histologically looks like that in goldens with more inflammation and can be confused with AD in adults

149
Q

What is the genetic variant for ichthyosis in Golden retrievers?

A

Type 1: Autosomal recessive mutation in PNPLA-1 (involved in fatty acid acid synthesis)
CLE absent or attenuated
Usually appears <1yr but can manifest in adults and be transient in puppies
Has large white to grey scale

Type 2: ABHD5 in a family in the US

150
Q

What is the genetic variant for ichthyosis in Jack Russel terriers?

A

TG1 (transgluaminase 1)
Autosomal recessive
CE markedly attenuated

151
Q

What keratins are primarily expressed in the granular cell layer?

A

K1/10 (and 2/11)

152
Q

What are lamellar granules?

A
  • Secretory granules secreted into the intercellular space of the stratum granulosum
  • Contain precursors of stratum corneum lipids (glycoproteins, glycolipids, phospholipids, free sterols, glycosylceramides, acid hydrolases) and proteins that respond to signals that occur during the transition from the granular to cornified layer
  • Are secreted via exocytosis
153
Q

What does transglutaminase 1 do to plankins and ivolucrin?

A

Links them together by forming NE-(y-glutamyl) lysine isopeptide crosslinks
- due to increase in Ca2+

154
Q

How much of the cornified envelope does loricrin make up?

A

80%

155
Q

What are the KIFs present in the cornified cell envelope?

A

K1/10 (and 2e - esp thickened sites)

156
Q

What percent protein mass of the epidermis do filaggrin and KIFs make up?

A

80-90%

157
Q

What enzymes are responsible for the extrusion of lamellar bodies and the release of their contents?

A

acid hydrolases

158
Q

What are the primary components involved in the complex changes in the lipid composition after the extrusion of lamellar bodies?

A
  • β glucocerebroside
  • acid sphingomyelinase
  • phospholipase A
159
Q

What are the transglutaminases involved in the formation of the cornified envelope?

A

TG1
TG3
TG5

160
Q

What mineral are transglutaminases dependent on?

A

Ca2+

161
Q

What is the function of S100 in the cornified envelope?

A

Are Ca binding proteins that transmit Ca dependent regulatory signals
Are substrates for TG1 and 2

162
Q

What is the main component of the epidermal cornified envelope?

A

Loricrin (70-85%)

163
Q

What does loricrin crosslink?

A

Other loricrin and SRP

164
Q

Which transglutaminases are involved in loricrin oligomerization by way of interchain crosslinks?

A

TG1 and TG5 initially then compacted by TG3

165
Q

Which KIFs are crosslinked by TGs?

A

Type II (K1, K2e, and K5)

166
Q

What is involucrin?

A

Created in spinous layer
Glutamine-rich protein (why it crosslinks with transglutaminase-1)
Connects corneocytes to extracellular lipid layer, scaffold
First protein that is deposited to create the CE so ends up outside

167
Q

What are the 4 distinct cellular events in the process of cornification?

A

1) Keratinization
2) Keratohyalin synthesis
3) Formation of the insoluble SC cornified envelope
4) Production of lipid-rich intercellular domains

168
Q

What is the epidermal differentiation complex?

A

Cassette of genes important in growth and differentiation of keratinocytes
2Mb region of the human chromosome 1q21

169
Q

What are small proline-rich proteins?

A

Members of the epidermal differentiation complex 1q21
Crosslink with one another and loricrin in the CE
SPR1
SPR2 (most rigid, induced with aging)
SPR3 (most flexible)

170
Q

Where on the body are more small proline-rich proteins found?

A

oral mucosa

171
Q

What are plankins?

A

Envoplakin, Periplakin
Proteins from desmosomal plaque expressed in superficial layers of epidermis –> incorporated into corneodesmosomes in SC
Attachment site for ceramides in SC

172
Q

What are minor molecules in the cornified envelope that play a role in barrier function?

