Autoimmune and Immune-Mediated Disorders Flashcards
1
Q
How can a dx of TEN be differentiated from a burn.
A
The dermis is not affected in TEN but is in a burn.
2
Q
Autoimmune Subepidermal Blistering Diseases
A
The common pathomechanism shared by these diseases is the autoimmune response against structural proteins of the dermo-epidermal junction.
The diagnosis of a specific AISBD is made by combining specific clinical features with histological and, more importantly, immunopathological data (e.g. direct IF, indirect IF on salt-split mucosa, antigen-specific assays).
3
Q
Diseases involving collagen XVII autoimmunity
A
1) Mucous membrane pemphigoid (MMP)
2) Bullous pemphigoid (BP)
3) Linear IgA disease (LAD)
4) Mixed AISBD
4
Q
Diseases involving Laminin-332 autoimmunity
A
1) Junctional epidermolysis bullosa acquisita (JEBA)
2) Mucous membrane pemphigoid
5
Q
Diseases involving Collagen VII autoimmunity
A
1) Epidermolysis bullosa acquisita (EBA)
2) Mixed autoimmune subepidermal blistering disease (Mixed AISBD)
3) Bullous systemic lupus erythematosus (bullous SLE)
6
Q
Mucous Membrane Pemphigoid (Dog)
A
- Mucous membrane pemphigoid is the most common AISBD recognized in dogs
- German shepherd dog and its crosses appear to be overrepresented
- The median age of onset was 6 years (range: 1-15 years), though almost one third of dogs (28%) was 8 years or older at the time of the disease onset
- Oral cavity involvement, the most commonly affected body area in dogs (33/53; 62%)
- Footpad involvement that is commonly seen in dogs with EBA is not a typical feature of MMP.
- Most dogs affected with MMP possessed tissue-bound autoantibodies, predominantly IgG and complement C3 deposited along the basement membrane zone.
- MMP has been shown to be immunologically heterogeneous with autoantibodies targeting proteins of the basement membrane such as collagen XVII, BP230 or laminin-332.
7
Q
MMP in Cats
A
A naturally occurring MMP has been described in two cats.
Both cats exhibited vesicles and/or erosions and ulcers on mucosae and mucocutaneous junctions (eyelids (1), lips (2), soft palate, and concave pinnae.
Histopathology revealed dermo- epidermal separation with none to minimal dermal inflammation composed of dendritic/histiocytic cells and occasional neutrophils and eosinophils.
Immunotesting revealed autoantibodies targeting collagen XVII in one and laminin- 332 in another cat.
8
Q
Bullous pemphigoid (BP)
A
- Bullous pemphigoid is rarely seen in dogs (10% of all AISBDs)
- Breed- or sex-predilection in canine BP cannot be made due to the small number of cases reported.
- Canine BP is a naturally occurring AISBD with collagen XVII autoreactivity affecting predominantly haired skin.
- Mucosal and mucocutaneous junction involvement is seen in about 50% of dogs with BP and footpad sloughing, in contrast to EBA, is only a rare feature.
- This disease is a clinical, histopathological and immunological homologue of the human BP.
9
Q
BP in other species
A
A naturally occurring BP has been described in cats, pigs, horses and, possibly, in a rhesus macaque.
10
Q
BP in cats
A
In cats, lesions of BP appear to be of minimal severity, with vesiculation and erosions occurring predominantly on the ears, trunk and extremities. Mucosal involvement can be seen, but appears to be mild. Like in people and dogs, the BP affected cat produced IgG against NC16A domain of collagen XVII.
11
Q
BP in Yucatan Mini-pigs
A
Clear to hemorrhagic tense vesicles progressing rapidly to erosions and ulcers were seen predominantly on the dorsum. In some pigs, erythema preceded vesicle formation. Mucosal involvement was usually not present. Similarly to other described species, sera from these pigs contained IgG against the NC16A domain of collagen XVII.
12
Q
BP in horses
A
In horses with BP, vesicles appeared suddenly and progressed rapidly into erosions and ulcers covered with crusts. The lesions were widespread with especially prominent oral ulcerations. Systemic signs such as lethargy and anorexia accompanied the skin lesions. Euthanasia was elected for humane reasons due to the severity of their disease. Sera from horses with BP contained IgG against the NC16A domain of collagen XVII.
13
Q
BP in a rhesus macaque
A
In the single case of macaque with BP (an animal undergoing experimental pancreatic transplantation), tense, clear vesicles appeared on the nipples, shoulders and scalp. No mucosal lesions were reported. The dermo-epidermal separation was above the PAS stained lamina densa, and direct immunofluorescence detected anti- BMZ IgG bound to the roof of the blister. The animal showed spontaneous resolution of clinical signs in two weeks.
14
Q
Linear IgA disease (LAD)
A
- Linear IgA disease is a rare AISBD in dogs (3% of all AISBDs). Two dogs only were described to be affected with this disease; one - Labrador retriever cross (3-year-old, female spayed) and one briard (4-year-old, male neutered).
- Dogs with LAD exhibited ulcerative lesions in the oral cavity, face and on the extremities including footpads.
- Vesicles were devoid of inflammatory cells or contained few neutrophils.
- Both dogs’ sera contained anti-BMZ IgA and IgG autoantibodies, which bound to the basal aspect of the epidermal side of the artificial cleft on a human salt-split substrate.
- Canine LAD is a naturally occurring AISBD with LAD-1 antigen autoreactivity and it is clinically, histopathologically and immunologically homologous to its human
15
Q
Junctional epidermolysis bullosa acquisita (JEBA)
A
Junctional EBA is a rare AISBD in dogs (6% of all AISBDs). Only five dogs total were reported to be affected with this disease. Three of them were Labrador or Chesapeake Bay retrievers, while the other two breeds included Cairn terrier and bearded collie The median age of onset was 2.5 years and there were three males and two females.
