BMZ, adhesion molecules, AISBDs Flashcards
(174 cards)
1
Q
What is the keratin composition of intermediate filaments?
A
Keratin-5 (basic), keratin-14 (acidic)
2
Q
Define intermediate filament
A
Connection between the keratinocyte nucleus to hemidesmosomes on the keratinocyte membrane. Responsible for structure of basal keratinocytes
3
Q
What is the composition of the inner plaque of the hemidesmosome?
A
Plectin
BPAG1-e
4
Q
What is the composition of the outer plaque of the hemidesmosome?
A
Integrin alpha6beta4
collagen XVII (cytoplasmic domain)
5
Q
Define anchoring fibrils
A
Connections extending from lamina densa to collagen fibers in the dermis
6
Q
What is the collagen composition of anchoring fibrils?
A
Collagen VII
7
Q
Define integrins
A
Cell adhesion molecules that connect the extracellular matrix to the cytoskeleton
8
Q
What family is BPAG1-e a member of?
A
Plakins
9
Q
What autoimmune conditions in dogs may result from autoantibodies against BPAG1e?
A
Bullous pemphigoid, MMP
10
Q
Which classes of adhesion molecules (CAMs) operate independent of Ca++?
A
integrins, IgCAMs
11
Q
Which classes of adhesion molecules (CAMs) are dependent on Ca++?
A
cadherins, selectins
12
Q
What class of adhesion molecules is present on leukocytes, allowing for leukocyte adhesion to the endothelium?
A
Integrins
13
Q
What type of integrins bind leukocytes to the endothelium?
A
Beta2
14
Q
What type of integrins bind T-cells to APCs?
A
Beta2
15
Q
What beta2 chain is common to many integrins?
A
CD18
16
Q
What is a primary role of beta3 integrins?
A
Clotting
17
Q
What integrin on T-cells binds to ICAM-1 on APCs to allow for successful antigen recognition?
A
LFA-1
18
Q
What integrin on endothelial cells is important for extravasation of leukocytes when bound?
A
ICAM-2 (bound by LFA-1 on neuts)
19
Q
What does alpha6beta4 bind to extracellularly?
A
Laminin 332
20
Q
In what layer(s) of the epidermis are integrins expressed?
A
Stratum basale only
21
Q
What cell adhesion molecule is present on inflamed endothelial cells and binds VLA-4 to allow for generation of ROS?
A
VCAM-1 (CD106)
22
Q
What are the classical type 1 cadherins?
A
E-cadherin, N-cadherin, P-cadherin
23
Q
What cell types express N-cadherin?
A
Myocytes, neurons, fibroblasts
24
Q
What are the classical type 2 cadherins?
A
VE-cadherin, M-cadherin
25
What cadherin becomes temporarily dysregulated to allow for diapedesis?
VE-cadherin
26
What is the major autoantigen in human PF?
Desmoglein-1
27
What is the major autoantigen in canine PF?
Desmocollin-1
28
What is the autoantigen in pemphigus vulgaris?
Desmoglein-3
29
Describe the locations of desmogleins 1-3 in the epidermis
Desmoglein-1: superficial epidermis
Desmoglein-2: basal layer
Desmoglein-3: deep epidermis
30
Name two major functions of selectins
1. Mediate initial low-affinity adhesion of WBC to endothelium
2. Lymphocyte homing
31
What cell types express P-selectin?
Endothelial cells, platelets
32
What structures within endothelial cells store P-selectin?
Weibel-palade bodies
33
What structures within platelets store P-selectin?
alpha granules
34
What activates P-selectin?
Histamine, thrombin
35
What cells express E-selectin?
Endothelial cells
36
What triggers activate E-selectin?
IL-1, TNF, LPS
37
What cells express L-selectin?
Leukocytes (NOT endothelial cells)
38
What dog breed is reported to be associated with canine leukocyte adhesion deficiency (CLAD)?
Irish Setters
39
Describe the pathogenesis of canine leukocyte adhesion deficiency
Single missense mutation in beta2-integrin subunit gene --> cysteine replaced by serine at AA36 --> disulfide bond disruption in CD18 leading to less WBC binding --> recurrent infections despite normal or high WBC counts
40
How would you diagnose CLAD?
PCR (can be done on oral swab)
41
What cow breed has been reported in bovine leukocyte adhesion deficiency (BLAD)?
