00:01
Right, now having given you a little overview of those four
different types, let’s now look
in a bit more detail at each one.
So Type I hypersensitivity -
IgE-mediated mast cell degranulation.
00:15
You’ve already seen this picture.
00:17
So these Type I hypersensitivity reactions,
IgE-mediated mast cell degranulation.
00:22
That’s what we usually think of as
allergic types of responses, allergy.
00:27
And this type of response often
referred to as atopy, an inappropriate
production of IgE antibodies is caused
by a multitude of different factors.
00:38
Genetics is important, but other
factors also are important.
00:43
Regarding the genes, there is not a
single dominant allergy gene; it’s rather
that several genes contribute to the
development of the allergic process.
00:54
Amongst them, the gene encoding the FcεR1, the gene
encoding the cytokine interleukin-4 which is very important
in causing B-cells to class switch to IgE production,
CD14, HLA-DR, there are a number of different genes.
01:11
So it’s really the combination of genes that’s
important, not any one single specific gene.
01:17
And of course the environment is also very important,
it’s not a purely genetic situation we have here.
01:23
And early microbial exposure, and early allergen exposure
perhaps in the uterus seem to play an important role.
01:31
Immune responsiveness overall is abnormal, with a decreased
production of gamma interferon, and perhaps overall a more Th2
type of environment with those Th2 cells that secrete cytokines
such as interleukin-4 and interleukin-5 and interleukin-6.
They’re the more dominant population.
01:53
And remember, all of these
responses are normal responses.
01:56
So a Type I hypersensitivity reaction is based upon
something that is a normal protective immune response.
02:01
For example against a
parasitic worm infection.
02:04
If you have a parasitic worm infection in
your gut for example, you’d be very grateful
to having this sort of response because it
would help expel the worms from the gut.
02:15
However in a substantial minority of
individuals, IgE-mediated mast cell
degranulation occurs in response to what
should be a harmless environmental antigen.
02:25
And afterall, grass pollen is not going to
cause you any harm, but in a significant
number of people, there’s a response to
this that actually leads to pathology.
02:34
Maybe you yourself
suffer from allergies.
02:36
You’ll certainly know people that
do, because it’s a very common
affliction of people to suffer from these allergic reactions.
02:45
In Type I hypersensitivity, there’s an immediate IgE
response, but this resolves within around about an hour.
02:55
However it is frequently followed by
what is referred to as the late phase reaction.
03:01
This occurs around
about 4-12 hours later.
03:03
And it involves CD4+ helper T-cells,
monocytes and eosinophils becoming activated.
03:14
So there are a number of different types of atopic allergy,
that is allergy caused by excessive production of IgE.
03:22
Rhinoconjunctivitis which you may know as hay
fever, affects around about 20-35% of individuals.
03:30
Asthma affects around about 10-20%
of individuals, atopic eczema again
around about 20% of individuals,
urticaria similar kinds of numbers,
food allergy maybe around about 3-5%
of individuals develop food allergy,
and insect venom hypersensitivity
in about one in a hundred people.
03:57
We use the term anaphylaxis to describe a
severe systemic hypersensitivity to allergen
in an injection, a sting or by epithelial
exposure, for example in the gut mucosa.
04:13
It involves a rapid vasodilation which leads
to a substantial drop in blood pressure.
04:21
There is constriction of the airways, edema and
anaphylactic shock can result that is often fatal.
04:32
However, immediate administration
of epinephrine can reverse the
bronchoconstriction and vasodilation and rescue the patient.
04:45
Let’s have a look at some of the mediators that mast cells
produce that contribute towards the inflammatory process.
04:53
We can divide these
mediators into two groups.
04:56
Ones that have already been made by the mast cell
and are stored within granules within the mast cell.
05:03
And then newly synthesized mediators
that are made from arachidonic acid.
05:10
Histamine is the classical mast
cell inflammatory mediator.
05:14
It causes smooth muscle contraction and
an increase in vascular permeability.
05:20
Heparin is produced and stored in
granules, and this is an anticoagulant.
05:26
And eosinophil chemotactic factor is a
third example of a pre-made mediator stored
in the granules, and this as its name
suggests mediates eosinophil chemotaxis.
05:39
So all these substances are ready to go, and the second the
mast cell degranulates, they can mediate their effects.
05:46
Regarding the newly synthesized mediators,
prostaglandin D2, prostaglandin E2 and prostaglandin
F2α can mediate smooth muscle contraction and
increase vascular permeability just like histamine.
06:01
Leukotriene B4 is a chemotactic
factor for neutrophils.
06:08
And leukotriene C4, D4 and E4 cause
smooth muscle contraction and
vascular permeability again just like the
prostaglandins and the histamine.
06:19
Let’s look at how the leukotrienes
and prostaglandins are synthesized.
06:25
They are both produced from phospholipids, by the use
of phospholipase A2 to generate arachidonic acid.
06:34
Then either via the lipoxygenase pathway which
produces leukotrienes or via the cyclooxygenase pathway
involving COX1 and COX2 which produces prostaglandins,
these mediators are generated within the mast cell.
06:56
This is a list of allergens.
06:59
You’ll be very familiar with
many of these I am sure.
07:02
So they include things like pollens, things
associated with animals like animal dander,
house dust mites and so forth, molds, various
chemicals, and a number of food allergens.