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Immediate Hypersensitivity Type I

Samah Abu-GhannamZiad Al-Nasser

Thursday, 4/8/2011

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Immediate Hypersensitivity (Type 1)

Chapter 26

We are still talking about the hypersensitivity reactions; Gel & Coombs classification of them

based on the mechanism of action.

Last time, we started talking about type one hypersensitivity reaction (immediate type). It

could be localized or generalized in what we call anaphylactic shock and how this is

mediated by IgE antibodies. When the patient develops specific IgE antibodies, he must

have the history of atopy and so the genetic susceptibility to develop allergies. Almost 20-

40% of people have the susceptibility of atopy. And then these antibodies have to sensitize

the mast cells binding to them through Fc receptor (Fc portion to Fc receptor) and then the

mast cells will be sensitized. Then we have the second exposure, the IgE antibodies are

going to be cross-linked resulting in the degranulation of the mast cells. Those mast cells

could be present on the mucous membranes, tissues, skin, and sometimes these mast cells

will differ in the vasoactive amines they have; for example, the mast cells in the mucous

membranes in the respiratory tract dont have histamine compared to those in the skin.

Then we talked about the activation of the mast cells and how it depends on activation

signals, cytokines, and it is regulated in this way:

- Th1 will suppress the activation of Th2 by producing transcription factor Tbet and IFN

gamma and so suppress the Th2 and the activation of mast cells and the production of IgEs.

- Th2 when it is activated, it will produce transcription factor GATA3 and IL4 resulting in the

activation of mast cells and the production of IgEs, and of course suppression of Th1.

- Also, we have what we call Treg cells; they produce the inhibitory cytokines IL 10 & TGF

that will suppress the immune system especially here, when Th2 is activated.

- How do people get hypersensitivity?

We said that we must have the history of atopy -the genetic susceptibility- and of course

we must have the allergens (pollens, food allergens, strawberry, peanuts, chocolate )

and it has been noticed recently that there is an INCREASE among people who started todevelop allergies against many of these environmental & food allergens. And of course

genetics play a major role in that, people have to have the atopy trait (40% in the west have

the trait of developing allergies) so you have always to ask about the family history of the

patient, ask about the presence of allergies and what type of allergens family members are

allergic to, this is so IMPORTANT in inherited allergies.

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- It was noticed that there is a polymorphism in IL4 that is produced & in Fc receptorone (FcR1) that is inherited more predominantly from the mother side for unknown

reason. So REMEMBER that genetics play a MAJOR role in type one hypersensitivity

reactions.

Ok, we also talked about the Hygiene Hypothesis, and that if you are exposed to an

antigenic environment, that means full of microorganisms, then you are LESS likely to

develop hypersensitivity, for example those people who are working in farms & with animals

are less likely to develop allergies compared to those living in clean environment and so the

latter are MORE susceptible to develop allergies.

For example, if the body is infected with microorganism, especially Mycobacterium Tb, so it

will not develop allergy. And so if you vaccinate people with less virulent Mycobacterium

antigen like M. vaccae or attenuated M. Bovis they will be less likely to develop allergies,

and you could get those antigens from animal fecal materials which are full ofMycobacterium antigens. And here in Tb, antigens in macrophages favor Th1 rather than

Th2, and so Th1 is going to be activated and suppress the activation of Th2, as well as the role

of Tregs since it is found that those organisms (Mycobacterium) also favor the activation of

Tregs in order to produce suppressor (inhibitory) cytokines (IL 10, TGF ) resulting in the

suppression of Th2.

In general, Mycobacterium antigens since they activate Th1 they will suppress Th2, and this

is what we call Hygienic Hypothesis.

- Well, what about chemical pollutions?! Sometimes, chemical pollutions might NOT beacting like microorganisms & bacterial contaminations, on the contrary, chemical

pollutions could help in triggering allergic reaction, and so people who are living near

factories for example, they are MORE likely to develop allergies compared to those

living in villages.

