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EV ACVD Study > Pemphigus/pemphigoid (NAVDF Tham + Olivry acantholytic 2009 review, Tham Deep Pemphigus review 2020, Tizard Autoimmune) > Flashcards

Pemphigus/pemphigoid (NAVDF Tham + Olivry acantholytic 2009 review, Tham Deep Pemphigus review 2020, Tizard Autoimmune) Flashcards

1
Q

What layer of epidermis does pemphigus foliaceus affect

A

Stratum spinosum + Stratum granulosum

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2
Q

What layer of epidermis does pemphigus vulgaris affect

A

Stratum basale

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3
Q

Major autoantigen for canine PF

A

DSC-1

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4
Q

Major autoantigen in PF in humans

A

DSG-1

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5
Q

Major autoantigen of PF in cats

A

Unknown.

Anti-keratinocyte IgG in 23/30 cats in 1 study

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6
Q

What is the etiology of PF usually?

A

*Spontaneous
Possibly UV triggered

Other triggers:
*Drug/insecticide

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7
Q

What drugs can cause PF in dogs?

A

*TMS
*Topical ketoconazole
*Insecticide (Promeris, Certifect (Amitraz/ metaflumizone), Vectra 3D. Nexgard!)
*Oxacillin, ampicillin, cephalexin

No drug challenged performed, so cannot CONFIRM it was drug

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8
Q

What drugs can cause PF in cats?

A

*Cimetidine
*Doxycycline

*Econazole/Neomycin/Triamcinolone/Amoxicillin
*Itraconazole/lime sulfur

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9
Q

What is ENDEMIC pemphigus foliaceus?

A

*Fogo salvagem (Brazil)
*Sand fly salivary antigen LJM11

Also: young, poor women in S Tunisia. High temp, UV radiation, contact with ruminants, infections, genetic susceptibility

IgE to insect, then transforms to TgG4 against Dsg1 on keratinocytes

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10
Q

Pathomechanism of endemic PF

A

*Body makes IgG4 (instead of nonpathogenic IgG1) against sandfly salivary antigen
*IgG4 binds to EC1 and EC2 of DSG1
*DSG1 then cannot function for cell adhesion –> acantholysis

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11
Q

Sandfly salivary antigen that can trigger PF

A

LJM11

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12
Q

Canine PF clinical distribution types

A

*Facial dominant
*Generalized
*Footpad exclusive
*Trunk-dominant

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13
Q

Is the ability to detect anti-DSC1 IgG lower in trunk-dominant or facial PF? (Bizikova 2022)

A

Trunk dominant has lower anti-DSC IgG (58%) compared to facial dominant PF (100%)

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14
Q

T or F: Absence of anti-DSC IgG can be used to rule out PF

A

FALSE.

Many dogs with trunk-dominant PF do not have detectable anti-DSC IgG, even though their major autoantigen is still DSC-1

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15
Q

How can you differentiate between trunk-dominant PF, pustular dermatophytosis, and pyoderma?

A

*Dermatophytosis: centrifugal expansion of lesions
*Pyoderma: footpads shouldn’t be affected

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16
Q

What are the clinical distribution types of feline PF?

A

*Claw fold exclusive (11%)
*Periareolar region (10%)

In addition to facial regions

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17
Q

Treatment canine PF

A

*Oral glucocorticoids to induce remission
*Consider PULSE GCs

+/- steroid-sparing agents
*Azathioprine
*Cyclosporine
*Mycophenolate
*Apoquel

+/- adjunct immunomodulatory drugs
*Doxy/niacinamide (only 1/8 dogs benefit)
*Polysulfated glucosaminoglycans (usually arthritis tx; can act as steroid sparing agent! Mechanism: inhibition of proteases in complement cascade?? Reduces inflammatory cell migration??)

