15. Hypersensitivity Reactions (I & II) Flashcards
What are the four types of hypersensitivity reactions?
- Allergy and atopy
- Antibody-mediated
- Immune complex-mediated
- Delayed type (DTH)
IgE is associated with which type of Hs?
Type I: Allergy and Atopy
Type I: Allergy and Atopy
- IgE
- Ag induces cross linking of IgE bound to mast cells and basophils with release of vasoactive mediators
- Includes a systemic anaphylaxis and localized anaphylaxis such as hay fever, asthma, hives, food allergies, and eczema
IgG and IgM are associated with which type of Hs?
Type II: Antibody Mediated Hs
Type II: Antibody Mediated Hypersensitivity
- IgG or IgM
- Ab directed against cell surface antigens mediates cell destruction via complement activation or ADCC
- Includes blood transfusion reactions, erythroblastosis fetalis, and autoimmune hemolytic anemia
Type III: Immune Complex-mediated Hypersensitivity
- Immune complexes
- Ag-Ab complexes deposited in various tissues induce complement activation and an ensuing inflammatory response mediated by massive infiltration of neutrophils
- Includes localized Arthus reaction and generalized reactions such as serum sickness, necrotizing vasculitis, glomerulonephritis, rheumatoid arthritis, and systemic lupus erythematosus
Type IV: Delayed Type Hypersensitivity
- T cells
- Sensitized T cells (TH1, TH2 and others) release cytokines that activate macrophages or Tc Cells which mediate direct cellular damage
- Includes contact dermatitis, tubercular lesions, and graft rejection
Type I Hypersensitivity – Release of inflammatory mediators
Primary mediators are _________________.
produced before degranulation and stored in granules
Type I Hypersensitivity – Release of inflammatory mediators
Secondary mediators are _______________.
synthesized after cell activation or released by breakdown of membrane phospholipids during degranulation
Type I Hs early responses occur within ___________ of allergen exposure.
minutes
Type I Hs late responses occur ______________ as a result of recruited cells.
hours later
Which Hs reaction involve inflammatory cells such as neutrophils and eosinophils?
Type I Hs
How do neutrophils and eosinophils cause tissue damage in Type I Hs reactions?
by releasing toxic enzymes, oxygen radicals and cytokines
Type I Hs reactions are mediated by ________________.
mast cell granule contents
The biological effects of histamine are seen within minutes. T or F?
TRUE
_________________ is a major component of mast cell granules (~10%).
histamine
List two effects of histamine.
- Binds to specific receptors on various target cells (FYI: H1, H2, H3 receptors)
- Induces contraction of intestinal and bronchial smooth muscles and increases vascular permeability, increased mucous
Histamine is formed by ___________________ of histidine.
decarboxylation
Leukocytes and Prostaglandins
- Secondary mediators
- Formed by enzymatic breakdown of phospholipids
- Effects are more pronounced and longer lasting than histamine – active at nM
- Mediate bronchoconstriction, vascular permeability, and mucous production
- Considered to be a major cause of asthma symptoms
Mast cells and basophils release several cytokines in Type I reactions; name the 6 discussed in lecture.
