Hypersensitivity and Atopic Dermatitis Flashcards
What has decreased expression in the epidermis of humans with AD?
Filaggrin
Loricrin
Involucrin
Corneodesmosin
S100A11
(may be due to IL-4, IL-13, TNF-a, IL-25, IL-22, or IL-17A)
What increases in the epidermis of humans with AD?
Desquamation
TEWL
Percutaneous penetration
What happens to extracellular lipids in dogs with CAD?
Similar to humans
Decreased total lipids, fatty acids, +/- cholesterol, +/- ceramides
- recent study found no difference in total ceramides but altered ratio
Abnormal, disorganized, and reduced intercellular lipid lamellae
- hexagonal rather than an orthorhombic
*in both lesional and non-lesional skin but worse in lesional
*no connection between lipid composition and predilection sites
What are the barrier effects of filaggrin mutations?
- decreased corneocyte osmolytes
- decreased organic acids (UA, PCA)
- decreased corneocyte hydration
- increased water loss
- increased pH
Which cytokines down regulate filaggrin expression and alter its function?
Th2 cytokines
What happens to extracellular lipids in humans with AD?
Composition and architecture are disrupted
Lamellar body secretion abnormal and some retained in corneocytes
Reduction in
- Total lipids in stratum corneum
- Proportion of long chain ceramides
- Chain length of fatty acids in ceramides and free fatty acids
What happens to tight junction in atopic dermatitis?
- decreased TJ expression b/c downregulation of claudin-1 by Th2 cytokines
- activation of PAR2 which disrupts claudin-1 and occludins
◦ reduces TJ barrier integrity, promotes Th2 inflammation and pruritus - keratinocytes drive inflammation following barrier disruption
◦ scratching further disrupts TJs
What are the primary Th2 cytokines?
*IL-4
*IL-5
*IL-13
IL-10
What does IL-4 do?
Promotes mast cell growth and development, stimulates eosinophils, and activates B cells
What does IL-5 do?
Drives eosinophil development in the bone marrow
What does IL-13 do?
Signals B cells to make a class of antibody called IgE
What does IL-10 do?
Has more of an anti-inflammatory response
What percentage of Caucasian European and Asian patients with AD harbor a FLG mutation?
20-25%
What is the structure and location of mast cells?
Large, round cells 15-20 um in diameter
Cytoplasm has large granules
Do not circulate
Are found in largest numbers in skin, intestine and airways
Tend to be close to blood vessels
- regulate blood flow and cellular migration
Also found in connective tissue, under mucosa, and around nerves
What stimuli trigger mast cell degranulation?
IgE-linked allergens (or IgG linked)
Cytokines and chemokines
Chemical agents
Physical stimuli
Insect and animal venom
Viruses
DAMPs (defensins, anaphalotoxins, IL-33, neuropeptides, etc)
What do bacterial peptidoglycans do to mast cells histamine release?
Trigger TLR2 = histamine release
What do bacterial lipopolysaccharides do to mast cells histamine release?
Trigger TLR4 = no histamine release
What are the primary cytokines that mast cells produce?
Primarily produce Th2 cytokines
- IL-4, IL-5, IL-6, IL-10, IL-13, and TNF-a
Capture/store IL-17 and release it during allergic reactions
How does degranulation of mast cells occur via IgE cross-linking?
Antigen cross-links IgE on two mast cell FcεRI –>
Activates their tyrosine kinases –>
activates phospholipase C –>
through mediators increases intracellular Ca2+ –>
more protein kinases –>
phosphorylation of myosin –>
granules move to cell surface, fuse with membrane, and release contents
Other than causing degranulation, what does IgE cross-linking do to mast cells?
activates phospholipase A –>
membrane phospholipids produce arachidonic acid –>
increase transcription of LOX, COX, and cytokines –>
make leukotrienes, prostaglandins, and cytokines
What do mast cell granules contain?
histamine
serotonin
dopamine
leukotrienes and prostaglandins
lysosomal enzymes (including chitinases)
cytokines and chemokines (including Th2 cytokines and PAF)
heparin-containing granules rich in TNF-a (heparin stabilizes it)
What does IL-33 do?