A

Cystatin A, elafin, annexin, S100A

173
Q

What is the function of ceramides?

A

Most important lipid component for lamellar arrangement in the SC
 Barrier function
 Plasticizing the SC to allow stretching and bending

174
Q

What are the types of fatty acids?

A

esterified ω-hydroxy fatty acids
α-hydroxy fatty acids
nonhydroxy fatty acids

175
Q

What is the major ceramide in the epidermis?

A

w-OH ceramide (hydroxyceramide)

176
Q

What is the rate limiting enzyme for production of ceramides?

A

serine-palmitoyltransferase (first step)

177
Q

What is the function of cholesterol in the stratum corneum?

A

Part of plasma membrane and intercellular lipid lamellae in SC
Cholesterol sulfate inhibits proteases, impairs desquamation

178
Q

Where is cholesterol synthesized in the epidermis?

A

Synthesized in lower epidermis from acetate
Then incorporated into lamellar bodies

179
Q

What is the rate limiting step in cholesterol synthesis?

A

hydroxymethylglutaryl (HMG)-CoA reductase

180
Q

What happens to the concentration of cholesterol in the stratum corneum during permeability barrier repair?

A

It increases

181
Q

What converts cholesterol to cholesterol sulfate?

A

Cholesterol sulfotransferase aka sterol sulfatase

182
Q

What is squalene broken down into?

A

Cholesterol

183
Q

What are the two primary products that acetyl-CoA can be broken down into?

A

Free fatty acids (acetyl-CoA carboxylase starts it)
Cholesterol (HMC-CoA synthase starts it)

184
Q

What are the recognized essential fatty acids?

A

Omega 6s:
Dogs, humans, and cats - linoleic acid (LA, 18:2n-6)
Just cats - also arachadonic acid (AA, 20:4n-6) for cats due to limited Δ6-desaturase

Omega 3s:
Only one needed in humans: α-linolenic acid (ALA, 18:3n-3) acids
Dogs and cats: eicosapentaenoic acid (EPA, 20:5) and docosahexaenoic acid (DHA, 22:6) due to poor conversion of ALA to EPA and DHA

185
Q

What do linoleic acid and α-linolenic acid do when supplied in the diet?

A

Are converted to long chain PUFA (>20 carbons with >2 double bonds) by desaturase and chain elongation enzymes in endoplasmic reticulum

186
Q

What do long chain PUFAs do?

A

Serves as precursor for eicosanoids, leukotrienes or prostanoids as well as structural and functional lipids

187
Q

What is the rate limiting enzyme in conversion of EFA (18 carbons) to longer PUFAs?

A

Δ6-desaturase in the ER
First step (also works further down on 24 carbon PUFAs)
*Cats have limited activity = decreased capacity to make arachidonic acid

188
Q

How is Acetyl CoA made?

A

by glycolysis of carbohydrates
- instead going into Krebs, citrate is broken down in cytoplasm

189
Q

How do fatty acids affect the pH of skin?

A

Acidify the stratum corneum

190
Q

What is the difference between saturated and non-saturated fatty acids?

A

Saturated = no double bonds (every carbon is saturated with hydrogen)
Unsaturated = a double bond

191
Q

What do deficiencies in omega-6 fatty acid do?

A

Cause skin and coat abnormalities, reproductive problems, and failure to thrive

192
Q

What happens in ichthyosis vulgaris?

A

Autosomal semidominant mutation on FLG so filaggrin is absent
Common and typically mild in humans –> named because it is common
Fine scale with superficial fissuring and relative flexural sparing but worse on lower extremities with hyperlinear palms and soles
Histopathology: hyperkeratosis, reduced or absent granular layer

193
Q

What is lamellar ichthyosis?

