Unit 4: hypersensitivity Flashcards
1
Q
Hypersensitivity reactions are___ immune reactions that cause tissue damage.
A
adaptive
2
Q
Hypersensitivity Reactions: A state of excessive antigen driven adaptive immune reactivity with a ___ rather than a ___ outcome. Leads to inflammation & tissue damage
A
deleterious
protective
3
Q
Ab dependent effector mechanism for ___ reaction
A
1,2,3
4
Q
Ab independent effector reaction for ___ reaction
A
4
5
Q
hypersensitivity reaction can be categorized as:
A
Effector mechanism - Ab dependent (I, II, III) vs. Ab
independent (IV)
Time of onset - Immediate to days
Isotype involved - IgE vs. IgG
Is antibody bound to cell surfaces or. soluble antigens
T cells are primary mediators (Type IV)
6
Q
atopic dermatitis is what type of hypersensitivity
A
Type 1
7
Q
bee sting is a ___
A
type 1 hypersensitivity
8
Q
arthus reaction
A
type III hypersensitivity
9
Q
poison ivy
A
type 4 hypersensitivity
10
Q
type 1 mechanism, onset and antigen
A
11
Q
type 2 mechanism, antigen, onset
A
12
Q
type 3 mechanism, antigen, onset
A
13
Q
type 4 mechanism, antigen onset
A
14
Q
Anaphylaxis, Atopic disease
A
type 1
15
Q
immediate hypersensitivity are referred to as ___
A
allergies
type 1 hypersensitivity
16
Q
___ are substances that so NOT cause any harm or trigger an immune response in 80% of the pop. These are IgE mediated
A
allergens
17
Q
___ are substances that trigger an immune response in 100% of the population
A
antigens
18
Q
type 1 HS reaction can cause what localized reactions:
A
Allergic conjunctivitis
allergic rhinitis (seasonal/hay fever). Airway obstruction in horses,
summer snuffles in Guernsey/Jersey cattle.
chronic allergic rhinitis. Dogs - (seasonal or year-round)
**allergic bronchiolitis**. Cats – low grade cough, wheezing, dyspnea – peribronchiolar density (rads).
allergic asthma. Cats, signs similar to humans. Transient and mild
reactions (wheezing, cough) develop in summer. Can be protracted and severe (exp. dyspnea, cyanosis, lung hyperinflation).
Intestinal/food allergies. Dogs/cats – vomiting 1-2 hr after eating
atopic dermatitis – dog and others. >10% of dogs affected (terriers,
dalmations, retrievers). Often triggered by inhaled antigens. In cats,
commonly due to food allergens.
19
Q
type 1 HS can cause what systemic reactions
A
A. Anaphylactic shock.
B. Urticarial reactions (hives).
C. Milk allergy.
20
Q
Type 1 : systemic reaction: anaphylactic shock;
A
After exposure to certain vaccines, drugs, food, insects
bites. Response takes seconds to minutes.
**Lungs are primary targets** in domestic species, but also portal mesenteric vasculature (except dogs are reverse).
Local or systemic (restlessness, excitement, pruritis, facial edema,
lacrimation, vomiting, diarrhea, dyspnea, cyanosis, shock, collapse,
convulsions, death.
Dogs: Liver is major target, portal hypertension, visceral blood pooling -GI vs respiratory.
21
Q
in dogs what does anaphylactic shock look like?
A
Anaphylactic shock. After exposure to certain vaccines, drugs, food, insects bites. Response takes seconds to minutes.
Dogs: Liver is major target, portal hypertension, visceral blood pooling - GI vs respiratory.
22
Q
Urticarial reactions
A
systemic reaction to type 1 HS
Edematous plaques in skin, lips, conjunctiva, facial skin (more severe) due to vaccines, drugs, foods, insect bites.