IF REFRACTORY:
*IVIG (efficacy may reduce over time)

IN THE FUTURE:
*Bruton’s tyrosine kinase inhibitor (BTKi)

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18
Q

Benefits of pulse GC therapy for canine PF

A

*Higher proportion of dogs achieve CR in 3 months
*Average dose of GC is lower overall
*Minimal AEs compared to conventional dosing

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19
Q

Feline PF treatments

A

*Oral glucocorticoids
*Pulse therapy not helpful in cats
*Apoquel (1 mg/kg BID tapered to 0.5mg/kg BID)
+/-
*Cyclosporine
*Chlorambucil

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20
Q

Pemphigus vulgaris major autoantigen in humans

A

Mucosal form: DSG-3 only
Mucocutaneous form: DSG-3 + DSG-1

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21
Q

Pemphigus vulgaris major autoantigen in dogs

A

DSG-3

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22
Q

Pemphigus vulgaris major autoantigen in cats

A

Unknown

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23
Q

Which layer of haired skin/foot pad as the most DSG3

A

Stratum basale

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24
Q

Which layer of haired skin/foot pad has the most DSC1

A

Stratum granulosum, Stratum spinosum

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25
Q

What layer of buccal mucosa has highest amount of DSG 3?

A

Stratum basale

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26
Q

How does autoantigen IgG lead to blisters in AISBDs?

A

Fab region binds to autoantigen, which induces C1q component of complement system –> Complement-dependent cytotoxicity –> Blisters

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27
Q

T or F: acantholysis requires interaction between IgG and complement system

A

FALSE.

PF/PV only need Fab region of IgG to induce acantholysis. Do NOT need Fc region/complement interactions

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28
Q

Mechanisms of acantholysis (3)

A

1) Steric hinderance
2) Desmoglein internalization and depletion
3) Signaling pathway interfering with cell adhesion

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29
Q

Mechanism of steric hinderance –> acantholysis

A

Binding of auto-Ab prevents bonding of desmoglein on same cell AND desmosomes between 2 cells

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30
Q

Mechanism of desmoglein depletion –> acantholysis

A

Binding of auto-Ab inhibits desmosome assembly

Also affects CLUSTERING of desmoglein, so it can’t function appropriately

When desmoglein is clustered (and nonfunctional), the desmosome is endocytosed and recycled –> depletion

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31
Q

Mechanism of signal transduction –> acantholysis

A

Auto-Ab affects the signal transduction pathway is affected. Leading to steric hinderance and desmoglein depletion

*Overexpression of c-myc in PV dogs interferes with signaling cascade needed for DSG-3 expression

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32
Q

Function of c-myc

A

Proto-oncogene

*Induces proliferation, transformation, and apoptosis

*Over expressed in canine PV

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33
Q

Clinical lesions of canine PV

A

*Erosions/ulcerations
*Mucous membranes +/- MC junctions involved
*Nail exclusive form (n=2), w/ onychomadesis
*Footpad only form (n=1)

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34
Q

Histopath of PV

A

Suprabasilar cleft w/tombstone appearance of basal keratinocytes

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35
Q

Treatment for canine PV

A

BEST FOR CR: GC + aza

*Apoquel 0.5mg/kg BID, CR in 6w
*GC, AZA, CsA, heparin, doxycycline

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36
Q

Diseases of pemphigoid complex

A

*MMP
*EBA
*BP

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37
Q

Most common AISBD in dogs

A

MMP > EBA > BP

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38
Q

Autoantigen for EBA

A

Type VII collagen (NC1 domain)

Lamina densa, anchoring fibrils

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39
Q

Autoantigen for BP

A

*BP180 (Collagen 17)
>
*BP230 (BPAG1e)

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40
Q

Autoantigen for MMP in dogs

A

*BP180 (Collagen 17, NC16A domain)
*BP230 (BPAG1e)
*Laminin 332

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41
Q

Pathogenesis of blister formation in AISBD

A

*Activation of complement system

Binding of autoantibodies –> antigen-antibody complex formation –> activation of complement pathway

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42
Q

3 Pathways for Complement Activation

A

1) Classical pathway (initiated by antigen-antibody complexes)
2) Lectin pathway (binding to mannose residues on cell or pathogen surfaces)
3) Alternative pathway (activated by spontaneous hydrolysis of C3 or via classical/lectin pathways)

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43
Q

Mechanism of classical complement pathway

A

*C1q binds to Ab-Ag complex
*Complement cascade activated
*Results in anaphylatoxins (C3a, C5a), opsonization (C3b), and MAC formation (C5b)

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44
Q

Which type of complement cascade activation occurs in AISBDs?