16
Q
What are the clinical signs of JEBA?
A
The clinical lesions and their distribution were similar to those described in EBA. The most commonly affected areas included concave pinnae (5/5; 100%), oral cavity (5/5; 100%), footpads (4/5; 80%) and nasal or perinasal skin (3/5; 60%). Extensive erosions and ulcers involving the haired skin were reported to affect the axillae (1/5; 20%), abdomen (1/5; 20%) and inguinal region (2/5; 40%).
17
Q
What is the histopathology and immunopathology of JEBA?
A
- Like in other AISBDs, dermo-epidermal separation leading to vesicle formation was a typical finding in JEBA. Formed vesicles were devoid of any inflammation.
- All five dogs were found to have serum IgG autoantibodies specific for the alpha-3 and beta-3 chains of laminin-332.
- Canine JEBA is a naturally occurring AISBD with laminin-332 autoreactivity resembling clinically the classic EBA. A single human case with similar clinical and immunological features can be found in the literature
18
Q
Epidermolysis bullosa acquisita (EBA)
A
- Epidermolysis bullosa acquisita is the second most common AISBD in dogs (26% of all AISBDs).
- Most affected dogs were young (median: 1.2 years) males (M:F ratio = 2.3) with lesions developing before one year of age in almost half of them (45%).
- In the largest case series of canine EBA, Great danes were overrepresented (55%).
- Canine EBA is a naturally occurring AISBD with collagen VII autoreactivity affecting mucosae as well as haired skin, particularly friction and pressure areas. This disease is a clinical, histopathological and immunological homologue of the human EBA
19
Q
What are the common clinical signs of EBA?
A
- Lesions are usually present on mucosae and mucocutaneous junctions as well as haired skin.
- Most frequently affected body areas include the oral cavity (21/23; 91%), lips (18/23; 78%), concave pinnae (18/23; 78%) and haired skin in areas of friction and pressure such as groin, axillae, pressure points (21/23; 91%).
- In contrast to dogs with MMP and BP, dogs with EBA often exhibited footpad sloughing (16/23; 70%).
- Pruritus and pain have been reported in 38% and 85% of affected dogs, respectively, and systemic signs such as fever, lethargy, lymphadenopathy and anorexia were seen in almost all cases
20
Q
What is the histopathology of EBA?
A
Because of the depth of the dermo-epidermal separation, immunohistochemical staining with collagen IV reveals positive staining on the roof of the blister in EBA and can be used as a valuable diagnostic tool to differentiate this entity from other AISBDs with relatively high positive and negative predictive values (84%).
21
Q
What is the immunopathology of EBA?
A
- Most dogs affected with EBA possessed tissue-bound autoantibodies, predominantly IgG (16/19; 84%), deposited along the basement membrane zone. Circulating anti- BMZ IgG autoantibodies could be detected using salt-split canine buccal mucosa tissue in 21 of 23 tested dogs (91%). - Similarly to people, sera from dogs with EBA contained autoantibodies targeting the NC1 domain of collagen VII.
22
Q
Mixed autoimmune subepidermal blistering disease (Mixed AISBD)
A
- Canine mixed AISBD is a naturally occurring AISBD with laminin-332 and collagen VII autoreactivity resembling clinically BP. People with similar clinical, histopathological and immunological findings have been described historically.
- Mixed AISBD is a rare autoimmune skin disease in dogs (4% of all AISBDs).4 Three dogs total were diagnosed with this disease entity; all of them of different breeds (Scottish terrier, Weimaraner, Labrador retriever). The median age of onset was 3 years and there were two males and one female.
23
Q
Immothopathology in Mixed AISBD
A
All three dogs were found to have serum IgG autoantibodies recognizing laminin-332 as well as the NC1 segments of collagen VII.
24
Q
Bullous systemic lupus erythematosus (bullous SLE)
A
- Bullous SLE is a disease in which a patient suffering with SLE develops cutaneous subepidermal blistering due to the individual’s production of antibodies specific for basement membrane antigens. Only one dog, a 4-year-old male Bichon frise, suffering with bullous SLE has been reported.
- Canine bullous SLE is a very rare AISBD described in a dog suffering with SLE. This case is clinical, histopathological and immunological homologue of the human disease. In people, in addition to the anti-collagen VII autoreactivity, multiple other target antigens have been uncovered (laminin-332, laminin-311, BPAg1).
25
Histopathology for Bullous SLE
- Like in other AISBDs, samples from the single bullous SLE dog revealed dermo- epidermal separation leading to vesicle formation.
- Vesicles were devoid of inflammatory cells or contained neutrophils and histiocytic cells.
- An interface dermatitis and basal cell apoptosis were not observed.
- Superficial, dermal perivascular to interstitial mixed inflammation was present in areas of blister formation.
26
Immunopathology for Bullous SLE
- Tissue-bound IgG and complement (C3) were detected along the basement membrane, specifically, in case of a dermo-epidermal separation, the deposit was on the dermal aspect of the formed blister.
- Circulating IgG targeting the dermal aspect of the salt-split buccal mucosa tissue were also seen.
- These circulating IgG were confirmed to bind to the NC1 domain of collagen VII
27
Pemphigus foliaceus (PF)
- Pemphigus foliaceus is the most common autoimmune skin disease recognized in dogs, cats, horses and small ruminants.
- The disease appears to occur equally between females and males in all described species.
- In dogs, Akitas and Chows appear to be at higher risk to develop PF.
- No breed predisposition has been confirmed in cats and horses.
28
Several case reports of drug-triggered PF in dogs and cats can be found in the literature, including the most recent cases of a drug- triggered PF in dogs following the administration of which specific flea and tick preventatives?
