Chapter 8 - hypersensitivity Flashcards
Urticaria occurs with which types of hypersensitivity reaction?
I and III
How long does an individual urticarial lesion last?
24 hours
How do you differentiate urticarial papules from bacterial folliculitis?
Urticaria blanches on diascopy
Name three drugs known to cause urticaria/angioedema
Penicillins, cefalexin, tetracycline, vitamin K, amitraz, ivermectin, moxidectin, radiocontrast agents, vincristine, azathioprine, propylthiouracil
Which cytokines are involved in acute urticaria?
IL-4, IL-13
Which cytokines are involved in chronic urticaria?
IL-2, IL-12, IFN-gamma
In atopic skin, is the number of Langerhan’s cells increased or decreaed?
Increased
In atopic skin, is the CD4:CD8 ratio increased or decreaed?
Increased
Which route of allergen exposure is most important in dogs?
epicutaneous
Which two anatomical sites have the highest frequency of isolation of Malassezia?
Interdigital skin and ears
Epithelial cells present superantigens to which type of T cells?
Th2
Which anatomical sites show lesions in both atopic dermatitis and contact dermatitis?
Hairless, ventral areas e.g. axillae, groin, interdigital skin
Name five reasons for false negative IDT
Too little allergen (out of date, too dilute, low volume)
Drugs (steroids, antihistamines, tranquilisers, progestatinal compounds)
Low blood pressure
Testing out of peak season
Oestrus, false pregancy
Severe stress
Parasites
Name five reasons for false positive IDT
Irritant allergens Contamination (bacteria, fungi) Skin-sensitising antibodies Poor technique Narcotics Irritable skin Dermatographism Mitogenic allergen
Can histamine reactivity on IDT return before allergen reactivity after drug therapy?
Yes - rarely
Which breeds may be predisposed to severe adverse reactions to IDT?
Boxers and Pitbulls
How long are allergen-specific IgE levels stable for?
~ 2 months
Is spongiotic dermatitis with eosinophilic exocytosis reported in acute or chornic atopic dermatitis?
Acute
How does ASIT change the Th2 and Th1 response?
It modulates the cytokine profile with an increased IFN-gamma:IL-4 ratio
Which cytokines, produced by Treg cells, induce a tolerance response?
IL-10, TGF-beta
Put the following in order of cross reactivity:
weeds, trees, grasses
Trees > weeds > grasses
Which cytokines does ciclosporin suppress?
IL-2, IL-1, IL-6, TNF-alpha
Giving ciclosporin with food decreases bio-availability by what %?
22%
In cats with atopic dermatitis, which T cells are increased in lesional skin?
CD4+ (4x more often than CD8+)
Facial and neck pruritus in feline atopic dermatitis may be linked to the distribution of which inflammatory cell in the skin?
Mast cells (found in highest numbers on caudal pinnae and chin)
Which primary skin lesions do you see with contact hypersensitivity?
Macular papular erythema
Which type of hypersensitivity reaction is contact?
IV
Which cells play an important role in hapten sensitisation?
Epidermal Langerhan’s cells
T memory cells are recruited by the expression of which adhesion molecules in contact hypersensitivity?
VCAM-1, E-selectin, ICAM-1 (on vascular endothelium)
Which otic preparation ingredient is frequently suspected to cause a contact reaction?
Propylene glycol
What is the rationale for using pentoxifylline to treat contact allergy?
Inhibition of TNF-alpha release
Flea bite hypersensitivity is assciated with which Th response?
Th2
Name two flea treatments that work by potentiating GABA
Spinosad, selamectin, milbemycin, moxidectin
Name an acetylcholine nicotinic receptor agonist flea treatment
Imidacloprid, nitenpyram
Which type of hypersensitivity reactions occur with tick bites?
III, IV and basophil
Type III hypersensitivity reactions to tick bites show what type of pattern on histopathology?
Leukocytoclastic vasculititis with haemorrhage, necrosis and ulceration
Type IV hypersensitivity reactions to tick bites show what type of pattern on histopathology?
