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Today's lecture is going to be on the subject of hypersensitivity.
Just a little history about hypersensitivity - now, this was recognized in the early part
of the 20th century by two scientists Portier and Richet. It was found... they realized
this condition because of swimmers who swimmed in the sea, and were repeatedly being stung
by jelly fishes. Now, that is what they realized later, that these individuals reacted to the
jelly fish toxin in different ways. Sometimes, these, this hypersensitivity due to toxin
also cause death. So, when they started looking for what could be there in the sting of the
jelly fish, they found that it was a toxin; so, purified the toxin and started injecting
in experimental dogs. Now, this was where an important finding was
made; an important observation was made that after a couple of injections in the dogs by
the jelly fish toxin, it was found that these animals did not respond by way of synthesizing
antibodies, the way normally other antigens do, but soon after, a few minutes after the
injection with the toxin, the dogs wend into a state of vomiting, diarrhea and a shock
like syndrome. So, they realized that in some cases, antigens
which now we know as allergens bring a shock like state and which brings an increased reaction
which they called anaphylaxis as oppose to prophylaxis. Prophylaxis is the treatment
which is going to decrease the symptoms, whereas anaphylaxis actually brought about a heightened
response which was not normal and which was unwanted.
So, what is hypersensitivity? This is better known as allergy, in common
man's language. So, hypersensitivity would mean that a heightened immune response. But
though the name suggests that, we know that hypersensitivity is actually unwanted immune
response, inappropriate immune response to a particular molecule. Normally, an immune
response generated to any pathogen - be it cell mediated or humeral, causes a localized
inflammation such that, that particular pathogen is deleted from the system. Now, this causes
some tissue damage to the host, but it is minimal and it is corrected very fast. However,
in case of hypersensitivity, the same immune response goes berserk and there are reactions
which may delete the organism, but all protein, but causes extensive tissue damage. And like
I said, in case of the jelly fish toxin, in which they found an allergen or hypersensitivity
inducing molecule, this can also be fatal. So, let us look at hypersensitivity and the
types of hypersensitivity, and look at the reactions that what actually causes.
Now, hypersensitivity can be understood in as being classified under four distinct types:
three of these four are antibody mediated and one is cell mediated, where T cells are
involved. Let us just go through very fast on the that four types and what mediates them,
and then will go to details of this. Type 1 is IgE mediated and the reactions can
be seen anyway between 2 to 30 minutes after exposure to that allergen or that molecule.
This is caused by antigen induced cross linking of IgE on mast cells or basophils. Now, we
will come to that in a little while in detail and in fact my talk today is going to be around
hypersensitivity type 1. Now, the symptoms are systemic and localized
anaphylaxis can cause hay fever, asthma, food allergy, eczyma - all these come under type
1 allergies which are mediated by IgE, which would mean that these molecules elicit a class
switching from IgM to IgE. Type 2, on the other hand, which is also antibody
mediated, it is because of cytotoxicity which is caused by the antibody. This includes blood
transfusion reactions, erythroblastosis fetalis and hemolytic anemia. This is because of antibodies
that are directed against cell surface antigens and because these antigen antibody interactions
triggers complement activation, as you might remember from their previous class, this brings
about antibody dependence cellular cytotoxicity. If there is too much of that, that might be
deleterious to the host tissue.
The third type is because of immune complexes. Now, this is immune complex mediated. Now,
what happens when there are antibodies in circulation and then there is an antigen which
enters? If it is in small amounts, then there is a complex that is found; antigen and antibody
form complexes which can be small to particulate, but this is very efficiently deleted from
the system by macrophages. However, in case the antigen is foreign exist
and the complexes are too small cannot be efficiently deleted from the system by macrophages,
through phagocytosis. These complexes can get deposited in tissues and though they are
small complexes, they are able to activate the complement.
