Hypersensitivity 1

Question 1

Types I, II and III are examples of antibody-mediated hypersensitivity, and all are characterized by what three qualities?

Answer 1

• a reaction that frequently develops rapidly over minutes or hours (hence the designation “immediate hypersensitivity”), but which can continue for months if the reactants remain available
• demonstrable antibodies in body fluids or cell surfaces
• the ability to be passively transferred by serum containing the appropriate antibody.

Question 2

How does Type IV differ from I, II, III?

Answer 2

Type IV (cell mediated reactions) develop after 1 or more days and can only be transferred adoptively with Ag-specific T cells.

Question 3

Define Type I Immediate Hypersensitivity:

Answer 3

• Type I immediate hypersensitivity occurs when an antibody response (usually IgE antibodies) against innocuous antigens (eg. eggs, peanuts, pollen) results in acute inflammation with symptoms such as rhinitis (runny nose), urticaria (hives) or bronchoconstriction.

Question 4

What is Atopy? Atopic? Anaphylaxis?

Answer 4

• Atopy – (literally “strange”) is the presence of specific IgE antibodies directed against common environmental allergens.
• Atopic can refer to the people (atopic individuals) and the clinical symptoms (e.g. atopic dermatitis).
• Anaphylaxis is a severe, whole-body allergic reaction resulting from the sudden release of mast cell- and basophil-derived mediators into the circulation. The extreme inflammatory reaction includes
o dilation and leakage of post-capillary venules (causing edema, life-threatening hypotension and cardiovascular collapse)
o constriction of airway smooth muscles, (bronchoconstriction, which can result in hypoxia and death).

Question 5

What are the target organs most commonly involved in hypersensitivity I reactions?

Answer 5

• the gastrointestinal tract
• the respiratory tract
• the skin.

Question 6

What are the routes that give rise to allergic manifestations?

Answer 6

1. Ingestants Foods, Drugs
2. Inhalants Pollens, Dusts, Molds
3. Injectants Drugs , Bee stings, Vaccines, Serum
4. Contactants Poison ivy, latex

Question 7

When does Generalized Anaphylaxis occur (timeline)?

Answer 7

It occurs after prior sensitization and is usually obvious within minutes in a sensitized individual. A very small amount of antigen can elicit a life-threatening response.

Question 8

What are the pathophysiologic changes which occur in a type I reaction?

Answer 8

• mast cell degranulation
• infiltration of eosinophils and neutrophils
• contraction of smooth muscle
• increased vascular permeability
• and finally, infiltration of mononuclear cells.

Question 9

Clinical symptoms may involve

Answer 9

a) skin: pruritis (itching); edema (swelling); wheal and flare (raised skin with radiating redness) = urticaria (hives).
b) Pulmonary: bronchospasm, mucosal edema with airway obstruction, laryngeal edema.
c) Cardiovascular: hypotension, arrhythmias, cardiovascular collapse
d) Gastrointestinal: cramps, vomiting, diarrhea.

Question 10

What are the similarities of Mast Cells and Basophils with regard to Hypersensitivity?

Answer 10

• Mast cells and basophils possess features that are critical for the initiation of Type I reactions.
• Both have high affinity receptors for IgE and contain histamine.
• They also have similar biochemical pathways for the release of mediators listed in the next section.

Question 11

What are the differences in the location, circulation, and basic function of Basophils and Mast cells?

Answer 11

• Basophils originate in the bone marrow, circulate in the blood, respond to chemotactic stimuli, and have H2 (histamine) receptors that probably transmit a negative feedback signal to turn off mediator release.
• Mast cells are found around blood vessels, in subcutaneous and submucus tissue, and in the peritoneal cavity. The variety of stimuli that can cause the release of mediators by mast cells are depicted in Figure 2; IgE-antigen complexes and complement-derived anaphylotoxins are probably the most important physiologically.

Question 12

What is Eosinophilia? Tissue Eosinophilia?

Answer 12

• Eosinophilia (high numbers of eosinophils in the blood) is a hallmark of allergic disease, and tissue eosinophilia can be dramatic at tissue sites where reactions involving IgE antibodies are occurring.

Question 13

Why are Eosinophils reactive with IgE?