Nodular to diffuse (pyo)granulomatous dermatitis
What type of hypersensitivity reaction occurs with feline mosquito hypersensitivity?
Type I
Which inflammatory cell predominates on histopathology of fire ant stings?
Neutrophils
Which species of storage mite is predominant in Europe?
Lepidoglyphus destructor
Name two differentials for canine eosinophilic furunculosis
Staphylococcus folliculitis/furunculosis and dermatophytosis
Which sex hormone most commonly triggers hypersensivitity?
Progesterone
Which receptors involved in pathogen detection are expressed by keratinocytes?
Toll-like receptors (TLRs)
Protease-activated receptors (PARs)
Acute lesions in atopic dermatitis are associated with which Th cells?
Th1
Th2
Th2
Keratinocyte expression of thymic stromal lymphopoietin (TSLP) in atopic dermatitis is:
Increased
Decreased
Increased and this correlated with dry skin/stratum corneum hydration
TSLP-stimulated dendritic cells prime CD4 T cells with features of Th1 or Th2 cells?
Th2
Dysbiosis has been reported in atopic dogs, what changes have been found?
Decreased bacterial diversity and increased proportions of Staphylococcus, particularly S. pseudintermedius and Corynebacterium spp. compared with healthy control dogs
In a pilot study evaluating five different methodologies (skin hydration, TEWL, pH, skin absorbance and erythema) for skin barrier function assessment done in both normal and atopic dogs, which was the most repeatable?
pH
Which tight junction proteins have been investigated in dogs with AD?
Claudin, occludin and Zonula Occludens 1 (ZO-1)
Decreased claudin 1 expression has been reported in samples from atopic dog skin (non-lesional skin)
Decreased intensity of staining for ZO-1 on immunohistochemical analysis also has been reported in atopic dogs
A cell wall component of Staphylococcus can induce transcription of _____ via TLR2 in canine keratinocytes and this could be a link to explain Th2 responses precipitated by Staphylococcus.
TSLP
True or false:
Treg cells are significantly increased in atopic dogs compared to normal and correlate with disease severity
True
In the study by Older et al (2021) looking at cats with asthma and FASS, they found significantly higher mRNA expression of Oncostatin M receptor (OSMR)-beta in samples obtained from allergic animals. What is OSMR-beta?
OSMR-beta is one of the subunits of the heterodimeric receptor complex for IL-31. Upon binding of IL-31, the IL-31 receptor complex induces signalling via the JAK/STAT/PI3K/AKT and several other pathways
In the study by Older et al (2021) looking at cats with asthma and FASS, did they find a significant role for IL-31?
No, neither the qPCR nor the RNA-ISH results demonstrated differences in systemic or cutaneous IL-31 expression between cats with allergic dermatitis and controls; this does not rule out that targeting molecules within the IL-31 pathway may still be valuable.
In the study by Combarros et al (2021), what was the difference between normal, non-lesional and lesional atopic skin on electron microscopy?
There was an abnormal appearance of the SC and corneocytes in both lesional and non-lesional skin of atopic dogs, as well as altered morphology of purified CEs. The SC presented irregular, wrinkled and thicker corneocytes, associated with a larger proportion of ruffled, immature CEs and increased TEWL, suggesting impaired cornification.
In the study by Pressanti et al (2021), which cytokine was found to be over-expressed in conjunctivae and tears of atopic dogs despite subtle signs of conjunctivitis?
IL-8
IL-8 is primarily a chemoattractant for neutrophils
Oclacitinib maleate mitigates the clinical effects of cAD through its action on the signalling pathways of Janus kinase 1 (JAK1) enzymes, which modify production of several interleukins (IL) such as?
IL-2 and IL-6 (pro-inflammatory)
IL-4 and IL-13 (pro-allergenic)
IL-31(pruritogenic)
True or false, increased numbers of CD4+T cells and an elevated CD4+/CD8+T-cell ratio were shown to be hallmarks of cAD.