So, let us say that these complexes are deposited on membranes. Then, that is where, there will
be complement trigger which will lead to mac formation that is membrane attack complex
formation and this would lead to tissue damage. Immune complex mediated hypersensitivity includes
serum sickness, importantly rheumatoid arthritis and systemic lupus erythematosus. Now, both
rheumatoid arthritis and SLE are ortho immune diseases, and we will come later, to why and
how immune complexes can be formed in these conditions which can lead to activating the
complement cascade. So, this comes under type 3.
Now, like I told you before, type 1 and 2, 3 are mediated through antibodies; either
IgE as if case in the first type or IgG and IgM type 2 and type 3. Type 4 is caused because
it is cell mediated; it comes under cell mediated immunity, and therefore, are involved T cells.
This condition includes contact dermatitis tubercular lesions and graft rejection. Now,
the reaction is because of sensitized T DTH cells. T DTH cells, you may have already discussed
this in earlier lectures; T DTH stands for T delay type hypersensitive cells. Now, these
are cells that release cytokines that activate macrophages and cytotoxicity T cells. This
leads to direct cellular damage at the site of where the sensitized T DTH cells arrive.
Let us get on with the type 1 which is IgE mediated hypersensitivity and look at the
molecular mechanisms. Now, IgE secretion - if you might remember,
should be the B cells should undergo the same set of steps in activation proliferation and
differentiation like any other T cell dependent B cell. Allergens are recognized by those
B cells which require T cell help. Therefore, always the first time the allergen is exposed
to the B cell which has a specific receptor in the form of immunoglobulin with the idiotope
corresponding to the allergen. This would lead to activation of the B cell, as would
happen internalization of the antigen and the receptor complex; Proteolytic degradation
of the allergen into peptides which are then presented to T hyper cells in the context
of class 2 molecules. The T cells would get activated, produce cytokines
which are beneficiary for the B cells interleukin 4 and interleukin 5; interleukin 4 which would
now allow proliferation of the B cell, clonal proliferation, which would now further lead
to generation of memory cells and plasma cells, now has not been shown here, but you might
remember from the previous lectures that the memory cell before becomes the memory cell
after the first immunization or exposure to the allergen. One would The B cell would be
making IgM type of antibodies which now switches to making IgE type of antibodies, let us say,
when this memory cell is exposed to the same allergen.
Now, this is a plasma cell which would be in the secondary immune response; that means
second time the cell is exposed to the antigen were now the plasma cell, again this differentiation
well again proliferation and differentiation of the memory cell to plasma cell producing
IgE. If you might remember, the IgE in circulation is very low concentration, but because even
if there are large number of plasma cell which are secreting good amount of IgE, the IgE
is sequestered very specifically to the surface of mast cells and basophils because of the
presence of a receptor, specific for IgE and that too for the FC region CH 2 and CH 3.
Now, here is the depicted mast cell which has large number of granules present in the
cytoplasm. Mast cells also have specific receptors which are talked about, which are known as
FC receptor for IgE type 1. Now, we will come to the types of receptors
which can now anchor, specifically these IgE molecules. So, all the IgE that is produced
or more than 90 percent gets in a non-specific manner; non-specific with respect to the antigen.
Non-specific manner gets sequester to the FC receptors of mast cells and the basophils.
Remember, the specificity here, lies in the FC region which binds to the FC receptor,
but it is non-specific with respect to the allergen because the plasma cell would be
specific with respect to its antigen recognition. Therefore, the antibodies that the plasma
cell would be made to one particular molecule, but the mast cell can bind to IgE of different
specificities because all IgE molecules would have the same CH2, CH3, CH4 domains.
Now, the mast cell has like I said large number of granules which are preformed and these
membrane coated granules are present and waiting to be secreted out of the cell, which happens
due to signaling caused by cross linking of the IgE via the allergen. So, what is released
now, would be immediate almost within minutes after cross linking takes place and these
are a large number of molecules; they are called vasoactive compounds what I mean what
is present in the mast cells. So, mast cell degranulation takes place.
Let us see, what are the granules of the mast cell and basophils. They consist of histamines,
serotonin, and eosinophil and neutrophil chemo attracting factors. What do these granules
or what are these pharmacologically active vasoactive compounds do? They bring about
smooth muscle contraction vascular permeability and vasodilation.