- What about drugs? We said that NON virulent Mycobacterium species will suppressTh2, actually we can also use drugs, those which will activate macrophages and soswitch the reaction into Th1 such as CpG acting on Toll-Like receptor 9 (TLR-9), those

when are activated they will favor the shift into Th1 and suppress Th2 by the

production of IL 12 .

From a clinical point of view, in Bronchial Asthma (BA) for example, mast cells will be

sensitized with IgEs, then IgEs will be cross-linked with the antigens (here called allergens )

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leading to degranulation of the MAST CELLS & the release of vasoactive amines, the

arachidonic acid (AA) metabolites, when those cytokines are produced they are going to act

on the bronchioles causing smooth muscle contraction, mucous secretion, increase the

narrowing of the airway, so patient start having shortness of breath (SOB) coughing and

wheezing at the same time, and this occurs after seconds of the exposure to the allergen(Early phase ). Then maybe hours after the exposure, EOSINOPHILS will be called into the

area, and when they come they will worsen the signs & symptoms, especially coz of the

tryptase, cationic protein, peroxidase that are going to cause more damage to the

bronchioles (Late phase). So, in BA we start with immediate narrowing coz of the vasoactive

amines of mast cells, and coz of the eosinophils in late phase, and then the damage of the

bronchiole caused by charcot-leyden crystals and the eosinophilia that will develop. And

some of the patients of BA will go into what we call Status Asthmaticus, continuously

narrowing of the airway and they will suffocate and die, and this is one of the emergencies

in Medicine.

- So, we have early phase mediators and late phase mediators.

- Early phase means: seconds, minutes after exposure, anaphylaxis follow the IgEcross-linking, Prostaglandins (PG) & Leukotrienes (LT), those are the ones that cause

smooth muscles contraction, vasodilatation, drop of blood pressure coz of oozing of

the plasma out of the endothelial cells, so eventually edema will take place coz of the

vasoactive amines and here to counteract the drop of blood pressure (which is so

serious) we should use adrenalin. Allergic rhinitis (local effect) where we have lots ofmucous, narrowing of the airway, sneezing, coughing. Bronchial Asthma, where we

have mucous secretion, smooth muscle contraction as long as allergen is present,

and here to relieve the situation you could block the receptors by using Sodium

chromoglycate or you can use Steroids.

- The late phase: occurs hours after the improvement of the early phase, this phase ismediated by eosinophils, peroxidases, major basic protein (MBP), cationic proteins

that will cause more injury to the respiratory tract & to the tissues in general. Here in

the late phase we have chronic allergic inflammation, smooth muscle hypertrophy,mucous secretion, and the airflow will be severely narrowed.

- Now, the Question is, what should we do in here?!! First, we should know that theproblem here is in the vasoactive amines produced by mast cells, so we can use mast

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cell stabilizers like the chromoglycate which will stop the degranulation process, we

can also use steroids. Also here we can block the effect of histamine and

leukotrienes. But the first thing to do is to use adrenalin, catecholamines in general

where we have and adrenergic receptors stimulants (agonists), so they are going

to increase the blood pressure, and to narrow the gaps in endothelial liningpreventing the oozing of plasma outside the blood vessels, so the blood pressure will

go up and you will save your patients life using these life-saving drugs, adrenalin in

particular. We can also use 2 adrenergic receptor agonists; like the Salbutamol,

ventolin, to relax smooth muscles and the patient will be much better. So we start

with adrenalin, then salbutamol or ventolin, then the hydrocortisone which has a

longer effect.

- What about treating allergies, not just solving the problem temporarily and relievingthe symptoms, how can we solve the problem once and for ever?!

They have noticed that if you inject the allergen subcutaneously rather than intradermally, it

is going to activate Th1, Tregs, more of IgGs rather than IgEs.

