Immuno: Hypersensitivities Flashcards
What is Hypersensitivity?
a state of heightened reactivity to antigen
What is a Hypersensitivity reaction?
immune response to innocuous antigens that lead to symptomatic reactions upon re-exposure
What is Hypersensitivity disease?
damage to host tissue cause by hypersensitivity reactions to typically innocuous antigens
Name and briefly describe the 4 types of hypersensitivity reactions.
Type I - IMMEDIATE TYPE; “allergy”; involves IgE-dependent triggering of mast cells
Type II - MODIFIED SELF; IgG antibody is specific for altered components of human cells (surface or matrix antigens)
Type III - IMMUNE COMPLEX; immune complexes formed from soluble antigen and IgG antibody
Type IV - DELAYED TYPE; antigen-specific effector T cell (mostly Th1) mediated hypersensitivity
What are properties common to all allergens?
Most allergens:
- are small proteins
- are highly soluble
- are carried on desiccated particles
- elute from delivery particles and diffuse into mucosa
- are presented in low doses
- have enzymatic activity
Which T helper cell induces class switching of B cells from IgM to IgE?
Th2 CD4+ cells
Antigens that selectively stimulate Th2 cells that drive an IgE response are known as ____.
allergens
One of the pre-requisites for type I hypersensitivity is that the initial response to an allergen must involve what?
it must be an IgE response
Antigens presented to Th0 cells at low doses tend to elicit differentiation into ____ cells.
Th2 CD4+ cells
What cytokines and signals are involved in the induction of class switching to IgE by Th2 cells?
- IL-4, IL-5, and IL-13
- T cell expression of CD40L –> binds CD40
- T cell expression of CD23 –> binds CR2
Type I hypersensitivities are initiated primarily by ____ cells, with some involvement from ____ and ____. All of these cells express high-affinity ____ receptor.
mast; eosinophils and basophils; IgE receptor
How does expressing the IgE receptor make an immune cell initiate inflammatory response?
the IgE receptor will be cross-linked when antigen binds; the cross linking induces degranulation of the cell, which releases cytokines that kick off the inflammatory response
The predisposed state of individuals who are more likely to produce IgE responses to common environmental allergens is termed ____.
atopy.
Atopic individuals have higher levels of what than non-atopic individuals?
higher levels of soluble IgE and circulating eosinophils
Genes on which 2 chromosomes appear to be involved in allergic predisposition?
Chromosomes 5 and 11
Polymorphism of which MHC molecule affects the IgE response to certain allergens, and how?
HLA Class II polymorphism; a certain HLA class II:peptide combination suspected to predispose to stimulation of a Th2 response
Describe the two steps of response to allergens in a test for sensitivity to particular allergens.
Step 1 response: immediate onset, lasts ~30min, reaction called “wheal and flare” - wheal is swelling and flare is redness
Step 2 response: 6-8hrs post injection, “late phase reaction”, more widespread swelling
*Both inflammatory reactions occur at the site of injection
True or False: only mast cells that reside at the site of allergen contact will be induced to degranulate.
True
What is systemic anaphylaxis?
widespread activation of mast cell degranulation causing both an increase in vascular permeability and a widespread constriction of smooth muscle
Fluid leaving the blood causes dramatic reduction of ____ ____; this is termed ____ ____.
blood pressure; anaphylactic shock
How can anaphylaxis lead to constriction of the airway?
swelling in the tissues caused by increased vascular permeability can compress the airway; swelling of the epiglottis can result in asphyxiation; this can lead to death
What is the most common cause of anaphylaxis in the US?
IgE-mediated allergy to penicillin or other drugs, either ingested or injected
What is an anaphylactoid reaction?
reaction that resembles anaphylaxis but does not involved interaction between allergen and IgE
What is the treatment for anaphylactoid reactions and how does it work?
injection of epinephrine; it closes the tight junctions in the permeable vasculature, which diminishes swelling and raises blood pressure; also relaxes constricted bronchial smooth muscle and stimulates the heart
What is hay fever?
also called allergic rhinitis; mild allergic response characterized by violent bursts of sneezing and runny nose in response to inhaled allergens; characterized by local edema, obstructed nasal airways, nasal discharge (eosinophil-rich)
Allergic asthma is what?
more serious condition in which allergic reactions to commonly inhaled allergens cause chronic breathing difficulties - chronic because there is persistent infiltration of leukocytes, chronic inflammation, and air trapped in the lungs
What triggers allergic asthma?
stimulation of submucosal mast cells in the lower respiratory tract by allergen:IgE interaction
True or false: allergic asthma inflammation can be perpetuated even after the absence of further antigen.