Let us look at mast cells. You have been introduced to mast cells so far and you know that mast
cells are found not in circulation, but in the connective tissue. Mast cells contribute
to a broad spectrum of physiological, immunological and pathological processes. They are found
throughout the connective tissue, especially near blood and lymphatic vessels. They are
present in the skin and the mucus membrane surfaces of the gastrointestinal or the GI
tract as well as respiratory tracts. Can you imagine how many such mast cells are
present in the skin? It is an enormous number. It is 10,000 cells per millimeter cube. So,
very small area under our skin has large number of these mast cells. You might remember that
allergic reactions are tested or the diagnosis is done by now coating the skin on the arm
of individuals who come with that complaint, trying to find out to which they are which
compound or which molecules they are allergic and the clinic has a large number of antigens
which are in fact put on the skin and within a few minutes reaction is observed.
Now, why is this done? Have you ever thought why is this done on the skin? Why is this
testing done on skin? This might reveal to you why; that the skin contains mast cells
in case of atopic individuals or those individuals we were allergic will have mast cells under
their skin with IgE to the allergen to which they are allergic to, and the IgE sitting
there when the antigen is put on the skin, the same mast reaches, now, the mast cells
which have IgE sequester; the antigen would bring about cross linking and giving rise
to that inflammatory reaction which the doctor now reads.
This is specific. They might use in the entire gamut of allergens which would could be 8
to 10. They will be able to find that the person is allergic to one such allergen. So,
coming back to mast cells now, electron microscopy reveals that mast cells have membrane granules
throughout the cytoplasm and these mast cells can secrete a variety of cytokines interleukin
,1 interleukin 3, interleukin 4, 5; interleukin 4 5 - does it ring a bell? These are the ones
that I told you as synthesized by the T cells, but also by the mast cell which can activate,
which can induce proliferation in B cells. Interleukin 6 is also made by mast cell, and
this cytokine, as you might remember, helps in differentiation of B cells to plasma cells.
GM CSF - that is colonist stimulating factor ,TGF beta and TNF alpha - all these cytokines
are secreted by mast cells; in fact these granules have these cytokines.
Let us look at the other cells which can also bind to IgE through the FC receptors. These
are basophils, and unlike the mast cell, basophils are present in circulation. They are the circulating
granulocytes of vertebrates and the percentage is very low; 0.5 to 1 percent of the total
white blood cell population. You all might remember from your earlier lectures that basophils
have multilobed nuclei and numerous glycogen molecules which are shown in blue here and
they also have electron dense membrane bound granules. Each of these basophils has been
estimated to have 40 to 60000 of those receptors which I talked about, which can anchor IgE.
Do you remember which allergens you may have heard of which are common? They can be proteins;
they can be plant pollen. Now, proteins of common allergens can be foreign serum, vaccines,
plant pollen, ragweed rye grass as well as parthenium. Now, parthenium is what we seem
to have imported in from another country and now we have fields of parthenium, and there
are quite a few people who are allergic to parthenium grass. Drugs such as penicillin,
sulfanomides, even anesthetics; foods such as nuts; this is rather, I mean not very common,
but yet yes, one can see many people are allergic to seafood, to egg, albumin, peas, beans.
Insect products - there are quite a few individuals who are allergic to bee and wasp as well as
ant venom, also cockroach calyx. Amongst common allergens are also animal dander that is the
hair, but one is not allergic to hair, not to the hair protein, but to the epithelium
which comes along with the hair. So, this is cat; people are allergic to cats because
of the epithelium of the cat skin which is associated with the hair when the hair falls;
also mold and spores; there are some individuals who are allergic to rooms; when you enter
a room which is which is little humid, that is because there would be spores lining the
wall and people are allergic to that.
Principal mediators in type 1 hypersensitivity are histamine/serotonin, as I said earlier.
They also include... so, what is there in the granules which come out? It also has proteases
and eosinophil neutrophil chemotactic factors. Now, histamine/serotonin increases the vascular
permeability and also brings about smooth muscle contraction. Proteases on the other
hand, induce bronchial mucus secretion, degradation of blood vessel basement membrane and generation
of complement split products.
