Hypersensitivity reactions Flashcards
Which type of bacteria are MAC (membrane associated attack complexes) most effective?
Gram NEGATIVE bacteria
Limited peptidoglycan to fight against
Which Ig doesn’t have a hinge region, making it harder for proteases to process the antibody
IgM
Which is better at activating complement/opsonization, IgG or IgM?
IgM
But IgG is smallest antibody, so can go through vessels into tissue easier!
Because IgM is so large, it rarely enters tissue
IgM can act as a BCR when bound to B cells
Type I hypersensitivity antibody type
IgE
Type I hypersensitivity’s other name
Immediate hypersensitivity
Type II hypersensitivity’s other name
Cytotoxic hypersensitivity
Type II hypersensitivity’s antibody type
IgG, IgM
Diseases associated with Type II hypersensitivity (6)
1) Drug reactions
2) Pemphigus
3) Pemphigoid
4) IMHA
5) Transfusion reaction
6) Cryoglobulinemia
T or F: Type II hypersensitivities need complement to work
False. Many mechanisms use complement, but not complement-dependent
Mechanism of Type II hypersensitivity (5)
Antibody binds autoantigen → +/- activate complement
1) Neutrophil cytotoxicity
*Complement binds Ig → chemotaxis for neutrophil → releases proteases/ROS →cell damage
*PF
2) Opsonization + Phagocytosis
*Complement binds Ig→ chemotaxis for macrophage → eat complement and bound Ig + cell
*IMHA
3) MAC formation
4) Apoptotic response
*Complement binds Ig → chemotaxis for NK cell → release perforin, granzymes that poke holes in cell PM →lysis
5) Disruption of cell function
*NO COMPLEMENT
*Ig binds autoantigen RECEPTOR → 2 options
A) Ab binds R; Noncompetitive inhibition for R
*Myasthenia gravis
B) Ab binds R; activates R without its normal signal
*Hyperthyroidism
Type III hypersensitivity antibody type
IgG, IgM
Type III hypersensitivity’s other name
Immune-Complex mediated hypersensitivity
Diseases from Type III hypersensitivity (4)
1) SLE
2) DLE
3) Purpura hemorrhagica
4) Vasculitis
Type IV hypersensitivity antibody type
None → cell mediated
Type IV hypersensitivity’s other name
Late phase, cell mediated hypersensitivity
4 types of Type IV hypersensitivity (A-D)
A) Th1 → macrophage activation → contact dermatitis
B) Th2 → eosinophil activation → chronic allergy/asthma
C) CD8 → Cytotoxic → Contact dermatitis, EM, SJS
D) T cell → neutrophil activation
True or False: Atopic dogs typically have less IgA
True. Theory that increased IgE may be compensatory for lack of IgA
Functions of basophils (3)
1) IgE-mediated anaphylaxis
2) IgG-mediated anaphylaxis via FcgR1
3) Release PAF, which is more effective than histamine at increasing vascular permeability
PAF relative to histamine
PAF is more effective than histamine at increasing vascular permeability
PAF made by neutrophils
What can trigger cutaneous basophil hypersensitivity
Ticks, fleas, insects
*Characterized by marked basophil infiltrate and fibrin deposition
*Mediated by T cells and IgE/IgG
*Pathogenesis of IBH
Type I hypersensitivity can result 3 major mast cell product families. What are they?
