ACVD Exam > Structure and Function - Basement Membrane Zone > Flashcards

Structure and Function - Basement Membrane Zone Flashcards

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1
Q

Hemidesmosome function

A

Facilitate the stable adhesion of basal epithelial cells to the underlying basement membrane.

(keratin intermediate filaments of the basal keratinocyte and anchoring filaments of the lamina lucida connect to hemidesmosomes)

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2
Q

The four main macromolecule constituents of the basement membrane

A

1) Collagen IV
2) laminins
3) nidogens
4) heparan sulfate proteoglycans

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3
Q

Where do anchoring filaments of the lamina lucida originate and insert?

A
  • originate in basal cell plasma membranes (at the the hemidesmosomes)
  • insert into the lamina densa
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4
Q

The major collagen of the lamina densa

A

Collagen IV

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5
Q

Where do anchoring FIBRILS (composed primarily of collagen VII) originate, project, and insert

A
  • originate in the lamina densa
  • project into the dermis
  • then horseback into the lamina densa after wrapping around collagen fibers of the dermis or attach to anchoring plaques
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6
Q

Primary collagen comprising anchoring FIBRILS that connect the lamina densa and sublamina densa

A

Collagen VII

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7
Q

Four major functions of the epidermal basement membrane

A

1) a structural foundation for the secure attachment and polarity of the epidermal basal cells
2) a barrier separating the epidermis and the dermis
3) firm attachment of the dermis to the epidermis through a continuous system of structural elements
4) modification of cellular functions, such as organization of the cytoskeleton, differentiation, or rescue from apoptotic signaling via outside-in signaling mechanisms

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8
Q

Which α chains are ubiquitous in collagen IV of the basement membrane?

A

α1 and α2

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9
Q

Large glycoproteins within the lamina lucida/lamina densa of all basement membranes

A

laminins

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10
Q

Laminins are made up of what 3 subunit chains?

A

trimeric aggregate of one α, β, and γ chain

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11
Q

The portion of laminins that harbors the binding site for integrins

A

The C-terminal laminin-type globular (LG) domain of the α chain

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12
Q

What do nidogens bind?

A
  • laminins (γ chain)
  • collagen IV
  • perlecan
  • fibulins
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13
Q

Three proteoglycans that are characteristically present in vascular and epithelial basement membranes

A
  • perlecan
  • agrin
  • Collagen XVIII
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14
Q

Proposed function of fibulins

A

act as intermolecular bridges that stabilize the supramolecular organization of extracellular matrix structures, such as elastic fibers and basement membranes

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15
Q

Which laminin and collagen are the main proteins of anchoring FILAMENTS in the lamina lucida

A
  • Laminin 332 (previously referred to as laminin 5)
  • Collagen XVII
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16
Q

Main collagen of anchoring FIBRILS

A

Collagen VII

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17
Q

The two keratins that are the main cytokeletal proteins of basal cell membranes that link to hemidesmosomes. Ie what keratins make up keratin intermediate filaments?

A

Keratins 5 and 14

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18
Q

Nidogens may act as connecting filaments between collagen IV and networks of what?

A

Laminins

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19
Q

Laminin 332 connects to what integrin in hemisdesmosomes of basal cells, and what collagen of the lamina densa?

A
  • hemidesmosomal integrin α6β4
  • collagen VII (NC-1 domain)
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20
Q

Tight binding of laminin 332 to integrin α6β4
and to collagen VII provides primary resistance to what type of forces?

A

frictional forces

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21
Q

What does collagen XVII in anchoring filaments bind to in basal cell hemidesmosomes (3)

A
  • Bullous pemphigoid antigen 1 (BPAG1/BP230)
  • integrin α6β4
  • plectin
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22
Q

Complex presumed to maintain basement membrane stability

A

laminin 332–311 complex

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23
Q

Mutations in what collagen cause junctional epidermal bullosa?

A

Collagen XVII (major collagen of anchoring filaments in the lamina lucida)

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24
Q

What integrin in basal keratinocytes is the receptor for the laminin 332-311 complex