Is a potent DAMP
- not secreted normally but released from nuclei of damaged cells
Promotes production of Th2 cytokines, IFN-y, TNF-a, and IL-2
Recruits eosinophils and promotes degranulation
Involved in M2 polarization and tissue repair
Enhances neutrophil phagocytosis
Activates mast cells and basophils
Binds to neurons to cause pruritus
What are the primary functions of mast cells?
Regulate local blood flow and influence cellular migration
Sentinel cells – can act as APC during ACD (get MCHII from DCs)
Control innate immunity
Promote wound healing, can kill bacteria in wounds
- IL-6 tells keratinocytes to make defensins
Influence eos fx
- IL-5, SCF, histamine, PAG, PGD2, leukotrienes, VEGF, adenosine, tryptase
What does the development and survival of mast cells depend on?
SCF signaling via KIT receptor on mast cells (c-kit gene)
Other than SCF, what cytokines/chemokines regulate mast cell development?
IL-3
IL-4
IL-9
IL-31
IL-33
CXCL 12
TNF-b
nerve growth factor
How do connective tissue and mucosal mast cells differ?
Connective tissue mast cells are constitutive and T cell-independent, whereas mucosal mast cells must be induced and are T cell-dependent
What is type I hypersensitivity?
Immediate IgE-mediated hypersensitivity resulting in mast cell degranulation
What is type II hypersensitivity?
Non-immediate IgG or IgM FcR-dependent activation of CD 8+ T cells, NK calls, macrophages, and neutrophils resulting in cell lysis
“cytotoxic hypersensitivity”
What is type III hypersensitivity?
Non-immediate IgG or IgM mediated formation of antigen-antibody complexes which deposit into tissue and drive complement to recruit neutrophils which then damage tissue
What is type IV hypersensitivity?
Delayed T cell-mediated hypersensitivity
- can take up to 2 weeks
What is type IVa hypersensitivity?
Delayed Th1 (IFNy) mediated leading to monocyte activation
What is type IVb hypersensitivity?
Delayed Th2 (IL-4, IL-5) mediated leading to eosinophilic inflammation
What is type IVd hypersensitivity?
Delayed T cells (IL-8) mediated neutrophil recruitment
What is type IVc hypersensitivity?
Delayed T cell-mediated cytotoxicity
What is the (pro-)hapten hypothesis of drug hypersensitivities?
Hapten = drugs that are too small to elicit an immune response
Prohaptens = drugs that are inert initially but reactive after metabolism
Then they bind to a protein –>
taken up by APCs and presented by MCH II to T cells
*sulfonamides and penicillin are the classic example
What is the danger theory hypothesis of drug hypersensitivities?
main concept is that the immune system is reactive not toward “foreignness” but rather to “danger”, such as cell debris, oxidative stress, or inflammation
- drug or its metabolites could trigger a “danger cascade”
What is the PI concept of drug hypersensitivities?
direct pharmacological interaction of drugs with immune receptors
- off-target drug bindings to MCH II and TCRs
What is the altered peptide repertoire model of drug hypersensitivities?
related to the PI concept
noncovalent binding of drug to the DLA molecule/MCH II itself
alters its conformation and the peptide repertoire it presents
What is the viral reactivation hypothesis of drug hypersensitivities?
a relationship exists between viral diseases and drug allergies
underlying viral infections may increase susceptibility to drug reactions
- viral specific CD 8+ T cells may recognize the drug
What is the endoplasmic reticulum stress and the unfolded protein response hypothesis of drug hypersensitivities?
series of pathways, termed the unfolded protein response (UPR), maintain quality control in the ER by sensing deficiencies in protein folding capacity
cytochrome P450 enzymes tend to localize in the ER so reactive metabolites can be formed in the ER and mess proteins up resulting in the UPR triggering apoptosis +/- the ER stress causing release of DAMPs
What is the mitochondrial hypothesis of drug hypersensitivities?
debated role in idiosyncratic drug reactions
drug induces mitochondrial damage which triggers inflammation
Which drug reactions cause urticaria and angioedema?
