Hypersensitivity Reactions

Question 1

Hypersensitivity (Allergy) (3)

Answer 1

• exaggerated and inappropriate reaction to an otherwise harmless antigen
• immune system is reacting in a damaging rather than a protective fashion
• may develop during humoral or cell-mediated immune responses

Question 2

Immediate hypersensitivity reactions

Answer 2

-Hypersensitivity reactions involving antibody or antibody-antigen complexes (i.e., humoral) are characterized by symptoms that manifest within minutes or hours

Question 3

Type I-IgE-mediated Hypersensitivity-First Exposure

Answer 3

• On first exposure, Th2 response to allergen results in IgE production by plasma cells
• IgE binds to high affinity Fcε receptors on the surface of eosinophils, basophils and mast cells, ‘sensitizing’ these cells.

Question 4

Type I-IgE-mediated Hypersensitivity-Second Exposure

Answer 4

Second exposure to the allergen cross-links Fc(E)RI-bound IgE, causing degranulation and release of pharmacologically active mediators

Question 5

Allergens

Answer 5

• nonparasitic antigens that stimulate type I hypersensitivity reactions in allergic individuals
• Most responses occur at mucous membranes

Question 6

Atopy

Answer 6

A hereditary tendency in some individuals to make IgE in response to common environmental antigens

• This results in tissue-damaging IgE-mediated hypersensitivity reactions
• have high serum IgE and increased number of circulation eosinophils

Question 7

Type 1 hypersensitivity-parasites

Answer 7

-believed to be related to clearance of parasites

Question 8

Systemic anaphylaxis

Answer 8

a shock-like and often fatal type I hypersensitivity reaction

Question 9

High affinity receptor for IgE (FcεRI)

Answer 9

• consists of 4 polypeptide chains
• The α chain interacts with IgE Fc region
• the β chain links the α chain to the disulfide- linked gamma chain homodimer.
• Each gamma and beta chain possesses an ITAM that interacts with TKs to transduce an activating signal

Question 10

Low affinity receptor for IgE (FcεRII; CD23)

Answer 10

• The FcεRII consists of a single type II polypeptide chain
• involved in regulating IgE response and depends on interactions between IgE/CD23 and soluble CD23 binding to CD21 on the B cell.

Question 11

Cell types expressing FCεR- Mast cells (4)

Answer 11

• Large, granulated mononuclear cells derived from bone marrow precursors
• Tissue mast cells are found in connective tissue near nerves and surrounding blood vessels
• Mucosal mast cells are found in the mucosa lining the gut and lungs
• Express high affinity receptors for the Fc portion of IgE
• Synthesize and secrete allergic mediators, as well as a large number of cytokines.

Question 12

Cell types expressing FCεR-Basophils

Answer 12

• Circulating white blood cell that resembles mast cells
• Recruited from the blood into inflamed tissue.
• Granulated morphology with a multi-lobed nucleus; Express high affinity receptors for the Fc portion of IgE.
• Synthesize and secrete allergic mediators

Question 13

Sensitization Phase of IgE mediated hypersensitivity reactions

Answer 13

• Following antigen presentation, Th2 cells make IL-4, IL-5 and IL-13, B cells switch to IgE
• IgE binds to high affinity IgE Fc receptors on tissue mast cells and blood-borne basophils
• IgE stable longer when bound to receptor

Question 14

Sensitization Phase of IgE mediated hypersensitivity reactions-PCA

Answer 14

• passive cutaneous anaphylaxis

- passive transfer of IgE-containing serum will sensitize skin mast cells

Question 15

Activation Phase of IgE mediated hypersensitivity reactions

Answer 15

-Cross linking of at least two high affinity IgE Fc receptors (and bound IgE) triggers mast cell and basophil degranulation
Cross linking by
-multivalent allergen
-anti-IgE antibody
-anti-Fc receptor antibody
-aggregated IgE.
-non IgE activators of mast cells include C3a, C5a, cold, exercise, neuropeptides

Question 16

Early Effector Phase of IgE mediated hypersensitivity reactions- Mediators

Answer 16

-effector phase mediated by primary and secondary mediators that are released by activated mast cells and basophils

Question 17

Effector Phase of IgE mediated hypersensitivity reactions-Primary Mediators (preformed) (5)