- Metaflumizone/amitraz (Promeris Duo; Pfizer)
- fipronil/amitraz/S-methoprene (Certifect; Merial)
- dinotefuran/pyriproxyfen/permethrin (Vectra 3D; Ceva Animal Health).
29
Immunopathology of PF
- Animal PF is believed to be is an antibody-mediated autoimmune blistering skin disease targeting keratinocyte adhesion organelles called desmosomes. The deposition of antikeratinocyte IgG and rarely IgM, IgA and complement C3 in the lesional skin of PF-affected dogs was demonstrated.
- When different IgG subclasses were evaluated, antikeratinocyte IgG4 were detected in most canine PF sera, but only in rare sera from healthy dogs.
- Those detected in healthy canine sera were predominantly of IgG1 subclass.
30
What is Fogo Selvagem?
- Human endemic PF in the Limao Verde reservation in Brazil
- Many healthy individuals produce anti-desmoglein-1 (DSG1) IgG1 autoantibodies, while a strong IgG4 response is usually typical for PF-affected individuals.
- This immunological response in FS is believed to be a response to a noninfectious environmental antigen such as a salivary protein from a sand fly.
31
Pemphigus erythematosus (PE)
- Pemphigus erythematosus is, even in people, a controversial clinical entity.
- Historically, it has been considered to be an overlap of pemphigus and lupus erythematosus, though recent proposals in human dermatology define PE to be a localized, relatively easy to treat form of pemphigus usually present on the face in the area typical for a malar rash of systemic lupus erythematosus.
- PE has been associated with clinical phenotype in which face-predominant PF lesions (pustules, erosions and crusts) present in conjunction with discoid lupus erythematosus (DLE)-like lesions usually on the nasal planum and/or dorsal muzzle (depigmentation, atrophy, erosions and ulcers)
32
Pemphigus vulgaris (PV)
- Pemphigus vulgaris is considered to be one of the rarest autoimmune dermatoses in animals.
- It appears that German shepherds and collies are overrepresented compared to other reported breeds.
- This disease usually affects middle-aged to older dogs (median age of onset: 6 years) with almost half of the patients developing the disease after seven years of age.
- Males appear to be slightly overrepresented
- Most commonly affected areas include mucosae/mucocutaneous junctions (oral cavity, nasal planum, lip margins, genitalia, anus and eyelids), and pinnae.
- Like in people, the major target autoantigen of canine PV is DSG3 with additional anti-DSG1 autoreactivity detected in some dogs with lesions affecting both mucosae and haired skin
33
Pemphigus vegetans (PVeg)
- Pemphigus vegetans, a variant of PV, is the rarest form of pemphigus in animals and people.
- Because of the limited number of described cases and uncertainty of the actual diagnosis, breed, age and sex predilections cannot be determined.
- Suprabasal acantholysis, a hallmark of PV, is often seen in PVeg, but may diminish with time, especially if extensive epidermal proliferation is present characterized by papillomatous or verrucous proliferation of the epithelium
34
Paraneoplastic pemphigus (PNP)
- PNP is a rare autoimmune blistering skin disease developed in people with concurrent neoplasia.
- In dogs, extensive erosions and ulcers affecting mucosae, mucocutaneous junctions, nasal planum and/or haired skin have been observed
- On post mortem examination, a thymoma, a metastatic thymic lymphoma and an undifferentiated splenic sarcoma were identified.
- In the three dogs and the cat, suprabasal acantholysis and apoptotic keratinocytes at multiple levels have been reported. In 2/3 dogs and the single cat, a lymphocytic interface dermatitis was also described.
35
Vesicular cutaneous lupus erythematosus
- Dogs with VCLE present with erythema and flaccid vesicles that slough to leave erosions and ulcers; these predominate on glabrous skin of the abdomen, axillae, groin and medial thighs- VCLE has been recognized almost entirely in collie-related breeds suggests the existence of a strong genetic predisposition.
- Systemic signs are typically not seen in dogs with VCLE.
- Histopathology reveals a lymphocyte cell-rich interface dermatitis is associated with prominent basal keratinocyte vacuolation, apoptosis and loss, which is often sufficient to cause intrabasal clefts and epidermal vesiculation.
- Calcineurin inhibitors might be the drug category of choice to treat canine VCLE.
36
In 2004, the same authors reported the detection of circulating anti-____ autoantibodies in dogs with VCLE, and they highlighted the similarity of this canine disease with human SCLE.
Ro
37
VCLE versus Dermatomyositis vs. AISBD
- Dermatomyositis presents with lesions of ischemic dermatopathy (i.e. cell-poor interface dermatitis and ischemic follicular atrophy), but cell- poor VCLE lesions have more lymphocyte exocytosis into the basal epidermal layer, with lymphocytic satellitosis of apoptotic basal keratinocytes.
- If the intrabasal level of epidermal clefts is not recognized, then vesiculation can be confused with subepidermal autoimmune blistering skin diseases
38
Exfoliative cutaneous lupus erythematosus
- This variant of CCLE is predominantly seen in GSHPs
- This disease was transmitted on an autosomal recessive manner
- A SNP on the CFA 18 chromosome was found to perfectly segregate with the trait.
- The first clinical signs usually occurred in juveniles or young adult dogs with a median age of onset of 8 months.
- While rare GSHPs with ECLE have mild anemia, fluctuating thrombocytopenia is seen more commonly in these dogs
39
Describe histopathology for ECLE
Cell-rich interface dermatitis characterized by moderate to marked dermal lymphocyte infiltrate that tended to be multifocal, rather than always organized into a subepidermal band. Typical of cell-rich interface lesions, the apoptosis of basal keratinocytes was accompanied by moderate to marked lymphocytic exocytosis in the lower epidermis.