A

Classical complement pathway (via C3a, C5a)

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45
Q

What factors are released by inflammatory cells that lead to blister formation in AISBDs?

A

*Neutrophil elastase
*MMP-9
*ROS

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46
Q

Clinical features of AISBDs

A

*Vesicles/bullae
*Ulcerations
*Crust
*Depigmentation/scarring if chronic

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47
Q

Histopath for AISBDs

A

*Subepidermal cleft on histopath

*intact vesicles, ulcers

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48
Q

Which AISBD is mucosal/MC dominant with minimal skin lesions

A

MMP

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49
Q

Which AISBD is haired skin only

A

BP

50
Q

EBA clinical features

A

*Young dogs (1-2 yrs old)
*Great Danes
*Severe systemic signs (fever, lymphadenopathy, lethargy, anorexia)

51
Q

Treatment AISBDs

A

*Chronic relapsing course

*MMP:
-Doxycycline/ niacinamide
-Oral GC + AZA/CsA/Dapson

*EBA:
-Oral GC +/- AZA, colchicine

*Other AISBD:
-Oclactinib
-Oral GC + MMF

52
Q

Which distribution of canine PF is more often pruritic?

A

Truncal (>60%)

But median pVAS of truncal and facial are similar. Similar in cats

53
Q

What is the desmoglein compensation theory

A

When only one desmoglein molecule is “destroyed” by anti-DSG-3 AA, the other desmoglein takes over all the adhesion responsibility

(aka, why only MM affected in PV, even though DSG-3 is also present in skin in low amounts. BC DSG-1 can hold skin together).

54
Q

Which non-DSG autoantibodies can contribute to blister formation in PV?

A

*Acetylcholine receptors
*Soluble Fas ligands
*Mitochondrial proteins
*E-cadherin

55
Q

T or F: A PV affecting only the claws has been reported

A

True

56
Q

T or F: PV affecting only the footpads has been reported

A

True.

Sloughing of footpads

57
Q

CsA at 4 mg/kg/d and vitamin E was successful in inducing CR of which pemphigus/pemphigoid disease

A

PV canine

58
Q

Most commonly affected body sites: MMP

A

Gingiva, hard palate

> > periocular, perioral, nasal planum, anogenital. Less likely haired skin

59
Q

Body regions EBA

A

Oral cavity, glaborous skin (axillae, groin), footpads

60
Q

Is footpad involvement more common in canine BP or EBA

A

EBA

61
Q

Which AISBDs do cats have

A

*BP (2 cases)
*MMP (1 case)

62
Q

Which species has a familial acantholysis; similar to acantholytic epidermolysis bullosa in humans?

A

Angus calves

63
Q

Which species has a hereditary suprabasal acantholytic mechanobullous dermatosis; similar to acantholytic epidermolysis bullosa in humans?

A

Buffaloes

64
Q

2 diseases that target DSG3 in dogs

A

*Pemphigus vulgaris
*Paraneoplastic pemphigus

65
Q

Targets for mucocutaneous pemphigus vulgaris

A

DSG1, DSG3

66
Q

Pemphigus vegetans target

A

DSG1

Perioral, perianal, skin folds

67
Q

Bacteria that causes Exudative Epidermitis in puglets

A

Staphylococcus hyicus

68
Q

What is the virulence factor and target in Exudative Epidermitis?