Holstein
42
Describe the pathogenesis of BLAD
Point mutation in CD18 gene --> aspartic acid replaced by glycine --> dysfunctional integrin assembly and lack of WBC diapedesis
43
What are the 4 major types of adhesive structures in the epidermis?
Adherens junctions, desmosomes, tight junctions, hemidesmosomes
44
What histologic stain could be useful to highlight the BMZ?
PAS
45
Name the layers of the basement membrane zone
Basal keratinocyte --> basal lamina (lamina lucida + lamina densa) --> sublamina densa
46
Know the locations of various molecules in each layer of the BMZ
47
Define the location of hemidesmosomes
Found along the ventral aspect of the basal keratinocyte
48
Name the 4 components of a hemidesmosome
BPAG-1
plectin
integrin alpha6beta4
collagen XVII
49
What is the molecular target of epidermolysis bullosa simplex in cattle and dogs?
KRT5
50
What is the molecular target of epidermolysis bullosa simplex in cats?
KRT14
51
What is the molecular target of epidermolysis bullosa simplex in Eurasier dogs?
Plectin
52
What is the molecular target of junctional epidermolysis bullosa in cattle?
ITGA6 (integrin alpha6), ITGB4 (integrin beta4)
53
What is the molecular target of junctional epidermolysis bullosa in sheep?
ITGB4 (integrin beta4)
54
What would be considered the primary inflammatory cell infiltrate in bullous pemphigoid in dogs?
Eosinophils
55
What is the target of bullous pemphigoid in dogs?
NC16A domain of collagen XVII
56
What does PAS stain in the lamina densa?
Nidogen and perlecan (proteoglycans)
57
What component of the basement membrane zone forms a hexagonal meshwork/lattice?
Collagen IV (lamina densa)
58
What is the main molecular target of epidermolysis bullosa acquisita (EBA) in dogs?
Collagen VII (esp NC1 domain)
59
What is unique in regards to EBA compared to other acquired AISBDs in dogs?
Age of onset- EBA has young onset (1-2 years though puppies may be affected), other AISBDs have 5-6 year of age onset
60
The "floor" stains on indirect immunofluorescence on salt split mucosa. What is/are the most likely differential(s)?
EBA
JEBA
bullous SLE
MMP (can be roof or floor)
mixed AISBD
61
The "roof"/epidermal side stains on indirect immunofluorescence on salt split mucosa. What is/are the most likely differential(s)?
BP (others: MMP, linear IgA)
62
There is "mixed" staining on indirect immunofluorescence on salt split mucosa. What is/are the most likely differential(s)?
MMP (usually roof stains but can be both)
JEBA
63
A ragged, intracellular split occurs on PAS staining of a suspect AISBD. What is the most likely differential?
EB simplex (targets KIF)
64
What is the major autoantigen in MMP?
NC16A domain of collagen XVII (BPAG2)
--BPAG1e and laminin 332 also reported
65
What is the major autoantigen in canine JEBA?
Laminin 332
66
What antigens stain on the floor of salt-split skin?
Laminin 332, collagen IV, collagen VII
67
What antigens stain on the roof of salt-split skin?
K5, K14, plectin, BPAG1, BPAG2, integrin alpha6beta4
68
What is the most common AISBD in dogs?
MMP
69
What dog breed has a suspected genetic predisposition to EBA?
Great Dane (and less so GSP)
70
What 3 collagen types are part of the BMZ?
Collagen XVII (hemidesmosome)
Collagen IV (lamina densa)
Collagen VII (sublamina densa)
71
What do KIF attach to within the BMZ?
BPAG1 and plectin on inner plaque
72
What does integrin alpha6beta4 bind to in the BMZ?
Inner plaque: BPAG1, plectin
Outer plaque: BPAG2
Lamina densa: laminin-332
73
What collagen type makes up most of the lamina densa?
Collagen IV
74
What collagen type makes up the anchoring fibrils that link the lamina densa to the sublamina densa?
Collagen VII
75
What parts of the BMZ are secreted by dermal fibroblasts?
Collagen IV, Collagen VII, laminin 332, laminin 311, laminin 511
76
Is epidermolysis bullosa cell-rich or cell-poor?
cell-poor
77
What cells secrete MOST components of the BMZ?
basal keratinocytes
78
What is another name for collagen XVII?