Answer 13

• Eosinophils have IgE receptors and are important cytotoxic effectors against IgE-coated targets such as shistosomes, but their exact role in asthma and other hypersensitivity reactions is still unclear.

Question 14

How do Lymphocytes, Monocytes, and Macrophages interact with IgE?

Answer 14

• Lymphocytes and monocytes also have IgE receptors, and are thought to down-regulate IgE production.
• Macrophages may provoke allergic responses, since they release inflammatory mediators in response to IgE-antigen complexes. The full role of these cells in allergy is still unknown.

Question 15

What are the stimuli that can induce release of histamine, leukotrienes, cytokines, and other mediators from mast cells?

Answer 15

Anti-IgE
Anti-IgE Receptor
Antigen
Lectins
Anti-Mast Cell Antibody
Anaphylotoxins C3a, C5a
FcERI is normally occupied by monovalent IgE

Question 16

VI. How does IgE receptor cross-linking evokes mediator release in Mast cells and Basophils?

Answer 16

• Mast cell and basophil IgE receptors are normally occupied by monomers of IgE in vivo.
• Exposure to the appropriate antigen (or experimentally, antibody to IgE) will result in crosslinking of the IgE receptors.
• Receptor crosslinking is the trigger for release of mediators.
• Receptor crosslinking triggers signaling events that result in fusion of the perigranular membranes with the plasma membrane, and subsequent release of the granule contents.

Question 17

Explain how the following mediators have pharmacologic effects on smooth muscle and mucous glands. Histamine on H1 and H2 Receptors:

Answer 17

• Acting on H1 receptors
o histamine contracts smooth muscle (eg. in airways), increases vascular permeability and increases mucous secretion by goblet cells.

• Via H2 receptors
o histamine increases gastric secretion, and feeds back to decrease mediator release by basophils and mast cells.

Question 18

pharmacologic effects on smooth muscle and mucous glands. B. Slow Reacting Substance of Anaphylaxis (SRS-A):

Answer 18

• SRS-A is an older name for the cysteinyl-leukotrienes (LTC4, LTD4, LTE4) and are derived from the membrane fatty acids (primarily arachidonic acid)
o potent constrictors of peripheral airways (i.e., bronchoconstrictors)
o cause dilation and increased permeability of microvessels, leading to edema.
o airway mucous secretion, constriction of coronary and cerebral arteries, decreased myocardial contractility and increased gastric acidity.

Question 19

Leukotriene B4 effects on smooth muscle and mucous glands

Answer 19

• Binding to a different receptor from SRS-A, LTB4 causes
o neutrophil chemotaxis
o adhesion of neutrophils to endothelium of post capillary venules
o and neutrophil degranulation.
• LTB4 also induces leakage of post capillary venules, leading to edema.

Question 20

Prostaglandin D2 on smooth muscle and mucous glands

Answer 20

•	Prostaglandin D2 is a 
o	bronchoconstrictor
o	peripheral vasodilator
o	coronary and pulmonary vasoconstrictor
o	inhibitor of platelet aggregation
o	neutrophil chemoattractant.

Question 21

E. Platelet Activating Factor (PAF) on smooth muscle and mucous glands

Answer 21

• produced by a variety of cells, including mast cells.
• PAF causes platelet aggregation with release of vasoactive mediators such as serotonin.
• A potent vasodilator and bronchoconstrictor, PAF contracts non-vascular smooth muscle directly and induces wheal and flare reactions even in the absence of platelets
• It causes chemotaxis and degranulation in eosinophils and neutrophils, and it increases vascular permeability and bronchoconstriction.

Question 22

F. Neutral Proteases: on smooth muscle and mucous glands

Answer 22

• Neutral proteases activate kinins (e.g. bradykinin) and complement to cause increased vascular permeability, decreased blood pressure and contraction of smooth muscle.

Question 23

A. Leukotriene-B4 (LTB4) as Pro-Inflammatory by Chemotactic Properties

Answer 23

• derived from membrane fatty acids, is a rapidly released and potent chemotactic factor for polymorphonuclear cells, eosinophils, and macrophages.

Question 24

What other pro-inflammatory compounds have chemotactic properties?