Type I hypersensitivity reactions
Very rare in cats
reported with many drugs including:
penicillin, ampicillin, tetracycline, vitamin K, propylthiouracil, amitraz, ivermectin, moxidectin, radiocontrast agents, and HyLyt efa shampoo
Which drugs have been implicated in causing an SLE-like drug reaction in dogs?
In dogs, sulfonamides, hydralazine, primidone, and vaccines
Is probably a form of type III
What type of hypersensitivity is most likely to cause vasculitis?
Type III
What drugs have been reported to cause superficial suppurative necrolytic dermatitis?
only in Miniature Schnauzers and is associated with shampoos
- patch testing was used to confirm
Is a type IV
48-72h later, develop erythematous papules, plaques, vesicles, pustules +/- concurrent systemic signs
What is the most common method used to help standardize assessment of causality for all adverse drug reactions?
Adverse Drug Reaction Probability Scale (Naranjo) Scale
has 10 questions
Why might a patch test or intradermal test be unreliable in identifying if the drug triggered a hypersensitivity response (especially delayed)?
You didn’t wait long enough (usually 72 hr)
tests was conducted with the parent drug are likely to be falsely negative if the immune system is sensitized against a drug metabolite or a drug-protein hapten
Assuming you do not want to re-challenge the patient, how can you test for type I hypersensitivity responses?
1) IgE concentrations
2) basophil activation test (BAT): measures the capacity of basophils to release histamine or upregulate activation markers in response to the drug
Assuming you do not want to re-challenge the patient, how can you test for delayed hypersensitivity responses?
1) Anti-drug IgG
2) lymphocyte transformation test (LTT): measures ex vivo (from the patient) T cell proliferation in response to a specific drug antigen
What are type A (dose-dependent) adverse drug reactions?
predictable, exaggerated, but otherwise normal pharmacological responses to the effects of the medicine at therapeutic doses due to the pharmacological mechanism of the drug or the direct chemical or physical properties of the drug
What are type B (dose independent) adverse drug reactions?
unpredictable reactions to a drug that are unrelated to the dose nor the pharmacological action of the drug
What is a pseudo-allergy?
Non-immune-mediated
Off-target drug binding activates mast cells, eosinophils, and basophils without evidence of drug sensitization
Immediate allergic/anaphylactic response
Caused by: NSAIDs, radiocontrast, vitamin K1, and liposomal drugs
What are some drugs that can cause facial pruritus in cats?
methimazole
spironolactone
Solensia
What type of drug reactions generally cause pemphigus foliaceus-like ADRs?
Type II
What is the difference between drug induced and drug triggered?
Drug-induced: the disease resolves once the drug is discontinued
Drug-triggered: the disease continues despite discontinuing drug
What are some drug associated with pemphigus foliaceus-like ADRs?
Sulfonamides, cephalexin, oxacillin, amoxicillin-clavulanic acid, oxytetracycline, Promeris Duo, Vectra3D, Certifect, NexGard, NSAIDs, etc.
What are some drugs associated with vasculitis?
Itraconazole, meloxicam, piroxicam, sulfonamides, human albumin, etc.
What type of drug eruptions are fixed drug eruptions?
Type IV (histopath shows satellitosis)
Repeated drug exposure produces identical lesion in identical location(s)
- scrotum is a common place
What is maculopapular exanthema?
most common cutaneous manifestation of drug allergy in human
non-immediate and can be type II-IV
erythematous macules and papules, variable pruritus, +/- vesicles & angioedema (miliary dermatitis in cats)
associated with penicillins, cephalexin, sulfonamides, griseofulvin, etc
What is the ALDEN algorithm?
Algorithm of drug causality for epidermal necrolysis (ALDEN)
designed for humans specifically for SJS/TEN
has 6 criteria
What is OX40L?
A costimulatory adhesion molecule on DC2s that is upregulated with AD
important in inducing T cells to make IL-4, IL-5, and IL-13
Upregulation of which chemokine receptor is associated with dendritic cell maturation and promotes migration to the lymph nodes?
CCR7R
What is the role of Type 2 CD8+ cells in atopic dermatitis?