For example, in patients who are allergic to bee venom, usually a bee will stimulate Th2 cells

after intradermal injection of its venom when it stands on your skin BUT they have noticed

that if you inject the bee venom continuously in a subcutaneous form of injection, this will

stimulate Th1 and production of IgG instead of IgE, and those IgGs are called Blocking

Antibodies, as well as the stimulation of Tregs. This process is called Desensitization or

Hypo sensitization, and this should be controlled of course, by keeping adrenalin with you

all the time, and by giving very small dose, and keep noticing the blood pressure (BP), theheart rate (HR) and we will keep doing that frequently, maybe twice a week, so while we are

doing that we notice that there will be a high level of IgG antibodies and memory cells to

that also will develop. So, when you are exposed to the allergen naturally, IgG will be

produced instead of IgE, and then it (IgG) is going to neutralize the antigen preventing its

binding to mast cells, and more of the Tregs will be produced so they will suppress the

immune response against that particular antigen permanently.

Important thing to remember is that this process should be started by the prick test, the

physician must be sure which allergen you are allergic to, if you are allergic to one or two

allergens then its going to be easy, but if you are allergic to many allergens, then its notthat easy, and the probability that you are allergic to more than one allergen is usually HIGH,

cross allergies as well are going to be there making the situation much harder to be solved.

Treatment:

- Wide range of symptoms

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- AvoidanceOf course if you live in an area where it has lots of olive trees, it's not easy to avoid inhaling

olive pollens during spring times. The only way is to change the place you live which is

sometimes very difficult to do. But you can avoid other things, like the house dust or fungi;

you can simply take them off.

Also people could be allergic to cats' dander or hair. Very small amount of that can induce

type 1 hypersensitivity reaction. So nowadays, they start to genetically engineer those cats

to develop dander that is not allergic. They call it FelD1 (Feline) cats; genetically engineered

& cannot induce allergy*.

*From the Internet: FelD1 is the allergen/protein in cats that causes anIgGorIgE reaction in

sensitive humans.

- Drugs:

- 2-adrenergic agonists (Salbutamol)

- The catecholamines,life saving in anaphylaxis

- Antihistamines, not that effective in asthma, and this is because we don't have

histamine in the mast cells around the bronchioles. Histamine presents mainly in the

skin.

- Receptor antagonists (Anti-leukotrienes); Montelukast against the leukotrienes.

- Corticosteroids, prevent the early and late phases ,recall from general pathology

course that steroid will BLOCK the enzyme phosholipase A2 which is needed in AA

metabolism ,so the effect will be more efficient coz no PG,LT will be produced .

- Sodium chromoglycate, a mast cell stabilizer.

- TH2 cytokine pathway blockers.

- IgE receptor blockers.

- Desensitization:

http://en.wikipedia.org/wiki/IgGhttp://en.wikipedia.org/wiki/IgGhttp://en.wikipedia.org/wiki/IgGhttp://en.wikipedia.org/wiki/IgEhttp://en.wikipedia.org/wiki/IgEhttp://en.wikipedia.org/wiki/IgEhttp://en.wikipedia.org/wiki/IgEhttp://en.wikipedia.org/wiki/IgG

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The permanent solution to treat the allergy, inject single Ag, TH1 stimulation rather than

TH2, so the site of injection of the allergen is going to determine whether I am going to

stimulate TH1 or TH2, Treg stimulated by this mechanism.

- Latex allergy:Surgeons who are working in operations for longer period of time could develop allergy to

latex particles that the gloves made of. So now we buy latex-free gloves to those who are

allergic to latex (more expensive). Also peanut allergy; some children are extremely allergic

to peanuts.

And nowadays we have noticed that the potato chips, ice-cream and other colored

preserved products cause severe allergy to many children. I still remember a friend of mine

developed severe bronchial asthma and massive edema after eating a strawberry-colored

ice-cream, and he was taken to the hospital where he was given adrenaline to save his life.

Also many people are allergic to fruits; strawberry, kiwi. Those ones also have colors.

This is the prick test that we are doing. In (1) we inject histamine as a positive control so it

will give you a reaction; we call it urticarial lesion with erythema, edema and itching. In (2)

we inject the normal saline as negative control, does not have any antigen so supposed tobe negative. And then you put the antigens you want to test the patient against. You can see

that the patient is allergic to 5, 6, 7 and 8. While he is not allergic to 3 and 4.