When I say primary, the primary products are those that are already set in as granules
in the mast cells and these are immediately secreted out of the cell as soon as cross
linking of the receptors takes place. Secondary, on the other hand, are those that
are synthesized in the latest stage of the signaling process. Now, the secondary include
platelet activating factor, which brings about contraction of pulmonary smooth muscles, platelet
aggregation and degranulation of platelets. Now, there are three very important molecules
got leukotrienes, prostaglandins and bradykinins. All three of them induce contraction of pulmonary
smooth muscle. So, immediately, you can think that these
are the ones that bring about asthma type of symptoms. Now, even histamine and serotonin
can induce that, but these three molecules are at least a 100 to a 1000 fold increased
vascular permeability and vasodilation what leukotrienes and prostaglandins induce.
So, what are the consequences of type 1 hypersensitivity? So, let us say, now, we go back to that jelly
fish example. People who are stung by the jelly fish, they immediately reacted first
to the sting by a shock like state breathlessness that is asphyxia, followed by vomiting and
diarrhea. This is if the hypersensitivity is of the systemic type. Now, if the jelly
fish is put its toxin into the blood stream, this would be systemic; however, one can have
type 1 hypersensitivity is locally localized. So, localized anaphylaxis allergic rhinitis
as well as asthma which is, of course, a most serious condition than allergic rhinitis,
but it is still localized in the in the respiratory tract; nevertheless, yes, it can lead to death
asthma, but rhinitis, of course, is a much mild form of allergy and it is restricted,
of course, to the upper respiratory tract.
So, biological effects of histamine - what happens to histamine? I am talking about those,
the primary mediators of type 1 hypersensitivity; binding of histamine to H 1 receptor induces
contraction of intestinal and bronchial smooth muscles. Remember, histamine is much lesser
potent than leukotrienes and bradykinins; histamine binding to H 1 receptors increases
permeability of venules; also increases mucus secretion of goblet cells mucus.
So, in any of these allergic conditions, there is a lot of coughing and there is a lot of
secretion. If it is rhinitis, secretion of mucus; now there are also there are in fact
four types of receptors. It is the first receptor which brings about... it binds to it brings
about contraction of intestinal bronchial smooth muscles in case of binding of histamine
to H2 receptors. This causes vasopermeability, vasodilation stimulation of exocrine glands,
increase in release of acid in stomach. Now, what is this when histamine binds to
the receptors on target, is not the mast cells H 1 and H2 binding to those receptors which
are present on muscles. All these contraction of the smooth muscle, relaxation of the smooth
muscles or the blood vessels and stimulation of exocrine glands takes place, but interestingly
binding of histamine to the H2 receptors on mast cells. Mast cells themselves have H2
receptors as well as basophils have H2 receptors and binding of histamine; it inhibits degranulation.
So, therefore, there is a small feedback loop. Now, too much of histamine release tells the
mast cells and the basophils to stop any more degranulation. Involvement of IgE in allergic
reactions that people knew that there is some kind of an allergic reaction; way back like
I said in the early part of the 20th century, but that is the IgE which is involved in this
allergic reaction and it is a type of antibody that came to be known only in the 1960s. That
late if you might remember from my previous lectures, serum IgE levels in normal individuals
in only 0.1 to 0.4 micrograms per ml and if you are thinking in comparison to immunoglobulin
g, then it is which is around 10 milligrams per ml. You can see milligram verses 0.1 to
0.4 micrograms, even in severe atopic individuals that the individuals were experiencing allergic
reactions. The concentration of IgE in circulation never exists 10 microgram per ml.
That is because, as I said little while ago, that IgE is sequestered by mast cells and
basophils because of the presence of very high affinity receptors called FC eta RI.
There are two types of receptors that can bind specifically to IgE in the FC region;
high affinity receptors which bind with affinity of 10 to the power 9 moles per litre, whereas
FC eta RII which is low affinity and it is about 1000 times lower affinity than FC eta
R 1.
