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:
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