A

integrin α3β1

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25
Collagen VII binds to what laminin and collagen in the lamina densa?
Laminin 332 Collagen IV
26
Collagen targeted by autoantibodies in epidermolysis bulla acquisita and Type I bullous systemic lupus erythematosus
Collagen VII (main collagen of anchoring fibrils which connect the lamina densa of the BMZ to the underlying dermis)
27
Most abundant proteins in the dermis
Collagens
28
The classic, cross­banded fibrils recognizable in electron microscope images of the dermis contain what collagens?
- collagen I - collagen III - collagen V - collagen XII - collagen XVIII
29
What collagen polymerizes into microfibrils?
Collagen VI
30
What molecules provide dermal elasticity?
Elastin molecules
31
The 2 major components of elastic fibers in the dermis
- elastin - microfibrils
32
The 3 main components of the amorphous extra-fibrillar dermal matrix that binds water and provides tautness to the skin?
- proteoglycans - glycoproteins - hyaluronic acid
33
Negatively charged polysaccharides that can bind large amounts of ions and water and bind proteins to form proteoglycans
Glycosaminoglycans
34
The four different proteoglycan-­bound glycosaminoglycans
- chondroitin sulfate - dermatan sulfate - keratan sulfate - heparan sulfate
35
The major proteoglycan in the dermis; it is associated with elastic fibers and forms huge complexes with hyaluronic acid
Versican
36
A ubiquitous glycosaminoglycan of the dermis without a protein core
hylauronic acid
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The major heparan sulfate proteoglycan of basement membranes that can sequester and present growth factors to their receptors
Perlecan
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A hybrid collagen/proteoglycan found in epidermal and vascular basement membranes in the skin
Collagen XVIII
39
Most common class of matrix receptors in the skin
family of β1 integrins
40
What keratins make up keratin intermediate filaments?
Keratins 5 and 14
41
What is CD151? What integrin does it interact with in the hemidesmosome?
- a tetraspanin that is expressed together with laminin-binding integrins - α6β4
42
4 zones of the BMZ (outside to inside)
- basal keratinocyte - lamina lucida - lamina densa - sublamina densa
43
What types of keratin are keratin 5 and keratin 14 that make up keratin intermediate filaments? What do they form together?
K5 - basic type II K14 - acidic type I they form a heterodimer
44
What do intermediate keratin filaments bind to in hemidesmosomes?
- Bullous pemphigoid antigen 1 (BPAG1/BP230) - plectin
45
Congenital epidermolysis bullosa simplex in cattle is caused by a mutation in what?
Keratin 5
46
Congenital epidermolysis bullosa simplex in Cardigan Welsh Corgis is caused by a mutation in what?
Keratin 5
47
Congenital epidermolysis bullosa simplex in felines is caused by a mutation in what?
Keratin 14
48
Plectin gene of interest
PLEC1
49
Plectin is a dumbbell-shaped protein that belongs to a family of what?
Plakins (size ~500kDa)
50
Where in the hemidesmosome is plectin located?
Inner plaque
51
What are the main roles of plectins?
- structural/mechanical integrity of hemidesmosomes - linkage of intracellular cytokeratin proteins - scaffold for signaling
52
What do plectins bind to?
- β4-subunit of α6β4 integrin (in the outer plaque of the hemidesmosome and in the lamina lucida) - Keratin intermediate filaments - Collagen XVII (component of anchoring filaments)
53
Congenital epidermolysis bullosa simplex is associated with a mutation in PLEC1 in what two animals?
- Eurasier dog - Horse (foal with EBS and laminitis)
54
Where in the hemidesmosome is BPAG1 (bullous pemphigoid antigen 1 located?
Intracellularly in the inner plaque of the hemidesmosome
55
Roles of BPAG1
- structural/mechanical integrity of hemidesmosomes, - signaling protein for epidermal migration and cell polarity
56
What does BPAG1 bind/what is it bound to?
- intermediate filaments - α6β4 integrin (β4 subunit) - Collgen XVII
57
BPAG1 is a minor target of autoantibodies in what two diseases in dogs?
- Bullous pemphigoid - Mucous membrane pemphigoid
58
BPAG1 is a dumbbell-shaped protein that belongs to a family of what?
Plakins
59
Genes for α6β4 integrin?
- ITGA6 - IGB4
60
Which is the short and which is the long chain of transmembrane integrin α6β4?
- α6 is shorter (~120kDA) with only a small intracytoplasmic portion - β4 is longer (~205 kDa)
61
Where is integrin α6β4 located?
- inner and outer plaque of hemidesmosomes (primarily outer) - lamina lucida
62
Roles of integrin α6β4?
- structural/mechanical integrity of hemidesmosomes - homeostasis (adhesion, differentiation, proliferation) - signaling - hair growth