Let us look at the structures of these receptors FC eta RI and FC eta RII; both of these as
represented on mast cell and basophils. The exact involvement or the association of FC
eta RII with IgE is not very well known sorry not IgE with respect to allergy is not very
well known. In fact there are contradictory results saying that FC eta RII enhances IgE
secretion, whereas in others, it is supposed to inhibit.
So, this is still a question mark; nevertheless it is known that this receptor which is made
up of a single polypeptide and which has low affinity for binding to IgE. It has been seen
that this molecule can be present as a soluble form or membrane anchored as I shown here
and there are proteolytic cleavage site, and like I said, that this contradictory with
respect to the allergic reaction. So, let us say it was not participated in
that. What really induces the allergic reaction is the high affinity FC eta RI to get the
structure. Here, it is made up of, in fact, four polypeptide chains, one of which like
in case of the immunoglobulin receptor, antigen receptor itself has one molecule which recognizes
the FC region of IgE and it is there are two immunoglobulin like domains and the alpha
chain which binds to the IgE, one of which only stabilizes; the second loop stabilizes
the binding where the first binding contact is made by the first immunoglobulin like domain.
Now, this particular polypeptide does not have signaling molecules. It is the gamma
and the beta which has ITAMs. Do you remember, what is ITAM? Immuno receptor tyrosine based
activation motive. Now, the B chain is traverses the membrane; other is the membrane; it traverses
the mast cell membrane four times and there are then two polypeptides, both of which belong
to the same gamma and these also have these ITAMs.
And let us look at the signaling events that lead to mast cell degranulation. What did
I say so far? That a B cell which is making IgM soon after its activation by the allergen,
which has the cognate, it has the idiotype idiotope for the cognate antigen present on
the allergen binds get activated, now starts proliferating. When it gets adequate amount
of interlukein 4 and 5 starts dividing to become memory cell or plasma cells. Now, when
the memory cell in this particular lineage gets exposed to the allergen again, that is
there is class switching and from IgM the cell starts to make IgE. As soon as the IgE
is made, it is sequestered; it gets into circulation where it is sequestered very fast by FC eta
RI receptors present on mast cells and basophils. And this if you might remember, as present
on the FC IgE has a very long life; it can be stable up to 3 weeks or more; in circulation,
the same IgE will get degraded within 3 to 4 days.
Now, once cross linking of the IgE takes place because of binding to allergen, there would
be cross linking which is experienced by the FC receptor which now sends a large number
of signals. What will the ITAMs do? As name suggests, immuno receptor tyrosine based activation
motive which should mean that there would be intense phosphorylation. They are different
type of kinases. There are kinases which phosphorylate a large number of molecules; the one being
adenylated cyclase, phospholipase C and phospholipase A 2. Activation phosphorylation of these three
membrane bound molecules now bring about signaling in different on different molecules. Now,
let us look at the phospholipase C. So, what is not shown here? because we have
already discussed in details the kinases which are activated after B cells, now the signaling
may be slightly different here, but the ITAMs could mediate the same kind of phosphorylation
as happens in B cells. Therefore, those are not depicted here; suffice here to say that
phospholipase C which is in its inactive form upon getting activated by the kinases, which
are phosphorylated by these ITAMs present on the FC receptor now get activates phosphorylates
PLC which gets activated. Activated PLC, the substrate for which is
PIP2 now hydrolyses PIP2 to diacylglycerol and IP3. The diacylglycerol now converts and
inactive phosphor kinase to an active form. IP3 on the other hand if you might remember
has I mean binds to specific receptors present on the endoplasmic reticulum which now activates
the release of stores of calcium from the endoplasmic reticulum to the cytosol.
