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