A

Autosomal recessive mutation in TGM1 in a JRT
Poor/no cornified envelope formation
Large dark scale and often have secondary Malassezia infections
Also reported in humans but is now considered a phenotype
At birth in humans, “collodion baby” is encased in coherent scale
Affected individuals may have ectropion, eclabium

194
Q

What is x-linked ichthyosis?

A

Recessive, x-linked STS deletion so reduction in cholesterol activity
Fine to large scales that are black and brown, comma shaped corneal opacities, cryptorchidism or delayed labor
Palms and sols are spared
Not reported in animals yet

195
Q

What gene causes Harlequin ichthyosis?

A

Autosomal recessive, ABCA12 gene –> defective ATP binding cassette subfamily A member 12 = altered lipid metabolism, membrane transport resulting in lamellar bodies with lipids that are TOO polar

196
Q

What is the clinical and histopathologic presentation of Harlequin ichthyosis?

A

Clinical: Markedly thickened skin with geometric, deep fissues; survivors develop severe congenital ichthyosiform erythroderm phenotype, often failure to thrive due to poor feeding, neonatal sepsis
Histopath: markedly thickened orthokeratotic SC with acanthosis

197
Q

What animals (and breeds) are reported to have Harlequin ichthyosis?

A

Bovine: Holstein-fresian, brown swiss, norweigan red polls
Greater kudu, llama, koala, wallabies

198
Q
A

Harlequin ichthyosis

199
Q

What causes the basket-weave appearance of the stratum corneum on light microscopy?

A

an artifact created by the loss of intercellular lipids during tissue processing

200
Q

What 3 extracellular lipids affect the permeability barrier of the stratum corneum?

A

cholesterol
free fatty acids
ceramides

201
Q

What is the current functional model used to understand how genotype drives disease phenotype?

A

Barrier-driven hypothesis

202
Q

How does epidermal hyperplasia influence lipid production?

A

Epidermal hyperplasia ensues to produce more cells, which in turn generate more lipids, restoring hydrophobicity

203
Q

What happens to lipid production when the skin barrier is disturbed and the epidermis needs to generate repair?

A

Increases

204
Q

Which pathogenesis-based therapy has been used in the rare x-linked dominant disorder, congenital hemidysplasia with ichthyosiform erythroderma and limb deficits (CHILD syndrome)?

A

Topical cholesterol in conjunction with systemic cholesterol lowering drugs (statins) because it is a failure to convert lanosterol to cholesterol

205
Q

What does premature keratinocyte death release?

A

DAMPs

206
Q
A

Lamellar ichthyosis in a JRT
Mutation in TG1
C= a normal age-matched dog cornified envelope
D= absence of cornified envelope in affected dog
Black arrows show corneodesmosomes

207
Q

What a mutation in which gene has been found for Norfolk terriers with epidermolytic ichthyosis?

A

KRT10
Is a mild form that only causes swelling/lysis in the upper spinous/granular cell layer and causes generalized, pigmented hyperkeratosis

208
Q

What are ceramides converted to in the cytosol of lamellar bodies?

A

Glycosylceramides, sphingomyelin and phospholipids
but then the first two get converted back once expelled

209
Q

What converts phospholipids to free fatty acids?

A

phospholipase A2 (increased activation with inflammatory stimuli)

210
Q

What is the ratio of ceramides, free fatty acids, and cholesterol in the SC lipid lamellae?

A

equimolar

211
Q

What is the pH of dog skin?

A

highly variable and typically neutral (6.8–7.7) and therefore more basic than humans

212
Q

What is the pH of human and hairless mouse skin?

A

acidic surface (5–5.5)

213
Q

What are primary scaling disorders caused by?

A

anomalies in genes that encode enzymes and structural proteins (e.g. TG1), or processes involved in lipid metabolism or lipid transport

214
Q

What are secondary scaling disorders caused by?

A

any insult that drives hyperkeratosis

215
Q

What is the onion skin approach?