Now, let us look at what the adenylate cyclase does. AC is the enzyme adenylate cyclase after
its gets activated which is because of phosphorylation. The adenylate cyclase converts ATP to cyclic
amp adenylate cyclase. So, it makes cyclic AMP which is also a signaling molecule. Adenylate
cyclase activation is a little bit transient and we will understand that as we go along;
I will come to that later. Now, within few seconds after the cross linking of these receptors,
there are molecules in the membrane that get activated, which bring about hydrolysis of
the lipids in the membrane. Formation of phosphatidylcholine, which now gets hydrolyse to arachidonic acid
which in turn breaks down to leukotriene and prostaglandin.
Now, when there is change in the membrane because of hydrolyses of the lipids in the
membrane, calcium channels are formed and extra cellular calcium now gains entry inside
the cell. This increases calcium levels to a very high concentration. All of these signaling
mechanisms are important because there are inhibitors of almost each step which can stop
the cell from degranulation. What is the role of the cyclic AMP? It now activates a protein
kinase to become now associated or brings about movement of cytoskeleton, such that
these granules which are small start to move to the membrane where there are proteins called
snare proteins in the inside of the membrane and the same proteins are also present on
the outside of the granule, fuse and the granule is then thrown out. Phospholipase A 2 which
hydrolyses which gets activated in hydrolyses lipids to the PC and lyso PC and phosphatidyl
ethanol from phosphatidylserine to phosphatidyl ethanol amine.
Now, PLA2 is also responsible for phosphorylating membrane proteins of the granules which now
allows a changes of permeability of the granules, so that now they can swell up allows entry
of water, so that these granules can swell up so that snare proteins can get accessible
and the small granules become larger granules. And only then can they fuse with accessibility
of the snare proteins and then these fusing with the snare proteins of the membrane, now,
brings about exocytosis of these granules. Now, you look at the signaling here. If one
can inhibit let us say calcium from entering and increasing the interested cellular stores
to a much higher level then one would not allow exocytosis. If I told you adenylate
cyclase activation is transient and it has been seen that cyclic AMP level have to come
down before for the exocytosis of these granules to take place.
So, suppose now cyclic one can inhibit the cyclic AMP levels from going down; that means
your cyclic AMP gets hydrolysed by a phosphodiesterase and if you can have now inhibitors of phosphodiesterase,
that cyclic AMP levels remain high. And if the cyclic AMP levels remain high, then exocytosis
does not take place. So, you can have inhibitor for the phosphodiesterase. So, cyclic AMP
levels are not decreased. You can have inhibitors of end formation of these calcium channels
not allowing calcium to come down; thereby, now you can decrease the degranulation of
mast cells. Now, I am telling you all these because there are molecules that can inhibit
these and are used as medication.
So, just let us look at the signaling events once more.
Allergen induced cross linking of FC eta RI activates a kinase called Lyn. Lyn phosphorylates
the ITAMs in the beta and gamma chains of FC eta RI, leading to phosphorylation of several
kinases. Now, this is what not something that I did not have in the picture those are Syk
and Fyn the Syk and Fyn in turn phosphorylate phospholipase C and adenylate cyclase. And
now, there is generation of secondary messengers - diacylgycerol as well as IP3 and these are
what mediate degranulation.
Now, let us come to the methylation, the cross linking of FC eta RI. What it does to phospholipids?
There is methylation of membrane phospholipids and this brings about increase in fluidity
of membrane and formation of calcium channels. Increase in the calcium through this channel
and not only by the release of intracellular calcium deposits of the endoplasmic reticulum.
This leads to assembly of microtubules and I told you this microtubules they are necessary
this organization of the microtubules is necessary for movement of the granules.
Now, snare proteins on the membrane and granules fuse for exocytosis. So, the granules which
by the way are present as small granules, there the membrane proteins on the surface
of these granules get phosphorylated, which now the granule membranes become permeable
to water so that there is swelling of these granules. So, snare proteins on the granules
now can bind to the snare proteins of the membrane. The cell membrane is used and exocytosis
is exocytosis of the granules happens. Phosphotyrosine kinase activates map kinases to activate PLA2,
the same Syk and Syk kinases, and then this activates secretion of cytokines phospholipase
A2 also hydrolyses hydrolyses phospholipids to arachadonic acid and to generate prostaglandins
and leukotrienes the second secondary molecules. Now, primary are serotonin and histamine;
the secondary are leukotrienes prostaglandins and bradykinins. These three, the last three
are products of the arachadonic acid which is because of membrane lipids; hydrolysis
of membrane lipids.