Antibody cross-links to FcER1-bound IgE →FcER1 with intracellular tyrosine kinase dimerize and produce (4):
1) Phospholipase A → arachidonic acid → prostaglandins and leukotrienes
2) Protein kinase → (phospholipase C) → intranuclear → gene transcription → Cytokines
3) Protein kinase → filament formation → Granule exocytosis
*Phospholipase A for Arachidonic (A)
*Phospholipase C for Cytokine (C)
What organs normally clear immune complexes
Spleen, liver
If not→ deposited in tissue
External antigens that can trigger immune complexes (5)
1) Drug
*Dobie + sulfa drug
2) Self antigens
3) Foreign serums
*Monoclonal antibodies
4) Bacteria
5) Diet hypersensitivity
2 major forms of Type III hypersensitivity
1) Local reaction → “Arthus reaction”
*Localized necrotic vasculitis
2) Generalized reaction → “Serum sickness”
*Complement gets stuck in small vessel → activates complement → recruits neutrophil → release protease + ROS → damage to endothelial cells + vessel BMZ → leaks to surrounding tissue
Clinical signs of serum sickness (Type III hypersensitivity, generalized)
*Systemic inflammation
*Splenomegaly
*Urticaria
*Fever
*Arthralgia
Which cells are involved in Type IV hypersensitivity
T cells, NK cells
What type of hypersensitivity is allergic contact dermatitis
Type IV
What pathogens are type IV hypersensitivites designed for?
Intracellular pathogens
*Mycobacteria
*Fungi
Also tumor immunity, transplant rejection
Why is type IV hypersensitivity DELAYED?
Requires recruitment of cells, which takes time
Mechanism of Type IV hypersensitivity?
Small molecule binds to self-cell → acts as a “hapten” to make “self” seem antigenic → APC presents haptenized self-antigen on MHC cl II → binds naive Th cell
*If LC releases IL-12, induces Th1 immune response → IFNg →recruit macrophages →TNFa, IL-1 → ROS, lysozymes attack “self”
*If LC releases IL-6 induces Th17 → activates neutrophils → ROS, proteases → tissue damage
Which type of hypersensitivity reaction often forms a vesicular rash?
Type IV hypersensitivity
**CD8+ T cells kill the haptenized cells –> necrosis –> vesicles
Diseases of type IV hypersensitivity (9)
1) Contact dermatitis
2) FAD
3) Bacterial hypersensitivity
4) Food
5) Tick bite
6) SJS
7) EM
8) TEN
9) Drug hypersensitivities
What type of hypersensitivity reaction is Urticaria and Angioedema
Type I & Type III
Predisposing factor for urticaria/angioedema in dogs
Atopic dermatitis
Autoantibodies to high affinity IgE receptors or IgE
Variably pruritic
T or F: Horses usually get angioedema along with their urticaria
False
If they are going to get angioedema, they usually also have urticaria (1st urticaria, then angioedema)
Location of angioedema: muzzle, eyelid, ventrum, distal extremities
Horse breeds predisposed to urticardia
Arabian, Thoroughbred
(also more predisposed to AD)
Locations of horse urticaria on body
Neck
Trunk
Proximal extremities
Drugs implicated in urticaria in horses
Penicillin
Phenylbutazone
T or F: histamine levels correlate with cAD severity
FALSE
Which cytokines promote Th1 response
IL-12, IL-18
(Goal of immunotherapy is to convert from Th2 to Th1 or Treg)
For CAFR, what infectious agent can trigger a Th1 response in Peyer’s patches → IGNg → suppress Treg → food allergy development
Reoviruses (intestinal infx)
(shown for Th1 gluten intolerance in humans)
What percent of CAFR dogs have GI signs
10-30%
Major allergen for FAD
Cte f1
What type of hypersensitivity reaction is FAD
Initially local type IV (mononuclear)
Over time, replaced with type I → eosinophils
What are causes for gyrate (polycyclic; bizarre shapes) urticaria in horses
*Drug reactions
*EM (does not pit)
Causes of papular urticaria in horses
*Stinging insects
*Folliculitis (esp if oozing, crusts, alopecia after)
Causes of giant urticaria in horses (up to 40 cm!)
Vasculitis
In dogs with cAD, are LC increased or decreased in epidermis
Increased
What are other risk factors for cAD?
- Month of birth → born during allergy season = ↑ risk
- Maternal diet → fed non-commercial diet during lactation = ↓ risk
- Use of probiotics → mixed results
Which cytokine suppresses contact hypersensitivity reactions (type IV)?