- Most dogs had mild lymphocytic exocytosis and keratinocyte apoptosis in the upper epidermis. Diffuse orthokeratotic hyperkeratosis was a notable feature of most biopsies and was usually moderate.
- Immunohistochemical staining confirmed the predominance of CD3-bearing T lymphocytes in the lower epidermis, superficial dermis, in the infundibulum of hair follicles and around sweat glands.
- Destroys sebaceous glands and sweat glands = confused with SA.
40
Hydroxychloroquine and ECLE
Hydroxychloroquine, an first-line antimalarial drug used in human CCLE, appeared to slow down the clinical progression in some dogs with ECLE; in contrast, high-dose ciclosporin reportedly was not able to halt lesion worsening. As the response to immunomodulators is heterogeneous in human CCLE variants, the use of high-dose oral glucocorticoids and adjunctive immunosuppressive regimens need to be investigated on an individual patient basis.
Taking into account all GSHPs with ECLE for which a long-term outcome has been reported, over half of dogs are eventually euthanized for their lack of disease response to therapy. This makes this CLE variant the most challenging to treat among all those of canine CCLE.
41
MCLE
- Majority of dogs with MCLE belonging to breeds related to German shepherds.
- Females appear nearly twice over-represented
- Noticeable mucocutaneous lesions in mid-adulthood
- Perimucosal ulcerative skin lesions with vocalization suggesting pain why defecating or urinating.
- The most relevant clinical differential diagnoses of MCLE are mucocutaneous pyoderma (MCP), MMP and EM variants.
42
MCLE Histopathology
Biopsies contain a cell-rich lymphocytic interface dermatitis with basal keratinocyte damage (i.e. basal cell apoptosis, loss and/or hydropic degeneration). This pattern was often patchy, or in limited areas, sometimes only being observed at close proximity to an ulcer margin. Interface dermatitis commonly extended to the infundibula of hair follicles, while inferior segments of hair follicles are sometimes also involved. Basement membrane thickening was found to be multifocal, patchy to diffuse. Pigmentary incontinence varied from mild to marked.
43
Discoid lupus erythematosus
- DLE represents the most common form: it is divided into a localized variant where skin lesions are confined to the head and neck, and a generalized form, in which skin lesions also occur below the neck.
- The early skin lesions in canine FDLE consist of erythema, depigmentation and scaling that progress into erosions and ulcerations with atrophy and loss of the architecture of the nasalplanum; crusting may be present if the epithelial integrity is damaged.
- Skin lesions usually affect the nasal planum and might even involve the nares; several dogs exhibit additional skin lesions on the dorso-proximal muzzle, lips, periorbital skin and pinnae.
44
Discoid lupus erythematosus Histopathology
The histology of DLE in dogs is similar to that of humans and is characterized by a lichenoid cell- rich, lymphocytic interface dermatitis reaction pattern with basal keratinocyte vacuolar degeneration, apoptosis, loss of basal cells and basement membrane thickening
45
FDLE versus GDLE Histopathology
In canine GDLE, in contrast to FDLE, the interface reaction is usually well developed, when an adequate number of biopsies are examined from the active margins of lesions. The epidermis may be atrophic or mildly hyperplastic as a consequence of regional variation in severity of the interface reaction. Pigmentary incontinence can be pronounced, especially at the margins of lesions, where the interface reaction extends into zones of secondary hyperpigmentation induced by chronic inflammation.
46
What are the three possible immunopathogenic pathways that have been proposed for PF
1. Ab may anti as steric hindrance.
2. Ab binding triggers signaling events leading to aberrant phosphorylation of Dsg2 and deplete desmosome formation.
2. acetylcholine receptors play an important role in controlling phosphorylation of adhesion molecules.
47
Atropine and other muscarinic aceytlcholine antagonists increase Dsg _____, leading to abnormal desmosome formation.
phosphorylation
48
The Nikolsky sign ay be present in Pemphigus ______ where the lack of epidermal cohesion enables the epidermis to be peeled back with a blunt intrsument
Vulgaris
49
Diagnosis using histopathology revealing a suprabasilar intraepidermal cleft, with the remaining basal cells exhibiting a thombstone appearance are consistent with what disease?
Pemphigus Vulgaris
50
Describe Salt-split skin indirect immnunoflouresence
Salt split canine lip or gingival skin has been used in indirect immunoflouresnce testing with the patient serum.
A 1 molar NaCl solution splits the skin through the lamina Lucida, allowing recognition of autoantibodies that bind to the top (epidermal side, lamina Lucida) , bottom (dermal, lamina densa) or combined on both sides.
51
How do you diagnose BP?
Definitive diagnosis of BP is based on history, physical examination skin biopsy and demonstration of basement membrane fixed autoantibodies and circulating antibodies that target the BP antigens.
52
What is the classic antigen in BP that was initially recognized as the target of autoantibodies in humans?
- BP antigen 1 (BPAG1, BP230)
| - This is an intracellular antigen that is a homolog to desmoplakin 1.
53
What is the other name for the second BP antigen (BPAG2, BP180)?
- Collagen XVII - hemidesmosomal transmembrane molecule.
| - Canine and feline cases of BP exhibit abs abasing multiple epitopes in the NC16A domain of collagen XVII.
54
Where are lesions mainly in BP?
Lesions mainly affect skin, oral cavity, and mucutaneous junctions; oral only involvement has not been described. Food pads are normally not effected.
55
BP Histopathology
BP is characterized histologically by subepidermal cleft and vesicle formation. Acantholysis does not occur.
Inflammatory infiltrates cary from mild and perivascular to marked and lichenoid.
Tissue eosinophilia is common in canine BP.
In contrast to MMP where there are non-inflammatory blisters and EBA cases have neutrophil rich vesicles.