They can produce Type 2 cytokines and IFN-g
The latter is believed to make keratinocytes more sensitive to Fas-mediated apoptosis
Apoptosis is believed to further contribute to the barrier defect
What does prostaglandin D2 do during atopic dermatitis?
stimulating chemotaxis in Th2, basophils, and eosinophils
have CRTH2/PgD2R2 receptors
Receptors for which cytokines are known to be present on neurons?
IL-31
IL-4
IL-13
TSLP
IL-33
How is AIT thought to desensitize mast cells, basophils, and eosinophils?
Happens very early after starting AIT
1) Increased expression and function of inhibitory Fc receptors (FcγRIIa and
FcγRIIb) which helps suppress activation through the FcεRI receptor
2) Increased expression of histamine receptor (HR2); when histamine binds
the HR2, which is believed to downmodulate the responses to histamine
Which cells are involved in the development of atopic dermatitis?
Lymphocytes
- T, B, NK, ILC, NK
Granulocytes
- Eosinophils, neutrophils, basophils
Antigen Presenting Cells
- Dendritic cells (there is DC hyperplasia)
- Macrophages
Mast cells
Keratinocytes
Which cytokines are involved in atopic dermatitis?
Change over the course of the disease
Type 2 cytokines are present throughout the disease
Involvement of other cytokines (e.g. Type 1, Type 17, Type 22) is determined by endotype in humans
- endotypes not completely identified in dogs but we know we have different common pattern in different breeds
miRNAs for cytokines are altered potentially indicating epigenetic component
What has been shown to happen to γδ T cells in humans and dogs with atopic dermatitis?
A source of IL-22 to limit staphylococcal growth
A source of IL-17A as well to call in neutrophils
May help control dysbiosis
Decreased in adult humans with AD
increased in kids and dogs with AD
What has been shown to happen to skin resident NKT cells in humans with atopic dermatitis?
Induced by allergen
Express CXCR4 as do skin memory T cells
Cluster around fibroblasts producing CXCL12/SDF 1a
Promote inflammation
How can super antigens affect atopic dermatitis?
Disrupt skin barrier
promote Type 2 polarization
production of IgE against staph superantigens makes disease worse
- AD, allergic rhinitis, asthma
What happens to innate lymphoid type 2 cells (ILC2) in atopic dermatitis?
Stimulated by epidermal alarmins (TSLP, IL-25, IL-33)
Make Type 2 cytokines (IL-4, IL-5, IL-13)
Make IL-9 too
Enhance Type 2 allergic response in atopic dermatitis
What changes occur in the skin of atopic patients that contribute to barrier dysfunction?
Reduced expression of structural proteins
Imbalances in protease/protease inhibitors
Altered composition and organization of lamellar layers
Altered lipid metabolism
Reduced expression of tight junction proteins
Dysbiosis with increased pathogenic staphylococci
Which monoclonal antibodies have worked well in the treatment of human atopic dermatitis?
Blocking IL-4 and IL-13
- Dupilumab
Blocking IL-13
- Tralokinumab
- Lebrikizumab
Blocking IL-31
- Anti-IL31Ralpha (nemolizumab)
- except Japanese adolescents and adults
- Anti-OSMRbeta (KPL-716)
Which monoclonal antibodies not have worked well in the treatment of human atopic dermatitis?
Blocking IL-33
- etokimab
Blocking TSLP
- tezepelumab
Blocking IL-17C
- MOR106
Blocking adhesion molecule OX40
- KHK4083
How do Tregs work in atopic dermatitis?
Produce inhibitory cytokines (IL-10, TGFb)
Suppress antigen presenting cells and ILCs by inhibitory surface molecules
Inhibit target cell metabolism
Induce cytolysis with Granzyme A and B
Impair B cell production of IgE
How does AIT work?
complicated and not fully known
Very early
- desensitization of mast cells and basophils to degranulation
Days to months, T cell tolerance
- T regulatory cells
- Altered ratio Th2:Th1 and cytokines (probably associated with Treg fxn)
Months to years
- Increase in blocking antibodies (allergen specific IgG4 and IgG1)
- Decrease in allergen-specific IgE
Decreased number of inflammatory cells (eosinophils, basophils, mast cells)
What types of regulatory cells does AIT generate?