- IL-4
- IL-13
- IL-5
- IL-8
- TNF-alpha
- GM-CSF
IL-5
recruits and activates eosinophiles and makes them live longer
TNF-alpha
contributes to shock in systemic anaphylaxis
IL-8
acts as a chemotactic factor, attracting other immune cells
GM-CSF
stimulates production and activation of more myeloid cells, including more granulocytes
IL-4 and IL-13
stimulate TH2 responses to increase IgE production by B cells
Allergy
-third phase (in skin primarily)
-starts three days after exposure, peaks at four days post-exposure
* massive eosinophil infiltration
* presence of basophils
* late-recruited WBCs add even more tissue damage
Type I
Systemic anaphylaxis:
o Occurs within minutes of second allergen exposure
o Often initiated by an injected or gut-absorbed allergen
Bee sting venom, penicillin, seafood, nuts are examples
o Symptoms include:
Labored respiration
Major drop in blood pressure leading to anaphylactic shock
Massive edema
Contraction of smooth muscles leading to defecation, urination, and bronchiolar constriction
* May lead to death by asphyxiation
o Epinephrine is the immediate treatment
(relaxes smooth muscle contraction, decreases vascular permeability, improves cardiac output)
Localized hs Reactions
- There are several categories of these
Pathology is limited to a specific tissue or organ
Symptoms result from release of mediators in immediate exposure area
o Examples:
Asthma
Allergic rhinitis (hay fever)
Food allergies
Atopic dermatitis - Eczema
Allergic Rhinitis – Hay Fever
- Most common atopic disorder ~50% of US population
- Airborne allergens interact with sensitized mast cells in nasal mucosa (by cross-linking IgE)
- Mediators cause localized vasodilation and increased capillary permeability
- Symptoms: sneezing, coughing, watery discharge from eyes, nasal mucosa, upper respiratory tract
Asthma
- Affects ~5% of US population
- Incidence increasing in developed countries
- Mortality highest among African-Americans (especially inner-city)
- Is there a different genetic basis amongst ethic groups?
- Allergic asthma -airborne allergens (pollens, dust, fumes, insect products) trigger an asthmatic attack
- Caused by degranulation of mast cells in lower respiratory tract
- Contraction of bronchial smooth muscles, airway edema, mucus secretion, and inflammation cause:
- Bronchoconstriction and airway obstruction
- Inflammatory disease divided into two phases: early and late responses (@ 4-6 hours lasting for up to 2 days)
- Note: Intrinsic asthma is a different entity– exercise, cold air can trigger, not allergen-dependent
- Chronic asthma leads to “remodeling” of the airways
- Also get edema, thickening of basement membrane and hypertrophy of bronchial smooth muscles
- Mucus plug contains detached epithelial cell fragments, eosinophils, neutrophils and spirals of bronchial tissue known as Churchman’s spirals
- Late phase begins to develop 4-6 h after initial reactions and persists for 1-2 days
Eosinophils in Asthma
- Account for 30% of accumulating cells
- ECF (eosinophil chemotactic factor) released by mast cells
- IL-5 contributes to differentiation and survival of eosinophils in the lung
- Express Fc receptors for IgE
- Degranulate to release more inflammatory mediators that cause tissue damage
- Contribute to chronic inflammation
- Eosinophil mediators include leukotrienes, major basic protine, PAF, eosinophil derived neurotoxin
- These factors important for fighting off parasitic infections, but cuase extensive tissue damage in late phase reactions
Atopic Dermatitis – Eczema
- Inflammatory disease of the skin
- Observed most frequently in young children
- Elevated IgE levels
- Skin eruptions that are redden and filled with pus
- Differs from poison oak reactions since lesions infiltrated by Th2 cells and eosinophils
Food Allergies
- Some foods induce localized anaphylaxis
- Increased vascular permeability can allow allergen to travel to other sites in the body so that asthma or hives can also accompany
- Allergen crosslinking of mast cells along GI tract induces localized smooth muscle contraction, vasodilation, capillary permeability
Symptoms:
* Vomiting and diarrhea
* If allergen enters blood stream various symptoms occur depending on where Ag enters blood stream
* Asthma attacks
* Hives – when Ag carried to skin
* Wheal and flare
* Swollen, red eruptions
* Most food allergens are water soluble glycoproteins that are relatively stable to heat, acid, and proteases (i.e., digest more slowly)
Why might some people have food allergies and not others?
- Temporary viral infection leads to short-term increase in permeability of gut – allowing increased absorption of allergens and sensitization
- Or may get sensitization via another route (respiratory or skin)
- Predisposition to Th2 phenotype?
What factors influence Type I Hs?