BPAG2
79
What is considered a crucial step in hemidesmosome assembly?
Binding of integrin alpha6beta4 to laminin-332
80
What structure of the BMZ looks like a cross?
Laminin-332
81
Are footpads commonly affected in canine bullous pemphigoid?
No (this helps differentiate it from EBA)
82
What breed is overrepresented in MMP?
GSD
83
Are footpads typically involved in MMP?
No
84
Is MMP rapidly or slowly progressive?
Slowly
85
Is EBA rapidly or slowly progressive?
Rapidly
86
Are footpads typically involved in EBA?
Yes- sloughing seen
87
What is the primary inflammatory infiltrate in EBA?
Neutrophils
88
In what layer of the BMZ would you find anchoring filaments?
Lamina lucida
89
What is the major target in dystrophic epidermolysis bullosa?
Collagen VII (COL7A1 gene)
90
What is the most common AISBD in humans?
Bullous pemphigoid
91
Where is the salt split for EBA?
Dermal side (both sides rare)
92
What is the pathogenesis of acquired junctional EB?
IgG autoantibodies to laminin 332
93
Where is the salt split for acquired junctional EB?
Dermal side or both
94
Where is the salt split for linear IgA bullous disease?
epidermal
95
When does the onset of epidermolysis bullosa simplex occur?
immediately after birth
96
Where do the blisters occur in junctional EB?
within the lamina lucida
97
Where do blisters occur in dystrophic epidermolysis bullosa?
Beneath lamina densa
98
What is the mutation in dystrophic epidermolysis bullosa?
COL7A1 (collagen VII)
99
What is the inheritance pattern for dystrophic epidermolysis bullosa in cats, dogs, and ruminants?
Autosomal recessive (humans also have a dominant form)
100
What is the PAS staining pattern for dystrophic EB?
BMZ attached to roof of cleft
101
What AISBD targets intermediate keratin filaments?
EB simplex
102
What AISBD targets plectin?
EB simplex (in Eurasier dogs and one horse case)
103
Where is integrin alpha6beta4 found in the BMZ?
Intracellular in the outer plaque AND extracellularly as part of lamina lucida
104
What AISBD occurs when integrin alpha6beta4 is affected?
Junctional EB
105
What congenital AISBD could result from targeting of collagen XVII?
Junctional EB (reported in 2 cats)
106
What autoimmune AISBDs could result from targeting of collagen XVII?
BP, MMP, linear IgA
107
Is laminin 332 located intracellularly or extracellularly?
Extracellularly
108
What congenital AISBD might result from targeting of laminin 332?
Junctional EB
109
What autoimmune AISBDs might result from targeting of laminin 332?
MMP, acquired JEB, mixed AISBD
110
What organ system is typically affected in congenital disorders affecting collagen IV?
Kidney (Samoyed, English Cocker Spaniel)
111
What diseases in vet med are associated with targeting of nidogens and perlecan?
none
112
What part of the BMZ loops around dermal collagen and helps anchor the epidermis to the dermis?
Collagen VII
113
What congenital AISBD might result from targeting of collagen VII?
Dystrophic EB
114
What autoimmune AISBDs might result from targeting of collagen VII?
EBA
type I bullous SLE
115
What breed is predisposed to EBA?
Great Dane
116
When doing salt split technique for an AISBD, where is the split occurring?
Through the lamina lucida (bottom is just lamina densa and dermis)
117
Are the blisters seen in AISBDs commonly tense or fragile?
Tense
118
How does BP in horses differ from that of other species?
More oral cavity involvement (haired skin predominance for other animals)
119
How does BP in pigs differ from that of other species?
Usually no mucosal involvement
120
What is the name of MMP in humans?
cicatricial pemphigoid
121
Are the larynx and esophagus usually involved in canine MMP?
No (they are in humans)
122
What has been the most helpful treatment for MMP?
Tetracycline/niacinamide
123
What is the main target for EBA?
Collagen VII (NC1 doman)
124
Are cats reported to be affected with EBA?
No (only dogs and humans)
125
Is the oral cavity involved in EBA?
Yes, always
126
What breeds are predisposed to JEB?
Australian Shepherds, GSP
127
What is the typical age of onset of JEB (not JEBA)?
Within a few weeks of birth (not right at birth)
128
What are the most common body regions affected with JEBA?
Pinnae, oral cavity
129
What AISBD in humans has a "string of pearls" clinical appearance?