63
What is integrin α6β4 bound to?
- intermediate filaments - Plectin - BPAG1e - Collagen XVII - Laminin 332
64
Congenital junctional epidermolysis bullosa in cattle is caused by a defect in what gene? What does that gene encode?
- ITGB4 and ITGA6 - Encodes integrin α6β4
65
Congenital junctional epidermolysis bullosa in SHEEP is caused by a defect in what gene? What does that gene encode?
- ITGB4 - Encodes integrin α6β4
66
Gene for Collagen XVII
COL17A1
67
Roles of Collagen XVII
- responsible for structural/mechanical integrity of hemidesmosomes - basal cell migration and adhesion - enamel formation
68
What does Collagen XVII (primary collagen of intermediate filaments) bind to?
- BPAG1e - plectin - integrin α6β4 - laminin 332
69
Congenital junctional epidermolysis bullosa is caused by a defect in what gene of cats?
COL17A1
70
What domains is laminin 332 composed of?
Heterotrimer: alpha-3, beta-3 and gamma-2 domains organized into a cross-shaped with a3A chain isoform being shorter
71
Is laminin 332 intracellular or extracellular?
Extracellular in the lamina lucida (then anchors into the lamina densa)
72
Roles of laminin 332?
- responsible for structural/mechanical integrity of the dermo-epidermal junction - embryogenesis - tissue morphogenesis - regulation of proliferation and differentiation - tumorigenesis
73
Laminin genes (3)
- LAMA3 - LAMB3 - LAMC2
74
What are the minor antigens targeted in membrane pemphigoid of the dog and cat
- Laminin 332 - BPAG1e (BP230)
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Congenital junctional epidermolysis bullosa has been reported in Shorthair pointers, Australian shepherds, American saddlebred horses, Belgian blue cattle, Hereford cattle, Belgian, Italian, and French draft horses, and German black headed mutton sheep due to genetic defects encoding what glycoprotein? What gene is affected?
Laminin 332 **LAMC2**
76
Genes encoding Collagen IV
COL4A1 to COL4A6
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Where is Collagen IV primarily located in the BMZ?
Lamina densa *there they are believed to form a tight hexagonal meshwork*
78
Roles of collagen IV
- responsible for structural/mechanical integrity of the dermo-epidermal junction by forming a three-dimensional lattice framework (majority of lamina densa) - tumorigenesis
79
What does Collagen IV bind to?
- laminin 332 - perlecan - nidogen - fibronectin - collagen VII
80
A defect in COL4A5 is known to cause what syndrome in Samoyeds?
Alport syndrome; early onset renal failure
81
A defect in COL4A4 in English Cocker Spaniels is known to cause what congenital disease?
Autosomal recessive hereditary nephropathy
82
Genes of nidogen 1 and 2
NID1 and NID2
83
What type of molecules are nidogens
sulfated monomeric glycoproteins
84
Why does PAS stain the lamina densa?
due to its composition of glycoproteins (ie laminins and nidogens) and proteoglycans (perlecan, etc)
85
Roles of nidogen
- responsible for structural/mechanical integrity of the dermo-epidermal junction - embryogenesis - tumorigenesis
86
What does nidogen bind to?
Collagen IV, other nidogens, laminins
87
Gene encoding perlecan
HSPG2
88
What type of molecules are nidogens?
glycoproteins
89
What type of molecule is perlecan?
Proteoglycan
90
Roles of perlecan?
- responsible for structural/mechanical integrity of the dermo-epidermal junction - epidermal morphogenesis - regulation of angiogenesis and chondrogenesis - cell signaling - growth factor delivery - main proteoglycan of the BMZ
91
What does perlecan bind to?
laminin 332 and collagen IV
92
Gene encoding collagen VII
COL7A1
93
What does Collagen VII form in the BMZ
Anchoring fibrils
94
Roles of Collagen VII
responsible for structural/mechanical integrity of the dermo-epidermal junction by looping around dermal collagen and thus anchoring the epidermis to the dermis
95
What does collagen VII bind to?
Collagen IV, laminins 331 and 332
96
Graphic of adhesion structures of the skin
97
Sub-epidermal blistering disease that predominantly impacts mucosa/mucous membrane junctions with minimal to no haired skin involvement
mucous membrane pemphigoid
98
Three important components of the hemidesmosome outer plaque
- Collagen XVII - integrin α6β4 - CD151
99
Infectious cause of acantholysis in dogs
- superficial pustular dermatophytosis (Trychophyton) - exfoliative pyoderma (due to SIET)
100
Infectious cause of acantholysis in horses
superficial pustular dermatophytosis (Trychophyton)
101
Infectious cause of acantholysis in piglets
Exudative epidermitis (Staphylococcus hyicus) d/t exfoliatin toxins -> Dsg1
102