56
What are the electron microscopic findings of BP?
Lesions revealed smudging, thickening, and interruption of the BMZ; fragmentation and disappearance of aching fibrils, anchoring filaments and hemidesmosomes; basal cell degeneration and separation occurring within the lamina lucida.
57
What disease mainly affects mucosal and perimucosal areas of the body and targets multiple epitopes of the BMZ, but primarily collagen XVII. This is also the most common AISBD of dogs.
MMP
58
What is the primary target in MMP?
NC16A domain of collagen XVII; with most dogs reacting to BPAG2 and many dogs reacting to BPAG1.
59
What breed is overrepresented in MMP?
German Shepherd (also....the Husky)
60
What are the most common lesion distribution in MMP?
Most commonly, lesions begin in the oral cavity, around the nose, eternal ear, paragenital area, lips and periocular region.
Footpads and haired skin distant to mucosal were only affected in 12% of cases
61
How is MMP diagnosed?
This presentation is suffieciently different from other AISBDs that a tentative diagnosis may be made with the characteristic clonal features of adult onset, slow progression and symmetrical mucosal dominated disease that often presented with tense vesicles and spares the pads.
62
Describe the histopathology of MMP
Intact vesicles will reveal the characteristic subepidermal vesicle most commonly with little or no inflammation.
63
Where is collagen IV staining in MMP?
Collagen IV staining of the vesicles revealed stain uptake BELOW the split in 91% of dogs.
64
Where is the direct and indirect immunoflorescense in MMP?
Direct immunofluorescence is positive at the BMZ.
Indirect immunofluorescence is positive on the epidermal side of the split.
65
What disease is a subepidermal blistering disease that targets collagen VII, an adhesion molecule and main component of anchoring fibrils?
EBA
Second most common AISBD - inflammatory from only.
66
What is the main target of EBA?
The NC1 domain of collagen VII is target by autoantibodies.
67
What disease generally affects young dogs and the Great Dane appears to be predisposed?
EBA
68
What lesions are seen in EBA?
Lesions begin on the face and oral cavity, concave pinna, axilla and groin. There generally is rapid progression over weeks. so that multiple body areas are affected. By presentation, the oral cavity is always involved and the majority with paw pad lesions (75%).
**Systemic sign are often present along with anemia and thrombocytopenia.
69
Describe the histopathology of EBA
Intact vescicles will reveal the characteristic subepidermal vesicle but the vesicles is generally acellular or contains erythrocytes.
The superficial dermis infiltrated with neutrophils and may have neutrophilic micro abscesses.
70
Where is collagen IV staining in EBA?
Collagen IV staining of the vescicles revealed stain update ABOVE the split in most cases. Below the split in 30% of cases and both sides in 30%.
71
Where is the direct and indirect immunofluorescence in EBA?
Direct immunofluorescence is positive at the BMZ.
Indirect immunofluorescence shows staining along the dermal side of the split.
72
How do you definitive diagnose EBA?
The definitive diagnosis of EBA required demonstration of autoantibodies again collagen VII.
73
How do you clinically manage EBA?
Colchicine is considered one of the initial treatments to add to GC, and IVIG is considered a good option for resistance cases.
74
What disease is characterized by IgG autoantibodies to laminin 332, the main adhesion molecule of the basement membrane?
Acquired JEB
75
What disease is characterized by IgA and sometimes IgG autoantibodies abasing processed extracellular components of collagen XVII?
Disease IgA Disease
The two cases reported both had IgA antibodies abasing LAD-1
76
Where is collagen IV staining in LAD with direct immunofluorescence? Indirect?
Vesicles occurred ABOVE collagen IV
Showed IgG or IgA ab located on the basal aspect of the epidermal side of the cleft.
77
Describe the histopathology of LAD
Mixed inflammatory, hemorrhagic, subepidermal vesicles without eosinophils.
78
What is the proposed pathogenesis of SLE?
Hallmarks of the immune dysregulation that accompanies SLE can be categorized under T-cell dysfunction, polyclonal B cell activation and abnormalities in cytokines profiles and function.
Lymphopenia is a feature of SLE, especially cytotoxic CD8 cells with relatively normal CD4 activity.
B-cell overactivity eating to hyperhammaglobulinemia with also the overproduction of IL-10 which suppresses IL-1 and IL-2.
79
SLE in dog - what are the clinical features?
Skin lesions are seen in about 40-50% of dogs.
The most common presenting sign in canine SLE is joint disease.
Anemia is evident in 30-60% of cases
Thrombocytopenia is 10-25% of cases
Profuse proteinuria is evident in 50% of cases
Ulcerative stomatitis may involve the soft palate or more rarely the tone and is seen in 10-20% of cases
Pleuritis/pericarditits is seen in 5-10% of cases
Convulsions and behavioral changes in 60-90% of cases.
Pyrexia in 60-90% of cases
80
What is LE Cell Phenomenon?
It is based on the ability of the ana to opsonize free nuclear material for phagocytosis nun neutrophils to yield the class LE cell which is a nuetrophil containing an engulfed monocular cell nuclear.
81
What is the specificity of ANA?
ANA in man has activity against dsDNA.
| This is not the same for dogs and cats due to acidic B-globulin that binds nonspecifically to DNA.
82
What is the relationship between histones and DLE diagnosis?
Histones are nucleoproteins associated with DNA and the present of antihistone antibodies is HIGHLY correlated with a positive diagnosis of SLE.
Majority of sera recognize H4 and H3 auto antigens.
83
What is the histopathology in SLE?
Lichenoid or hydrophobic interface dermatitis that dugs the DEJ and may extend to the hair follicle os ORS.
Apoptosis of basal or suprabasal cells ma occur, as may subepidermal vacuolar alteration with thickening of the BM.
