Cytotoxic and Misc Immune-mediated Diseases Flashcards
How often do autoantibodies spontaneously arise?
Frequently
Up to ~50% of new T and B cells may bind self-antigens
Usually these are vigorously suppressed
Low-titer, low-affinity IgG or IgM antibodies are important for homeostasis
What are the two major categories of autoimmune diseases?
1) normal response to an unusual antigen
2) abnormal immune response to a usual antigen
* latter is more common
What are the primary ways that abnormal, autoimmune responses are thought to occur?
Failure of regulatory control
- ex. defects in CD95 or CD95L on T cells or lymphoid tumors
Infection induced (especially viruses)
- molecular mimicry (same epitopes in infection and autoantigen)
- epitope spreading (reaction to other epitopes on same protein)
- bystander activation (previously hidden tissue antigens exposed)
Microchimerism (ex. maternal cells in boys with dermatomyositis)
How does genetic disposition usually associated with autoimmune diseases?
- mutations most commonly associated with MHC
–> usually role of genes is complex - dog underwent bottleneck with domestication (~20,000 yr ago) and again when dog breeds were created (~200 yr ago) = loss of MHC polymorphism
Which TLR is associated with the development of systemic lupus in humans?
TLR7
How can the intestinal microbiota contribute to autoimmunity/immune-mediated disease?
since the GI microbiota is associated with immunological tolerance, dysbiosis can affect the development of autoimmune disease
How can gonadectomy contribute to autoimmunity/immune-mediated disease?
Alteration in sex hormones that affect immune function
2016 study found neuter F/M dogs has higher risk for:
- atopic dermatitis
- hypoadrenocorticism
- hypothyroidism
Neuter females were at higher risk for lupus erythematosus than intact
What does “lichenoid” mean?
dense band of mononuclear cells in the superficial dermis, whether or not there is evidence of epidermal cell death
tends to be lymphocytic but can be lymphoplasmacytic (esp around mucous membranes) or lymphohistiocytic
What does “interface” mean?
a cytotoxic reaction pattern where keratinocyte cell death is largely restricted to the basal levels of the epidermis (occasional extension into the lower stratum spinosum)
* Lymphocyte exocytosis into the epidermis blurring BMZ
* Apoptosis
* Pigmentary incontinence
* Pronounced vacuolation
* Vesicles (genuine vs. “usable artifact”)
What is “panepidermal” cytotoxic dermatitis?
a cytotoxic reaction pattern where keratinocyte death occurs throughout epidermal layers
Which diseases have a cytotoxic interface dermatitis pattern?
- Chronic lupus erythematosus (discoid lupus erythematosus)
- Pemphigus erythematosus
- Epitheliotropic T-cell lymphoma
- Fixed drug reaction
- Mucocutaneous lupus erythematosus
- Ischemic dermatopathy/dermatomyositis
- Exfoliative cutaneous lupus erythematosus
- Vesicular cutaneous lupus erythematosus
- Thymoma-associated exfoliative dermatitis
- Intraepidermal viral diseases
- Lupoid onychitis
- Erythema ab igne
- Uveodermatologic syndrome (as a minor pattern)
Which diseases have a panepidermal cytotoxic dermatitis pattern?
- Staphylococcal toxic shock syndrome
- Proliferative necrotizing otitis externa of kittens
- Epitheliotropic T-cell lymphoma
- Erythema multiforme
- Stephen-Johnson syndrome
- Toxic epidermal necrolysis
- Thymoma-associated exfoliative dermatitis
- Graft versus host disease
- Intraepidermal viral diseases
- Superficial necrolytic dermatitis (as a minor pattern)
- Vitamin A responsive seborrheic dermatitis (as a minor pattern)
Which diseases have a follicular cytotoxic dermatitis?
