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Hypersensitivity reactions

+ Type 1 HS

Mahmood SqourZiad Al-Nasser

Wednesday,3/8/2011

30

23

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Lecture: #23

Wednesday, 3/8/2011

Done by: Mahmood Sqour

Chapter #25: Hypersensitivity reactions

At first, if you please; check these abbreviations: (HS= HyperSensitivity)

)ID= Infectious Disease) , (Ig= Immunoglobulin) , (Ab= Antibody), (Ag= AntiGen)

* Introduction *

Yesterday we were talking about the Hypersensitivity reactions, and wesaid that Hypersensitivity (HS) it means an exaggeration of the immune

response; the immune response is supposed to clear out infectious

agents and tumor cells , but sometimes it gets excessive and it causes

damage to tissues.

And we said that excessive activity (which we considered as one of thefailures of the immune system) - could sometimes have advantages in

protecting us against infectious diseases (IDs) in general, or against

tumors, so ones that are hypersensitive; they have excessive immunity,

but this excessive immunity could damage our tissues, and so we should

reduce this excessive immunity.

And we said that excessive immune response could be related to threetypes of antigen:

(1) infection : we could be infected by bacteria or viruses , and our body

respond excessively to these infections , so the signs and symptoms will

be exaggerated; feeling bad and tired (because of Cytokines released).

and we gave some of the examples of common cold and influenza , and

how the damage could occur because of the immune response against

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infection; e.g. (MycobacteriumTuberculoses lungs) , (hepatitis B - liver

) , (Group A Beta hemolytic strep , and immune complexes develop and

kidney damage.)

All of those are types of HS reactions.

(2) Environmental substances (Harmless): like pollens, they could lead

to allergic rhinitis, causing coughing at that time, or we could have

bronchial asthma, and we could die because of that.

(3) Self antigens: and those can be antigens if we have failure of

tolerance (central or peripheral tolerance), then we could have an action

against self antigens with different mechanisms, this type of

hypersensitivity is called auto immune disease (autoimmunity).

Hypersensitivity is part of the failure of the adaptive immune system

and they bring upon many of the cells of the innate which will add up

to the damage.

Those 3main etiological agents can be classified into 4 different typesof Hypersensitivity reactions based on mechanism of the triggering of

the reaction:

(1) Type 1 : the immediate type or the anaphylactic type, this one is

mediated by IgE Ab , Mast cells , Basophiles & eosinophils. This type

occurs within minutes, and then we have some delayed type could occur

after hours.

(2) Type 2: the cytotoxic; we have Igs : IgG type that binds to the surface

of a cell wherever that cell is present, and the complement is going to

be activated, and then damage could occur to that particular cell.

(We call it Drug-induced hypersensitivity; the drugs could bind into the

surface of RBCs and act as hapten, then the Ab which develops, willdevelop against the hapten and the carrier at the same time making

injury to where those are located).

We have autoimmune diseases related to Type (2), we dont see

autoimmune diseases related to Type (1). While the others 2, 3 & 4 we see

auto immune phenomena related to that

(3) Type 3: this is what we call (immune complex type) immune

complexes; antigens and antibodies are soluble they react and the

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immune complexes precipitate in tissues basement membrane, (e.g. in

the kidney, skin, heart, whatever), then this activates complement

bringing upon inflammatory cells into the area and causes damage to

the tissues where these immune complexes are precipitating. The Ab

which is involved here is like Type (2); i.e. IgG.

(4) Type 4: is delayed type, it occurs in 48-72 hours (2-3 days), we are

talking about T helper cell and macrophages, activated macrophages,

development of granuloma and the (PPD testing)

; MycobacteriaTuberculoses is the classical

example of the delayed type Hypersensitivity.

We have also contact dermatitis*.

So there are the different types of the Hypersensitivity: (Type 1, 2, 3, 4) ;

related to three types of Antigens : (1) Infection, (2)environmental

substances, (3) self antigen.

Types of antigen:

(1) Infectious agent

We said about the infection antigen that the signs and symptoms willexaggerated and we will feel bad and tired; and that happened because

of releasing cytokines, so the reaction has to do with Cytokines storm!

Also we have to measure the infectious dose. About genetics: whether you are responder or non-responder. We talked about hepatitis B and the reaction which will take aplace in

the liver and the liver failure and how it happens.