True
What are Favrot’s criteria?
Onset of signs under 3 years of age Dog living mostly indoors Glucocorticoid-responsive pruritus Pruritus without lesions at onset Affected front feet Affected ear pinnae Non-affected ear margins (Sarcoptes) Non-affected dorso-lumbar area (FBH)
mRNA for inflammatory and immunology markers is up or down regulated in lesional atopic skin?
Up-regulated
mRNA from genes involved in transcription and regulation is up or down regulated in non-lesional atopic skin?
Down-regulated
S100A8 gene is a pro-inflammatory marker that correlates with what?
Severity of canine AD and TNF-alpha
Thymic stromal lymphopoetin (TSLP) is induced by epidermal damage and involved in which type of Th response?
Th2
Which environmental factors appear to be protective from canine AD?
Rural lifestyle, multi-animal household, non-commercial foods, skin barrier protective diet
Which environmental factors may be associated with developing CAD?
Urban lifestyle, late homing, regular bathing, c-section, household hygiene and HDM exposure
In the study (Hemida et al, 2020) on the modifiable early risk factors for AD development in dogs, which types of diet affected the development of cAD?
Diets based on non-processed meat were significantly associated with a decreased prevalence of owner-reported AD, while a diet based on ultra-processed carbohydrate-rich foods were significantly associated with an increased risk for owner-reported AD
Which Dermatophagoides farinae major allergen has been confirmed to be clinically relevant through response to monoallergen immunotherapy?
Der f2
ASIT response in HDM sensitised dogs and cats
D. farinae IgE can cross react with which endoparasite?
Toxocara canis
Do dogs with sarcoptes show positive IgE levels to D. farinae?
No, but dogs with D. farinae IgE can show positive reactions to sarcoptes
What are the skin barrier defects reported in dogs with AD?
- Abnormal keratinocyte morphology
- Abnormal filaggrin expression
- Altered lipid lamellae
- Altered lipid metabolism
- Abnormal ceramide profiles
- Increased TEWL
In cAD, keratinocytes can initiate and activate the release of which inflammatory markers?
ICAM-1 MHC II TARC TNF-alpha IL-8 TSLP
Esumi et al. (2021) found that emollient bathing had what effect on Malassezia, pruritus and skin lesions in dogs?
Decreased
Skin barrier modulation can impact Malassezia dysbiosis
In cAD there is early activation of which Th pathways?
Th2 and Th22
Is IL-31 expressed in the early or late phase of atopic inflammation?
Early
Peak 24-48 hours
TSLP is mostly produced by keratinocytes and has what effects?
- Activates Langerhans cells and T cells, induces maturation and activation of dendritic cells and mast cells
- Promotes Th2 differentiation
- IL-4 and IL-13 production
SNP in TSLP receptor has been associated with canine AD in various breeds
Is there a clear association with AD and altered levels of IL-10 and TGF-beta in dogs as there is in people?
No, some studies have found similar levels in healthy and atopic dogs
Could the number of Treg cells in early life influence the development of cAD?
In Swiss WHWT, lower levels of Treg at 3-12 months were associated with AD later in life
Treg numbers declined in adulthood in healthy dogs but didn’t in atopic dogs
Apart from IL-31, what are the itch pathways/mediators in dogs?
Histamine PAR2 TRPM8 - menthol TRPV1 - capsaicin Cannabinoid receptors Opioid receptors Substance P - NK1 and GABA
Give examples of Th1 cytokines
IL-2 and interferon-gamma
Give examples of Th2 cytokines
IL-4, IL-5, IL-6, IL-9, IL-10 and IL-13
CCR4 is the receptor for which T-cell chemotactic factor?
TARC (thymus and activation regulated chemokine) CCL 17 (chemokine (C-C motif) ligand 17)
Circulating CCR4+ T cells are present in greater number in spontaneously allergic dogs compared to healthy non-allergic dogs, is the same true for experimentally sensitised dogs?