23
Q
milk allergy
A
systemic reaction to Type 1 HS
Cows (+/- mares). Anti-milk casein IgE autoantibodies. Increased intramammary pressure pushes milk proteins into circulation (local or systemic, milking leads to recovery)
24
Q
mechanism for type 1 HS
A
Sensitization phase: TH2 cell secrete IL4 and IL13 that turn B cell from IgM to IgE memory and plasma cells. Plasma cells produce allergen specific IgE
Activation phase allergen specific IgE will bind to mast cells at Fc receptor,
Effector phase: allergen binds to IgE on mast cell surface. this will cause release of granules that leads to anaphylactic response- (histamine, heparin and protease release)
25
what are some common IgE mediated allergic reactions
26
\_\_\_: Antigens capable of stimulating Type I reactions. In industrialized countries, IgE responses to ___ predominate
innocuous antigen
27
The majority of humans mount significant IgE responses only
to \_\_\_
parasitic infection.
28
Most allergic IgE responses occur on mucous membrane
surfaces in response to allergens that enter the body by
\_\_\_
inhalation or ingestion.
29
Atopic allergy
atopy
pertains to (inherited) clinical manifestations of type I IgE-mediated hypersensitivity to common environmental allergens
20%
runs in families- genetic link?
30
Hygiene hypothesis
Less hygienic environments help to protect against atopy (developing allergy)
31
air pollution and low fiber diets lead to \_\_\_\_
increased allergies
predisposition to develop allergies
32
TSLP
Produced by **epithelial cells**, especially in the lung in
response the certain allergens such as mite proteases
Produced by **basophils and mast cells**
Production can be upregulated by IL-4
Prompts dendritic cells to activate Th2 type responses → **type 1 HS response**
33
Allergen induced TSLP production by epithelial cells, mast cells, or basophils promotes DC maturation & \_\_\_
Th2 responses (type 1 HS response)
34
Basophils (IL-4 and TSLP producers) act as ___ to promote Th2 responses
APCs
Th2→ type 1 HS response
35
certain allergens directly cross link FcR on mast cells leading to __ release
IL-4
Will switch immature B to mature B
36
TSLP will cause ___ to help with the class switch of B cells with the help of ___ made by ___ cells
DC cells
IL4, TH2
(type 1 HS- will produce IgE cells)
37
mast cells release:
**preformed/primary mediators:** histamine, proteases, chemotactic factor (ECF, NCF)
**newly synthesized/ secondary mediators:** PAF, leukotrienes (B4, C4, D4) and prostaglandin (D2)
38
immediate vs late phase reaction of Type 1 HS reaction
antigen binds to **TH2** which will release **IL-4** and cause B cell switch to **IgE B cell** will produce IgE antibody which bind to Fc receptor on Mast cell
new antigen will bind to the IgE Fc recptor on the mast cell and cause release of primary and secondary mediators
39
late phase of type 1 HS will cause the accumulation of \_\_
Eosinophils • Neutrophils • Basophils • Lymphocytes & macrophages
40
Eosinophils
Express a **low affinity receptor for IgE,** as well as Fc receptors
for IgG. Therefore, both IgE and IgG bound antigen can bind
to eosinophils leading to their activation.
**Activated by:**
• Leukotrienes • Platelet-Activating Factor • Major Basic Protein (MBP) • Eosinophil cationic protein
41
Key features of Allergens
allergens are antigens capable of causing allergic reaction
Proteins or glycoproteins
• Often enzymatically active
• May have non-enzymatic biological activity
• Often exposure is to very low doses
• Often **exposure is via the mucosa**
• Often low molecular weight
• Often with high solubility
42
What makes an antigen an allergen?
Triggering an allergic response requires IL-4/IL-13 producing Th2 cells to initiate B cells to class switch to IgE which will bind to Fc on mast cell
43
Pollen from birch trees contains an allergen that structurally and functionally resembles PGE 2 and can inhibit \_\_-production by DCs to promote __ cell differentiation
IL-12
Th2
44
Certain peanut allergens can cross link IgE on ___ while others have been shown to bind to DC- SIGN and stimulate \_\_\_development
mast cells
Th2
45
how to diagnosis type 1 HS
**skin test**
**RAST test: radioallergosorbent test:** Determine the serum levels
of total IgE (RIST) or serum IgE specific for an allergen (RAST)
46
anaphylaxis causes
**Difficulty breathing**
**Asphyxiation** due to constriction of smooth muscles around the bronchi of the lung (H1).
**Drop in blood pressure,** due to blood leaking into tissue **(edema)** spaces due to increased permeability of blood vessels (H2).