Regulatory dendritic cells (DCreg) producing IL-10, IL-27, and TGFb to polarize T cells into FoxP3+ Treg
IL-10+ innate lymphoid cells (ILCreg)
Regulatory B cells
- make IL-10, TGFb, IL-35
- Expression of allergen-specific IgD
How does AIT leading to a decrease of IgE and increase in IgG1,IgG2, IgG4 and IgA influence atopic dermatitis?
Compete for allergen binding
Associated with conversion of macrophage from M2A proinflammatory phenotype to the M2B anti-inflammatory phenotype
What are the routes that AIT can be administered?
Subcutaneous (SCIT)
- Rush
Sublingual (SLIT)
Intralymphatic (ILIT)
Oral (OIT)
Epicutaneous (EPIT)
What is the effect on concomitant use of glucocorticoids during AIT?
upregulates IL-10 production
Which cytokines predominate in the initial AD response?
Th2 dominant: IL-4, IL-5, IL-6, IL-13, IL-31
Which cytokines predominate in the chronic AD response?
Mixed: Th1, Th2, Th17, Th22
Th17: neutrophil effector function, protect against extracellular pathogens at epithelial surfaces
Th22: regulate tissue inflammation and repair –> proliferation (lichenification comes from this being upregulated chronically)
What is the mean heritability of AD in British guide dogs (Labrador Retrievers and Golden Retrievers)?
0.47, indicating that nearly 50% of the risk of developing atopic dermatitis is determined by an individual’s genotype
- highest risk if both parents affected
- moderate risk of one parent is affected
- low risk if neither parent is affected
In which breed is a filaggrin mutation implicated in the development of AD?
Labs/Golden Retrievers (a SNP was identified for dogs in the UK)
- not identified outside that region
In which breed is there a skin barrier defect associated with the development of AD that is not caused by a filaggrin mutation?
West Highland White Terriers
- but are reported to have decreased filaggrin mRNA in the skin
What are some proteins for which genetic mutations are implicated in the development of AD in dogs?
filaggrin (not all dogs)
TSLP receptor (all dogs so far)
protein tyrosine phosphatase (modulates T- and B-cell responses)
plakophilin 2
What changes have been shown to occur in the stratum corneum of atopic patients?
lacks cellular cohesion resulting in “holes”
- leads to excessive and constant TEWL
bacteria tend to adhere more tenaciously and abundantly
- may be the basis for dysbiosis
reduction in the content of natural hydration factors
- reduce hydration
- increase pH (leads to more activity of desquamation proteases)
alteration of the composition and arrangement of the lipid layers
What happens to dendritic cells that are activated in atopic dermatitis?
capable of extending to reach the most superficial layers
- increasing contact with external agents
increase in the presence of IgE receptors
What happens to the microbiome of patients with atopic dermatitis?
reduction in species diversity
predominant increase in the Staphylococcal population
Predominance of Malassezia pachydermatis instead of M. globosa
What does a dysbiotic state correlate with in atopic dermatitis?
presence of clinical exacerbation and with the increase in pH and loss of transdermal water
What is the atopic march?
In humans, the progression from cutaneous manifestations of atopic disease to respiratory signs
~ 50% of young children with severe AD will develop asthma and
approximately 75% will develop allergic rhinitis
What is the definition of canine atopic dermatitis?
Canine atopic dermatitis is a hereditary, typically pruritic and predominantly T- cell driven inflammatory skin disease involving interplay between skin barrier abnormalities, allergen sensitization and microbial dysbiosis
*not necessarily IgE mediated anymore (though historically has been)
- presence of IgE in ~80% of cases
*not a single entity, but more a descriptive term for a clinical syndrome
- often synonymous with environmental allergic skin disease
- now no longer separate out food allergy because clinically similar
In addition to AD signs, what are some other manifestations of food allergies?
urticarial plaques
vasculitis
gastrointestinal signs
What is the relationship between skin barrier dysfunction and allergic sensitization/inflammation?
two way street: skin barrier function is worsened by inflammation and the worse is the skin barrier, the more propensity exists toward allergic sensitization
skin barrier impairment promotes a Th2 response and increased propensity for allergic sensitization
Why does increased expression of TSLP occur in canine AD?
may be linked to skin damage or stimulation by Staphylococcus via
Toll-like receptors
What is the “hygiene hypothesis”?
posits that a lack, or a decrease, of microbial exposure leads to Th2 dysregulation and allergy development
What is the “microflora hypothesis”?
suggests that alterations in the microbiota disrupt immune tolerance
lifestyle changes, whether dietary or environmental, promotes the development of an atopic state
What are common sites for clinical signs associated with atopic dermatitis in dogs?
muzzle, neck, chest, periocular areas, the pinnae, the antebrachial
area, and the axillary and inguinal areas
Can vary by breed
Which breed is most likely to have body-wide phenotype of atopic dermatitis?
