Disease Profile: Type I Hypersensitivity Reactions

Have you ever wondered why some of your friends carry around epi pens? What are allergies, anyway?

Allergic reactions, also known as hypersensitivity reactions, are divided into four classes. To sum up, in the case of an allergic reaction, your body's immune system is identifying "self" molecules as "foreign" and firing off an immune attack against its own cells. Most of what we typically think of as "allergic reactions" include those in the first category, type I hypersensitivity. 

 Hypersensitivity Type I

Cases of type 1 hypersensitivity include localized reactions, e.g., allergic rhinitis (hay fever), atopic dermatitis (eczema),  food allergies, hives, and asthma, and systemic reactions, which may lead to life-threatening anaphylaxis.

What Happens at the Cellular Level:

Overview:

An allergic reaction is triggered by exposure to an allergen, which is usually a harmless antigen such as pollen, dust, peanuts, etc. Immunoglobulin Epsilon (IgE) binds to high affinity FC receptors (FcεR1) expressed on mast cells and basophils. Mast cells and basophils degranulate, or release, cytokines (such as histamine) which leads clinical symptoms (hives, asthma attack, swelling, itching…) and in severe cases may cause anaphylactic shock.

In Detail:

In type I hypersensitivity, an individual's immune system responds to an allergen, a small, usually harmless molecule, by identifying it as a pathogen and activating an Immunoglobulin Epsilon (IgE) antibody-mediated immune response.

This reaction occurs in 3 chronological phases, the sensitization phase, the activation phase, and the effector phase.

During the sensitization phase, IgE antibodies are produced in response to an antigenic stimulus and bind to specific receptors on mast cells and basophils. IgE antibody production is T-cell dependent, meaning TH2s (T-Helper Cell type 2) must be present in order for the antibody to be produced.  TH2 cells produce Interleukin 4 (IL-4) and IL-13 cytokines that are essential to activate IgE antibody production. IgE levels appear to be much higher (as many as 10 times) in atopic, or allergic, individuals. TH1 cells usually maintain lower levels of IgEs via secreting interferon gamma (Inf γ).

During the activation phase, IgE antibodies bind to mast cells and/or basophils, causing these cells to release their granules, which contain early mediators―histamine, heparin, tumor necrosis factor alpha (TNFα), and late mediators―cytokines IL-4, IL-5 and IL-13; leukotrienes; and arachidonic acid.

During the effector phase, the combined pharmacologic effects of these chemicals produce symptoms of an allergic reaction including increased vascular permeability, the constriction of smooth muscle, and an influx of basophils via early and late mediators.

Early mediators of type I hypersensitivity reactions include histamine, heparin, and TNFα. Histamine binds to a variety of cells via H1, H2, and H3 receptors. Histamine binds to H1 on  capillary endothelial cells and smooth muscle cells, causing systemic vasodilation and increased cell permeability which leads to inflammation. Antihistamines, common allergy OTC medications such as Benadryl, Claritin, and Zyrtec, block these H1 receptors to reduce inflammation. Heparin increases blood flow. TNFα increases production of cell adhesion molecules (CAMS) that act on capillary endothelial cells to increase macrophage extravasation from the blood into the infected tissue, furthering inflammation.

Late phase mediators  are released in a second wave of degranulation six to eight hours later. These mediators include cytokines IL-4, IL-5, and IL-13, leukotrienes, and arachidonic acid. IL-4 is essential for IgE production, and IL-5 and IL-13 attract other leukocytes, especially basophils, which increase inflammation. Arachidonic acid activates two oxidative pathways, the cyclooxygenase pathway and the lipooxygenase pathway.

In the cyclooxygenase pathway, prostaglandins and thromboxanes are produced which further inflammation, causing bronchial constriction and chemotaxis. Aspirin, ibuprofin, and other antiinflammatory medications work on this pathway to decrease inflammation.

In the lipooxygenase pathway, leukotrienes cause intense smooth muscle contraction, including bronchoconstriction. This pathway is believed to be responsible for most cases of anti-histamine resistant asthma.

TH2 cells are also activated by these late phase mediators, and they will speed up B cell conversion into plasma cells that then release more IgE. TH2 cells also release cytokines that further inflammation by attractin more eosinophils, basophils, and neutrophils to the site of infection. Eosinophils cause major damage to local tissue because they release deadly eosinophil-derived neurotoxin, eosinophil catioonic protein, and major basic protein. All of these chemicals are toxic to the surrounding tissue and stimulate degranulation of any other mast cells in the vicinity, exacerbating the problem.

How do you treat these type I hypersensitivity reactions? Firstly, prevent patient exposure to the allergen. Secondly, pharmacologic interventions may be administered. These include the following:

1.       Inhalers - decrease or prevent mast cell degranulation

2.       Corticosteroids - block many genes in many types of cells, including cytokines from immune cells

3.       Sodium chromoglycate - treats asthma; prevents both the immediate and late phase mediators following bronchial provocation with allergen

4.       Epinephrine - treats the life-threatening symptoms of anaphylaxis by directly reversing the effects of histamine by relaxing smooth muscle and decreasing vascular permeability; stops mast cell degranulation, dilates your bronchioles, reforms tight junctions between capillary endothelial cells, and increases blood pressure.

Patients may also be given desensitization shots, an immunologic intervention, to anergize t cells.

Want more information? Here's a cool video to get you started: 

IgE Mediated Type I Hypersensitivity

Also, check out these webpages:

1. For an academic view, go here: http://pathmicro.med.sc.edu/ghaffar/hyper00.htm

2. For a more generalized view, go here: http://emedicine.medscape.com/article/136217-overview