**Death** is a possibility
47
major organ effected by anaphylaxis in ruminants, horse, swine, cat and humans
respiratory tract (type 1 )
48
what is the major organ effected by anaphylaxis in dogs
**Primarily hepatic veins**. Dogs show initial excitement followed by vomiting, defecation and urination. Progressive with muscular weakness, depressed respiration, become comatose, convulse and die within an hour.
49
how to treat anaphylaxis
**in severe case:** epinephrine, corticosteroids, atropine and/or aminophylline
**in mild case:** antihistamine and steroids
50
type 2 HS responses involving \_\_\_antibodies. This
effector arm of the immune response normally participates in protective immunity to infection. However, Abs occasionally react with noninfectious antigens to trigger acute or chronic hypersensitivity reactions.
IgG
51
Antibodies against extrinsic antigens are normally \_\_\_
ok
52
Antibodies against intrinsic antigens are normally\_\_
NOT ok
53
Type 2 HS cause AB to bind to blood cells causing
destruction of red blood cells (hemolytic anemia) or platelets (thrombocytopenia).
54
In type 2, Certain drugs (\_\_\_) bind non-specifically to cell surfaces and trigger Ab production and cell destruction.
i.e., penicillin, sulfas
55
in type 2, Antibodies can be generated against cell receptors (\_\_\_) to extracellular matrix molecules (\_\_\_) and skin proteins (\_\_\_.)
Not common but very serious.
TSHR, AcHR
Goodpasture’s syndrome
Pemphigus
56
example of type 2 HS
immune mediated disease
57
mechanism of type 2 HS
**IgG driven**
1. **Complement** mediated target cell lysis - MAC complex lyses
cell.
2. Antibody mediated **opsonization** promotes Fc receptor
dependent phagocytosis by macrophages.
3. **Antibody dependent cell-mediated cytotoxicity (ADCC).**
Complement fragments (C3a/C5a) attract neutrophils, which
undergo Fc receptor mediated activation. Activated
neutrophils release ROS and other cytotoxic molecules.
4. **Lysis and apoptosis via NK cells** via Fc receptor activation.
Perforin release causes cell lysis and granzymes trigger target
cell apoptosis.
5. **Target cell dysfunction** – Antibodies block or activate receptor
targets.
58
\_\_mediated target cell lysis - MAC complex lyses
cell
Complement
| (type 2 HS)
59
Antibody mediated ___ promotes Fc receptor dependent phagocytosis by macrophages.
opsonization
| (Type 2 HS)
60
\_\_\_ : Complement fragments (C3a/C5a) attract neutrophils, which
undergo Fc receptor mediated activation. Activated
neutrophils release ROS and other cytotoxic molecules.
Antibody dependent cell-mediated cytotoxicity (ADCC).
type 2 HS
61
\_\_\_ via Fc receptor activation. Perforin release causes cell lysis and granzymes trigger target cell apoptosis.
Lysis and apoptosis via NK cells
| (type 2 HS)
62
\_\_\_: Antibodies block or activate receptor targets.
Target cell dysfunction
| (type 2 HS)
63
Antibody and Complement-dependent responses
Type 2 HS response → **killing normal tissue**
a. Antibody binds to target cell Ag, triggers classical C activation and
formation of a membrane attack complex (MAC) and cell lysis.
b. Antibody opsonizes(surrounds) the target cell and triggers phagocytosis by macrophages.
**Examples**: AIHA, Erythoblastosis fetalis, Goodpasture’s disease, transfusion reactions
64
Rh reaction
mom is RH-, fetus in +
mom gives antibodies to child by colostrum or placenta, which include anti RH
this will cause fetus to attack itself
prevent by giving rhogam
**(hemolytic disease- erythroblastosis fetalis)**
type 2 HS response
65
what happens with mix matched blood type
type 2 HS reaction
first time usually okay, second exposure will result in severe reaction
66
hemolytic disease in newborns
type 2 HS reaction
## Footnote
HDN in the foal is not uncommon. (0.05 to 2%), in mules even more common (8-10%)
* The foal inherits a **RC antigen from sire not present in mother.**
* The mare is sensitized to the antigen due to transplacental hemorrhage in late gestation
* Foal **ingests colostrum** containing high titer alloantibodies to its RBCs.