Direct immunofluroesence or IHC revealed deposits of Ig and complement at the DEJ.
84
______ and _____ are proteins that precipitate from serum and plasma respectively, bu cooling, and redissolve on rewarming.
Cryglobulins and cryofibrinogens
85
What are the three types of cyroglobulins?
Type 1 - composed solely of monoclonal immunoglobulin or free light chains and are most commonly associated with lymphoproliferative disorders.
Type 2 - cryblobulins ash are composed of monoclonal and polyclonal immunoglobulins and are most commonly associated with autoimmune and connective tissue disease.
Type 3 - composed of polyclonal immunoglobulins and occur with infections, autoimmune disorders and connective tissue disease.
86
What are Bence Jones proteins?
monoclonal immunoglobulin or free light chain
87
When cryoblulins are autoantibodies directed against ______ (cold agglutination disease, cold hemagglutin disease, cryopathic hemolytic anemia), it is an autoimmune disorder associated with cold-reacting ____ (usually IgM) autoantibodies.
erythrocytes
88
What are the two forms of cryopathic autoantibodies?
The first is associated with cold agglutinins that are IgM antibodies.
The second form is a non agglutinating type, usually associated with IgG = not known to cause skin disease.
89
What are the clinical features of cryglobulinemia and cryofibrinogenemia?
Rarely occurs in dog and cats
Lesions include pain, erythema, purport, acrocyanosis, necrosis, and ulceration. Skin lesions usually involve the extremities and are exacerbating by exposure to cold.
Biopsy is not usually helpful
90
What are the principle target organs in Graft Versus Host Disease?
skin, liver and intestinal tract
91
GVHD
In dogs, acute GVHD develops about 2 weeks after grafting and is characterized by erythroderma, jaundice, diarrhea and gram negative infections.
Chronic develops 3 to 4 months after grafting.
92
What are the histopathologic findings of GVHD?
Varying degrees of dermal lymphoid infiltrates, and interface dermatitis with apoptosis and satelitosis. The lymphocytic exocytosis and apoptosis also target the follicular epithelium. = similar to EM
93
What are the immunohistochemical differences with GVHD and EM?
Epidermal and follicular keratinocytes of affected skin up regulate ICAM1, CD44 and MHCII, similar to EM.
BUT - overall lymphocyte infiltration in these two diseases is different.
Both disease have CD3, CD8ab+ and TCRab+. HVHD has fewer CD4 T cells, CD1 and CD11 dendritic cells and NO CD21 B cells.
94
Epidermal and follicular ICAM1 expression may play a role in tethering what cell to enable interactions between T cells and keratinocytes?
CD8 T cells
95
What diseases is a rare syndrome of concurrent granulomatous uveitis and depigmenting dermatitis in dogs, characterized histologically by lichenoid dermatosis.
Uveodermatologic syndrome (UDS)
96
In what breed does there appear to be an associated (genetic basis) seen with UDS?
Akita
DLA-DQA1*00201
97
What are the clinical features of UDS?
The syndrome is characterized by acute onset of bilateral uveitis . Following that, the onset of uveitis there will be depigmentation of the hair, usually on the face and skin of the nose, lips, eyelids and occasionally footpads scrotum annual and hard palate.
98
Describe histopathology of UDS (skin, eye)
Skin: Lichenoid interface granulomatous dermatitis with large histiocytes present. Pigmentary incontience is pronouced but hydronic degeneration of epidermal basal cells are rare.
Eye: granulantes panuveitis and retinitis and degenerative changes of the optic nerve and tract may occur. Results of direct and indirect immunofluorescence testing are usually negative.
99
Patients with poorly controlled uveitis often experience ______ and secondary glaucoma, cataracts, and vision loss.
posterior synechiae - eye condition where the iris adheres to lens. In posterior synechia, the iris adheres to the lens, blocking the flow of aqueous humor from the posterior chamber to the anterior chamber. This blocked drainage raises the intraocular pressure.
100
What breeds are predisposed to local injection reactions?
Poodles, Bichon Frise, Yorkshire Terriers, silky terriers, Pekingese and Maltese.
101
What breeds are predisposed to sulfonamide reactions?
Doberman Pinchers (type III reaction with vasculitis) and Miniature schnauzers
102
The syndrome of superficial suppurative necrolytic dermatitis of what breed has been associated with shampoos and in one a case was documented by patch testing with the shampoo?
Miniature Schnauzers
103
What disease is an uncommon disease in dogs and cats, characterized by acute onset of a cutaneous inflammatory reaction featuring epidermal apoptosis and lymphocytic satelitosis.
EM
104
The role of viral particles in epidermal cell has not been well evaluated in dogs and cats. What virus has been seen in canine; while EM was associated with herpes in cats?
Parvovirus
105
In dogs, _____ is thought to represent a host-specific cell-mediated hypersensitivity reaction directed toward some antigenic stimulus.
EM
106
In cases of EM, ____ was markedly unregulated in keratinocytes and infiltrating cells, and it is involved in T-lymphocyte activation and site specific extravasation of l lymphocytes into tissues.
CD44
107
Based on what has been published, what percentage of patients diagnosed with EM had the classical target lesions?
38%
108
The most commonly affected body site for patients diagnosed with EM is where?
Ventrum (axilla and groin)
* * Old dog EM tends to involve the face and ears
* * Cats are affected mainly on trunk and MCJ
109
A variety of drugs are associated with TEN in dogs, most notable are which antibiotics?
TMS, Cephalosporins and penicillins
* and flea dips
110
What are the two proposed pathomechanisms of TEN?
Massive apoptosis appears to be triggered by two pathways:
1 Perforin granzyme pathway which involves formation of perforin channels in the cell membrane that allow granzyme to enter the cell and activate the intracellular caspase enzyme system.