A

*Exfoliatin toxin
*DSG-1

69
Q

3 general etiologies of acantholytic diseases

A

*Genetic
*Autoimmune
*Proteolytic (bacteria, fungal)

70
Q

Acantholytic epidermolysis bullosa simplex in Angus cattle and Murrah buffalo: clinical lesions

A

Erosions, ulcers on pressure points of limbs, + tail. + Oral cavity + hoof sloughing

71
Q

Prognosis of Acantholytic epidermolysis bullosa simplex in Angus cattle and Murrah buffalo

A

Lethal

72
Q

Level of split for Acantholytic epidermolysis bullosa simplex in Angus cattle and Murrah buffalo

A

Suprabasilar + intrabasilar acantholysis

ABSENT DESMOSOMES

73
Q

Protein/Gene mutated for Darier diseases

A

SERCA2 (? Disproven, ATP2A2

74
Q

Protein/Gene mutated for Hailey Hailey disease

A

SPCA1, ATP2C1

75
Q

Age of onset for Darier, Hailey Hailey

A

<2 months for canines

Puberty for humans

76
Q

Clinical lesions Darier disease

A

Hyperplastic, scaly/greasey papules and plaques on head & lateral limbs

77
Q

Clinical lesions Hailey Hailey disease

A

Vesicular lesions –> crusts, scaling on flexural surfaces

78
Q

Histopath Darier Disease

A

*Suprabasilar acantholysis
*Corps ronds/ round bodies = dyskeratotic keratinocytes
*Basal cell vacuolation
*Decreased lateral desmosome adhesion
*Separation of keratin filaments from desmosomes –> Circular accumulation of keratin around nucleus, “perinuclear keratin rings”

79
Q

Etiology Darier Disease, Hailey Hailey disease

A

*2’ impaired desmosome function (Cadherins need Ca to function) vs abnormal epidermal differentiation (abnormal Ca = more time in cell cycle, more mutations)

*Altered intracellular calcium homeostasis

80
Q

Disease with “corps ronds”

A

Darier disease
= dyskeratotic keratinocytes

81
Q

Hailey Hailey disease histopath

A

*Suprabasilar acanthylosis
*Separation of keratin filaments from desmosomes –> perinuclear keratin rings

82
Q

Which level of epidermis are corps ronds present in Darier Disease

A

Stratum spinosum

Parakeratotic stratum corneum: “grains”

83
Q

Breeds predisposed to pemphigus vulgaris

A

*German Shepherd dog
*Collies

84
Q

Where are DSG1, DSG2, plakoglobin and desmoplakins in dog with Darier disease?

A

Cytoplasm. NOT at cell membrane

85
Q

Sex predisposed to pemphigus vulgaris

A

*Males

86
Q

Which type of antibody against DSG3 can be found in circulation in dogs with pemphigus vulgaris

A

IgG4

(Also IgG4 in PF)

87
Q

Histopath of paraneoplastic pemphigus

A

*Suprabasilar acantholysis
*Apoptotic keratinocytes w/satellitosis

PV + EM = paraneoplastic pemhigus

88
Q

Target of paraneoplastic pemphigus

A

*DSG3
*Plakins (envoplakin, periplakin)

89
Q

Dog breed w/ Pemphigus Vegetans (1 case)

A

Greater Swiss Mountain Dog

90
Q

Histopath finding of Pemphigus Vegetans

A

*Epidermal hyperplasia
*Neutrophilic, eosinophilic acantholytic pustules in MULTIPLE LEVELS
-Suprabasal
-Intrasponous
-Subcorneal

91
Q

Clinical lesions of pemphigus erythematosus (PE)

A

*Superficial pustular lesions (like PF)
*Deep nasal ulcers (like DLE)

92
Q

Trichophyton proteases that may cause proteolytic acantholysis

A

*Substilisins
*Fungalysin metalloproteases
*Di-peptyl-peptidases
*Amino- or caroboxy- peptidases

93
Q

Histopath of superficial pustular dermatophytosis

A

*Neutrophilic subcorneal pustules w/acantholytic keratinocytes
*Lymphocyte-rich interface dermatitis
*Dermatophyte hyphae in stratum corneum
*MINIMAL DERMATOPHYTE HAIR INVASION (dif than classical dermatophytosis)

94
Q

3 Staphylococcus species that can cause Exudative epidermitis in piglets

A

1) Staphylococcus hyicus
2) Staphylococcus chromogenes
3) Staphylococcus sciuri

95
Q

Where do clinical lesions of Exudative epidermitis begin?