These are immunological sequely of an infection:

Streptococcus pyogenes and the immune complexes that precipitate in

kidney , grop A beta hemolytic strep , rheumatic fever , rheumatic

heart disease , post streptococcal, glomerular nephritis.

i.e. We get infected , then tissues are damaged because of allergiesrather than the microorganism in general.

*contact dermatitis: adelayed type of allergic

reaction of the skin

resulting from skin contact

with a specific allergen

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(2) Environmental Substances, like pollens and drugs and other.

Small, IgE, IgG, haptens (like penicillin), drugs (any abnormal reaction of

drug we call it Idiosyncratic drug reactions),The Ab of the IgE type we call it reaginic Ab.

And we have term we call it Atopy ; it is just simply the genetic

susceptibility of getting Type (1) HS which is IgE mediated, so when I say

I have atopic response I mean by that I am allergic and I have IgE type.

So atopy is related to the genetic susceptibility of getting IgE Ab response

sometimes you could use it interchangeably Allergy or Atopic

(3) Self antigen (Autoimmune)

Autoimmune diseases will caused by these self antigens, it is type 2,3

&4 of HS reaction.

Types of HyperSensitivity:

Look at the figure below: it is just a summary for these 4 types:

Type (1): the immediate type.- The first exposure (onset) when you start getting the IgE Ab and then

the sensitization to mast cells, basophiles and eosinophils.

- Infectious trigger: for example schistosomiasis can induce IgE Ab.- Environmental trigger: house, dust, mice and feces of insects.- Is not related to Autoimmuntiy!

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- Adaptive mediator: IgE- Innate mediator: Mast cells and eosinophils.

Type(2)- You have to be sensitized an IgG Abs , the trigger for infectious agents

and environmental and autoimmunity is immune hemolytic anemias

(treated with blood transfusion)

- Adaptive mediator: IgG- Innate : complement and phagocytoses

Type(3)- It takes hours- IgG Has to be sensitized.- Infection : post streptococcal sequely and glomerular nephritis.- Environmental: we have farmers lung syndrome (it is new complexes in

the alveoli) or allergic pneumonitis.

- Autoimmunity: Systemic lupus erythematosus (DNA anti DNA)- Adaptive mediator: IgG- Innate mediator: complement and neutrophils.

Type(4): delayed type , takes 2 to 3 days- Infectious trigger: Hepatitis B is a classical example at the interferon

gamma

- Environmental : contact dermatitis- Autoimmunity: Diabetes mellitus (DM)- Adaptive mediator: T cells are involved, while the other types (B cell)!- Innate mediator: Macrophages are involved because of activated

Macrophages and granuloma formation.

We call this type of classification for 4 types of Hypersensitivity is

(Coomba and Gel classification )This is based on the type of

mechanism; type of reaction that involved.

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Hypersensitivity is Mediated by adaptive and innate, but the damagewhich happened to tissues is mediated by the innate (macrophages,

neutrophils, vasoactive amines, mast cells etc).

Adaptive and innate are involved in:- Type I: IgE, mast cells and eosinophils. Immediate type, allergy,

anaphylactic type, we do prick test: you inject the antigen intradermally

where mast cells are located, and see simple signs and symptoms of

inflammation.

- Type II: IgG to cell surface Ag, Complement and PMNs.- Type III: Immune complexes could be local, systemic or all over the body.- Type IV: Slow, T cells, and we do the patch test.

Note: the two types of Hypersensitivity which we can do skin testing is

(Type 2 & 4)

Mechanisms of Hypersensitivity for these 4 types

Type(1): Look at the picture in the slide #7 for (HYPERSENSITIVITYreactions) urticarial lesion:

Dr: This is for example urticarial lesion, you can see the erythema and

the edema, all the manifestation of Type (1) HYPERSENSITIVITYreaction,

erythema because of vasodilatation, edema because of the

extravasation, it is itchy because of the Histamine that will be produced.

This is Type (2) HYPERSENSITIVITYreactions >>>>Look at penicillin; it acts as a

hapten, and it cant produce an

immune response , but when it

binds to (e.g. RBC protein), so

reaction will go to take place,

complement will be activated, and

damage to RBC will take place.

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- Macrophages because it has Fc receptors; it binds to Fc portion of theIg, it will be activated, and also complement causes damage to cells.