A

A way to diagnose disorders of cornification in humans
(i) clinical features
(ii) skin localization with or without involvement of other organs
(iii) heritability
(iv) mutation
(v) loss of the target protein or enzyme

216
Q

What is one of the few instances that electron microscopy can be helpful as the sole diagnostic tool for pathogenesis of a disorder of cornification?

A

thinning of cornified envelopes in TGM1-deficient lamellar ichthyosis

217
Q

Which form of ichthyosis is more common?

A

Non-epidermolytic

218
Q

What is epidermolytic ichthyosis correlated with?

A

Defects in keratin formation (aka keratinopathic ichthyosis)

219
Q
A

from Mauldin and Elias
A= NIPAL4 and FATP4
B= PNPLA1
C= NIPAL4 and FATP4

220
Q

What pattern of inheritance do most ichthyoses in dogs have?

A

Autosomal recessive

221
Q

What is the most severe form of ichthyosis in humans?

A

Harlequin (potentially fatal)

222
Q

What is the genetic variant for ichthyosis in great Danes?

A

Autosomal recessive mutation in SLC27a4 (encodes FATP4 synthesis of very long chain fatty acids)
Appears at birth
Greasy scale, wrinkling of face and extremities
Non-viable into adulthood
histological lesions are typical of nonepidermolytic ichthyosis, but have eosinophilic material (glycosaminoglycan)
in hair follicles

223
Q
A

Autosomal recessive mutation in SLC27a4 (great Dane ichthyosis)

224
Q

What is the genetic variant for ichthyosis in Cavalier King Charles spaniels?

A

Autosomal recessive mutation in FAM83H (unknown function)
Appears at birth/first few weeks of life
Keratoconjunctivitis sicca from eyelid opening, scaling, abdominal pigmentation, curly pelage, pawpad hyperkeratosis, nail dystrophy

225
Q

What is the genetic variant for ichthyosis in German shepherd dogs?

A

A de novo mutation in ASPRV (profilaggrin processing)
Generalized scale since birth

226
Q

What is the genetic variant for the cornification disorder in Labrador retrievers?

A

x-linked semidominant mutation in NSDHL (cholesterol processing)
Appears when a puppy
Linear hyperkeratotic plaques and follicular fronds and pawpad hyperkeratosis

227
Q

What is the genetic variant for the cornification disorder in Chihuahuas?

A

probable x-linked semidominant mutation in NSDHL (cholesterol processing)
Appears when a puppy
Linear verrucous nevi

228
Q

What are the unique histopathologic features of ichthyosis in Norfolk terriers?

A

Unique histological features are a combination of acanthosis with hyperkeratosis, cytolysis in the granular layer, coarse keratohyalin granules and eosinophilic perinuclear bodies which represent clumped keratin filaments

229
Q

Skin of a Norfolk terrier

A

Epidermolytic ichthyosis (KRT10 mutation)
* vesicle in stratum granulosum
Arrowhead – coarse KHG
Arrows (pink) – keratin clumps

230
Q

What genetic mutation cause hereditary footpad hyperkeratosis in douges de Bordeaux aka plamoplantar keratoderma?

A

Spontaneous, autosomal recessive KRT16 mutation
Lesions develop between 10 wks and 1 yr and become fissures/cracks
Histologically, the SC is expanded by tremendous orthokeratotic hyperkeratosis with mild parakeratosis at the tips of villae

231
Q

What causes hereditary nasal parakeratosis (HNPK) arises in Labrador retrievers and greyhounds?

A

mutation in SUV39H2 (decreases the expression of loricrin in the SC)
develop thick, brown scale on the nasal planum with variable depigmentation

232
Q

How do you diagnose ichthyoses in veterinary medicine?

A

Signalment
◦ Young patient
◦ Breed predilections

Clinical signs
◦ Scale, hyperkeratosis
◦ Non-pruritic (unless secondary infections)

Rule out secondary disorders of cornification
◦ Skin scrapes, cytology, histopathology
Breeders

+/- DNA testing

233
Q

How do you treat ichthyoses in veterinary medicine?