Shar-pei
Which breeds are most likely to have a phenotype of atopic dermatitis affecting their face?
Boxers and Frenchies
Which breeds is most likely to have severe phenotype of atopic dermatitis affecting their ventral abdomen?
German shepherds
What is atopic dermatitis in humans?
also known as eczema or atopic eczema) is a complex, chronic, inflammatory
skin condition
hallmarks of the disease are epidermal barrier impairment and an abnormal immune response to environmental allergens/antigens
- 80% of AD patients (so-called extrinsic) have high serum IgE levels, develop other allergic disorders at some point in their life, and can have positive prick tests to foods or aeroallergens
- 20% are indistinguishable but have normal levels of IgE, no identifiable allergic triggers, and negative prick tests
What is Netherton syndrome?
In humans
Mutation in SPINK5 encoding LEKTI
also present with elevated IgE and have a high incidence of AD, asthma, allergic rhinitis, and food allergies
A mutation in which gene in humans has been associated with severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome?
desmoglein 1 gene
What is the role of filaggrin mutation in human atopic dermatitis?
filaggrin (FLG) loss of function mutations are major predisposing factor for AD
but FLG mutations show in up to 10% of non-atopic subjects (Irish cohort)
When measuring weather data, including weekly mean pollen count, rainfall, relative humidity, hours of sunshine and temperature, which are associated with worse PVAS?
relative humidity was significantly associated
- high humidity can play a significant role in aeroallergen release
- high increase trans-epidermal water loss in atopic skin
- low humidity can induce epidermal DNA synthesis and mast cell degranulation leading to epidermal hyperplasia
weekly mean pollen count was not
- not consistent in humans and often lower than expected
- usually measured on pollen traps on roofs so may not reflect the exposure of dogs on the ground and pollen traps are not necessarily reliable
- aero carriers loaded with allergens can remain airborne longer than intact pollen grains (ex. high Phl p1 when whole Timothy pollen count is low)
- pollen allergens may survive longer inside
How can carbon dioxide being elevated in urban environments play a role in the development of atopic dermatitis?
which alters plant growth and the timing of pollen release
urban carbon dioxide concentrations are approximately 30% higher
dogs in urban areas react more strongly to pollen allergens in IDATs
What is the link between clinical history and IDAT results?
Undetermined
Traditionally considered that they should be strong but in a French study, there was no evidence for a link between sensitization to grass pollen and seasonality of clinical signs of atopic dogs
in another study a poor correlation was found between the IDT results of dogs and their clinical history
How does an IDAT measure response to allergens?
indirect measure of cutaneous mast cell reactivity due to the presence of IgE
What is the role of Malassezia in the pathogenesis and exacerbation of canine AD?
may contribute both directly (by the induction of inflammatory cytokines) and indirectly (by acting as an allergen)
production of phospholipase A2 is a possible initiating factor for Malassezia dermatitis secondary to AD in dogs
Malassezia induce IL-1β, IL-6, IL-8 and TNF-α in human keratinocytes
M. pachydermatis acts as a conventional allergen in canine AD
- a major and minor antigen were found in people
- serum specific IgE, positive IDAT, positive passive transfer reactions and stimulation of peripheral blood mononuclear cell proliferation
How is TEWL correlated to clinical severity of canine AD?
positively correlated with the clinical severity of the dis-ease
How is pH correlated to clinical severity of canine AD?
negative correlation between pH and severity of the clinical signs
What is filaggrin 2?
a very similar S100 fused-type protein
involved in the production of natural moisturizing factors (NMFs), and also is an integral component of the cornified envelope
What happens to caspase-14 in dogs with atopic dermatitis?
