Lecture 20: Allergic response- a deleterious Th2 driven

response to innocuous agents?

The allergic response involves a response that is deleterious and involves
a Th2 type immune response to an otherwise harmless antigen which
should be ignored. These harmless antigens are termed allergens
Instead of ignoring this
harmless antigen we
overreact to it- called a
hypersensitivity
reaction.
Virtually any immune
response has a
damaging effect e.g.
CD8 response is
damaging- kills infected
cells during viral
infection. There should
be a balance
autoimmune diseases are caused by hypersensitivity to self antigen
There are 4 types of hypersensitivity reactions. Type 1 will be the focus: an
allergic reaction
Type 2: involves antibody
mediated responses to cell
surface antigens. The cell
labelled K is a cell that is
mediating antibodydependence cytotoxicy.
There is something on the
surface of the target cell:
either antibody or a drug
that has bound. The
immune response develops
to these cell-surface
molecules. Antibodies
target this bound molecule
which leads to destruction of the cell. Type 2: antibody-mediated
responses to cell surface antigen

Type 3: We also
make responses
to soluble
antigen. An
immune
complex forms
somewhere in
the body e.g.
the kidney and
then this is
targeted by the
immune system
and causes damage to the tissue. This is antibody-mediated activity
against soluble antigens. The activity of the immune complexes binding to
tissues where they shouldnt is also type 3.
Type 4: different cells involved. T cells that produce cytokines and activate
macrophages and cause an over-stimulation of immunological activity. We
want activity of these cells but this response can be driven into overdrive
where the macrophages produce dangerous levels of inflammatory
mediators causing tissue destruction. This can be seen in TB where
macrophages cause destruction of lung tissue and coughing up of blood
Type 1 hypersensitivity reactions are
the focus of this lecture. They are
allergic reactions present in many
different forms: hayfever which is
inflammation of the nasal passages.
Do not confuse allergies with
intolerance. Intolerance is where you
cant process something. Allergy is
where there is a type 1
hypersensitivity reaction- this is very
different

Mast cells are at the heart of allergic reactions. They

are found at mucosal surfaces and lining blood
vessels.
At mucosal surfaces: lung and GIT
if you think about allergies most of the responses are
occurring at these muscosal surfaces
Mast cells are sensitised by their acquisition of free
IgE from solution. IgE is taken by the mast cell. An
allergen then has to come along and cross-link the
IgE. it is the cross-linking that causes activation and
degranulation of the mast cell. There is then a release
of mediators of pre-formed inflammatory agents.
Then more inflammatory mediators are produced
after the activation event. Cross-linking of IgE on the surface of the mast
cells is the activator.
There are other triggers that will cause it to degranulate. Nerve
stimulation also causes degranulation mast cells have nerve endings.
There are interactions between the nervous system and immune system
e.g. hives are caused by nervous stimulation of the immune system
during times of stress.
IgE is Y-shaped like the
other antibodies.
This has 4 constant
region domains. It is
different to other
antibodies in that it is
found in extremely low
levels in the blood.
However this low
concentration is due
to the fact that they
are very powerful
antibodies

Mast cell bound IgE needs to be cross-linked for the mast cell to
degranulate.

People are allergic to the molecules

associated with the house dust mite.
It is a molecule in their faeces coming
from a digestive enzyme.
The level of exposure to this allergen
is really low however it can trigger a
large response

The allergic response is made up of 2

phases

This is due to house

dust mite allergen.
The site of allergen
there is a red area of
swelling- this is the
immediate reaction.
respiratory function
similar in the
asthmatic patient:
graph below.
The decline in the late phase is mirrored in the house mite skin
experiment where you can see a broader area of swelling

is

Binding of IgE triggers the release

of granules stored in the mast cell
releasing histamine and heparin
along with lots of other proteases.
These released proteases
contribute to the damage to the
surrounding tissue. The cell the
starts producing the lipid mediators
of inflammation then later
cytokines and chemokines. These
are produced, released or even
stored in the cell.