Lethal acantholytic epidermolysis bullosa in people is caused by an autosomal recessive mutation in what?
DSP (desmoplakin gene)
103
What mutation causes Darier's disease in dogs (mainly Irish Terriers, English Setters, and sometimes Shih Tzu's)
Mutation of the ATP2A2 gene
104
Is Darier's disease autosomal recessive or autosomal dominant?
Autosomal dominant
105
Histo findings in Darier's disease
acanthosis with orthokeratotic and parakeratotic hyperkeratosis and marked, diffuse, multifocal areas of acantholysis of the lower and middle portions of the epidermis and follicular outer root sheath. The acantholysis is often so marked that the appearance of the affected epidermis is likened to that of a dilapidated brick wall. Acantholytic dyskeratotic keratinocytes (corps ronds) may be visible.
106
Clinical signs of Darier's disease
proliferative, crusted plaques esp on pressure points on the limbs,on the ventral chest, or the pinnae
107
Trychophyton spp. proteases that cause acantholysis
- subtilisins - fungalysin metalloproteases - dipeptylpeptidases - aminopeptidases - carboxypeptidases
108
Infectious causes of acantholysis in humans
- bullous impetigo - Staphylococcal scalded skin syndrome
109
Exfoliative toxins of Staph hyicus (exfoliative epidermitis/Greasy pig) that cause acantholysis
ExhA, ExhB, ExhC, ExhD, SHETA, SHETB (Exh = exfoliative toxin)
110
Clinical signs of exfoliative epidermitis in pigs
- Acute to peracute dermatitis, starts on face → generalized haired skin + coronary bands & heels - Erythema, brown exudate, shallow erosions, crusts
111
Histo features of exfoliative epidermitis in pigs
Intragranular acantholysis (pustules) & subcorneal cleft formation (vesicles), variable superficial neutrophilic folliculitis.
112
Acantholytic disorders impact what layers of the epidermis
stratum spinosum and granulosum
113
Injection of what purified Staph pseud toxin into dogs can result in acantholysis and a positive Nikolsky's signs?
Staphylococcus intermedius exfoliative toxin (SIET)
114
Two phenotypes of exfoliative superficial pyoderma (ESP) in dogs
- superficial spreading pyoderma: Rapidly expanding epidermal collarettes - resembling Staphylococcus Scalded Skin (SSS) in people: Acute onset of regional/generalized erythema with overlying scale, often large sheets.
115
The autosomal dominant ATP2A2 mutation that causes canine Darier's disease alters the homeostasis of what mineral?
Calcium
116
How does altered Ca homeostasis in canine Darier's disease lead to keratinocyte apoptosis?
altered intracellular Ca homeostasis in epidermis → abnormal processing/function of desmosomal cadherins (no E cadherin, upreg P cadherin) & delayed exit from cell cycle → keratinocyte apoptosis
117
Human disease that is caused by an ATP2A2 mutation
Hailey-Hailey disease (benign familial chronic pemphigus)
118
Ectodermal dysplasia-skin fragility syndrome in Chesapeake Bay retriever dogs occurs due to a mutation in what gene?
PKP1 gene
119
What does the PKP1 gene encode?
plakophilin-1
120
Main body sites affected in junctional EB
- oral cavity - haired skin - claws - foot pads - skin over bony prominences and frictional sites preferentially affected
121
JEB histopath (where is the separation?)
Clean separation of epidermis from dermis at dermal epidermal junction
122
Congenital junctional epidermolysis bullosa can look histologically similar to dystrophic epidermal bullosa. What stains can be used to distinguish the two?
PAS (stains lamina densa) or anti-collagen IV (most abundant in lamina densa) IHC -> floor of blister is stained in JEB (integrin a6B4, collagen XVII, or laminin 332 targeted) -> roof of blister is stained in DEB (collagen VII is targeted in the sublamina densa)
123
Dystrophic epidermolysis bullosa causes a separation in the skin. Where does that separation occur?
within the lamina densa (d/t defect in collagen VII)
124
Clinical signs of dystrophic epidermolysis bullosa
- Extensive ulceration of oral cavity, oropharynx, paw pads, claw beds, pressure points, and skin overlying bony prominences (metacarpal or metatarsal joints), and tail tip - Claws may slough - May see defective tooth enamel and growth retardation
125
What clinical sign can be used to differentiate EBA from MMP?
Foot pad sloughing
126
Clinical signs of EBA
- Ulceration of the oral cavity, lips, concave pinnae, hair skin in areas of friction/pressure (groin, axillae, pressure points). - Tense vesicles & bullae → deep erosions & ulcers - Foot pad sloughing (differentiates EBA from MMP). - Erythematous macules, patches, papules, wheals (these all may come before blisters) - Variable pruritus. - Systemic signs of illness
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