(Refer to Fig. 26.11) Here you can see what's happening. Mast cells will be sensitized with

the IgE antibodies while you do the prick test. We expose them to the allergens so that

vasoactive amines are going to be produced and then you are going to have the signs and

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symptoms of inflammation because of the vasoactive amines and other related mediators

that cause capillary vasodilation, edema, itching and so on.

This boy is having allergy, maybe to peanuts. You can see the edema around the eyes,

conjunctivitis, the eyes are very itchy as well. Here you have to be aware when making

diagnosis that this is not a viral infection. Sometimes it is extremely difficult to differentiate

between allergy and viral infection but you have to be able to do that in order to assess the

appropriate treatment for each one.

These are the urticarial lesions; you can see the edema and these are itchy of course.

Sometimes patients could develop chronic itching (chronic type of an illness).

Allergies that develop repeatedly and not seasonably (you could not pinpoint a cause) could

be caused by stimulation of mast cells by physical agents:

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- Medications like morphine could induce these urticarial lesions, we call it cholinergicurticaria*.

- Change of heat. For example, after taking a cold shower, urticaria or bronchialasthmatic attack could be developed.

- Following an exercise, running.

* Cholinergic urticaria: is a subcategory of physicalurticaria that is a skin rash brought on by

a hypersensitive reaction to body heat. Symptoms follow any stimulus to sweat such as

exercise (sometimes called exercise-induced urticaria), heat from the sun, saunas, hot

showers, etc (Wiki)

Those are simply treated with hydrocortisone, anti-histamines. We can NOT do the

desensitization here. Just avoid exposure to that physical environment that causes the

allergy.

This is the Eczema. Eczema is a manifestation of hypersensitivity type 1 reaction to the skin.

People with eczema are allergic to certain substances that induce type 1 hypersensitivity

reaction. For example, children and sometimes house-wives who are using gloves or certain

detergents.

You have to differentiate that from viral or parasitic type of disease. For example, we have adisease called scabies caused by a mite that could resemble that and the treatment is

completely different. By history and physical examination you should be sure about the case.

How Autoimmune Disease Develops

Chapter 27

http://en.wikipedia.org/wiki/Urticariahttp://en.wikipedia.org/wiki/Urticariahttp://en.wikipedia.org/wiki/Urticariahttp://en.wikipedia.org/wiki/Urticaria

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If you remember, we said that hypersensitivity reactions could occur in response to an

infection, against environmental antigens, or against self antigens.

- How is hypersensitivity against self antigens going to take place?We talked about tolerance in the past. We said we have central tolerance wherelymphocytes that react against self antigens in the thymus gland or in the bone marrow

should be deleted. The ones that escape this central tolerance go to the periphery where we

have whats called peripheral tolerance, so any lymphocyte that reacts against a self antigen

and managed to escape from the bone marrow or the thymus gland will be deleted in the

periphery. Sometimes, this scenario might not be successful!

First of all, I want you to remember that some autoimmunity (reaction against self antigens)

could be part of our normal physiologyif its controlled. We talked before about the anti-

idiotypic antibodies and the B1 cells which produce the natural antibodies; these auto-

antibodies are part of the normal physiological reactions and are needed by our body. But

when they go over-reactive, damage could happen to our tissues; we call that autoimmune

disease.

So, autoimmunity could be a normal physiological process. We see that on a daily basis when

we do testing for anti-nuclear antibodies (we can see some antibodies against DNA). But

these have to be cleared out if its part of the normal physiological process.

Remember that autoimmune disease is a property of the adaptive immune response. The

main problem in autoimmune disease is the breakdown of tolerance - central tolerance or

peripheral tolerance-. This breakdown can be mediated by genes, infections, or

environmental factors:

- It can be mediated by genes; producing B cells specific against self antigens.- When certain microorganisms infect us, our body produces antibodies or cell-mediated

immunity against these infectious agents; this immune response could cross-react with

self antigens, so the outcome of the immune response against these microbes could turn

into a reaction against self antigens.We talked, for example, about group A -hemolytic

strep. which causes rheumatic heart disease and post-streptococcal glomerulonephritis.