**• Antibodies in mare do not cross the placenta.** Therefore, **foals are born healthy** and **sicken several hours** after suckling.
67
How to test for Type 2 HS
**look for antibodies to normal tissues**
detection of **circulating antibody against the tissues** involved, presence of antibody and complement in the lesion (biopsy) by IF. The staining pattern is normally smooth and linear, such as that seen below in a case of Goodpasture's\* nephritis (renal and lung basement membrane).
Goodpasture's: anti-glomerular basement membrane antibody disease
68
\_\_\_: anti-glomerular basement membrane antibody disease
Goodpasture's (type 2 HS)
69
Antibody-dependent cell mediated cytotoxicity
(Type 2 HS response)
Ab bound cells are **targeted through Fc** receptors on:
Macrophages • NK cells • Eosinophils • Neutrophils
**Examples:**
* Drug induced hemolytic anemia
* Drug induced thrombocytopenia
* Drug induced neutropenia
* Transplant rejection
70
Pemphigus foliaceus
**type 2 HS in skin (Autoantibodies generated against intracellular cement proteins in the epidermis)**
## Footnote
dogs \> cats \> horses
Erosions, ulcerations, & thick encrustations of the skin and mucocutaneous junctions.
Auto-Abs to IC cement (desmoglein)
Degradation and separation of the cornified and uncornified cell layers.
71
Pemphigus vulgaris
**type 2 HS in skin (Autoantibodies generated against intracellular cement proteins in the epidermis)**
## Footnote
Less common than p. foliaceus.
Vesicles form along the **mucocutaneous junctions** of the mouth, anus, prepuce, and vulva, and in the oral cavity.
Other areas of the skin are only mildly involved.
72
Bullous pemphigoid
**type 2 HS in skin (Autoantibodies generated against intracellular cement proteins in the epidermis)**
## Footnote
Rare canine skin disease often in Collies and Doberman Pinschers.
Lesions are often widespread but tend to be concentrated in the groin.
Involved skin resembles a severe scald
73
myasthenia gravis
type 2 HS → cause target cell dysfunction
**AcH Receptor** destruction → disrupts neural transmission → flaccid muscles
74
graves disease
type 2 HS → target cell dysfunction
**Anti-TSHR** antibodies cause increased T3/T4
75
Type 3 HS
**Immune Complex Disease:** Mediated by antibodies to soluble antigens in circulation and the formation of poorly catabolized immune complexes
**Local response**: Arthus reaction refers to a localized reaction
```
**Systemic response:** antibody- antigen immune complexes causing
systemic pathology (e.g., serum sickness).
```
76
Arthus reaction refers to a ___ reaction
localized
## Footnote
**type 3 HS**
77
mechanism of type 3
**antigen/antibody complex** form
there is too much and will deposit in tissues
complex will change shape and **activate complement system**, which will not only attack the complex but what ever it is attached to
C3a & C5a attract neutrophils/mast cells
**Neutrophil activation** - release of neutrophil lysosomal enzymes, leading to tissue destruction.
Increased vascular permeability
78
why do type 3 HS occur
persistent or overwhelming infection will increase amount of immune complexes (antigen and antibody) formed
the normal system of removing extra IC, the **RES** (reticuloenothelial system) will **get overwhelmed** and excess IC will deposit in tissues
79
the normal system of removing extra immune complexes
the RES (reticuloendothelial system)
this is what goes wrong in type 3 HS
80
arthus reaction
**type 3 HS**
1. Involves the in situ formation of antigen/antibody complexes after the
intradermal injection of an antigen.
2. Animal/patient has to be previously sensitized (has circulating Ab),
3. Manifests as local **vasculitis** due to deposition of IgG-based immune
complexes in dermal blood vessels.
4. Activation of complement primarily results in cleavage of soluble
complement proteins forming C5a and C3a
5. C3a and C5a recruit **PMNs** and trigger local mast cell degranulation
(requiring the binding of the immune complex onto FcγRIII), resulting
in an inflammatory response)
81
type 3 reaction in vessel wall create
hemorrhage and necrosis
82
type 3 at glomerular basement membrane cause
loss of integrity, release of protein and RBCs into the urine, renal failure
83
type 3 at joints cause
destruction of synovial membranes & cartilage.
