Transcript ANAPHYLAXIS - Fat Tuesday Productions

THE BIOLOGY OF
ANAPHYLAXIS
LFSC 609E
JASON RUCKER
OUTLINE
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Introduction
The Biology of Anaphylaxis
Gell-Coombs Responses
Type 1 Allergic Reactions and Anaphylaxis
Biochemical Pathways
Conclusion
References
INTRODUCTION
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Anaphylaxis is defined as a life-threatening allergic reaction set in
action by a wide range of antigens and involving multiple organ
systems. The true incidence is difficult to estimate, but in 1973
the Boston Collaborative Drug Surveillance Program reported
six anaphylactic reactions and 0.87 deaths from anaphylaxis per
10,000 patients. Reactions to insect stings alone are responsible
for at least 50 deaths in the United States each year.1 These
figures reveal the importance of continued research into the
biology of anaphylaxis along with developing new (and
improving existing) therapies.
BIOLOGY OF ANAPHYLAXIS
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Anaphylaxis is brought about by
the release of mediators such as
histamine from the mast cells
and basophils. These actions
are responsible for the
immediate symptoms of
anaphylaxis.
A late-phase response initiated
by the mobilization of other
inflammatory cells, including
eosinophils, can occur hours
after the initial reaction.
Anaphylaxis is considered an
IgE-mediated allergic reaction
to such things as foods, insect
venoms, drugs, and latex.1
www.postgradmed.comissues199608_96wyatt1.gif
BIOLOGY OF ANAPHYLAXIS
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The mast cell can be persuaded to
react by additional means,
including:
(1) direct activation by exercise,
opiates, and possibly radiocontrast
agents
(2) disturbances of arachidonic
acid metabolism by cyclooxygenase inhibitors such as aspirin
and nonsteroidal anti-inflammatory
drugs (NSAIDs), and
(3) complement activation by
immune complexes, caused by
reactions to blood products and
resulting in production of C3a and
C5a.1
http://www.britannica.com/nobelprize/article-215500
BIOLOGY OF ANAPHYLAXIS
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Anaphylaxic symptoms can occur within
seconds of antigen exposure. With fatal
reactions, the respiratory and
cardiovascular systems are affected.
Upper airway obstruction caused by
angioedema usually lead to asphyxia.
Lower airway obstruction with wheezing
and chest tightness is caused by
bronchospasm.
Hypotension is caused by a shift of fluid
from the intravascular to the
extravascular space.
Losses of intravascular volume can occur
quickly as a result of increased vascular
permeability.
Patients normally compensate through
maximal vasoconstriction initiated by the
release of catecholamines and
angiotensin.1
GELL-COOMBS RESPONSES
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The manifestations of a particular
allergic reaction depend on which of
the immune mechanisms predominates
in the response. Based on this criterion,
immunologists use the Gell-Coombs
classification system to recognize four
types of hypersensitivity reactions.
Types I, II, and III involve antibodymediated mechanisms and are of rapid
onset.
The type IV reaction stems from cellmediated mechanisms and has a
delayed onset.1, 2
Immunology, 5th Edition. New York. W.H. Freeman and Company
TYPE I HYPERSENSITIVITY
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www-immuno.path.cam.ac.uk/.../lec13/type2a.gif
A Type I Hypersensitive reaction is
mediated by IgE antibodies whose Fc
region binds to receptors on the mast
cells or blood basophils.
Crosslinkage of the fixed IgE by
allergen leads to mast cell or basophil
degranulation with release of
pharmologically active mediators.
The primary effects of these mediators
are smooth-muscle contraction and
vasodilation.
Symptoms of type I reactions include
potentially life- threatening systemic
anaphylaxis and localized response
such as hay fever and asthma.2
TYPE II HYPERSENSITIVITY
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Type II Hypersensitive
reactions occurs when
antibodies reacts with
antigenic determinants
present on the surface of
the cell.
This results in cell damage
or cell death through
complement-mediated lysis
or antibody-dependent
cell-mediated cytotoxic
(ADCC).2
www-immuno.path.cam.ac.uk/.../lec13/type2a.gif
TYPE III HYPERSENSITIVITY
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www-immuno.path.cam.ac.uk/.../lec13/type2a.gif
Type III, or immune-complex,
Hypersensitive reactions are represented by
tissue damage caused by the activation of
complement in response to antigen-antibody
(immune) complexes that are deposited in
tissues.