- If both parents are allergic, 50% chance child will be allergic
- If only one parent is allergic, 30% chance a child we be allergic
- There is a genetic basis for type I hypersensitivity
- Multiple allergy-linked genes include:
- Proteins involved in generation and regulation of immune responsiveness
- (Innate immune receptors, cytokines/chemokines and their receptors, MHC proteins)
- Multiple genetic loci involved – complicated to dissect
Name the two types of cells whose distribution is an important determinant in allergy.
Th1/Th2 balance
-Th1 cells reduce atopy
-Th2 cells enhance atopy
-IL-4 increases EgE production
-IFN Gamma decreases IgE production
Explain the confirmation of the role of Th1/Th2 subsets in atopy.
If Ag specific T cells from allergic individuals are isolated and and cytokine expression is profiled, we typically see more of the Th2 subset.
Skin testing can be used as a relatively safe, cheap way to detect what type of Hs?
Type I Hs
Skin testing to detect Type I Hs involves injecting large quantities of random allergens under the skin and observing for any kind of allergic response. T or F?
FALSE: Skin testing to detect Type I Hs involves injecting small quantities of known allergens under the skin and observing for swelling and redness, indicative of allergic response.
Why are Type I Hs increasing in developed countries?
- Incidence of asthma has increased dramatically over past two decades
- Is it related to poorer air quality?
- No, not the only factor
- Why do children raised in farm environment have lower incidence of allergy?
- Suggests that early exposure to pathogens and potential allergens has a role
- Unpasteurized cow milk
- Not being only child
Explain the “Hygiene Hypothesis”
- Proposes that exposure to some pathogens early in life provides a better T-cell balance
- Avoids dominance of TH2 subset, which promotes IgE production by B cells (stimulating allergic responses)
- Exposure to viruses may be a “good thing” since it induces IFN gamma, and this cytokine directs towards Th1 phenotype
- May explain why countries with improved hygiene are experiencing increases in asthma and allergy rates
- Still under investigation
(Type II Hypersensitivity)
Antibody Mediated Cytotoxicity
- Antibody can activate complement - MAC
- Antibodies can mediate ADCC (see fig below – focus on NK cell and target cell only)
- Antibodies can serve as opsonin
- Destruction via Ab other than IgE
- Creating pores in foreign cells
- ADCC mediated by cytotoxic cells the express Fc receptors – which bind to Ab on target cells
- Opsonin enables phagocytic cells with Fc or C3b receptors to bind and phagocytose Ab coated target cell
Opsonization (Review)
- Opsonin enables phagocytic cells with Fc or C3b receptors to bind and phagocytose Ab coated target cell
- C3b is major opsonin resulting in coating on particulate Ag or immune complexes
- C3b targets Ag directly to phagocyte enhancing initiation of Ag processing
What type of hypersensitivity are transfusion reactions?
Type II Hypersensitivity
What happens if a blood type A individual is transfused with blood from a type O individual?
Recipient anti-B Abs have nothing to bind to on donor blood cells – this is why type O blood is called the universal donor
Describe Type III Hypersensitivities
Caused by large amounts of immune complexes that aren’t removed by normal mechanism
* Immune complex = Ab plus soluble Ag
* Immune complexes can damage tissue
* Symptoms depend on where immune complexes are deposited
* If immune complexes deposited near site of Ag entry localized reaction
* If complexes formed in blood reactions develop where deposited
* Synovial membrane of joints
* Glomerular basement membrane of kidney
* Blood vessel walls - vasculitis
* Immune complex activates complement which
* Generate anaphylatoxins (C3a, C4a, C5a) then
* Recruit neutrophils and granule release thus
* Anaphylatoxins cause mast cell degranulation
Can hemolytic anemia be drug induced?