- Chronic lupus erythematosus
- Staphylococcal toxic shock syndrome
- PLIMFD with apoptosis and parakeratosis in dogs
- Epitheliotropic T-cell lymphoma
- Exfoliative cutaneous lupus erythematosus
- Erythema multiforme
- Stephen-Johnson syndrome
- Toxic epidermal necrolysis
- Intraepidermal viral diseases
- Graft versus host disease
What is responsible for confluent epidermal lesions of SJS/TEN in people?
necroptosis, an RIPK3-dependent and sometimes RIPK1-dependent regulated cell death pathway that typically exhibits a necrotic morphotype and NETosis
What is hydropic degeneration/vacuolar change?
prominent swollen keratinocytes with pale-staining cytoplasm and vacuoles
What are the triggering mechanisms initiating hydropic degeneration?
may differ in cell-rich and cell-poor forms of cytotoxic dermatitis
- not fully known in cell-rich but cytotoxic T cells (CTLs) and natural killer cells (NK cells) are present at the dermo-epidermal junction where they mediate apoptotic cell death
- in cell-poor cytotoxic dermatitis hypoxia due to chronic vascular damage likely contributes to the loss of basal keratinocyte viability by inducing endoplasmic reticulum stress and autophagy-associated cell death
What are the triggering mechanisms for vacuolar change along the dermo-epidermal junction?
disruptions to the basement membrane by edema or deposition of immune complexes trigger apoptosis of basal keratinocytes because b1-integrin sites become vacant (normally protect the keratinocytes)
What is “satellitosis”?
close approximation of small lymphocytes to apoptotic keratinocytes in the epidermis and/or follicular epithelia
is a morphological representation of CTL-mediated cytotoxicity
What are “sunburn” cells?
feature of human and animal photodermatoses
isolated apoptotic keratinocytes, typically occurring in the stratum spinosum, unassociated with lymphocytes
What is the lymphocyte population usually associated with cytotoxic dermatitis?
Th1 immunity comprising INF-y producing CD4+ T cells, CD8+ CTL, and type 1 innate lymphoid cells, including NK and NK-T cells
+/- Th17 cells
What lymphocyte population predominates in canine EM?
CD8+ T cells
some CD21+ B cells were observed in the superficial dermis
What lymphocyte population predominates in graft versus host disease?
CD8+ T cells
Which cytokine is upregulated in dogs with CLE?
CXCL10 (IP-10)
main source with systemic signs: lymphocytes
main source for dogs without systemic signs: keratinocytes
When are numerous neutrophils clustering around apoptotic keratinocytes resembling lymphocytic satellitosis typically seen?
exotoxin-mediated staphylococcal toxic shock syndrome
- result of rigorous interleukin (IL)-17A production
Which cytotoxic dermatitis disease in humans frequently has a large number of eosinophils?
drug-induced EM
* rare in animals
What causes pigmentary incontinence?
Keratinocyte death leads to failure of melanin transfer and depigmentation
- free melanin granules are phagocytosed by dermal macrophages
May also result from hyperpigmentation
What is squamatization?
change in orientation of the normally cuboidal and vertically orientated basal epidermal cell layer to a flattened and horizontally oriented layer
Why does thickening of the basement membrane zone occur in cytotoxic dermatoses?
reflects deposition of immunoglobulins and immune complexes
Which cytotoxic dermatoses have thickening of the basement membrane zone as a prominent lesion?
canine DLE
mucocutaneous lupus erythematosus
canine hyperkeratotic EM
In which cytotoxic diseases is parakeratotic hyperkeratosis commonly seen?
idiopathic scaling panepidermal cytotoxic diseases
ex. proliferative and necrotizing otitis externa in cats and hyperkeratotic EM in dogs
- marked follicular targeting with infundibular parakeratosis and cytotoxicity often more severe than in the interfollicular epidermis
What is dermal fibrosis?
separating band of fibrosis between the dermo-epidermal junction and lichenoid inflammation
What are some environmental factors that contribute to abnormal immune responses?
ultraviolet radiation (UVB)
infections
drugs
Which virus in dogs can present with primary lesions of cytotoxic dermatitis?
rare manifestation of canine parvovirus infection with lesions affecting skin and mucous membranes
- originally reported as canine parvovirus–associated “EM”
- represents an active viral infection
Is human herpesvirus-associated EM associated with an active or prior viral infection?