84
serum sickness
systemic type 3 response
## Footnote
Serum sickness (manifests 6-15 days after exposure
The administration of large amounts of “foreign” serum lead to an
immune response and generation of antibodies.
Results from administration of certain drugs (sulfas, penicillin)
The “antigen” in this case are all foreign molecules at concentrations
high enough to promote massive immune complex formation.
**Case of Serum sickness**
Snake venom-producing farm
Technician bit by a Egyptian cobra
Rushed to ER: IV anti-venom serum given.
Patient left the hospital 7 days later
10 days discharge, patient developed joint pain, fever, recurrent itchy hives.
Dx: “serum sickness”
85
Snake venom-producing farm
Technician bit by a Egyptian cobra
Rushed to ER: IV anti-venom serum given.
Patient left the hospital 7 days later
10 days discharge, patient developed joint pain, fever, recurrent itchy hives.
what is the diagnosis?
serum sickness
systemic type 3 response
86
Glomerulonephritis
Immune complex deposition- complement activation, leading to
increased permeability in the glomeruli. This results in loss of plasma proteins in the urine.
Immune complexes trapped in the glomerulus fix complement. PMNs respond and destroy the glomerulus.
The clinical picture is relatively unpredictable, with some animals having IC deposition, but no clinical disease.
**systemic type 3 response**
87
Rheumatoid Arthritis
ICs deposit in joints, pericardium, lungs
## Footnote
**systemic type 3 response**
88
SLE
an AI disease that affects skin, joints, kidney – Ab’s are directed against DNA
**a type 3 HS response**
89
Type 4 HS reaction
1. Antibodies are not involved.
2. It is a **cell mediated response**
3. **CD4+ T cells (TH1) and/or CD8+ T cells (CTL)** drive the response, also macrophages play a key role (+/- eosinophils and neutrophils).
4. A pathological response **occurs only after previous exposure**
or sustained exposure.
5. The pathological response is delayed, t**ypically it takes 1-2 days** to develop, thus the name ”Delayed Type Hypersensitivity” (DTH).
90
two major types of type 4 HS
Those triggered by absorbable chemical substances - **contact dermatitis**
Those triggered by **intercellular pathogens** and in certain situations cellular antigens – **granulomatous inflammation:**
91
: Mycobacterium (TB, leprosy) • Viruses • Fungi • Certain autoantigens can trigger a DTH reaction
these are intercellular pathogens that trigger type 4 reaction → granulomatous inflammation
92
how do chemical substances cause type 4 HS
cell mediated response
will try to kill→ but unable and results in dermatitis
requires previous exposure
Cell-mediated → CD8+ CTL’s drive the response
- Chemicals are absorbed through skin & haptenize cellular proteins
- Skin cells present haptenized Ag on MHC I
- CD8+ TCR binds Ag and cells proliferate and differentiate.
- Subsequent exposure activates CD8+ memory cells.
- Perforin and granzyme release kills epidermal cells and leads to
blistering.
93
how does poison ivy work
type 4 HS
## Footnote
TH1, TH17, & CD8+ T lymphocytes in contact dermatitis
Molecules such as **pentadecacatechol (Urushiol)** complex with skin proteins. This complex is internalized by APCs, processed and presented by MHC II to **activate TH1 cells.** Urushiol also haptenizes proteins in skin cells and is presented on MHC I to activate CD8+ lymphocytes.
Subsequent exposure to pentadecacatechol will activate these TH1 and cells & induce cytokine production and CTL mediated cytotoxicity
Macrophages also accumulate and **release lytic enzymes**
Together these actions **lead to inflammation, cell damage, and blister formation**
94
how to detect type 4 HS
**DTH test** – Used to test for **TB exposure in humans**, not commonly used in Veterinary Medicine. This does not mean that Type IV reactions do not occur in animals, rather that using DTH to assess pathogen exposure in animals is unreliable.
## Footnote
**do we have memory reaction??**