True. That sucks.
Chronic asthma is considered which type of hypersensitivity reaction?
Type IV
Urticaria, angioedema, and eczema are all considered what type of reactions in the skin?
allergic reactions
Describe the development of urticaria (hives).
antigen activates mast cells; they release histamine which causes itchy swellings; essentially a wheal and flare reaction
Is the swelling in angioedema more or less diffuse than that of urticaria?
More diffuse
Angioedema is inflammation caused by activation of what cells and where?
activation of mast cells in deep subcutaneous tissue
What particle is in food that causes allergies?
protein
True or false: once an individual is sensitized to a food allergen, any subsequent intake of that allergen has no effect.
False - any subsequent intake of that allergen has the effect of immediately eliciting a response in the GI tract
Describe the process of a food allergen causing a reaction in the GI tract.
- allergen passes through wall of gut
- binds to IgE on mast cells triggering degranulation
- histamine causes increase in vascular permeability, accumulation of fluid in gut lumen
- smooth muscle contractions produce vomiting, cramps, diarrhea
What are methods to treat and prevent allergic reactions?
3 distinct strategies:
- modification: change behavior to reduce allergen contact
- pharmacologic: drugs that reduce the impact of allergen contact
- immunologic: prevent production of allergen-specific IgE
Name and describe the types of drugs that are used to reduce the impact of allergen exposure.
antihistamines–prevents binding of histamine to H1 receptors
corticosteroids–suppress leukocyte function
cromolyn sulfate–prevent degranulation of mast cells and granulocytes
epinephrine–reverses anaphylaxis
How does desensitization work as an immunological treatment for preventing allergic reactions?
a series of injections with increasing doses of the allergen will gradually change a Th2/IgE response to a Th1 response (no IgE produced)
How does vaccination work as an immunological treatment for preventing allergic reactions?
inject patients with allergen-derived peptides that are known to be presented by MHC class II molecules to Th2 cells in an attempt to induce anergy
Describe the process of IgE production in the case of parasite infections.
parasite induces a potent immune response in which lots of IgE is produced, only a small percent of which is parasite-specific and the rest is non-specific (represents a non-specific, polyclonal B- and T-cell activation by the parasite); the non-specific IgE out-competes the parasite-specific IgE for binding to FceRI on mast cells/basophils/eosinophils which allows the parasite to evade host immune responses. People who live in regions with lots of parasite infections tend to have reduced incidence of allergic disease
Hemolytic anemia or thrombocytopenia are common examples of what type of hypersensitivity?
Type II
In cases of Type II hypersensitivities associated with drug administration, the chemically active drug binds to the surface of ____ or ____ and creates new epitopes to which the immune system is not tolerant.
RBCs or platelets
The generation of new epitopes by penicillin stimulates the production of what antibodies, specific for the epitope?
IgM and IgG
What is the process for destroying RBCs in Type II hypersensitivity reactions?
- allergen binds the RBCV and expresses new epitopes not recognized by immune system
- the modified RBCs are coated by complement
- macrophages ingest the RBCs and present new epitopes to CD4+ T cells, creating new armed effector T cells
- effector Th2 cells present epitope to B cells which ultimately produce antigen-specific IgG
- IgG binds the altered RBCs and stimulates complement or phagocytosis; RBCs are destroyed
True or False: small immune complexes fix complement efficiently and are removed without incident, whereas large immune complexes tend to remain in circulation longer and may be deposited along vessel walls.
False - LARGE immune complexes fix complement efficiently and are removed without incident, whereas SMALL immune complexes tend to remain in circulation longer and may be deposited along vessel walls.