IL-10
Which plants can cause contact hypersensitivity (6 plants + 5 miscellaneous causes)
*Wandering Jew plant
*Spiderwort
* Spreading dayflower
*Doveweed
*Hippeastrum leaves and bulbs
* Asian jasmine
* Dandelion
Misc:
*Cedar wood
*Carpet deoderizer
*Cement
*Feathers
*Tobacco
Which medications can cause contact hypersensitivity (5)
1) Neomycin
2) Propylene glycol
3) Bacitracin
4) Tetracaine, other “caines”
5) Benzoyl peroxide
T or F: contact hypersensitivity is pruritic
True. Highly pruritic
What type of hypersensitivity reactions are drug reactions
Type I
Type II
Type III
Type IV
What is the secretory component relative to IgA
Secretory component is a peptide –> binds IgA dimers to form secretory IgA (SIgA) –> protects IgA from digestion by intestinal proteases
Can IgA act as an opsonin
No
Can IgA induce agglutination of antigens
Yes. Adheres to microbes to prevent entrance to body surfaces
Which cell does IgD attach to
B cells
Acts as BCR
Rarely in blood stream
NOT in rabbits or cats (yet)
Destroyed with heat (like IgE)
What is the function of IgD
regulates B cell responses
Activates basophils (IL-1, IL-4, B-cell activating factor production)
How many constant regions does IgG have compared to IgE in its heavy chain
IgG: 3 (has 1 in its light chain also)
IgE: 4
Which Ig can fix complement
IgM
IgG
Which Ig can cross the placenta
IgG only
What type of hypersensitivity reaction is mosquito bite hypersensitivity
Type I
Although MOST of the time, demodectic mange is cleared by the innate immune response w/o need for adaptive immunity, which type of hypersensitivity can occur 2’ demodex
Type IV hypersensitivity
-CD8+ T cells are rare, but present on histopath
(mostly monocytes)
What type of hypersensitivity is an arachnid (and insect) hypersensitivity
Type I (anaphylaxis)
Type III
While we dont KNOW that canine eosinophilic F&F is a hypersensitivity rxn, if it IS, which hypersensitivity would it be?
Type I hypersensitivity (eos)
What triggers canine eosinophilic F&F
Insect bites
BUT usually, insect bites get better over time, but this dz smolders
Nasal bridge = site most affected
What type of hypersensitivity reaction is Staphylococcal hypersensitivity?
Type I (eosinophil, immediate)
Type III (immune complex, vasculitis, neutrophils)
Type IV (delayed, cell mediated)
Neutrophilic dermal vasculitis (type III)
Breed predisposition to Malassezia hypersensitivity
Dogs:
*American Cocker Spaniel
*Australian Silky Terrier
*Basset Hound
*Boxer
*Dachshund
*English Poodle
*Setter
*Shih Tzu
*West Highland White Terrier
Cats:
*Devon Rex
*Sphynx
Most common environmental fungal hypersensitivity
Alternaria
What type of hypersensitivity is fungal hypersensitivity
Type I
T or F: hypersensitivity to dermatophytes are reported
True
Can have IgE to trichophyton
What type of hypersensitivity reaction is Purpura hemorrhagica
Type III- immune complexing
Organisms that can trigger Purpura Hemorrhagic (5)
*Staphylococcus equi (or its vaccine)
*Corynebacterium pseudotuberculosis
*Rhodococcus equi
*Equine influenza virus
*Equine herpes virus type I
Occurs 2-4w post infection
Clinical signs of purpura hemorrhagica
Urticaria, SC edema, Hemorrhage on mucosa + SC. Vasculitis
(febrile, depressed, anorexic).
Other than horses, what other animal gets Purpura hemorrhagica
Pigs
Anaphylotoxins Definition
Complement components: *Potent neutrophil chemoattractants.
*Promote smooth muscle contraction
*Increased vascular permeability
Anaphylotoxins, name 2
C3a, C5a
2 types of adverse drug reactions
*Type A: Dose-dependent
*Type B: Dose-independent
What is a Type A adverse drug reaction
Dose dependent
Exaggerated, but normal response to medication. Result is due to the drug itself.