Unknown, decreased in some studies but increased in others
Which structural adhesion proteins are decreased in acute canine atopic dermatitis (after HDM exposure)?
corneodesmosin and claudin-1
What happens to the microbiome of an ear in a dog with atopic dermatitis?
dysbiosis characterized by a lower species diversity
higher relative abundance of Staphylococcus spp. and M. pachydermatis
What is the role of AMPs in canine atopic dermatitis?
May be more AMPs mRNA but lower AMPs activity in atopic subjections
- may adhere to the external horny layer rather than being released
- role may not be due to levels, but functionality/secretion
Which genes are associated with increased risk of AD in WHWTs?
PTPN22 (lymphoid tyrosine phosphatase prevents of spontaneous activation of T and B cells) for Australia
F2R (thrombin receptor) gene which is a member of the protease- activated receptor (PAR) family for the USA
- involved in normal desquamation and epidermal barrier function
*The two genes were found in different regions
Which breeds of dogs are predisposed to atopic dermatitis world-wide?
boxer, bulldog, Labrador retriever, pug and WHWT
*various regional studies will also include other breeds
Which genes are associated with increased risk of AD in golden retrievers?
filaggrin in the UK
Prominin 1 (PROM1) and Ras-related protein Rab- 3c (RAB3C)
Which gene is associated with increased risk of AD in German Shepherds?
plakophilin 2 (PKP2) gene region on chromosome 27
disputed because there is no difference between the expression in affected and unaffected dogs
What are the protective environmental factors for human atopic dermatitis?
growing up in a rural environment with contact with farm animals (“farming effect”)
a diet rich in dietary fiber
high food diversity
early contact with siblings or peers
potentially early-life exposure to infectious diseases/microbial agents
- including helminths
- not proven
*all might be important for the development of a highly diverse microbiome in barrier organs, such as skin, gastrointestinal tract and lungs
What has consistently been found to be a protective environmental factor against the development of atopic dermatitis?
rural environment/time outdoors
Toxocara canis infections may be protective against D. farinae- induced cAD flares
Others: multi-animal household, walking in forests, fields and beaches, having been born in the current owner’s household, living in a detached house and being fed a non-processed meat- based diet
Der f 1 has been found to enhance CPEK production of which cytokines?
GM-CSF, IL-8/CXCL8 and TNF-a
Other than trigger IgE, what do house dust allergens do in atopic dermatitis?
are cysteine and serine proteases
degradation of occludin, claudin and zona occludens 1
can cause proteolytic degradation of epithelial surfaces in addition to inflammation
upregulate IL- 33 mRNA expression in CPEK cells
potential to activate a variety of cell types via cleavage of PAR-2
may enhance Langerhans cell migration to lymph nodes due to decrease E-cadherin
some can act as molecular mimics part of the extracellular portion of TLR4
- Group 2 and 7
What are the most common allergens in humans and dogs?
house dust mite species belonging to the genus Dermatophagoides
- positivity rate in humans: 40%– 80%
- positivity rate in dogs: 60% and 90% but many clinically normal dogs are too
frequently (≥45%) co-sensitized to house dust and storage mites
- parallel exposure/sensitization and/or of in vitro cross-reactivity
May also cross react with Sarcoptes
Which Dermatophagoides farinae allergens are considered major allergens in dogs?
Der f 2
Der f 15
Der f 18
Zen 1
Which Japanese cedar allergens are considered major allergens in dogs?
Cry j 1
Cry j 3
Which Short ragweed allergens are considered major allergens in dogs?
Amb a 1 (including five isoallergens)
Which Ctenocephalides felis allergens are considered major allergens in dogs?
Cte f 1
What are the molds that are commonly identified as allergens in dogs?
prevalence seems variable, related to geographical and climatic factors
Rhizopus
Pullularia
Alternaria
Aspergillus fumigatus
Malassezia pachydermatis
What makes an allergen a “major allergen”?
if ≥50% of patients allergic to the “parent” allergen source have detectable positive IgE serological results or immediate skin test reactivity
Which miRNA are potential biomarkers for canine atopic dermatitis?
miR-141
miR-187
miR-200a
miR-203
miR-215
Which genes are potential biomarkers for canine atopic dermatitis (not genes implicated in hereditability)?