When/how does tissue damage occur in type III hypersensitivity?
when sufficient immune complexes accumulate, circulating leukocytes recognize them through Fc and complement receptors which activates inflammatory activities
What is serum sickness?
chills, fever, rash, arthritis, vasculitis, and sometimes glomerulonephritis, resulting from systemic accumulation of immune complexes and eventual systemic inflammatory response; due to the immune responses to non-self material administered into the bloodstream as a treatment for a variety of illnesses
Describe farmer’s lung.
type III hypersensitivity condition that results from continual inhalation of antigens (in farmers’ case: hay dust and mold spores) that elicit IgG instead of IgE antibody responses; accumulation of immune complexes in the walls of lung alveoli leads to inflammatory immune responses which include accumulation of fluid, antigen, and immune cells that prevent proper lung function
What is post-streptococcal glomerulonephritis?
an immune complex disorder that sometimes follows infections with group A streptococcus; immune complexes of GAS-derived antigen become deposited in the kidney glomeruli, resulting in inflammation that hinders kidney function
Type IV hypersensitivity reactions are mediated by what cells/substances?
antigen-specific effector Th1 cells, which activate macrophages which produce inflammatory cytokines
When do type IV hypersensitivity reactions occur?
about 1-3 days after antigen contact (because it takes time for T cells to activate and activate macrophages); therefore also called delayed-type hypersensitivity (DTH) reactions
What are the most common antigens that elicit DTH responses?
mycobacterial proteins, insect venoms, pentadecacatechol (poison ivy), and small metal ions
Now that you know about Type IV hypersensitivity reactions, you can tell us how the TB skin test works.
A small amount of protein (tuberculin) extracted from mycobacterium tuberculosis is injected subcutaneously. An individual that has produced immune response to M. tuberculosis produces an inflammatory reaction around the site of injection 24-72hrs post-injection. The inflammatory response is mediated by effector Th1 cells that recognize peptides (presented by MHC II) from the injected protein and then produce cytokines that activate and recruit macrophages to the site.
How does poison ivy make a rash?
pentadecacatechol penetrates outer skin, indiscriminately forms covalent bonds with EC proteins and skin cell surface proteins, forming new antigens not recognized as self; MHC II presentation to naive CD4+ cells as well as MHC I presentation to naive CD8+ cells (for the toxin that gets inside cells). Response to initial contact activates antigen-specific T cells and produces immunological memory; it’s the subsequent contact that results in inflammatory response and rash mediated by: antigen-specific effector CTLs killing cells exposed to pentadecacatechol, as well as antigen-specific Th1 cells that produce cytokines that activate macrophages and induce inflammation.
Why is poison ivy an example of contact sensitivity?
because contact of the allergen with the skin is required to initiate the allergic response
True or false: everyone is born with an effector response to an allergen.
False - no one is born with an effector response to an allergen, a first exposure is required wherein the immune response is generated (but no symptoms of hypersensitivity are experience)
What characteristics of inhaled allergens promote the priming of Th2 cells that tend to elicit IgE responses and lead to immediate type hypersensitivity? Describes characteristics according to the following features: molecular type function dose molecular weight solubility stability MHC class
molecular type = proteins (T cells only recognize peptides) function = most often proteases, which allow pathogens to move through tissues dose = low dose favors IL-4-producing CD4 T cells (differentiation of Th0-->Th2 cells) molecular weight = low MW allergens can diffuse out of particle into mucus solubility = high solubility means the allergen is readily eluted from particle stability = high stability means allergen can survive in desiccated particle MHC class = peptides that bind MHC class II are required for T cell priming
Describe the function of these components of mast cell granules: enzymes tryptase, chymase, cathepsin G, carboxypeptidase
remodeling of connective tissue matrix
Describe the function of these components of mast cell granules: toxic mediator histamine and heparin
toxic to parasites. increase vascular permeability, and cause smooth muscle contraction
Describe the function of these components of mast cell granules: cytokine TNF-alpha
promotes inflammation, stimulates cytokine production by many cell types, activates endothelium
Describe the function of these components of mast cell granules: cytokines IL4, IL-13
stimulate and amplify Th2 cell response
Describe the function of these components of mast cell granules: lipid mediators LTs C4, D4, E4
cause smooth muscle contraction (pericytes), increase vascular permeability, cause mucus secretion
The primary role of mast cells appears to be …?
expulsion of parasites from the body
Describe what happens in an allergic reaction to penicillin.
Penicillin binds to the surface of RBCs and is recognized by complement (active since an infection is already ongoing). Th2 cells are induced by the presentation of the peptides from the penicillin-protein conjugate, which then activate RBC antigen-specific B cells. Antibodies are made, which opsonize the RBCs and are destroyed (MAC) or phagocytosed.