A

Topical “soak and slather” regimens
◦Management of barrier defects
◦ Lifelong treatments

Maybe there will be more targeted therapies eventually

234
Q

What are the patterns of the stratum corneum that can be seen on histopathology?

A

Basket weave (lacy) **normal
Lamellar/laminated (condensed, but separates)
Compact (dense, does not separate)
Parakeratotic (retained nuclei) versus normal orthokeratotic

235
Q

What is parakeratosis indicate on histopathology?

A

Incomplete keratinocyte maturation or a defect in filaggrin conversion

236
Q

What is primary, idiopathic seborrhea?

A

A defect in cornification
Clinical excessive scaling, crusting, +/ greasiness (oleosa) or dryness (sicca)
No known cause, usually juvenile onset
Typically trunk, pinna with ceruminous otitis externa common
Cocker Spaniels, Persian kittens, horses (mane/tail) most represented

237
Q

Young Cocker spaniel

A

Epidermal hyperplasia (mild to papillated
Alternating vertical tiers of ortho- and parakeratosis)
Follicular plugging and follicular ostia w/ parakeratotic caps/epaulettes
Suggestive of primary seborrhea (ddx: allergy, Vit A-responsive)

238
Q

What is Vitamin A responsive dermatosis?

A

Do not actually have a measurable vitamin A deficiency
Cocker spaniels, miniature Schnauzers, and labs at risk
Usually adult-onset
Alopecic plaques w/ follicular casts esp lateroventral trunk
Ceruminous otitis also common
Confirm by response to vit A supplementation in 3 to 8 weeks

238
Q

Which animals get true vitamin A deficiency?

A

Birds (on a seed-rich diet)
- White plaques on mucosa, rhinitis, blepharitis
- Rhinolith

Reptiles (esp box turtles)
- Squamous metaplasia, conjunctivitis, aural “abscesses”…

239
Q

What are the active metabolites of vitamin A?

A

Retinoic acid and retinal

240
Q

What is the primary effect of vitamin A on the skin?

A

Increases cell turn over

241
Q

10 yr MC Cocker spaniel with alopecic plaques and follicular casts

A

Severe follicular keratosis
Distended ostia with plug protrusion (follicular fronds)
Suggestive of vitamin A-responsive dermatosis

242
Q

What do you expect to see on histopathology of non-epidermolytic ichthyosis?

A

Lamellar / laminated to compact orthohyperkeratosis (mild to severe)
- “filo dough effect”
- Goldens: abnormal keratin rather than ↑
- Focal parakeratosis can happen
Perinuclear clear spaces in granular layer

243
Q

What do you expect to see on histopathology of epidermolytic ichthyosis?

A

Lamellar / laminated to compact orthohyperkeratosis (mild to severe)
Lysis of upper epidermal layers
Hypergranulosis with abnormal keratohyalin granules
Diffuse keratinocyte ballooning

244
Q

What form of ichthyosis is this?

A

Non-epidermolytic

245
Q

What form of ichthyosis is this?

A

Epidermolytic

246
Q

What is free arachidonic acid a substrate for?

A

cyclo-oxygenase (COX) –> prostaglandins and thromboxanes
lipoxygenase (LOX) –> leukotrienes
cytochrome P450 enzymes

247
Q

Describe the stratum basale/stratum germativum/basal layer.

A
  • Single row of columnar to cuboidal cells resting on the basement membrane zone
  • Most of the cells are mitotically active keratinocytes
  • small polar, undifferentiated cells
  • attach to the basement membrane at hemidesmosomes
248
Q

Which are the primary keratins expressed in the stratum basale?

A

K5/K14 (but dogs also have K1/K6)

249
Q

How thick is the stratum spinosum?