Yes
Has expression of CCR4 mRNA been demonstrated in atopic canine skin?
Yes
IFN-gamma RNA transcripts have been detected in skin biopsies of dogs with spontaneous AD, most frequently from which type of skin lesions?
Chronic, lichenified lesional skin
Levels in canine lesional atopic skin are higher than in non-lesional or healthy skin
S1008A, a calcium binding protein, is a pro-inflammatory protein that can induce chemotaxis of which cells in dogs?
Neutrophils
The S100 gene is also located on the epidermal differentiation complex with genes that are essential for which aspects of keratinocyte and epidermal barrier differentiation?
Profilaggrin, loricrin and involucrin
Do serum levels of S1008A correlate with CADESI scores in atopic dogs?
Yes and increased gene expression was demonstrated in lesional atopic skin.
IgE has been demonstrated to be expressed on the surface of Langerhans cells in the epidermis of atopic dogs; has the same been found in non-atopic dogs?
No
In food induced atopic dermatitis in dogs, clinical signs are present at under 12 months of age in what % of cases?
~50%
In food induced atopic dermatitis in dogs, Malassezia dermatitis is associated in what % of dogs?
43%
A dysregulated immune response in cAD includes increased Th2, Th17 and which cells expressing CD4+ and CD25+?
Treg - significantly increased in atopic dogs compared to normal and correlate with disease severity
What is oral allergy syndrome and has it been reported in dogs?
Oral or perioral pruritus and inflammation may be observed following ingestion of a food item that cross-reacts with an aeroallergen to which the patient is sensitised.
Reported after ingestion of tomato in a dog sensitized to Japanese cedar extract.
Is there evidence to suggest that Fel d1 may represent an autoallergen in cats with EGC?
Yes – as in humans with AD that may eventually develop IgE reactive to self-proteins and these autoallergen–antibody interactions may perpetuate allergic disease
Do human keratinocytes from atopic patients have higher expression of the receptor for IL-31 when compared to healthy controls?
Yes - they are very sensitive to this cytokine
IL-34 is thought to be largely produced by which cells?
Keratinocytes
Is IL-34 important in dogs?
- Increased expression of IL-34 in serum in atopic dogs compared to healthy controls
- Correlated with disease severity but did not decrease with treatment
- Possibly produced by damaged keratinocytes – no evaluation of skin expression yet
Increased expression of IL-33 can have negative consequences on the function of which intercellular structures?
Tight junction proteins such as claudin – inflammatory cytokines can modulate skin barrier function and exacerbate existing deficiencies
In the study by Piccione and DeBoer (2019), were anti-CCD IgE found in healthy and atopic dogs?
Yes, 16.8% (17/101) atopic dogs and 13.1% (8/61) healthy dogs
All healthy and atopic dogs with anti-CCD IgE had strong reactivity to grass pollens.
Keratinocytes express the receptor for IL-31 and this cytokine can greatly suppress differentiation markers such as?
Filaggrin and cornified cell envelope formation
Which aspects of the canine microbiome are reduced in atopic dermatitis?
Decreased diversity, richness and evenness
Apart from atopic dermatitis, which other factors can affect the canine cutaneous microbiome?
Household > sex, health, body site
Breed variations
Has gut dysbiosis been associated with cAD?
Yes, as in people
A nutraceutical/low allergen diet improved gut dysbiosis, faecal scores, pruritus and lesional scores
What are complex carbohydrate determinants (CCDs)?
Carbohydrate components of glycoproteins commonly found on the cell surface of plants or insects
What is the average age of onset of FASS in cats?
2 - 3.4 years
(Ravens 2014, Hobi 2011)
WAVD 0.5-4.8 years
Which feline breeds are predisposed to FASS?
Abyssinian
Also Siamese, Persian, Devon Rex, Himalayan, Maine coon
Which inflammatory cells predominate in allergic and non-allergic asthma?