If high enough concentrations of ____ are in the vasculature, the result will be too many immune complexes to be ________.
allergen; cleared efficiently
How is systemic inflammation produced by the presence of immune complexes in the vasculature?
the immune complexes get deposited and recognized by complement activation and phagocytes, which produce anaphylatoxins and other inflammatory mediators (C5 initiates mast cell degranulation); patients present much like septic shock
What 3 diseases can result from a Type III hypersensitivity to intravenous drug administration?
vasculitis, nephritis, and arthritis
What disease is the result of Type III hypersensitivity to subcutaneous drug administration?
Arthus reaction in the perivascular space
Why are some people not allergic to poison ivy?
some people are tolerant to the non-self antigens formed by pentadecacatechol; this is thought to be due to their MHC class isotype which may not be able to bind the peptide in the toxin, and therefore can’t present the peptide to activate the T cells
A hypersensitivity that develops within a few minutes of antigen exposure is most likely ____ mediated.
IgE mediated (Type I hypersensitivity)
A hypersensitivity that develops within a couple/few hours of antigen exposure is most likely ____ mediated.
IgG mediated (Type II/III hypersensitivity)
A hypersensitivity that develops within 1-2 days of antigen exposure is most likely ____ mediated.
T cell mediated (Type IV hypersensitivity, delayed type response)
Do individuals experience a symptomatic allergic response upon first exposure to an allergen?
No. No one is born with an allergy, it has to be developed at first exposure. People treated with something like penicillin can develop an allergy to it because of the long treatment time.
Which type of T cells are involved in mediated delayed type hypersensitivity reactions?
Both CD4+ and CD8+ cells; take-home point is that without CD4 cells you’ll still see this response, same without CD8 cells
How long does a delayed type hypersensitivity reaction last?
until the host cells with altered determinants (altered by pentadecacatechol) are removed; how long they survive is a debated issue
Why do many people exposed to poison ivy develop the rash in places that didn’t touch the plant?
because they scratch the site of exposure and get the oily pentadecacatechol on their hands; anywhere else they touch can be affected.
An individual with which of the following inherited immunodeficiencies would be unable to mount a DTH response to pentadecacatechol?
- AID
- MHC Class I bare lymphocyte syndrome
- MHC Class II bare lymphocyte syndrome
- CD40L
- ZAP-70
Remember: pentadecacatechol is a T cell mediated hypersensitivity:
- ZAP-70 - YES because this will prevent TCR signaling.
- AID - no because that’s in B cells
- Bare lymphocyte syndromes - no because even without one type of CD T cell the other type will mount the DTH response
- CD40L - no because this won’t wipe out all the T cells
Patient with a history of heart problems presents in the ER with a suspected MI. About 1hr after streptokinase treatment she has a rash over arms, legs, and back. Which of these is causing the symptoms?
- altered self hypersensitivity
- immediate-type hypersensitivity
- immune complex hypersensitivity
- delayed type hypersensitivity
- immune complex hypersensitivity Because streptokinase (enzyme given to treat MI) is known to cause an antibody response in some patients that have been treated with it before. Systemic symptoms indicate an immune complex disorder.
Why might immune complex hypersensitivity cause neurologic problems?
vasculitis in the brain
If the question stems talks about lung inflammation in someone with a pet bird, it’s most like talking about a type ____ hypersensitivity.
Type III
Bird-Fancier disease - feathers and droppings
A patient with a known penicillin allergy mistakenly received IV penicillin in the ER. Minutes later, she develops hives over most of her body and begins to wheeze. What condition is the patient experiencing?
immediate-type hypersensitivity; worst-case scenario could progress to anaphylactic shock
What’s the difference between altered self and immune complex hypersensitivity?
they are basically the same thing, but immune complex is just when there’s enough antigen to cause an overload of immune complexes
What are the characteristics shared by allergens that cause an immediate-type hypersensitivity?
- proteins
- T-independent antigens
- often have enzyme activity
Why are there more people with immediate-type hypersensitivities in the US (45%) than in third-world countries (1%)?
parasites are more common in people in third world countries, and when infected with parasites a non-specific IgE response is made which is trapped on the surface of mast cells and it means that the IgE is not directed at allergens like peanuts
