Autoimmune and Immune-Mediated Disorders Flashcards
How can a dx of TEN be differentiated from a burn.
The dermis is not affected in TEN but is in a burn.
Autoimmune Subepidermal Blistering Diseases
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).
Diseases involving collagen XVII autoimmunity
1) Mucous membrane pemphigoid (MMP)
2) Bullous pemphigoid (BP)
3) Linear IgA disease (LAD)
4) Mixed AISBD
Diseases involving Laminin-332 autoimmunity
1) Junctional epidermolysis bullosa acquisita (JEBA)
2) Mucous membrane pemphigoid
Diseases involving Collagen VII autoimmunity
1) Epidermolysis bullosa acquisita (EBA)
2) Mixed autoimmune subepidermal blistering disease (Mixed AISBD)
3) Bullous systemic lupus erythematosus (bullous SLE)
Mucous Membrane Pemphigoid (Dog)
- 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.
MMP in Cats
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.
Bullous pemphigoid (BP)
- 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.
BP in other species
A naturally occurring BP has been described in cats, pigs, horses and, possibly, in a rhesus macaque.
BP in cats
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.
BP in Yucatan Mini-pigs
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.
BP in horses
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.
BP in a rhesus macaque
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.
Linear IgA disease (LAD)
- 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
Junctional epidermolysis bullosa acquisita (JEBA)
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.
What are the clinical signs of JEBA?
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%).
What is the histopathology and immunopathology of JEBA?
- 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
Epidermolysis bullosa acquisita (EBA)
- 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
What are the common clinical signs of EBA?
- 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
What is the histopathology of EBA?
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%).
What is the immunopathology of EBA?
- 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.
Mixed autoimmune subepidermal blistering disease (Mixed AISBD)
- 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.
Immothopathology in Mixed AISBD
All three dogs were found to have serum IgG autoantibodies recognizing laminin-332 as well as the NC1 segments of collagen VII.
Bullous systemic lupus erythematosus (bullous SLE)
- 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).
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.
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
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.
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).
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.
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.
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)
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
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
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.
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.
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
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
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
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.
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.
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.
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.
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.
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
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.
What are the three possible immunopathogenic pathways that have been proposed for PF
- Ab may anti as steric hindrance.
- Ab binding triggers signaling events leading to aberrant phosphorylation of Dsg2 and deplete desmosome formation.
- acetylcholine receptors play an important role in controlling phosphorylation of adhesion molecules.
Atropine and other muscarinic aceytlcholine antagonists increase Dsg _____, leading to abnormal desmosome formation.
phosphorylation
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
Diagnosis using histopathology revealing a suprabasilar intraepidermal cleft, with the remaining basal cells exhibiting a thombstone appearance are consistent with what disease?
Pemphigus Vulgaris
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.
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.
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.
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.
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.
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.
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.
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
What is the primary target in MMP?
NC16A domain of collagen XVII; with most dogs reacting to BPAG2 and many dogs reacting to BPAG1.
What breed is overrepresented in MMP?
German Shepherd (also….the Husky)
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
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.