Answer 24

• Interleukin 8 (IL-8)
• Complement Factor C5a
• platelet activating factor (PAF)
• RANTES
• eotaxins

Question 25

What are mediators that cause tissue destruction?

Answer 25

Toxic oxygen radicals (e.g., superoxide) released from neutrophils, macrophages and mast cells.
B. Acid hydrolases and neutral proteases (e.g. tryptase) from mast cells.

	C. Major basic protein: a protein from the larger eosinophil granule can damage airway               epithelium.

Question 26

VIII. What Non Immunologic Mechanisms Can Lead to Anaphylaxis?

Answer 26

• Non-steroidal anti-inflammatory drugs (NSAID’s) such as aspirin and ibuprofen can induce anaphylactic reactions that are independent of adaptive immune mechanisms.
• In some individuals, exercise and cold air has similar effects.
• Generalized hypersensitivity-like reactions can also result from certain drugs, such as iodinated radiocontrast material.

Question 27

How are Drugs and Immunotherapy Used to Intervene in Type I Reactions?

Most drugs used to counteract immediate hypersensitivity act at one of what two levels?

Answer 27

• Inhibitors of mediator action.

* Inhibitors of the production or release of inflammatory mediators.

Question 28

What are inhibitors of mediator action and how do they work?

Answer 28

• Histamine receptor antagonists including Benadryl and chlortrimeton are H1-blocking antihistamines.
o They are most useful for relief of the sneezing, rhinorrhea (runny nose) and itching eyes associated with hay fever.
o They are not useful for bronchial asthma or systemic anaphylaxis, where treatment with leukotriene receptor antagonists or antibody to IgE can be beneficial.
• Synthetic steroids (glucocorticoids) also inhibit some of the actions of inflammatory mediators.
• Other drugs such as epinephrine and long acting beta-2 receptor agonists (e.g. serevent) are used to counteract mediator effects such as low blood pressure and bronchospasm.

Question 29

What are inhibitors of the production or release of inflammatory mediators and how do they work?

Answer 29

• These include glucocorticoids such as dexamethasone, beclomethasone, and fluticasone that are potent inhibitors of inflammatory cytokine production
• Inhibitors of leukotriene synthesis
• Inhibitor of histamine release, cromolyn
• Antibodies to IgE (e.g. Xolair) decrease both IgE levels in plasma and IgE receptor levels on Mast Cells.

Question 30

What is Subcutaneous Immunotherapy (SCIT)?

Answer 30

• Once the offending antigen (allergen) has been identified, a protocol referred to as hyposensitization or immunotherapy can be helpful.
• This involves the subcutaneous (and recently, sublingual) administration of gradually increasing doses of antigen.
• Allergen-specific T-regulatory cells are activated by the hyposensitization protocols, and increasing levels of allergen-specific IgG and IgA generally coincide with decreased allergic symptoms.
• This may be due to removal of allergen-antibody complexes by mononuclear phagocytes with less mediator-release than is triggered by IgE-allergen complexes. The allergens that are known to be effective for use in SCIT include several tree, grass, and weed pollens; cat and dog danders; dust mites; certain molds; and hymenoptera venom.

Question 31

The most common type of hypersensitivity is mediated by IgE and causes mild to life threatening clinical situations. IgE antibody production requires CD4 positive Th2 T cells to induce class switching of antigen specific B cells. I

Answer 31

Summary

Question 32

Drugs used to counteract Type I hypersensitivity inhibit production, release, or action of inflammatory mediators.
• Epinephrine and bronchodilators are used to counteract severe effects such as low blood pressure and bronchospasm.
• Glucocorticoids inhibit synthesis of inflammatory mediators; and antihistamines, mucolytics, decongestants can relieve symptoms.
• Inhibitors that specifically block the synthesis of leukotrienes or their binding to receptors are also FDA-approved for the treatment of hypersensitivity.
• A mast cell granule stabilizing agent called cromolyn can be used prophylactically to inhibit mast cell degranulation.
• The aim of subcutaneous and sublingual immunotherapy is to induce an IgG immune response and/or divert the immune response away from production of IgE.
• Therapeutic antibodies to IgE (e.g. Xolair) decrease both IgE levels in plasma and IgE receptor levels on Mast Cells.

Answer 32

Summary