LMP299Y1 Lecture Notes - Platelet-Activating Factor, Cell-Mediated Immunity, Oral Allergy Syndrome

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3 Jun 2013
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LMP403 February 6, 2013
Mechanisms of hypersensitivity
KNOW THE DIFFERENT MECHANISMS OF REACTIONS they lead to diseases how these mechiasms
relate to the diseases, KNOW THIS
Specific type of hypersensitivity reaction and what you might predict as to what happens as to the
reaction KNOW THIS
Four mechanisms
Type 1 hypersensitivity reactions
Hypersensitivity in general implies that person`s immune system is responding to something in
environment is is intrinsictly NOT HARMFUL ex. Poison ivy is not deadly, but can elicit nasty reaction;
ex. Ragweed
An aberrant response of immune system not intended as protective response, hence aberrant
Four types of hypersensitivity reactions mediated by antibody IgE
Type 2 reactions that are cytotoxic also antibody mediated type 3 reactions also antibody mediated
but not through immediate
Type 4 not antibody rection; cell mediated reaction; cells take time to get to site of reaction, so
reaction delayed, hence name
Hypersensitivity reaction
Pictorial
Prevalence of allergic disease has skyrocketed allergies in general and especialy those that are type 1
hypersentivity reactions, the prevalence has doubled
Reasons:
Allergic disease
Genetics polygenic allergic disease is not caused by one single gene, or mutation
Multiple factors in play
No dominant pattern of inheritance of most types of allergies
Changes in lifestyle compelling way to account for increase in allergic disease hygiene hypothesis,
which says that we are born with Th2 bias, which is to say that were more prone to mount allergic
responses in early developmental phases; as we come in contact with bacteria, and bacterial products,
or become bacterially infected, shifts bias to Th1 bias hwe this happens, less prone to developing
allergies
But live in hygeniec environment, little burden and exposure to bacteria and bacterial products, less
likely to undergo switch from Th2 to Th1 bias, and more likely to retain predisposition to allergic disease
Changes in lifestyle continued only children tend to have ; youngest sibling tend to exposed to less
hygienic environment;
Changes in lifestyle someone with a brisk immune system will have a stronger allergic reaction than
those with immunosuppression or immunocompromised in context of allergy, do nto want to boost
immune system
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Immediate hypersensitivity reactions
Immunologic non-IgE mediated reactions
Pathway sensitization gives rise to allergen-specific IgE, IgE leaves bone marrow, in circulation, lands
on mast cells in tissue; mast cells have high affinity receptors for IgE; IgE binds to mast cells, waits until
person is re exposed to allergen, which may set of allergic reaction but soneties people are exposed to
substances that do not interact with IgE no need for specific IgE when substances activate mast cells,
release variety of products
Substances that can act directly on mast cells, no need for prior exposure, no prior sensitization with
production of specific IgE mast cells, once activated, release all the products that would have been
released in IgE reaction, giving same manifestions clinically, same because mediators are the same
Drugs that can cause this listed radio contrast agents
Non-immunologic reactions
Reactions that are not mediated by mast cells, mediated by conplement activation generation of two
complement split product C3a and C5a these act on vasculature give rise to manifestations that
look like immediate hypersensitivity reaction but are infact not prototype for this is reaction to blood
products in course of hemodialysis, reaction to dialyszer membrane
Spectrum of reactions
Person makes specific IgE to binding site on pollen; IgE cross reacts with structurally similar proteins in
some fruits, vegetables; immune systems that when consuming the product, thinks eating pollen this
is oral allergy syndrome
Far right clearly non-IgE mediated
IgE without it, immune system does not have good way of interacting in specific sense with
environment IgE transmits signal from environment to effector cells (mast cells; basophils)
IgE present in circulation in very low concentrations prefers to sit on receptors
IgE most of it in tissue, with a tiny portion in serum
When IgE binds to high affinity receptor on mast cells or basophils termed sensitization of mast cells or
basophils
When IgE binds to high affinity receptors, molecule is stabilized resistant to proteolytic digestion so
when in tissue, IgE is very stable; when in circulation, not protected fromn degradation, and half life is
very short in circulation
To mount IgE mediated reaction needs IgE needs prior exposure to allergen in order for immune
system to recognize it in order for immune system to initiate IgE switch release into circulation, allow
recirculate, find its way onto mast cells receptors nothing happens until the person is re-exposed to
what is an allergen for them
PRIOR EXPOSURE MUST OCCUR TO GIVE RISE TO REACTION
IgE C epsilon 3 is what binds to high affinity receptors on mast cells
There is an antibody that binds to the Ce3 usd to treat people with moderate to severe asthma
Effector portion is
Need a few IgE molecules to reside on surface of molecule
Mast cells activate produce newly synthesized mediators these mediators are mainly lipid mediators
that are the nasty players in allergic reactions, give rise to life threatening manifestations
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Mast cells IgE on suface called SENSITIIZED MAST CELLS
Transmembrane loops
Allergen binding to continguous IgE molecules
Granules
Mast cells
Mast cell undergoes degranulations
Pathogenic mechanisms
Three classes of mediators those that are preformed; newly formed; cytokines produced by activated
mast cells
Give rise to inflammatory second phase, called late phase reaction
Immediate response
Late phase response mediated by cytokines that recruit inflammatory cells, like monocytes,
eosinophils, macrophages, lymphocytes that give rise to late response that happens hours later
Anti-histamine is not going to help with late response this is cell-mediate response
If blood vessels leaky, have surrounding edema
If happens in gut, crampy abodominal pain; vomiting; diarrhea
Later manifestations give rise to inflammatory responses as opposed to allergic responses
First phase is allergic; follow up phase is inflammatory
Histamine what do they do?
Anti-histamines given for anaphylapsis does not help; they get better because they’re young, healthy
Platelet activating factor newly formed lipid mediator produced when mast cells and basophils are
activated
A lot of immediate hypersensitivity reactions are neuisances can use anti-histamines
But in situations where life is threatened, major mediator giving rise to the manifestations is the platelet
activating factor
Lowers blood pressure, etc.
LDL cholesterol is the bad form of cholesterol
Higher the LDL level, the more PAF acetyl hydrolase in bloodstream, the better at breaking down or
inactivating platelet activating factor, which does bad stuff in allergic reactions
Effect of human PAF-AH in two anaphylactic shock models
Pretreat mouse with recombinant form of pAF AH ouse better at inactivating PAF and it’s protected
from anaphylaxis in dose-dependent fashion
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