Lecture 21 - Hypersensitivities Flashcards
Learning Objective 1
List the 4 types of hypersensitivities and the basic mechanisms for each.
- Type 1 - Immediate. Mediated by IgE, mast cells, Th2 cells, and eosinophils.
- Type 2 - Cytotoxic. Mediated by antibody binding to a cell or cell matrix.
- Type 3 - Immune complex. Mediated by IgG binding to soluble antigen and complement fixation.
- Type 4 - Delayed. Mediated by Th1 and Tc cells.
Learning Objective 2
Define Sensitization
The first exposure to an allergen.
Essentially the same thing as a primary immune response, but the immune system is responding inappropriately to an antigen.
Activation of Th2 cells, class switching of B cells to IgE, binding of IgE to Fc epsilon receptors on mast cells.
True or False
Mast cells produce IgE
FALSE
IgE is produced by B cells. The secreted IgE attaches to the Fc epsilon receptor of the mast cell.
Where is most of the IgE in the body found?
Attached to mast cells at mucosal surfaces.
True or False
A mast cell can have more than one type of IgE attached to it.
TRUE
List a few common allergens
Drugs
Venoms
Foods
Animal hair
Pollen
SO MANY ALLERGENS
List a few factors that make a molecule a good allergen.
- Protein with carbohydrate side chains
- Enzymatically active (often proteases, allowing penetration through the mucosa)
- Highly soluble
- Low doses over time (favors IL4 production)
- Stable
- Peptides that can be presented on MHC2
- Can cross-link IgE receptors
Learning Objective 3
Explain the important factors responsible for IgE production, e.g. type of antigen, location in the body, antigen presenting cell, Th cell, B cell, cytokines.
Allergens in general and parasites stimulate IgE production. Antigens typically enter on mucosal surfaces and are detected by a B cell, a macrophage, or a dendritic cell.
IL4 secreted from APCs influences naive T cells to class switch to Th2 cells.
Th2 cells release IL4, IL5, IL10, and IL13 to influence B cells to class-switch to IgE.
IgE has a high affinity for Fc epsilon receptors on mast cells, so most of the IgE in the body is located on mast cells.
What are the signature Th2 cytokines?
IL4
IL5
IL10
IL13
Does IgE fix complement?
NO
IgE binds to the Fc epsilon receptor on mast cells. IgE will only bind to this receptor if it has not bound to an antigen.
This is different than IgG, which will only fix complement if it has bound to an antigen.
Learning Objective 4
List the cell responsible for the early phase Type I reaction and special features about that cell (eg Fcε receptors).
Mast cell
Located along mucosal surfaces.
Possessed Fc epsilon RI receptor. This receptor has a high affinity for IgE that is not bound to antigen.
What is the half-life of IgE in the serum?
2-3 days
Recall that IgG has a half-life of 21 days in the serum. IgE has such a shorter time in the serum because it quickly becomes bound to mast cells on mucosal surfaces.
List some factors that can cause mast cell degranulation.
Physical stimuli
Complement anaphylatoxins (C3a, C5a)
Cross-linking of antigen with IgE and Fc epsilon RI receptor.
List the timing for waves of mast cell mediator release
Seconds
Minutes
Hours
List the mast cell mediators released seconds after a mast cell is activated
Molecules stored in mast cell granules (do not need to be manufactured)
- Toxic mediators - histamine, serotonin, heparin
- Toxic to parasites. Cause increased vascular permeability, bronchus contraction.
- Enzymes - trypsin, proteases
- Remodel connective tissue, cause pruritis
- Chemotactic factors
- Cause influx of eosinophils and neutrophils
List the mast cell mediators released minutes after mast cell activation.
Arachidonic acid metabolites and platelet activating factor (PAF)
- Prostaglandins, leukotrienes, PAF are more potent than histamine.
- Smooth muscle contraction (bronchoconstriction)
- Increased vascular permeability
- Chemotactic for Th2 cells, eosinophils, basophils
List the mast cell mediators hours following mast cell activation.
Cytokine synthesis (must be manufactured by the mast cell)
- IL4, IL13
- stimulate the formation of more Th2 cells
- Contributes to the allergy cycle - Th2 cause more B cell class-switching to IgE, which will cause more sensitization and degranulation of mast cells.
- IL3, GM-CSF, IL5
- promote eosinophil production and activation
- TNF alpha
- increased adhesion molecules on endothelium to promote influx of leukocytes
Learning Objective 5
List the 3 waves of mediators released from mast cells, approximately when they are released, and give examples of each including function.
Seconds, Minutes, Hours
- Seconds
- Release of pre-formed mediators in granules. Histamine. Causes vasodilation, vessel leakiness, bronchoconstriction.
- Minutes
- Arachidonic acid metabolites. Same function as histamine, but more potent.
- Hours
- Cytokine production. Similar to Th2 cytokines (IL4, 5, and 13). Recruits Th2 response and IgE production.
Learning Objective 6
Explain how some of the mediators in the Type I response contribute to the allergy cycle, give an example or two.
IL4 and IL13 stimulate the production and activation of more Th2 cells.
This in turn causes more B cell class-switching to IgE. Results in more mast cell sensitization and degranulation (the allergy cycle).
IL5 recruits and activates more eosinophils.
This cycle must be broken to stop the hypersensitivity.
What is the late-phase cell in a type 1 hypersensitivity?