Common, predictable
Can happen in any individual
What is a Type B drug reaction
Dose-independent
Bizarre reaction to drug. Not related to dose, normal pharmacological action of drug
These occur at therapeutic doses.
Uncommon, unpredictable
Often severe: high morbidity, mortality.
4 mechanisms for drug allergy
1) Hapten hypothesis
2) Danger theory
3) Pharmacological interaction concept
4) Viral reactivation
What is the Hapten Hypothesis, with regards to ADR
Hapten + Autologous protein (ie albumin, transferrin, integrins, selectins) = hapten-protein complex
Hapten-protein complex = immunogenic. Initiate adaptive immune response
Example of a medication that is a hapten
Beta-lactam antibiotics (penicillin)
Bind to albumin via lysine residues
Example of a medication that is a prohapten
Sulfamethoxazole. Metabolized by CYP2C6 to form sulfamethoxazole hydroxylamine. This can bind to autologous proteins w/cysteine residues –> antigenic
PRO hapten means it needs to be PROCESSED to become a hapten.
What is the Danger Theory of ADR
*Danger signals (inflammation, oxidative stress, necrosis) trigger adaptive immune response
*Danger signal can be induced by:
-Drugs
-Diseases treated by the drug
This means the immune system is responding to the danger signal, rather than the foreignness of the drug itself
What is the pharmacological interaction concept of ADR
*Off-target binding of the drug to receptors on T cells –> T cell activation
*Non-covalent binding with TCR or MHC on T cells
*Immediate + independent of drug processing or metabolism
Which cells can be activated by haptens
B cells AND T cells
Which cells can be activated by pharmacological interaction concept
T cells ONLY
Drugs known to induce pharmacological interaction ADR
*Amoxicillin
*Sulfamethoxazole
*Ciprofloxacin
*Iohexol
*Lidocaine
*Allopurinol
Diseases that are possibly a result of pharmcological interaction (ADR)
*Hepatotoxicity
*SJS/TEN
*MaculoPapular Exanthema (MPE)
*Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
What is Viral Reactivation of ADR
*Viral infections that INCREASE susceptibility to drug hypersensitivity (ie HIV, herpesvirus)
*Selective expansion of viral-specific CD8 T cells that CROSS REACT with the drug
What is “Pseudo-allergy”
Non-immune-mediated activation of mast cells, eosinophils, basophils –> anaphylaxis
*Off-target binding of drugs to MRGPRX2, C3a R, C5aR on these cells to activate
*Do NOT use IgE or IgG Fc R
Drugs that cause Pseudo-allergy (AD)
*Opiods
*NSAIDs
*Radiocontrast
*Vitamin K1
*Liposomal drugs
T or F: Mast cells need to be SENSITIZED to a drug prior to onset of a “pseudo-allergic” anaphylaxis
FALSE. Can occur IMMEDIATELY after drug exposure
Do not need IgE, IgG4 to initiate this reaction. Use MRGPRX2 or anaphylotoxin receptors
Which receptor do opiods bind to on Mast Cells, which can initiate anaphylaxis?
MRGPRX2
Which medications can cause facial pruritus in cats?
*Methimazole
*Spironolactone
*Solensia
What type of hypersensitivity reaction causes pruritus
Types 1 and 4
What type of hypersensitivity reaction causes urticaria and angioedema
Type 1
Where is edema in the skin that causes urticaria
Dermis
Where is edema in the skin that causes angioedema
SQ
Drugs that cause a Type 1 Hypersensitivity reaction
*Penicillin
*ampicillin
*tetracycline
*vitamin K
*Amitraz
*ivermectin, moxidectin
*sulfonamides, *radiocontrast agents
*chlorhexidine
*HyLyt® shampoo
*vaccinations
What type of hypersensitivity reaction is a pemphigus foliaceus-like ADR
Type 2. Antibodies bind to DSC1.