A
  • Typically 1-2 layers thick in haired skin
  • Thicker at foot pads, nasal planum, and mucocutaneous junctions (can be 20 cells thick)
250
Q

What are the primary keratins in the stratum spinosum and how does this vary in hyperproliferative disorders?

A
  • Retain stable K5/K14 with new synthesis of K1/K10
    • dogs also have K4 and K15/16
  • Hyperproliferative disorders have down regulation of K1/K10 mRNA and protein while K6/K16 are favored
251
Q

In what layer of the skin are lamellar granules (aka keratinosomes/membrane-coated granules/Odland bodies) formed?

A

Upper stratum spinosum but more prominent in granulosum

252
Q

What are lamellar granules?

A
  • Secretory granules secreted into the intercellular space of the stratum granulosum
  • Contain precursors of stratum corneum lipids (glycoproteins, glycolipids, phospholipids, free sterols, glycosylceramides, acid hydrolases) and proteins that respond to signals that occur during the transition from the granular to cornified layer
  • Are secreted via exocytosis
253
Q

When is profilaggrin produced?

A

Stratum spinosum (cleaved into filaggrin in the granular layer)

254
Q

What is involucrin?

A
  • First major component to be activated that will be cross-linked in the emerging cornified envelope
  • Initiated in the spinous layer soon after K1/K10 expression
  • Glutamine-rich
  • Largest protein in the stratum corneum
  • Synthesized in the spinous layer
  • Cross-linked in the granular layer by transglutaminases
  • Is rigid and firm, forming an insoluble cell boundary and connecting corneocytes to the extracellular lipid layer
255
Q

What are the two primary categories of things that occur in the stratum spinosum?

A

1) keratinocytes start differentiating
2) things that will be needed later start to be made

256
Q

Describe the histopathologic appearance of the spinous layer.

A
  • Cells are lightly basophilic to eosinophilic, nucleated, and polyhedral to flattened cuboidal
  • Have a spine-like appearance of the cell margins which are abundant desmosomes
257
Q

What is the final layer of the epidermis in which keratinocytes are alive?

A

Stratum granulosum

258
Q

What is the primary roles of the stratum granulosum?

A
  • A final packaging stage which generates a number of structural components that will form the epidermal barrier
  • The final stage of granular cell differentiation into a corneocyte is the cell’s programed destruction, destroying almost all cellular contents with the exception of keratin filaments and filaggrin matrix
259
Q

What are keratohyalin granules composed of?

A
  • Profilaggrin, keratin filaments, and loricrin
  • But not true granules as they lack a membrane
260
Q

What are the two types of keratohyalin granules?

A
  • F granules
  • L granules
261
Q

What are F granules?

A
  • Named for filaggrin
  • A type of keratohyalin granules
  • Irregularly shaped
262
Q

What are L granules?

A
  • Contain loricrin
  • Are smaller and more rounded
263
Q

Describe the fate of profilaggrin.

A
  • Profilaggrin becomes dephosphorylated and undergoes Ca2+- dependent proteolytic cleavage
  • Filaggrin is later degraded into the natural moisturizing factors, urocanic acid (UCA) and pyrrolidone carboxylic acid (PCA)
264
Q

What is loricirin?

A
  • A cystine-rich, highly flexible protein with glycine loops
  • A major structural component of the cornified envelope, binding keratin filaments together in the corneocyte and anchoring them to the cross-linked envelope
  • Most prevalent structural protein in the stratum corneum (~80% of volume of cornified envelope)
  • Synthesized in the upper spinous layer and throughout the granular layers
265
Q

How is keratin expression modified in the stratum granulosum?

A

Modified from K1/K10 to also include K2/K11

266
Q

What is the stratum lucidum/stratum conjunctum?

A
  • A fully keratinized, compact, thin layer of dead cells which is anuclear, homogenous, and hyaline-like, containing refractile droplets and semifluid eleidin
  • Present in canine footpads (sometimes nasal planum) and coronary band of horses but absent elsewhere
267
Q

What is the stratum corneum?

