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Immunology > 15. Hypersensitivity Reactions (I & II) > Flashcards

15. Hypersensitivity Reactions (I & II) Flashcards

1
Q

What are the four types of hypersensitivity reactions?

A
  1. Allergy and atopy
  2. Antibody-mediated
  3. Immune complex-mediated
  4. Delayed type (DTH)
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2
Q

IgE is associated with which type of Hs?

A

Type I: Allergy and Atopy

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3
Q

Type I: Allergy and Atopy

A
  • 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
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4
Q

IgG and IgM are associated with which type of Hs?

A

Type II: Antibody Mediated Hs

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5
Q

Type II: Antibody Mediated Hypersensitivity

A
  • 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
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6
Q

Type III: Immune Complex-mediated Hypersensitivity

A
  • 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
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7
Q

Type IV: Delayed Type Hypersensitivity

A
  • 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
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8
Q

Type I Hypersensitivity – Release of inflammatory mediators
Primary mediators are _________________.

A

produced before degranulation and stored in granules

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9
Q

Type I Hypersensitivity – Release of inflammatory mediators
Secondary mediators are _______________.

A

synthesized after cell activation or released by breakdown of membrane phospholipids during degranulation

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10
Q

Type I Hs early responses occur within ___________ of allergen exposure.

A

minutes

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11
Q

Type I Hs late responses occur ______________ as a result of recruited cells.

A

hours later

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12
Q

Which Hs reaction involve inflammatory cells such as neutrophils and eosinophils?

A

Type I Hs

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13
Q

How do neutrophils and eosinophils cause tissue damage in Type I Hs reactions?

A

by releasing toxic enzymes, oxygen radicals and cytokines

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14
Q

Type I Hs reactions are mediated by ________________.

A

mast cell granule contents

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15
Q

The biological effects of histamine are seen within minutes. T or F?

A

TRUE

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16
Q

_________________ is a major component of mast cell granules (~10%).

A

histamine

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17
Q

List two effects of histamine.

A
  1. Binds to specific receptors on various target cells (FYI: H1, H2, H3 receptors)
  2. Induces contraction of intestinal and bronchial smooth muscles and increases vascular permeability, increased mucous
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18
Q

Histamine is formed by ___________________ of histidine.

A

decarboxylation

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19
Q

Leukocytes and Prostaglandins

A
  • 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
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20
Q

Mast cells and basophils release several cytokines in Type I reactions; name the 6 discussed in lecture.

A
  1. IL-4
  2. IL-13
  3. IL-5
  4. IL-8
  5. TNF-alpha
  6. GM-CSF
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21
Q

IL-5

A

recruits and activates eosinophiles and makes them live longer

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22
Q

TNF-alpha

A

contributes to shock in systemic anaphylaxis

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23
Q

IL-8

A

acts as a chemotactic factor, attracting other immune cells

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24
Q

GM-CSF

A

stimulates production and activation of more myeloid cells, including more granulocytes

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25
Q

IL-4 and IL-13

A

stimulate TH2 responses to increase IgE production by B cells

26
Q

Allergy

A

-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

27
Q

Type I
Systemic anaphylaxis:

A

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)

28
Q

Localized hs Reactions

A
  • 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
29
Q

Allergic Rhinitis – Hay Fever

A
  • 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
30
Q

Asthma

A
  • 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
31
Q

Eosinophils in Asthma

A
  • 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
32
Q

Atopic Dermatitis – Eczema

A
  • 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
33
Q

Food Allergies

A
  • 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)

34
Q

Why might some people have food allergies and not others?

A
  • 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?
35
Q

What factors influence Type I Hs?

A
  • 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
36
Q

Name the two types of cells whose distribution is an important determinant in allergy.

A

Th1/Th2 balance
-Th1 cells reduce atopy
-Th2 cells enhance atopy
-IL-4 increases EgE production
-IFN Gamma decreases IgE production

37
Q

Explain the confirmation of the role of Th1/Th2 subsets in atopy.

A

If Ag specific T cells from allergic individuals are isolated and and cytokine expression is profiled, we typically see more of the Th2 subset.

38
Q

Skin testing can be used as a relatively safe, cheap way to detect what type of Hs?

A

Type I Hs

39
Q

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?

A

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.

40
Q

Why are Type I Hs increasing in developed countries?

A
  • 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
41
Q

Explain the “Hygiene Hypothesis”

A
  • 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
42
Q

(Type II Hypersensitivity)
Antibody Mediated Cytotoxicity

A
  • 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
43
Q

Opsonization (Review)

A
  • 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
44
Q

What type of hypersensitivity are transfusion reactions?

A

Type II Hypersensitivity

45
Q

What happens if a blood type A individual is transfused with blood from a type O individual?

A

Recipient anti-B Abs have nothing to bind to on donor blood cells – this is why type O blood is called the universal donor

46
Q

Describe Type III Hypersensitivities

A

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

47
Q

Can hemolytic anemia be drug induced?

A

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

48
Q

Type II Hs
Hemolytic Disease of the Newborn

A

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)

49
Q

Why is the first pregnancy not severely affected by hemolytic disease of the newborn?

A
  • 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
50
Q

In what Type II reaction can there be a build-up of toxic TBC components (bilirubin)?

A

hemolytic disease of the newborn

51
Q

An Rh- mother fertilized by a Rh+ father is at risk of ________________ .

A

Rejecting the Rh+ fetus

52
Q

Why are there different blood types? (A, B, O)

A

Polymorphisms in the carbohydrates found in glycolipids and glycoproteins expressed on the surface of RBC

53
Q

What is the most common clinical transplantation procedure?

A

blood transfusions

54
Q

RBCs don’t express MHC I or II. T or F?

A

TRUE; major immunogenetic barrier to transfusion as a result of different carbohydrates being attached to glycolipids of RBC

55
Q

Why don’t alloantibodies against O get made in Type A individuals?

A

Type A individuals express an enzyme that adds an additional N-acetyl galactosamine to the core structure

56
Q

Adults possess antibodies to their own blood type. T or F?

A

FALSE: Adults posess Abs to the blood type they do NOT have

57
Q

During bacterial infections, people who lack the “A” and “B” Ags (are not/are) tolerant to them and make Abs against them.

A

are not

58
Q

If blood type A individual is transfused with blood from a type B individual, what will happen?

A
  • 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
59
Q

Clinical Manifestations (Blood Transfusions)

A
  • 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
60
Q

Medical Approaches for Type I Hypersensitivity

A
  • 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)
61
Q

Another reason Immunotherapy can work with respect to inducing competitive IgG

A
  • 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
62
Q

Other medical approaches for treatment of Type I Hs include:

A
  • 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

Immunology (14 decks)

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