Allergic: eosinophils (neutrophils, lymphocytes, macrophages and mast cells)
Non-allergic: neutrophils
CD__ / IL-__ positive cells are more prominent in lesional skin in FASS than non-lesional or healthy skin
CD4 / IL-4
In cats with FASS, do serum IL-5 levels correlate with peripheral eosinophilia, allergen specific IgE or skin lesions?
No, no consistent correlation found
What is a reason why we see complex, heterogenous cytokine expression patterns in cats with FASS?
They can present with lesions of varying stages rather than show a more linear progression from acute to chronic
They have a variety of clinical presentations e.g. EGC
Which chemokines have been associated with FASS?
TARC / CCL17 (Th2)
RANTES / CCL5 (attract and activate T cells, eosinophils and basophils)
Do cats with FASS show a pro-inflammatory Th1/Th2 response?
Yes
Why do diester steroids have a low risk of systemic adverse effects when used topically?
- Double esterification enhances rapid penetration of the drug through the stratum corneum and ensures specific metabolism in the deep dermis.
- This minimizes effects on hair follicles, dermal fibroblasts and blood vessels, decreasing the likelihood of local cutaneous and systemic adverse effects
- Can still cause dermal atrophy!
HCA spray (Cortavance) has been shown to be effective in dogs in which scenarios?
- SID use for up to 14 days for acute AD and 7 days for FAD
- Used two consecutive days a week to help reduce time to relapse and need for systemic medication
- Used SID for 7 days then EOD when tapering oclacitinib from BID to SID (prevented relapse of pruritus and clinical lesions)
- Equally as effective as ciclosporin when used daily for at least 28 days then tapered to EOD or BIW depending on response
In a study of 10 cats, what treatment regime was used for topical application of HCA (from FASS treatment guidelines)?
- Two sprays from 10 cm to cover a 10 x 10 cm area
- Once daily for 28 days then every other day
- Two were lost to follow up, one was withdrawn due to poor efficacy
- 77% reduction in FeDESI and 76% reduction in pruritus by day 56
- 50% improvement seen by day 14
- 6/7 cats maintained on EOD treatment, 1/7 on SID
Where are GC receptors found and which is the main effector of GC functions?
Glucocorticoid receptors (GCR) are found in all tissues, with the isoform GCR-α being the most widely expressed and the main effector of GC functions. It is cytoplasmic.
What does GC receptor-beta do?
Glucocorticoid receptor-β does not bind GC, but it can modulate steroid response by its interactions with DNA of GC responsive genes, a mechanism possibly contributing to resistance to treatment.
What does binding of GC to GC receptor-alpha do?
It causes the release of chaperone molecules and subsequent translocation of the GC-GCR complex to the nucleus. There, the interactions with GC responsive elements lead to transactivation (increase in gene expression) of anti-inflammatory genes, such as interleukin (IL)-10, or transrepression (decrease in gene expression) of pro-inflammatory genes.
Glucocorticoids also suppress humoral immunity, causing B cells to express lower amounts of IL-__ and IL-__ receptors
IL-2 and IL-2 receptors
Glucocorticoids induce lipocortin-1 (annexin-1) synthesis, which then binds to cell membranes preventing __________ from coming into contact with its substrate arachidonic acid.
Phospholipase A2
Which two main products in inflammation are reduced by GCs?
Prostaglandins and leukotrienes (any of a group of biologically active compounds, originally isolated from leucocytes. They are metabolites of arachidonic acid)
Topical steroids can cause cutaneous atrophy, which other adverse effects have been reported with their use?
- Localised demodicosis reported in cats and dogs using steroid inhalers
- Iatrogenic hypercortisolism reported with clobestasol lotion in Persian kitten
In the study by Leonard et al. (2021), did the use of twice weekly otic mometasone furoate affect the skin microbiome?
No - topical corticosteroids used as proactive treatment is unlikely to increase the risk of secondary microbial overgrowth
Are adverse effects associated with genomic or non-genomic actions of steroids?
Typically associated with genomic actions of GCs