Phosphor tyrosine kinases which are because of the phosphorylation of ITAMs and other
molecules - now these activate adenylate cyclase transiently, remember, leading to the generation
of cyclic AMP and this can be seen one minute after cross linking. Activation of PKA that
is protein kinase which is dependent on cyclic AMP, brings about phosphorylation of proteins
and granules, which I said just a little while ago, increasing permeability of membrane to
water and calcium, swelling of the granules which is required for fusion. Decrease in
cyclic AMP. This is an important thing; decrease of cyclic AMP required is required for degranulation
process. So, if we can keep the cyclic AMP at elevated levels, this will inhibit degranulation
of mast cells and thereby decrease the symptoms of hypersensitivity.
So, soon after signaling, I will like to touch upon the drugs that are used to treat hypersensitivity.
Like I said, it is the signaling mechanism which was unfurled, which gave well doctors
and immunologist a hand to use certain drugs which can block. For example, antihistamines
- this blocks H 1 and H2 receptors on targets. So, if binding of histamine to the receptor
does not take place and you will not have smooth muscle contraction vasodilation etcetera.
Cromolyn - this blocks calcium influx; thereby it will inhibit the generation of the secondary
mediators and those are much more important than the primary theophylline.
This molecule inhibits phosphodiesterase PDE; this inhibition of PDE would mean that cyclic
AMP has not broken down, and therefore, there are still elevated levels of cyclic AMP. This
will again inhibit degranulation. Epinephrine is another drug that is used because it stimulates
cyclic AMP production. So, well, in a sense theophylline and epinephrine, both of them
do the same job though in different ways. They both bring about elevated cyclic AMP
levels, and like I told you before, decrease in cyclic AMP levels is a must for the actual
degranulation process to take place. Lastly, Cortisone - this is this molecule
blocks the conversion of histidine to histamine and also stimulates cyclic AMP production.
What is the treatment for type 1 hypersensitivity? Other than the drugs that I discussed a little
while ago, now the best would be to avoid the allergen source. Now, for example, now
you cannot always avoid. Let us say that you are allergic to cat dander;
so, you see that you do not have cat as a pet. Of course, you do not visit people who
have cats as pets; so, avoidance. People who are allergic to pollen or ragweed or parthenium
should see that when they are going out, they always... they should not inhale these because
allergic reactions to these grass because of inhalation. So, one can use a mask when
you go to areas were they put these. So, avoidance would be the best. But of course, if it is
not possible for that matter, if you do not know what you are allergic to, it is a big
problem, but if you do know what you are allergic to, there are clinics were a method of hyposensitisation
is initiated. It is a regimen of immunotherapy, where repeated injections of increasing doses
of the allergen are given subcutaneously, so that there is a shift from IgE to IgG.
Now, how will this happen? It has been shown that the way the route of immunization also
matters with respect to what type of antibody, what class of antibody is generated. And it
has been seen that if subcutaneous injections are given with increasing dosage as compared
to, let us say, exposure by way of the through the nose or the mucus membrane may give raise
to or often does give raise to IgG verses IgE.
So, people who are allergic to let us say pollen, if they are given repeated injections
subcutaneously of the pollen extract, then they have a shift from IgE to IgG and definitely
now if you have more of IgG, the IgG will sequester away. The IgE, before cross linking
can takes place. T regulatory cells also are in the pipeline now. To try treatment to for
treatment of hypersensitivity type 1 and also there is a possibility one can give injections
with anti IgE such that the FC eta receptor interacting domain actually sequesters the
IgE away. This is important because the antibody itself should not induce cross linking.