Eosinophil
Increase in number in bone marrow in response to GM-CSF
Activated by IL5
What factors influence the clinical manifestations of immediate type hypersensitivity (Type 1 hypersensitivity)?
Amount of allergen-specific IgE present on mast cells
Route that the allergen is introduced
Dose of allergen
Learning Objective 7
Describe a systemic Type I hypersensitivity reaction and give an example.
Example: Anaphylaxis
Mast cells throughout the body degranulate.
Rapid vasodilation, vessel permeability, and bronchoconstriction.
Leads to shock and respiratory distress.
Learning Objective 8
Describe a local Type I hypersensitivity reaction and give an example.
Example: Allergic dermatitis
Localized to just the skin.
Mast cell degranulation occurs in one specific area of the body (local, not generalized)
When does a late-phase response to a type 1 hypersensitivity reaction occur?
4-8 hours
Caused by eosinophil influx and release of eosinophil mediators
May or may not be observed
What is considered the “gold standard” of allergy testing?
Intradermal skin testing
What is being pictured here?
Mast cell minutes after activation.
At this point, degranulation has occurred (release of histamine, etc.) and the mast cell has begun producing arachidonic acid metabolites.
What cell type is this?
Eosinophil
Specifically, this is a horse eosinophil.
Eosinophils are late-phase cells in Type 1 hypersensitivities.
What is the effect of mast cell degranulation on the respiratory system?
Mucus secretion
Bronchoconstriction
Enough mast cell degranulation will result in respiratory distress
Describe what is happening in these immediate and late-phase type 1 hypersensitivity reactions.
Immediate-phase: mast cell degranulation resulting in increased vascular permeability and vasoconstriction.
Late-phase: eosinophil recruitment, resulting in release of eosinophil mediators, Th2 recruitment, further IgE production, and further mast cell sensitization.
What is being pictured here?
Intra-dermal skin testing.
Holy crap, that animal reacted to everything.
Learning Objective 9
Describe the mechanism of an intradermal allergy test and explain why it is used to determine type I hypersensitivity. Describe a positive and a negative result. What would be used for a positive control?
- Inject antigens into the dermis.
- Positve result: If mast cells have IgE that recognize the antigens, they will degranulate. This will cause vasodilation and increased vascular permeability, resulting in a characteristic wheal and flare (urticaria).
- Negative result: mast cells do not have IgE that recognizes the antigen, so they do not degranulate.
- Control: inject histamine. Histamine causes increased vascular permeability and vasodilation, producing wheal and flare.
Learning Objective 10
Give and explanation for why an intradermal skin test is preferred over serological tests for diagnosing allergy.
Most IgE in the body is found attached to mast cells at mucosal surfaces. IgE in the serum only has a half-life of 2-3 days and is present in low concentrations. Thus, serum testing for IgE may show false negative results (i.e. the animal has an allergy, but you failed to detect IgE in the serum due to low concentrations).
How would you detect IgE in the serum?
ELISA test
Anti-IgE at the base of the well to bind IgE in the serum. Then add enzyme-linked anti-IgE that will cause a color change in a substrate if bound to IgE.
What is an antihistamine?
Blocks the effects of histamine.
Benadryl acts as an H1 receptor antagonist.
(H1 is the receptor that binds histamine from mast cells. Depending on the tissue type, will cause vasodilation, vessel permeability, bronchoconstriction, etc.)
How is epinephrine effective in treating anaphylaxis?
Causes vasoconstriction and bronchodilation
Essentially, these are the opposite effects of histamine
Learning Objective 11
Give an explanation of how hyposensitization, “allergy shots” can be effective at reducing an allergy.
Type 1 hypersensitivities involve IgE and Th2 responses.
- Injecting antigen over time can push the immune response to Th1 and IgG.
- IgG can bind to antigen before it can cause mast cell degranulation. “Blocking antibody.”
- Administer antigen under the tongue can push the immune response to IgA and Treg.
Learning Objective 12
Draw and compare and contrast IgE on a mast cell, IgE on a B cell that will produce IgE (BCR), and IgE binding a parasite it recognizes.
Major differences:
- IgE on mast cells is bound to Fc epsilon receptors. Mast cells can have multiple IgE types bound to their surface.
- B cells produce IgE specific to a single antigen. The IgE BCR can be secreted.
- On a parasite, IgE will bind to the epitope it recognizes through its antigen binding sites.
Learning Objective 13
Explain the difference in the reaction of low grade fever, lack of appetite, and lethargy the day after a vaccination and a Type I hypersensitivity adverse vaccine reaction, include timing, and mechanism (important cells and molecules).
Day after vaccination
- Vaccinating causes production of pro-inflammatory cytokines (IL1, IL6, TNF), which act on the hypothalamus to cause fever and sick feeling.
- Happens on first exposure to vaccine.
Type 1 hypersensitivity to vaccine
- Animal becomes sensitized to first vaccine. Produces IgE against vaccine component, which gets bound to mast cells.
- On subsequent vaccination, mast cell degranulates, resulting in pruritis and swelling around the eyes and face. Can cause anaphylaxis.
How would you treat an adverse vaccine reaction?
Glucocorticoids
Antihistamines
Epinephrine and supportive care in severe reactions
Learning Objective 14
Describe what kind of pretreatment you might give to an animal that you suspect might have a type I adverse reaction to a vaccine.
Administer antihistamines before administering the vaccine to prevent mast cell degranulation.