Yes; examples include penicillin, streptomycin, ibuprofen, naproxen
-some drugs can adsorb nonspecifically to proteins on RBC membranes
-these drug-protein complexes act as ne “Ags”, and can stimulate Ab production
-Ab can then bind to RBCs when the drug is present, stimulating complement mediated destruction
-Penicillin can actually induce all four types of hypersensitivities under the right circumstances for each
Type II Hs
Hemolytic Disease of the Newborn
Develops when maternal IgG Ab specific for fetal blood group antigens crosses the placenta
o Destroys fetal RBCs by binding and activating complement
Can be fatal, but can be treated by intrauterine blood-exchange transfusion and other methods
Can be prevented by use of Rhogam (anti-Rh Abs to mask Rh Ag)
Why is the first pregnancy not severely affected by hemolytic disease of the newborn?
- Recall what class of Abs are made in primary response
- IgM does not cross placenta
- Note: the majority of hemolytic disease of newborn is caused by ABO blood group incompatibility between mother and father – but not severe in nature
In what Type II reaction can there be a build-up of toxic TBC components (bilirubin)?
hemolytic disease of the newborn
An Rh- mother fertilized by a Rh+ father is at risk of ________________ .
Rejecting the Rh+ fetus
Why are there different blood types? (A, B, O)
Polymorphisms in the carbohydrates found in glycolipids and glycoproteins expressed on the surface of RBC
What is the most common clinical transplantation procedure?
blood transfusions
RBCs don’t express MHC I or II. T or F?
TRUE; major immunogenetic barrier to transfusion as a result of different carbohydrates being attached to glycolipids of RBC
Why don’t alloantibodies against O get made in Type A individuals?
Type A individuals express an enzyme that adds an additional N-acetyl galactosamine to the core structure
Adults possess antibodies to their own blood type. T or F?
FALSE: Adults posess Abs to the blood type they do NOT have
During bacterial infections, people who lack the “A” and “B” Ags (are not/are) tolerant to them and make Abs against them.
are not
If blood type A individual is transfused with blood from a type B individual, what will happen?
- Their Abs will quickly attach to the donor blood cells and activate complement
- Abs to other blood group Ag (Rh factor) may also result due to minor allelic difference when repeated blood transfusions are performed
Clinical Manifestations (Blood Transfusions)
- Lysis of RBC (via complement)
- Free hemoglobin in the blood converted to bilirubin
- Fever, chills, nausea, lower back pain (kidney involvement trying to filter out immune complexes and large amounts of hemoglobin)
- Free hemoglobin within hours
- High levels of bilirubin is toxic
- Lower back pain due to kidneys trying to filter out immune complexes and large amounts of hemoglobin
- Must stop transfusion and treat with large amounts of water
- Usually IgG mediated so RBC complement mediated lysis is incomplete and destruction of RBC occurs in extvascular sites by opsonization
Medical Approaches for Type I Hypersensitivity
- Immunotherapy – repeated injections of increasing doses of allergen
- Causes a gradual shift from IgE to IgG
- Reduces allergen specific Th2 cells (recall Th2 cells promote allergy)
- Decreases eosinophils, basophils, and mast cells in target organ
- May induce regulatory immune cells (Treg)
Another reason Immunotherapy can work with respect to inducing competitive IgG
- Mast cells express both FcεR1 (activating) and FcγRIIB (inhibiting) Ig receptors
- If a cell binds IgE and IgG, the inhibiting signal induced by IgG binding wins out
- This is partially why inducing IgG in atopic individuals (through “allergy shots”) helps treat their allergies
Other medical approaches for treatment of Type I Hs include:
- Antihistamines, leukotriene antagonists, and corticosteroids
o Antihistamines block H1 receptors on target cells
First-generation drugs can cross into central nervous system and cause side-effects
Second-generation drugs have fewer side-effects (FYI: don’t bind to muscarinic receptor) - Leukotriene antagonists work in a manner similar to antihistamines
- Inhaled/systemic corticosteroids inhibit immune cell activity in airways, treating asthma
- Cyclic AMP inducing drugs (albuterol) counter bronchoconstriction in asthma: epinephrine used for anaphylaxis