The antibody binds to the Fc receptor on the splenic macrophage, the

RBC will be destroyed as an outcome to that; by two mechanisms:

1- Complement activation.2- Macrophage activation.

Immune complexes mechanism (type 3):This is the antigen which enters, induces antibody response, these

antibodies interact with antigens and form complexes; the amount of

complexes that will develop it depends on the proportion of the Antigen

to the antibody (Ag: Ab)... remember that from Precipitations reactions!

I.e. There are Antibody excesszone, antigen excess zone and thezone of equivalence (when you have the ultimate proportion of

antigen to antibody to form the Immune complexes).

So; here (figure page#7) we see the antigen excess ; we dont

have many complexes but at the zone of optimal proportion you have

plenty of immune complexes , we have a condition we call it serum

sickness ; when we get a serum from horses for example and give it

to people ; serum against serum , and here the serum is foreign , so

1

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reaction take place against the animal serum, and Immune complexes

start to develop , and at the optimal proportion where these immune

complexes will develop the most.

- These immune complexes precipitate in the tissues, and complementwill be activated, calling upon macrophages and neutrophils to cometo the area, and the damage is caused because of the involvement of

these polymorphonuclear neutrophil leukocytes(PMNs)activation.

This what happens in Hepatitis B>When the virus enters, the Ab will

develop, react with the Virus, and

make immune complexes, so oneof the manifestation of Hepatitis

B , when the patients have

jaundice , patients will develop

skin rash , and this skin rash which develops in Hepatitis B , because of

the development of the Immune complexes of the Abs and the virus ,

Hepatitis is not controlled by Abs , it is controlled by cell-mediated

Immunity , but those they develop Immune complexes , and add up to

1

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the sign and symptoms , high level of Ab and Ag may occur together,

leading to soluble Immune complexes production.

Remember... one of the explanation of skin rash develops, in hepatitis

B (serum hepatitis) , is the development of the Immune complexes

with the Abs & Ags.

Where the defense in this viral diseases mainly is cell-mediatedimmunity and the interferons; interferon Alpha is the best one against

these viruses, interferon Gamma the delayed Hypersensitivity that

could lead to liver damage.

The delayed type Hypersensitivityreaction (Type 4):(look at picture slide#12)

Occurs 2-3 days after being exposed to Ag, for example he is a farmer

who was exposed to one of the plants , it is called dandelion , it is a

form of contact dermatitis , it occurs 2-3 days , and mediated by

macrophages and TH1 , and there is sign of inflammation and

granuloma. And you should know the importance of asking the patient

when he or she was exposed to the trigger substance, the

inflammation is extremely important, if 2-3 days have pasts, then you

have to think of delayed type HYPERSENSITIVITY reaction.

* and of course the main manifestation of immediate type is urticarial

lesion, the development of a wheal where you see edema, And

inflammation and vesicle because of extravasation.

Patch test: (Look at picture Slide #13):-We do this test in the back of patient, and in each well you can call it- , you

inject intradermally the substance that you want to see if the patient

allergic to or not, making a positive (+) control and the negative (-) control,

the negative control normal saline injection {{not sure}}, the positive

control is just any substance that induces inflammation like histamine, and

we compare each one in a map represent a substance that you want to see

which ones the patient allergic to, In allergy it is extremely important to

know what you are allergic to , and this to prevent Hypersensitivity

reactions if that possible, by avoiding being exposed to that substance.

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Chapter #26:

Immediate Hypersensitivity(Type 1) : Allergy So the first type we call it: immediate type of Hypersensitivity

reactions, and this is the most dangerous that kills because it occurs in

second to minutes and we could have a delayed type of that after

hours, but it could kill, and the killing is because of the vasoactive

amines and the degranulation of the mast cells prostaglandins

histamines and leukotrienes, those are the ones that may kill !

- At first, here we have Atopy; we have to be susceptible for theallergens whether those are Infectious agent or environmental, I must

have genes, and you will see later that Type (1) Hypersensitivity runs in

families, they said: that you have to write the history of atopy; it

means history of Hypersensitivity reaction of Type (1), and if you have

a history of atopy, then you are more susceptible to many of those

diseases involved in Type (1) Hypersensitivity.