2. Activation of the cell surface death receptors also occurs by binding of cytokines from TNF family = TNFa and Fas-ligand. Activation of death receptors results in activation of intracellular caspase system that Griggs apoptosis.
111
There are elevations in which cytokine that is seen in TEN but not in EM?
IL-13
112
What cytokine has been shown to correlate with severity and mortality of people with SJS?
IL-15
113
What percentages of body affected are used to differentiate SJS from TEN?
<10% SJS (less than)
| >30% TEN (greater)
114
What are the key histopathologic findings in TEN? how are they different from EM?
Full thickness devitalization of the epidermis evidences by hypereosinophilic cytoplasm dn pale or hyper chromatic nuclei, and minimal dermal inflammation. The relative lack of dermal inflammation is in contrast with cell-rich inflammation that occurs in EM.
PAS-stained BMZ should be at bottom of the vesicle.
It's not ab mediated therefore immunofluroesnce is useless.
115
What group of diseases are recognized histopathologically by pale staining collagen, atrophy of hair follicles and cell poor interface dermatitis.
Vasculitis
116
Eosinophilic vasculitis has been associated with what 4 underlying causes?
1. arthropod reactions
2. food hypersensitivities
3. canine eosinophilic dermatitis
4. mast cell tumors
117
The path-mechanism of most cutaneous vasculitides is assumed to involved type ____ hypersensitivities?
Type 3
Immune complexed formed during antigen excess are deposited in the vessel wall.s There is evidence that alterations in blood flow - increased turbulence, alterations in vessel permeability, activation of immune receptors on e endothelial cells in venues, defected in immune complex clearance and autoantibodies may also be involved in many cases.
118
Proliferative Thrombovascular Necrosis of the Pinnae
The etiology is unknown but in one case report, Fendbenazole drug reaction was associated with the disease.
Lesions being on the apical margins of the pinnae and spread along the concave surface. An elongated necrotic ulcer is at the center of the lesions leading to deformed pinnae margins.
119
Proliferative Arteritis of the Nasal Philtrum
The majority of dogs effected are Saint Bernards.
Young adult onset.
The lesions are striking as only the philtrum is affected.
120
Focal Cutaneous Vasculitis and Alopecia at the sites of Rabies Vaccinations
Poodles and Yorkies appear to be predisposed.
Reactions are characterized by roughly annular areas of variable alopecia, hyperpigmentation and less commonly, scaling or erythema.
Lesions occur 2 to 6 months after injection.
121
Solar Vasculopathy
This is associated with solar damage in non-or lightly pigmented skin. It has occurred in conjunction with DLE and vitiligo.
Lesions are described as generally well demarcated areas of erythema, swelling, erosions, and ulcers and with chronicity, alopecia and scarring.
122
Cutaneous and Renal Glomerular Vasculopathy
"Alabama Rot" or "Greentrack Disease"
This has been described in kenneled and racing Grey Hounds.
Usually young to middle aged dogs are affected and there I snow sex predilection.
Palpable purpura, with lesions pinpoint to 10cm in diameter is characterized by reddened areas that rapidly become dark red to purple to black then slough.
Lesions occur on the limbs and less commonly, the groin and trunk.
Some dogs experience pyrexia, lethargy, PU/PD, vomiting, tarry stool.
123
Cutaneous and Renal Glomerular Vasculopathy is caused by what microorganism?
Shia-like toxin (verotoxin) elaborated by E. coli in contaminated raw beef production.
**Possible genetic component since Grey Hounds are affected
124
Familial Cutaneous Vasculopathy of GSD
Autosomal recessive
GSD puppies experience pyrexia, lethargy, most commonly associated with swollen depigmented footpads.
Footpad biopsies demonstrate varying degrees and combinations of nodular dermatitis, collangenolysis, vascular degeneration, vasculitis and cell poor interface dermatitis with basal cell apoptosis.
125
Ischemic Dermatopathy
This is a syndrome the results from a loss of blood supple from either vasculitis or vasculopathy.
= cell poor vasculitis
126
Vaccine induced vasculitis, lesions typically develop how long after inciting vaccine?
2-6 months
127
Many vasculitis cases will have thrombus formation, and subsequently the fibrin in the thrombus is broken down, and this results in the formation of a fibrin degradation productions know as what?
D-Dimers
128
How do you test for D-Dimers in Vasculitis cases?
A monoclonal antibody-based assay is available to detect D-dimers in the blood. Using a cutoff of greater than 500 ng/ml - there was a specificity of 100% and sensitivity of 64%.
129
Proliferative Thrombovascular Necrosis of The Pinnae
Slowly progressive and usually unresponsive disease affecting the pinnae margins.
Sometimes surgical resection is the only treatment.
130
What is the generic term associated with the abnormal extraceullar deposition of one of the a family of low-molecular right protein fibrils that share certain characteristic staining propers and ultrastructural features?
Amyloidosis
** In the dog and cat, it is related to deposition of immunoglobulin light chains and are systemic in nature.
131
Amyloid deposits contain a non fibrillar protein called ____, which is identical to a normal circulating plasma globulins known asn serum amyloid-P (an elastase inhibitor that may help protect amyloid deposits from degradation and phagocytosis).
Amyloid P
132
Primary and myeloma associated systemic amyloidosis have immunoglobulins light chains as precursors to the amyloid fibril protein which is called ______.
Amyloid L
**Lambda type
133
In secondary amyloidosis (chronic inflammation), a serum precursor protein, ________, which is a high-density lipoprotein and acute-phase reactant), forms the fibril in the amyloid deposits.
Amyloid A
134
What are the clinical features of amyloidosis?
This is an internal disease, usually affecting the kidneys, spleen, liver and death often resulting from the renal involvement.