The classes of antibody involved are the
same ones that participate in type II
reactions—IgG and IgM—but the
mechanism by which tissue damage is
brought about is different. The antigen to
which the antibody binds is not attached to a
cell.
Once the antigen-antibody complexes form,
they are deposited in various tissues of the
body, including the blood vessels, kidneys,
lungs, skin, and joints.
Deposition of the immune complexes causes
an inflammatory response, causing the
release of tissue-damaging substances, such
as enzymes that destroy tissues locally, and
interleukin-1, which, among its other effects,
bringing about fever.2
TYPE IV HYPERSENSITIVITY
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Immunology, 5th Edition. New York. W.H. Freeman and Company
A Type IV Hypersensitivity
reaction involves the cellmediated branch of the immune
system.
Antigen activation of sensitized
TH1 cells induces release of
various cytokines that cause
macrophages to accumulate and
activate.
The net effect of the activation
of macrophages is to release
lytic enzymes that cause
localized tissue damage.2
BIOCHEMICAL PATHWAYS
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Research in mice, which have a similar immune system to
humans, had hinted that high amounts of nitric oxide (NO)
throughout the body could play a role in anaphylactic
attacks.
Researcher Peter Brouckaert et al induced anaphylactic
shock in mice using two methods: by injecting a molecule to
deliberately lower blood pressure, and by creating an allergic
reaction similar to those experienced in humans.
By injecting nitric-oxide blockers into some of the mice
before attempting to give them anaphylactic shock, the
researchers were able to confirm that nitric oxide was the
cause.3
BIOCHEMICAL PATHWAYS
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Researchers believed at one time that a protein called
Inducible Nitric Oxide Synthase (iNOS) was the top
suspect for anaphylactic shock.
Brouckaert and his team determined that Endothelial Nitric
Oxide Synthase (eNOS), a protein previously thought to
produce only small amounts of nitric oxide in order to
regulate the body's normal blood pressure variations, was
the actual cause of anaphylactic shock.
Mice genetically engineered to lack eNOS were immune to
potentially fatal allergens, whereas mice missing iNOS fell
victim to them.3
BIOCHEMICAL PATHWAYS
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Another biological pathway is
the Complement System. It
contains a group of serum
proteins, many of which exists
in inactive forms.
Activation occurs by the
Classical, Alternative, or Lectin
pathways, each of which is
launched differently.
The three pathways merge in a
sequence of events that lead to
the production of a molecular
complex that causes cell lysis.2
www.britannica.com
BIOCHEMICAL PATHWAYS
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The Classical pathway is initiated by
antibody binding to a target cell;
reactions of IgM and certain IgG
subclasses activate this pathway.
Activation of the Alternate and Lectin
pathways is antibody-independent.
These pathways are initiated by
reaction of complement proteins with
surface molecules of microorganisms.2
Complement can opsonize bacteria for
enhanced phagocytosis; it can recruit
and activate various cells including
polymorphonuclear cells (PMNs) and
macrophages; it can participate in
regulation of antibody responses and it
can aid in the clearance of immune
complexes and apoptotic cells.
Complement can have detrimental
effects for the host because it
contributes to inflammation and tissue
damage and it can trigger anaphylaxis.4
Immunology, 5th Edition. New York. W.H. Freeman and Company
CONCLUSION
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Anaphylaxis is a potentially fatal
allergic reaction. Causes can range
from bee stings to drugs, foods, and
exercise.
Onset is usually sudden, and a
delayed reaction can occur several
hours after the first reaction.
Treatment consists of airway
maintenance and support of the
blood pressure with fluid expanders,
epinephrine, and oxygen.
Additional medicines, such as
corticosteroids, antihistamines,
vasopressors, glucagon, atropine
sulfate, and isoproterenol
hydrochloride, may be beneficial.
Prevention is the most important
part of anaphylaxis management.1
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REFERENCES
1.
2.
3.
4.
Immune System Disorder
http://www.britannica.com/nobelprize/article-215500. Accessed
20070804.
Goldsby. Richard T. and Thomas J. Kindt. (2003). Immunology,
5th Edition. New York. W.H. Freeman and Company.
Mice saved from lethal allergic reaction.
http://www.vetscite.org/publish/items/003112/index.html.
Accessed 20070804.
COMPLEMENT
http://pathmicro.med.sc.edu/ghaffar/complement.htm. Accessed
20070804.