Linear IgA disease
130
What are the autoimmune targets in mixed AISBD?
laminin 332 and collagen VII
131
What is the recommended treatment for pemphigoid gestationis?
Ovariohysterectomy--> complete remission within a few months
132
Is dystrophic EB congenital or acquired?
Congenital
133
Is the inheritance of dystrophic EB recessive or dominant in animals?
Recessive (humans also have a dominant form)
134
What are the two subtypes of human EBA?
Mechanobullous ("classic")
Inflammatory
135
What subtype of human EBA does the canine form most closely represent?
Inflammatory
136
What 3 clinical features help differentiate EBA from other AISBD?
Age of onset (young)
Oral cavity, glabrous skin, foot pads involved
More severe systemic CS
137
What is the most common treatment for canine MMP?
Tetracycline + niacinamide
138
What histopath stain is used to highlight the basement membrane?
PAS
139
Identify the structures of the basement membrane zone
140
What layer of the BMZ is an artifact of tissue processing?
Lamina lucida
141
What do intermediate filaments bind to within the hemidesmosome?
Plectin
BPAG1e
142
What hemidesmosome component is one of the earliest seen as the hemidesmosome develops?
CD151
143
What BMZ components does the alpha6 subunit of integrin alpha6beta4 interact with?
CD151
collagen XVII
144
What is the main component of anchoring filaments?
Laminin 332
145
What structures make up the lamina densa?
Collagen IV
Laminin-332
Nidogen
Perlecan
Collagen VII
146
What BMZ structure resembles a hockey stick?
Collagen IV
147
Is the sublamina densa part of the epidermis or part of the dermis?
Dermis
148
How do type II hemisdesmosomes differ from type I?
Type II found only in fetal skin
Type II contain only integrin alpha6beta4 and plectin
149
What components of the BMZ have been associated with tumor progression?
integrin alpha6beta4
laminin-332
CD151
Collagen VII
150
What is the staining pattern on salt-split mucosa for MMP?
Epidermal (most cases)
Dermal
Both
151
True or false: most cases of canine MMP went into remission with glucocorticoid monotherapy
False - tetracycline + niacinamide work best
GC alone are least successful in dz control
152
What test can be done to differentiate MMP from EBA?
PAS - stains floor/dermal side in MMP
153
What would the expected PAS staining pattern be for canine EBA?
Positive staining on roof/epidermal side
154
What would the expected salt-split staining pattern be for canine EBA?
Positive on the floor/dermal side
155
True or false: Systemic clinical signs are uncommonly seen in canine EBA
False - systemic signs are common
156
What species have been reported to be affected by EBA?
Dogs only
157
Is bullous pemphigoid primarily a disease of haired or non-haired skin?
Haired skin (exception: horses)
158
What is the PAS staining pattern for BP?
Stains floor/dermal side
159
What is the salt-split staining pattern for BP?
Roof/epidermal side
160
How can you differentiate canine EBA from JEBA?
PAS stain: JEBA has floor/dermal side staining
161
What is the salt-split staining pattern for JEBA?
Dermal or both
162
What are the targets of linear IgA disease?
cleavage products of collagen XVII
163
What AISBD exhibits a biphasic age distribution in humans?
Linear IgA disease
164
What is the salt-split staining pattern for linear IgA disease?
Roof/epidermal side
165
What is the PAS staining pattern for pemphigoid gestationis?
Floor/dermal side
166
What is the salt-split staining pattern for pemphigoid gestationis?
Roof/epidermal side
167
What is the target of pemphigoid gestationis?
Collagen XVII
168
What dog breed has been reported in pemphigoid gestationis?
Tibetan spaniel
169
What is the salt-split staining pattern for type I bullous SLE?
Floor/dermal side
170
What is the PAS staining pattern for type I bullous SLE?
Roof/epidermal side
171
What AISBD can be diagnosed solely on clinical and histopathologic features?
MMP (due to its restriction to mucous membranes)
172
What AISBD has been shown to have "rowing" of neutrophils along the BMZ?
EBA
173
What AISBD typically lacks inflammation on histopath?
MMP (though many AISBDs are not highly inflammatory)
174
What non-steroidal immunosuppressive drug can be particularly helpful for tx of EBA?
Colchicine (because of higher proportion of neutrophils seen in this AISBD)