The Fc epsilon receptors on the

mast cells capture the IgE. The
mast cells are very granulated. On
the right a lot of granules have
been released. It is a very quick
response that happens in almost
seconds. the inflammatory
mediators are secreted quickly into
the tissues

Histamine is one such inflammatory

mediator that causes constriction
of smooth muscle.

Diahorea in food
allergies is due
to constriction
of GIT.
Blood vessels:
cause relaxation
and increased
blood flow.
Increased blood
flow leads to
redness. There
is increased
vascular
permeability
into tissue:
causes swelling.
The H1
receptors are involved in the allergic
response. H1 receptor antagonists are
used for allergy treatment
lipid mediators of inflammation.
They have similar effects to histamine

Many of the cytokines produced by

Th2 cells are also produced by mast
cells. They also produce the
inflammatory cytokines such as TNF
alpha. Mast cells store TNF
Mast cells also produce IL-5. This
acts on eosinophils and promotes

their activation and

formation. If you look at
the cells involved in
allergy it is mast cells and
eosinophils: mast cells
recruit eosinophils. They
are responsible for most
of the tissue damage you
observe.
Eosinophils also produce highly damaging mediators.
Eosinophils fight multi-cellular parasites along with mast cells and IgE. We
need powerful mediators of inflammation for these parasites, they are
difficult to deal with. if the release of mediators is directed toward the host
it can be extremely damaging because it is targeted to eukaryotic
organisms.
IL-5 is being produced.
They also produce the lipid mediators.
These slides demonstrate the allergic response to be a positive feedback
mechanism that is out of control. These signals amplify as they continue
each other.

The
cells
that
produce
the IgE
are not
shown.
The
most

important cell is the T cell that instructs the B cell to make IgE not the
mast or eosinophils.
Swelling of the mucosal tissues restricts the airway.
Ventalin allows the dilation of the
airway
stabilising the mast cell so they
dont degranulate too easily

Sodium.. stabilises the mast cell so

its not degranulating: we dont see
the early or late phase.
Steroids eliminate only the late
phase

Desensitisation is where they are repeatedly

exposed to very low doses or the allergen.
Normal exposure of the allergen is already very
low so this treatment is really low. The levels of
allergen are gradually increased.

Repeated exposure does lead to a

decline in the IgE and the symptoms. An
increase in the IgG is also observed

Should a mother avoid

peanuts during
pregnancy? some
evidence suggests the
mothers exposure can prevent sensitisation. It is very difficult to avoid
allergens.

There is certainly a genetic link in

this disease but this does not
explain why allergic disease is on
the increase.
Factor X in concert with having
genetics for high IgE response
where you go through the allergic
breakthrough

How long were the babies fed for blab

la
overexposure to allergens causes the
allergic breakthrough. This was
concluded.
people who are overexposed to animals
become allergic to them.
Exposure to pollutants does the same
thing

Virokines are chemicals produced by a virus that mimics the bodys

cytokines. This drives cytokine production and the immune system is
caused to overreact which is problematic for the host by beneficial for the
virus.

While children are still unhygienic why is there still allergies

Because we dont have enough infection

we get allergies
in early life our immune system is directed
toward the Th2 response.

Is there evidence for the

hygiene hypothesis? yes, there
is but it is indirect
large families= more spreading
of disease, less allergies.

parasitic infections are rare in

developed countries- allergic
disease is reversed

People are now looking at persistent

infections because these are caused
by parasites
Persistent infections may cause
activation of Tregs which will

decrease inflammation

Hepatitis has been associated with

reduced allergies

the community of organisms

within us may protect us from
allergic disease. we may
change their populations by
taking antibiotics or by diet

Class switching. What is

the relationship between
IgG and IgE? once we
learn this we can
understand allergic
disease. We need to
better understand the
function of antibodies.