A

Face (acute or peracute) + Coronary bands, heels

Generalized erythema, brown exudate, crusting over shallow erosions

96
Q

Which toxins are implicated in Exudative epidermitis

A

Exfoliatin toxins
*ExhA
*ExhB
*ExhC
*ExhD
*SHETA
*SHETB

–> Digest DSG1

97
Q

Target of Exudative epidermitis

A

DSG1

98
Q

Bacteria implicated in bullous impetigo and exfoliative superficial pyoderma in dogs

A

Staphylococcus pseudintermedius

99
Q

Age of dogs overrepresented for Bullous Impetigo

A

Puppies or immunosuppresse old dogs

100
Q

Clinical lesions in Bullous Impetigo

A

Large non-follicular pustules –> rupture into yellow crusts, epidermal collarettes

USUALLY NO PAPULES

101
Q

Location in epidermis of pustules of bullous impetigo

A

Subcorneal or Intragranular (like PF)

Neutrophilic w/AKs + Gram positive cocci

102
Q

Superficial spreading pyoderma clinical lesions

A

Rapidly expanding epidermal collarettes, polycyclic pattern

Centrifugal peeling of stratum ocrneum

103
Q

Staphylococcal scalded skin syndrome clinical lesions

A

Acute onset regional/generalized erythema with large sheets of scale

104
Q

Toxin associated with Exfoliative Superficial Pyoderma

A

Exfoliatin toxin
*SIET

DIFFERENT than exfoliatin toxins of Staph aureus and hyicus.

105
Q

T or F: If you inject ETA, ETB or ETD from S aureus into a dog, they will develop acantholytic epidermal pustules

A

FALSE.
Each exfoliatin toxin is species specific

106
Q

Idiopathic linear pustular acantholytic dermatosis in 2 dogs, clinical lesions

A

Linear coalescing papules, pustules, crusts with peripheral erythema on face, limbs

107
Q

Idiopathic linear pustular acantholytic dermatosis in 2 dogs, treatment

A

Responsive to high dose medrol in both dogs. Recurrence in 1 dog.

Infectious etiologies were ruled out. Each dog only had a SINGLE lesion!

108
Q

Dog Breeds overrepresented for Pemphigus foliaceus

A

*Akita
*Chow Chows

(+others, but varies based on the study/geographic region)

109
Q

Horse Breeds overrepresented for Pemphigus foliaceus

A

*Appaloosa

110
Q

Unusual clinical sign in horses with Pemphigus foliaceus

A

Ventral edema

111
Q

Diseases encompassed by Panepidermal Pustular Pemphigus

A

Pemphigus vegetans (DSG1) + Pemphigus erythematosus (unknown target)

112
Q

Breed for Darier disease

A

Irish Setter

(Also shih tzu)

113
Q

Genetic acantholytic dermatoses (acantholytic EBS, Darier): desmosomes on electron microscopy

A

Rare to absent
Keratin intermediate filaments often detached from desmosomes, with cytoplasmic aggregation

114
Q

Which types of pemphigus have a positive Direct Nikolskiy sign

A

Pemphigus vulgaris
Paraneoplastic pemphigus

(unknown if pemphigus vegetans does)

115
Q

IgA pemphigus targets, layers in epidermis affected

A

IgA against DSC1, DSC3

Affects spinous and granular layers of epidermis

116
Q

Breed pemphigus erythematosus

A

GSD, Sheltie, Collie

117
Q

Immune response causing pemphigus vulgaris

A

T cell-mediated component: Th1 via IFNg

Also, Th2 cytokines (IL-4) promote B cell proliferation, antibody production, antibody class switching
Th17 also involved

118
Q

Linear IgA Dermatosis target, location in BMZ

A

Collagen 17
Lamina densa

119
Q

Clinical sign of linear IgA dermatosis

A

Eosinophilic papules, pustules
Pruritic

Dachshunds

120
Q

Target of MMP in cats

A

Laminin 5

(usually collagen 17 CN16A domain in dogs)

121
Q

JEBA target

A

Laminin 332

122
Q

Which cells are implicated in bullous pemhigoid

A

Treg dysfunction

Allows Th2 to make IL-4, which stimulates B cell antibody production

Th17 recruits neutrophils

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