Regulation of class switching to IgE - I would just like to remind you that when we talk,
when I discuss the regulation of immunoglobulin expression, I did mention that at the DNA
level Id2, a factor Id2 binds to a transcription factor E2A which is involved in class switch
recombination to IgE. Therefore, one can imagine that if it is at the DNA level, then there
would be genetic susceptibility to type1 hypersensitivity that, that was a question mark. And now it
is well known that if both parents of a child are atopic, there is fifty percent chance
that the child is also atopic; that means the capacity to generate more IgE.
There are, of course, certain molecules which will generate IgE in the normal course of
in immune response. We do know that the type of antigen, the type of immunogen actually
regulates the class switching, so that it is beneficial to the host to reject or obliterate
that type of molecule. Now, in allergic individuals IgE is being
made towards even other molecules, where normal people would be making IgG. Therefore, if
fifty percent chance for the child whose parents are both atopic and allergic to certain molecules,
but if only one parent is atopic, then there is thirty percent chance of the child being
atopic or the capacity to generate IgE in an inappropriate way.
So, therefore, now, let us look at this hypersensitive type 1 reaction. So far, what I have said
is hypersensitive reactions are inflammatory reaction. Now, this is within the cell mediated
and humoral system, but why they are called hypersensitive because these culminate in
extensive tissue damage and this can also lead to death.
Let us now classify these. If you have type 1 hypersensitivity of the systemic type as
happens in case of allergy to bee venom, or well again let us go back to allergy to the
jelly fish toxin or allergies to penicillin. Now, this is something which I did not deal
with; penicillin is a very small molecule. We discussed about immunogens that is small
molecules such as penicillin or sulphonamides. Now, these on their own are not immunogenic,
but when they react with skin proteins or proteins in the body, they become immunogenic
because they use the skin proteins are well systemic than any proteins, as they carry
a protein. Many people are known to be allergic to penicillin.
So, you do know that doctors always test whether you are allergic or not, before prescribing
penicillin or sulphonamides for that matter. But, in case this has not happened and an
individual has been injected with penicillin to take care of an infection, then now there
already IgE antibody that are synthesized by this individual to penicillin and these
IgE anti-penicillin IgE would be sitting in on all almost all the mast cells. Now, mast
cells and basophils, now mast cells because they are present in the connective tissue
allover. Therefore, now you will have IgE and you have
now the allergen also, that gets sequestered in circulation through circulation to all
the connective tissue which has mast cells. And you can imagine that there would be an
intense reaction. Once cross linking of this mast cell FC eta receptor takes place, this
becomes systemic if you have, now, a systemic reaction. And one thing, there is a cascade
of reaction that starts taking place and then this can, of course, lead to death because
inflammation on skin is localized, but inflammation in the system is not localized. And what would
have started of as an allergen, and specific IgE interaction now culminates in extenuative
extensive tissue damage because of the recruitment of these mast cells and basophils, which are
throughout the body; this can cause death. And we do know penicillin of other matter,
eating sea foods a eating sea food Why is this not localized is because that whatever
is the allergen of the sea food is now in the elementary canal. Through the elementary
canal, it is absorbed into the intestine and you do know that you do have immune cells
in the intestine. You do have mast cells through the intestine. Of course, through the blood,
this allergen is spread systemically. So, therefore, even sea food allergy is because
food can also become systemic. Type 1 hypersensitivity is mediated by IgE which gets bound to high
affinity receptors on mast cells and basophils, and then allergen induced cross linking of
the FC eta RI triggers the signaling which, as I discussed in detail for the release of
pharmacologically active molecules. Now, clinical manifestation of type 1 allergy reaction includes
hay fever, asthma and rhinitis. Now, just imagine the signaling in the mast cell is
so very intensive. You have so many molecules that kept which
participate in the signaling, all of which finally culminate in exocytosis of the principle
primary mediators which are present in granules in the mast cell, but the secondary molecules
are generated after the phospholipids in the membrane now get hydrolyzed and very potent
molecules like bradykinins, leukotriene and prostaglandins are synthesized. All of these
go to inducing vascular permeability as well as smooth muscle contraction, which can lead
to respiratory problems, can lead to vomiting because the gastrointestinal tract is also
affected and which can actually bring a shock like syndrome.
Thank you.