not the result of an active viral infection
occur after the initial infection and at distant sites from the primary viral-induced lesion
responses against keratinocytes whose antigenicity is altered following the transport of viral components (typically gene fragments) by progenitor dendritic cells to sites distant from the initiating infection
In which species has virus-associated “EM” been described?
humans, horses, cats, and pigs
How are environmental factors thought to induce lesions of chronic cytotoxic interface dermatitis (lupus erythematosus) in humans?
inducing a skewed type I interferon response in genetically predisposed individuals
drive innate and adaptive autoreactive immune reactions through a variety of mechanisms including induction of chemokines like CXCL10
How does CXCL10 (IP-10) contribute to cytotoxic dermatoses?
attract CXCR3 CD8+ cytotoxic lymphocytes to the dermo-epidermal junction
How can drug or drug metabolites alter the epidermis and cause immune reactions?
covalently binding as a hapten to cell surface proteins
directly interacting with the MCH/T-cell receptor complex
potentially altering endogenous peptides presented to T cells
In cutaneous adverse drug reactions, what are the main mediators of keratinocyte death?
drug-specific CD8+ CTL and activated NK cells
Why do fixed drug reactions happen at the same anatomic site ?
because drug-specific CD8+ memory T cells remain in situ
Which are the cytotoxic interface diseases most commonly triggered by drugs in people and animals?
drug-induced EM and SJS/TEN
In a study on canine adverse drug reactions, what percentage of dogs were highly likely to have a drug induce their EM?
19%
(in another it was 59%)
In a study on canine adverse drug reactions, what percentage of dogs were highly likely to have a drug induce their SJS/TEN?
90%
What are 5 ways you can divide epidermal cytotoxic dermatitis in groups depending on contributions from epidermis, immune system, and environment?
Response of normally immune system to pathogens/altered keratinocytes
- ex. viruses and EM
Immune-mediated/autoimmune due to environmental factors
- ex. UVB and lupus erythematosus
- ex. drugs and EM/SJS/TEN
Attack of abnormal immune system on keratinocytes
- paraneoplastic
Altered environment affects both epidermis and immune system
- graft versus host disease
Cytotoxic dermatitis of yet to be identified mechanisms
What species has thymoma-associated exfoliative dermatitis been reported in?
cats, rabbits, and goats
In which disease has intraepithelial neoplastic CD8+ T cells been shown to exhibit cytotoxic activity against keratinocytes?
Lymphoma
- lichenoid mycosis fungoides in people
- canine epitheliotropic T-cell lymphomas
In which situation has graft versus host disease been reported in dogs?
bone marrow transplants
engrafted lymphocytes attack host epidermis due to different MCH I
Which diseases are characterized histologically by cytotoxic panepidermal dermatitis with marked hyperkeratosis and often parakeratosis?
feline proliferative and necrotizing otitis externa
PLIMFD with apoptosis and parakeratosis in dogs
hyperkeratotic EM
subset of cases of superficial necrolytic dermatitis
lesions in one young lab that got better with Vitamin A
What are examples of lupus erythematosus-nonspecific skin lesions
those due to vasculitis, cryoglobulinemias, vesicobullous lesions associated with basement-membrane autoantibodies (i.e. bullous SLE), “lupus panniculitis”
Which canine variant of lupus is the equivalent to the human subacute cutaneous LE?
vesicular cutaneous LE
Which canine variant of lupus is the equivalent to the human chronic cutaneous LE?
Exfoliative cutaneous LE
Discoid LE
Mucocutaneous LE
What breeds are predisposed to vesicular cutaneous lupus erythematosus?
Collies, Shetland sheepdogs and their crosses
What breeds are predisposed to exfoliative cutaneous lupus erythematosus?
German shorthaired pointers and Magyar viszlas
What breeds are predisposed to mucocutaneous lupus erythematosus?
German shepherd dogs
What breeds are predisposed to facial discoid lupus erythematosus?
German shepherd dogs
also Collie, Shetland Sheepdog, and Siberian Husky
What breeds are predisposed to generalized lupus erythematosus?
Chinese crested dogs