PDE4D
PIAS1
RORA
SH2B1
What can happen to IL-33 to further enhance allergic inflammation?
released full-length IL- 33 is already active but can be processed by inflammatory proteases into a shorter ‘hyperactive’ mature form
What happens to IL-33 in canine atopic dermatitis?
increased in chronic lesional skin
- including keratinocytes, endothelial cells and dermal infiltrating cells
- higher in skin lesions with excoriation
–> may also be elevated in other pruritic diseases
What happens to TSLP in canine atopic dermatitis?
inconsistent results
What is C- C motif chemokine ligand 17 (CCL17)?
also known as thymus and activation regulated chemokine (TARC)
is a potent Th2 chemoattractant via its receptor CCR4 that is selectively expressed on Th2 cells
What happens to CCL17/TARC in canine atopic dermatitis?
increased
serves as a biomarker for disease in humans
may in dogs too as it seems to correlate with severity of disease
- two were positive in the control group but one went on to develop cAD
attempt to inhibit had variable response
- immunological diversity could explain this
What is C-C motif chemokine ligand 22 (CCL22)?
also known as macrophage- derived chemokine (MDC)
another ligand for CCR4 so can recruit Th2 cells
What happens to CCL22/MDC in atopic dermatitis?
May be upregulated in lesion and nonlesional skin
positive correlation with pVAS
need more studies
How IL-4 involved in canine atopic dermatitis?
potent regulator of immunity - key Th2 cytokine
secreted by Th2 cells, mast cells, eosinophils and basophils
plays an important role in leucocyte survival in Th2 responses
involved in IgE class switching of B cells
What happens to gene and protein expression of IL-4 in dogs with atopic dermatitis?
commonly considered to be a cornerstone cytokine in the pathogenesis of AD
actual results are variable
possible it only plays an important role during the induction or acute phase
effect of IL- 4 may be enhanced due to increased susceptibility of its effector cells
How IL-5 involved in atopic dermatitis?
produced primarily by Th2 cells and mast cells
induces survival, activation and migration of eosinophils
IL- 5 is considered as acritical cytokine in allergic diseases
What happens to gene and protein expression of IL-5 in dogs with atopic dermatitis?
studies have consistently reported upregulation of IL- 5 mRNA expression
but IL-5 monoclonal antibodies haven’t been great in humans
How IL-13 involved in atopic dermatitis?
Regarded as a primary disease- inducing effector cytokine in allergic diseases
Contributes to IgE production and differentiation Th2 subtype
Shares a common receptor with IL-4
monoclonal antibody in humans targeting IL-4/IL-13 shows promise
What happens to gene and protein expression of IL-5 in dogs with atopic dermatitis?
Pretty consistently increased in experimental and client-owned dogs
How IL-31 involved in atopic dermatitis?
known to cause severe itch in humans, dogs and other animal species
five mRNA splice variants of IL- 31RA in dogs encoding two protein isoforms
- full-length isoform X1
- truncated isoform X2
unknown if there is a functional difference between these
What happens to gene and protein expression of IL-5 in dogs with atopic dermatitis?
consistently upregulated
may be one of the earliest and major cytokines involved in acute cAD
lokivetmab works for more than one year in 28% of client- owned dogs when it was used as proactive monotherapy
experimental anti-IL-31vaccine (coupled to virus- like particles) decreased itch
Which T helper subset may play the largest role in food allergies?
Th9
What are some plants that can cause allergic contact dermatitis in dogs?
hippeastrum, Asian jasmine, oleander, dandelion, and plants belonging to the family Commelinceae (spiderworts) such as Commelina cyanea and Callista fragrans (commonly called the inch plant or basket plant)
What is allergic contact dermatitis?
T cell-mediated delayed hypersensitivity (~24h) reaction
divided into two distinct phases: sensitization and elicitation
Why might endotoxins produced by gram negative bacteria have a protective effect against the development of atopic dermatitis?
augment the stimulation of Th1 which will in turn inhibit the generation of helper Th2