What is the difference between drug-induced and drug-triggered PF
Drug INDUCED: disease resolves once the drug is discontinued
Drug TRIGGERED: disease continues despite d/c of drug
Which medications are associated with pemphigus foliaceus-like ADR
*Sulfonamides
*Cephalexin
*Oxacillin
*Clavamox
*Tetracycline
*Promeris
*Vectra 3D
*Certifect
*Nexgard
*NSAIDs
What type of hypersensitivity reaction is vasculitis
Type 3- immune complexes
Which drugs have been associated with vasculitis
*Itraconazole
*Meloxicam
*Piroxicam
*Sulfonamides
*Human albumin
T or F: vasculitis is usually drug induced
False. Most often idiopathic
What are fixed drug eruptions
Delayed reactions to a drug that affect 1+ body region.
Well circumscribed erythema –> edema –> bullae –> ulcerations.
Scrotum commonly affected.
Repeatable with re-exposure.
What type of hypersensitivity reactions are fixed drug eruptions
Type 4
What type of hypersensitivity reaction is EM, SJS, and TEN
Type 4
Amount of epidermal detachment for SJS vs TEN
SJS <10%
TEN >30%
What type of hypersensitivity reaction is lupus erythematous-like ADR
Type 3 (+/- vasculitis)
What are systemic signs of a type 3 hypersensitivity reaction
*anemia
*thrombocytopenia
*polyarthropathy
*protein-losing nephropathy.
What type of hypersensitivity reaction is Sweets Syndrome/ Neutrophilic dermatitis
Type 4
What medications are associated with Sweets syndrome
NSAIDs, antibiotics (metronidazole, beta-lactams), vaccinations
What type of hypersensitivity reaction is Superficial Suppurative Necrolytic Dermatitis (SSND)
Type IV. May be a CONTACT dermatitis
What breed develops Superficial Suppurative Necrolytic Dermatitis (SSND)
Miniature Schnauzers
What is the trigger for Superficial Suppurative Necrolytic Dermatitis (SSND)
Shampoos (natural OTC)
What is the difference between Superficial Suppurative Necrolytic Dermatitis (SSND) and Post-Grooming Furunculosis
Post-grooming furunculosis is infectious, SSND is sterile
Which non-skin clinical sign is common in CAEDE (Wells-like syndrome)
GI signs
Which non-skin clinical sign is common in Sweets like syndrome
IMPA, lameness
Which breeds are overrepresented for CAEDE
Mini schnauzer
English bulldog
T or F: Drug allergy is dependent on the dose of the drug
FALSE. Its a Type B Adverse drug reaction (dose independent)
What body region is usually associated with allergic contact dermatitis
Sparsely haired regions (contact!)
*Ventrum
*Face
*Ears
*Scrotum
*Perineum
*Ventral paws
What is the different between allergic contact dermatitis (ACD) and irritant contact dermatitis (ICD)
ICD is a nonspecific reaction to an irritating, caustace substance. NO PRIOR EXPOSURE NEEDED. More directly cytotoxic to keratinocytes.
ACD requires prior exposure/ sensitization (type 4 hypersensitivity, with possible type 1 component?)
Cause of SJS/TEN
Drugs
EM is NOT usually drug induced
Pathomechanism for EM, SJS, TEN
Cytotoxic response by CD8 T cells and NK cells against keratinocytes
*Keratinocytes are primed for targetting by infectious agents or drugs.
*Apoptosis via:
1) EM: direct cellular cytotoxicity 2) SJS/TEN: soluble mediators of cell death
Soluble mediators include Fas ligand, granzymes, perforin and, most importantly, granulysin
What is the possible animal equivalent to human EM (herpesviral
Feline herpes-associated EM
Soluble mediators of cell death in SJS/TEN
Granulysin
Also:
*Fas ligand
*Granzymes
*Perforin
Etiology of EM in animals
Idiopathic
