Types I, II and III are examples of antibody-mediated hypersensitivity, and all are characterized by what three qualities?
- 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.
How does Type IV differ from I, II, III?
Type IV (cell mediated reactions) develop after 1 or more days and can only be transferred adoptively with Ag-specific T cells.
Define Type I Immediate Hypersensitivity:
• 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.
What is Atopy? Atopic? Anaphylaxis?
• 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).
What are the target organs most commonly involved in hypersensitivity I reactions?
- the gastrointestinal tract
- the respiratory tract
- the skin.
What are the routes that give rise to allergic manifestations?
- Ingestants Foods, Drugs
- Inhalants Pollens, Dusts, Molds
- Injectants Drugs , Bee stings, Vaccines, Serum
- Contactants Poison ivy, latex
When does Generalized Anaphylaxis occur (timeline)?
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.
What are the pathophysiologic changes which occur in a type I reaction?
- mast cell degranulation
- infiltration of eosinophils and neutrophils
- contraction of smooth muscle
- increased vascular permeability
- and finally, infiltration of mononuclear cells.
Clinical symptoms may involve
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.
What are the similarities of Mast Cells and Basophils with regard to Hypersensitivity?
- 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.
What are the differences in the location, circulation, and basic function of Basophils and Mast cells?
- 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.
What is Eosinophilia? Tissue Eosinophilia?
• 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.
Why are Eosinophils reactive with IgE?
• 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.
How do Lymphocytes, Monocytes, and Macrophages interact with IgE?
- 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.
What are the stimuli that can induce release of histamine, leukotrienes, cytokines, and other mediators from mast cells?
Anti-IgE Anti-IgE Receptor Antigen Lectins Anti-Mast Cell Antibody Anaphylotoxins C3a, C5a FcERI is normally occupied by monovalent IgE
VI. How does IgE receptor cross-linking evokes mediator release in Mast cells and Basophils?
- 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.
Explain how the following mediators have pharmacologic effects on smooth muscle and mucous glands. Histamine on H1 and H2 Receptors:
• 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.
pharmacologic effects on smooth muscle and mucous glands. B. Slow Reacting Substance of Anaphylaxis (SRS-A):
• 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.
Leukotriene B4 effects on smooth muscle and mucous glands
• 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.
Prostaglandin D2 on smooth muscle and mucous glands
• Prostaglandin D2 is a o bronchoconstrictor o peripheral vasodilator o coronary and pulmonary vasoconstrictor o inhibitor of platelet aggregation o neutrophil chemoattractant.
E. Platelet Activating Factor (PAF) on smooth muscle and mucous glands
- 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.
F. Neutral Proteases: on smooth muscle and mucous glands
• Neutral proteases activate kinins (e.g. bradykinin) and complement to cause increased vascular permeability, decreased blood pressure and contraction of smooth muscle.
A. Leukotriene-B4 (LTB4) as Pro-Inflammatory by Chemotactic Properties
• derived from membrane fatty acids, is a rapidly released and potent chemotactic factor for polymorphonuclear cells, eosinophils, and macrophages.
What other pro-inflammatory compounds have chemotactic properties?
- Interleukin 8 (IL-8)
- Complement Factor C5a
- platelet activating factor (PAF)
- RANTES
- eotaxins