- Well talk about some environmental factors and how the environment could modifycertain antigens in us, so they will be recognized as foreign and the body would turn

against itself.

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So, autoimmunity could be a normal finding process occurring on a daily basis, but it

shouldnt go excessive or over-reactive.

Autoimmune disease has to do with genetics (a certain genetic setup); HLA types forexample. You remember that HLA-B27 is associated with ankylosing spondylitis, HLA-DQ2

with celiac disease and insulin-dependent diabetes mellitus (IDDM), HLA-DR2 with systemic

lupus erythematosus (SLE), and so on.

We need to do tests for diagnosis (Diagnostic Tests) of autoimmune diseases; what are the

tests that we are going to do?

Simply, we're going to detect auto-antibodies. If were talking about SLE, here we have anti-

DNA antibodies against DNA, so we detect the anti-DNA antibodies. There are many other

antibodies that could be detected: anti-nuclear antibodies, anti-smooth muscle antibodies,anti-gluten antibodies, or anti-endomysial antibodies (the last two are detected in celiac

disease).

So, you have to know what the antigen is and what antibody is going to react against that

antigen, and then you detect that antibody that isnt supposed to be present normally; or if

its present normally, the titer of that is going to be extremely high.

Well be talking about some specific diseases, IDDM, celiac disease, and SLE. Well see how

each disease is either of type II, III, or IV hypersensitivity reaction. IDDM and celiac disease

are type IV, while SLE is type III. Idiopathic thrombocytopenic purpura (ITP) andHashimoto's thyroiditis are type II.

Autoimmune disease could be so general all over our body or it could be organ specific. For

example, Addison's disease is against the suprarenal gland and IDDM is against the

Langerhans cells, and so on.

So, naturally, we have in our body the B1 lymphocytes (beside the conventional lymphocytes

(B2)). When B1 lymphocytes are produced early, they produce IgM antibodies; those IgM

antibodies have a broad specificity and are designed to react against any antigen they

encounter.

(Refer to fig. 27.1) Here you have damaged cells and the DNA is coming out; these natural

IgM antibodies could react to and clear out this DNA.

Natural antibodies could bind to A or B antigens on the surface of RBCs. Those natural

antibodies (the IgM antibodies) are the isohemagglutinins; the anti-A and anti-B antibodies

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Autoimmune disease can affect any organ in our body and any age. We have to understand

the mechanisms of autoimmunity because this is going to help in diagnosis, treatment, and

prevention if its possible.

B1 cells are NOT involved in autoimmune disease without T cell help.

Whats the evidence that T cells initiate the process?!

1. They require T cell help: the antigen is going to act exactly like a foreign antigen; it hasto be presented with an antigen presenting cell.

[In the book: Even autoimmune diseases caused by IgG-mediated mechanisms

(types II & III) require T cell help for affinity maturation to produce pathogenic

antibodies]. This is the first evidence!

2. Transfer of auto-antibodies cause the disease: if you take the serum of animal havingauto-antibodies or auto-reactive T cells and transfer that to another animal, the other

animal is going to develop an autoimmune disease. Those auto-antibodies that

developed in the first animal are abnormal; something wrong went on in the breakage

of tolerance.

[Were talking about evidence that T cells initiate the process; the Doctor should

have said: Transfer ofauto-reactive T cellscause the disease; NOT auto-

antibodies!]

3. Autoimmune diseases are linked to MHC genes; exactly like those of the specificantigens.

[He should have said that these MHC genes regulate T cells, of course, and not B

cells; which is evidence that autoimmune disease is initiated by T cells!]

Special Thanks To Basma Deeb & Mai Mazen. May Allah Bless You Dear Sisters

DoNe, AlHAMdUlillAH

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