Cutaneous lesions are primary nodular amyloidosis.
135
What is the histopathology of amyloidosis skin lesions?
Amorphous, homogenous, eosinophilic superficial Ermis. The walls of the blood vessel in the involved area were thickened by deposition of the homogenous eosinophilic material.
The material was Congo red positive and birefringent when polarized.
136
What disease is characterized by inflammation and destruction of auricular cartilage?
Auricular chondriits
Dapsone was effective in treating in 4 cats
137
In humans, relapsing polychondritis is often classified among the immune-mediated disease because autoantibodies to which collagen are commonly seen in these cases?
Collagen Type II
138
What is the biopsy findings in auricular chondritis?
Lymphoplasmacytic inflammation, loss of cartilage basophilia, and cartilage necrosis.
139
Pseudopalade
Rare disorder in dogs and cats, and is characterized u some pennant alopecia that is non-inflammatory.
140
A key feature in pseudopalade is lymphocytic inflammation that targets what part of the hair follicle?
mid-isthmus of the hair follicle where the follicular bulge cells (stem cells) are present.
Destruction of these stem cells results in permeant scarring alopecia.
141
What are the histopathologic findings in early cases of pseudopalade?
Variably severe accumulation f lymphocytes, histopcytes and fewer plasma cells that are most intense at the follicular isthmus. Sebaceous glands are present.
142
What is the key transcription factor involved in controlling T-lymphocyte trafficking?
Kruppel-like factor 2 (KLF2) controls T-lymphocyte trafficking. The transcription factor KLF2 controls key molecules (starred) that are involved in T-lymphocyte trafficking. Mature T cells in the thymus require the sphingosine 1 phosphate receptor 1 (S1P1) for egress into circulation. Once circulating, T cells require L-selectin (CD62L) for entry into lymph nodes through high endothelial vessels. Egress from the lymph node into lymphatic vessels again requires S1P1. As KLF2 controls these 'keys' to the front and back door on the lymph node, when naïve T cells express KLF2 (and subsequently S1P1 and CD62L) they circulate through secondary lymphoid tissue (red arrows). When T cells are activated, they downregulate KLF2, causing a loss of S1P1 and CD62L, and express chemokine receptors. This results in thymic retention (if the T cell is in the thymus) or movement from circulation to tissues (if the T cell is in the periphery) (shaded blue).
143
Key Features: AJEB
Target antigens: Laminin 332
Dermpath features: May be acellular
Clinical features: ears, oral, pads, nasal
Collagen IV Location: 100% bottom of blisters
SS Ab Deposition: Both or Bottom
Breed: none
144
Key Features: BP
Target antigens: Collagen XVII
Dermpath features: Eosinophils intact (or degranulated) and numerous
Clinical features: Haired skin, rare mucosal ( spares pads)
Collagen IV Location: Both
SS Ab Deposition: Top
Breed: None
145
Key Features: BSLE
```
Target antigens: Collagen VII
Dermpath features: Neutrophils and histiocytes
Clinical features: NA
Collagen IV Location: NA
SS Ab Deposition: Bottom
Breed: None
```
146
Key Features: EBA
Target antigens: Collagen VII
Dermpath features: Neutrophils +/- eosinophils +/- subepidermal microabcesses
Clinical features: Pinna, oral cavity, pads
Collagen IV Location: Mixed
SS Ab Deposition: Bottom
Breed: Great Danes
147
Key Features: Linear IgA disease
```
Target antigens: Shed Collagen XVII
Dermpath features: no or mild inflammation
Clinical features: One case report
Collagen IV Location: Below
SS Ab Deposition: Top
Breed: None
```
148
Key Features: Mixed AISBD
Target antigens: Laminin 332 and collagen VII
Dermpath features: cellular vesicles and dermal neutrophils/eosinophils
Clinical features:
Collagen IV Location: Below
SS Ab Deposition: Bottom
Breed: None
149
Key Features: MMP
Target antigens: BPAG, Collagen XVII, laminin 332
Dermpath features: Variable; acellular or may have neutrophils/eosinophils; B-lichenoid
Clinical features: Mostly mucosa
Collagen IV Location: Mostly below (or both)
SS Ab Deposition: Top (most) or Bottom or Both
Breed: Huskies and GSD
150
Arthrus Reaction
neutrophilic vasculitis
Deposition & formation of immune complexes
Occurs when an animal with circulating antibodies is exposed to antigen
Any foreign antigen capable of inciting antibody response should be considered as a potential cause:
Infectious organisms (bacterial, mycobacterial, viral, rickettsial, fungal), neoplasia, drugs and food additives, sera (serum sickness syndrome) and sources of autoantibody (cryoglobulins, collagen vascular diseases)
Acute inflammation occurs at the site of injection
Red, edematous, swelling hemorrhage & thrombosis
Circulating antibodies (often IgG – specifically IgG1, IgG2, IgG3, and IgM) activate complement via classic pathway
C3b-containing immune complexes bind to CR1 on erythrocytes, cleared by Kupffer cells & macrophages of the liver and spleen
ICs are deposited between & beneath vascular endothelial cells
ICs bind to Mast Cells via FcγIII and other Fc receptors
Release vasoactive molecules, neutrophil chemotactic factors and proteases
Neutrophils (attracted by C5a and Mast Cell derived molecules) adhere to IC to phagocytose them
151
IHC reveals what populations of T cells in the dermis versus epidermis of VCLE?
CD8 - epidermis
| CD4 - dermis
152
What is the major antigen targeted in alopecia areata?
trichohyalin
153
What breeds are predisposed to alopecia areata?
GSD, Dachshunds and Beagles
154
What are the two recommended treatments for Linear immunoglobulin A pustular dermatosis?
GC or dapsone