Answer 17

• histamine
• eosinophil chemotactic factor-attract to site of mast cell degranulation
• neutrophil chemotactic factor
• proteases (degrade blood vessel basement membrane, stimulate mucus secretion, generate complement split products)
• stored in granules attached to matrix protein (heparin) by electrostatic attraction

Question 18

Effector Phase of IgE mediated hypersensitivity reactions-Primary Mediator Histamine

Answer 18

• binds to H1-4 receptors
• histamine interaction w/ H1 receptors causes intestinal and bronchial smooth muscle contraction, increased vascular permeability, increased mucus secretion by goblet cells
• H2 receptors cause vasodilation, increases vascular permeability, stimulates exocrine glands, causes acid release in the stomach
• H2 receptors on mast cells and basophils suppresses further degranulation, acting as negative feedback control mechanism

Question 19

Effector Phase of IgE mediated hypersensitivity reactions-Secondary Mediators

Answer 19

• must be synthesized
• leukotrienes
• prostaglandins
• bradykinin
• cytokines

Question 20

leukotrienes

Answer 20

• a set of peptides that cause prolonged smooth muscle constriction (bronchoconstriction) that is independent of H1 receptor engagement
• Vascular permeability and mucus production are also increased by leukotrienes.

Question 21

Prostaglandins

Answer 21

-cause platelet aggregation, vasodilation, and bronchoconstriction

Question 22

Platelet Activating Factor (PAF)

Answer 22

-causes platelets to aggregate and degranulate, releasing additional histamine that causes bronchoconstriction and vasodilation

Question 23

Bradykinin

Answer 23

-increases vascular permeability and causes smooth muscle contraction

Question 24

Cytokines

Answer 24

• IL-4
• IL-5
• IL-6
• IL-13
• TNF

Question 25

Late Effector Phase of IgE mediated hypersensitivity reactions

Answer 25

- localized inflammatory reactions within 4-6 hours of the initial allergic response that may persist for 1-2 days - infiltration of neutrophils, eosinophils, basophils, macrophages, and Th2 cells, likely a response to cytokines released by activated mast cells

Question 26

Late Effector Phase of IgE mediated hypersensitivity reactions-Eosinophils

Answer 26

- attracted by eosinophil chemotactic factor - activated by binding to antibody-coated allergen via FcR for IgE and IgG, releasing inflammatory mediators (such as Major Basic Protein: MBP) that cause tissue damage. - IL-3, IL-5, and GM-CSF secreted by activated mast cells promote eosinophil growth and differentiation.

Question 27

Late Effector Phase of IgE mediated hypersensitivity reactions-Neutrophils

Answer 27

neutrophils are also attracted to the site of degranulation by NCF and IL- 8 released at the site -Neutrophils release their granule contents including lytic enzymes, platelet-activating factor, and leukotrienes

Question 28

Systemic Anaphylaxis

Answer 28

- life-threatening impaired breathing due to airway swelling - Uterine cramps, involuntary urination and defecation additional symptoms - due to smooth muscle contraction - hives, edema may result from fluid leaking into tissue spaces - blood pressure may drop, leading to anaphylactic shock

Question 29

Localized anaphylaxis

Answer 29

reaction in a specific tissue or organ -allergen into the skin, cutaneous anaphylaxis characterized by erythema (redness, blood vessel dilation) and edema (swelling due to release of serum into tissue) - peaks ~10-15 min of challenge with the allergen (wheal and flare reaction) -allergic rhinitis (hay fever) and asthma -In asthma patients, infiltrating eosinophils and neutrophils can cause significant tissue damage.

Question 30

RAST and RIST

Answer 30

- measure serum IgE levels - radioimmunosorbent test - radioallergosorbent test

Question 31

Environmental Medical Treatment of type1 hypersensitivity

Answer 31

-avoid the allergen

Question 32

Pharmacologic Medical Treatment of type1 hypersensitivity

Answer 32

- antihistamines - Leukotriene antagonists - cortisone - epinephrine

Question 33

Immunologic Medical Treatment of type1 hypersensitivity

Answer 33

Hyposensitization - repeated subcutaneous injections of the allergen to induce the production of circulating allergen-specific IgG, to remove the allergen before it can trigger IgE sensitized mast cells and basophils -May also cause a shift to a Th1 response -Humanized monoclonal anti-IgE Ab that bind only to free IgE, can lower serum IgE levels and prevent mast cell/basophil sensitization