A

Outer layer of terminally differentiated keratinocytes that are constantly being shed (balanced by proliferation of basal layer)
- Multilayer zone of anucleate, flattened, lipid-depleted, protein-enriched corneocytes as the bricks and a continuous extracellular lipid matrix comprised of ceramides, FFAs, and cholesterol as the mortar

268
Q

What does the lipid matrix of the stratum corneum do?

A
  • Serves as the mortar
  • Mechanical protection
  • Barrier to water loss
  • Regulates permeation of soluble substances
269
Q

What keratins are primarily expressed in the stratum corneum?

A

K1/K10/K2e

270
Q

What are the major proteins of the stratum corneum?

A
  • Involucrin
  • Loricrin
  • Envoplankin
  • Periplankin
  • Small protein rich proteins (SPRPs)
271
Q

What do envoplankin and periplankin do in stratum corneum?

A

Link the cornified envelope to desmosomes and keratin filaments

272
Q

What do small protein rich proteins do in the stratum corneum?

A

Cross-link with loricrin in the cornified envelope

273
Q

What is desquamation?

A
  • A process of enzymatic cleavage of corneodesmosomes
  • Balance between KLKs, LEKTI
  • Promoted by acidic pH, decreases in Ca, increased natural moisturizing factors, and decreased water
274
Q

What is KLK7?

A
  • Stratum corneum chymotryptic enzyme aka kallikrein 7
  • One of the two serine proteases of the kallikrein family that are implicated in dequamation
  • Degrades corneodesmosin and desmocollin 1
275
Q

What is KLK5?

A
  • Stratum corneum tryptic enzyme aka kallikrein 5
  • One of the two serine proteases of the kallikrein family that are implicated in dequamation
  • Degrades corneodesmosin, desmocollin 1, and desmoglein 1
276
Q

What is corneodesmosin?

A
  • Synthesized as a glycine- and serine-rich glycoprotein in lamellar bodies then released from the lamellar bodies and associated with desmosomal desmogleins and desmocollines until activated by chemotryptic enzymes
277
Q

What is LEKTI?

A
  • Lymphoepithelial Kazal-type inhibitor
  • Inhibits desquamation
  • A serine protease inhibitor secreted from lamellar bodies
  • Most effective at neutral pH
278
Q

Rank the layers of the epidermis based on Ca2+ concentration.

A

Granulosum>spinosum>basale>corneum

279
Q

What are the roles of Ca2+ on keratinocyte differentiation?

A
  • Depletion regulates lamellar body exocytosis
  • Regulator of protein synthesis (primarily transglutaminase 1 activity)
  • Important for cell-to-cell adhesion
280
Q

What is Darier disease (keratosis follicularis)?

A
  • A disease with an increase in transepidermal water loss, altered calcium regulation, loss of adhesion between suprabasalar epidermal cells, and abnormal keratinization
  • Caused by one gene involved in Ca transport, SERCA2
281
Q

What is Hailey-Hailey disease (benign chronic pemphigus)?

A
  • Loss of cell-cell adhesion
  • Caused by a calcium-regulating gene, ATP2C1
282
Q

Describe holoclones?

A
  • Epidermal stem cells
  • Slow dividing cells
  • Proposed to maintain an “immortal strand” of DNA at each division
  • May divide symmetrically (useful when skin needs to be stabilized) or asymmetrically
283
Q

What are meroclones?

A
  • Transient amplifying cells
  • Rapidly dividing
  • Typically divide symmetrically
284
Q

What are paraclones?

A

Terminally differentiated/daughter cells

285
Q

How does calcium regulate stem cell fate and maintenance?

A
  • Low calcium environment promotes maintenance and prevents differentiation, thereby stimulating proliferation
  • High calcium environment inhibits it
286
Q

What are the categories of regulatory mediators which play a role in keratinocyte stem cell differentiation?

A
  • Stimuli that direct progenitor cells toward a particular type of terminal differentiation
  • Molecules and pathways characteristic of the microenvironment and stem cell homeostasis
  • Molecules that differently alter stem cells and transient amplifying cell proliferation
  • Positive and negative regulators involved in commitment and terminal differentiation
287
Q

What stimuli are involved in directing progenitor epithelial cells into hair follicle cells?

A
  • Positively by Wnt/β-catenin
  • Negatively by DiKK1 and Lef1/Tcf
288
Q

What molecules are involved in maintenance of stem cell quiescence in the epidermis?

A

Lrig1

289
Q

What molecules are involved in modifying the differentiation of stem cells into transient amplifying cells and stem cell renewal?

A
  • Myc
  • p63
  • miR203 microRNA
  • Histone
290
Q

What are negative regulators of terminal differentiation?

A
  • Extracellular matrix
  • pcG repression
291
Q

What are markers for stem cells in the epidermis?

A
  • β-integrin
  • CD71 (transferrin receptor)
  • LRIG1
292
Q

What markers of proliferation are upregulated in psoriasis?

A
  • Ki67
  • C-myc
293
Q

What is the [interfollicular] epidermal proliferative unit?

A
  • A proliferative unit arranged in a hexagon consisting of approximately 10 basal cells with a clonogenic cell in the center overlaid by the suprabasal and corneocyte progeny
  • Functionally independent and self-renewing
294
Q

What is the epidermal differentiation complex in humans?

A
  • Genes present in a 2mb region of the human chromosome 1q21
  • Epigenetic mechanisms play an important role in growth and differentiation of keratinocytes by regulating expression of the cassette of genes in this region
  • Encode structural proteins involucrin, loricrin, and SPRPs as well as a number of Ca-binding proteins including profilaggrin, trichohyalin and several S100A proteins
295
Q

How many layers does the stratum granulosum have?

A

3 - numbering starts superficial to deep

296
Q

What components start to be produced in the stratum spinosum?

A

◦ Involucrin
◦ Profilaggrin
◦ Lamellar bodies

297
Q

What are the “spines” in the stratum spinosum?

A

They represent desmosomes

298
Q

What happens in SG2?

A

It creates a permeability barrier due to tight junctions holding water inside and preventing entry of antigens

299
Q

Where are tight junctions found in the epidermis?

A

SG2

300
Q

What happens in SG1?

A
  • Keratin filament assembly
  • Cornified envelope construction
  • lamellar body exocytosis –> creation of lipid envelope and intracellular lamellae
301
Q

What links corneocytes together?

A

Corneodesmosomes

302
Q

How far do activated Langerhans cells reach?

A

SG1, they now can get through tight junction barrier
(normally can only get to SG2)

303
Q

What promotes the transition from spinous to granular layer cells?

A

Protein kinase C

304
Q

What role does calcium play in terminal keratinocyte differentiation?

A

low calcium = high proliferation (less differentiation)
high calcium = promotes terminal differentiation

305
Q

Where are S100 proteins primary expressed in the normal epidermis?

A

Stratum basale and spinosum

306
Q

Why does the 2018 report of the Nomenclature Committee on Cell Death (NCCD) recommend that programmed cell death and terminal differentiation of keratinocytes be conceptually well discriminated?

A

terminal differentiation of keratinocytes involves caspase 14, but not executioner caspases

307
Q

How long does it take for keratinization and cornification to occur in healthy skin?

A

21 days

308
Q

What adhesion method is the main block to the penetration of external agents into the epidermis?

A

tight junctions

309
Q

What is the pH of equine skin?

A

7-7.4

310
Q

What are the layers of the avian epidermis?

A

Stratum germinativum
- stratum basale
- stratum intermedium
- stratum transitivum
Stratum corneum (vacuolated and flattened cells that only retain hard keratin)

ACVD Exam (25 decks)

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