So, at the first you must have Atopy gene. Second: Hygienic environment : they have found out that if you have

been exposed to those Ags in the past and living in the area where

those Ags are prevalent; you are less likely to develop hypersensitivity

reactions compared to a patient who is living in hygienic environment

not exposed to these Ags before, it makes sense, being exposed to

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antigens alleviate or minimizes the chance that you will develop

hypersensitivity thats what we called hygienic theory ; and this has to

do with the activation with TH2 i.e. when you are exposed to much

specially to Ags of mycobacterium tuberculosis; we have note that

people working in farms and living with animals they are less likely to

develop Type (1) hypersensitivity reaction; because they are exposed

to mycobacterium Ags ; that will suppress the TH2 .

* atopy genes TH2 activation will act on B-cells to produce IgE

antibodies, IgE antibodies they are going to synthesis mast cells they

will be degranulated and the degarnulation will give you all of these

manifestation of Type (1)Hypersensitivity:

- Anaphylactic shock systemic or local.- Bronchial constriction and death .- angioedema massive extravasation vasodilatation drop in

blood pressure.- Edema- Urticaria: a Wheals and flare type of lesion of the skin.- Allergic Rhinitis.- Hay fever- asthma wheezing , and status asthmaticus lead to death.- Eczema Itchy rash bcz of exposure to environmental substance or

infection agent.- Dermatitis histamine vasodilatation redness You should know about these manifestations, This is immediate

hypersensitivity or Type (1) and IgE mediated, and IgE is controlled by

TH2.

So the hygienic environment is extremely important; it determents

whether TH2 is going to be activated or not, when TH2 is activated IL-4

and IgE antibodies switching is going to take place.

Atopy, and atopy trait, and allergy; you must have a genetic

susceptibility , in Europe in united states approximately 20-40% of

people they have the atopy trait ,so it varies from mild to severe;

depending on how you are responding to allergens.

http://en.wikipedia.org/wiki/Cutaneous_conditionshttp://en.wikipedia.org/wiki/Rashhttp://en.wikipedia.org/wiki/Rashhttp://en.wikipedia.org/wiki/Cutaneous_conditions

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You have to differentiate between allergy and other causes or otherclinical condition:

e.g. in the eye if you are allergic you are going to have conjunctivitis

(red eye), and if you get infected you are going to have (red eye); so

this is so important to make diagnosis whether you are going to have

allergy or infection because the outcome is the sameinflammation,

but the cause of inflammation is different.

It is so important to know and to differentiate between allergies andother causes; because the treatment is going to be different, if you

consider the infection as allergy and you treated that with

hydrocortisone, you suppress the immunity and increase the infection;

so we need to make accurate diagnosis.

*Notes About grandmothers: the doctor said that the grandmother can

treat the simple signs and symptoms but she cant treat the difficult

one and thats the difference between the good and bad physician.

Type (1) Hypersensitivity, it occurs in seconds, we have to besensitization to mast cells, then the second time you are exposed to

the allergen; degranulation is going to take place and inflammation

because of the vasoactive amines. among the vasoactive amines that

are going to be produced There are chemotactic factors for

eosinophils, so eosinophils will come to the area then it is going to add

up into the tissue damage and those will occur hours after the initial

response, so you will start have severe inflammation and hours you

could get tissue damage because of the eosinophils.

Types of allergens in Type (1) Hypersensitivity:1. Drugs: penicillin for example, and antihypertensive drugs.2. Inhaledpollensenvironmental.3. Fungal spores; can induce allergies like aspergillus that occurs

on walls at humid environment ,black funges that appear onwalls, some people inhale these spores and become sensitized,(e.g. aspergilloses and allergic punomonitis .)

4.

Feces of house dust mite, insectvenoms, and some people areallergic to beesvenoms and they could die !

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5. Beta-Lactams: cross allergy of beta lactams. The sign and symptoms is almost the same in all of these Type (1)

HYPERSENSITIVITY reaction, it depends where it occurs:

Systemic (e.g. anaphylaxis), air ways (e.g. asthma) or the skin

- see the table below , then read the next paragraph:

**Notes from the Dr about the table **.1)anaphylaxis, you have low blood pressure so we are going toreverse the condition and increase the blood pressure; By giving the

magic drug for this which is epinephrineadrenalin,catecholamines,this is a life saving drug acts as alpha and betaadrenergicstimulant; itincreases the blood pressure, stoppage of the loosing of plasma outof endothelial lining, and the blood pressure starts to go up and losingwill stop here, so its a life saving drug. Maybe fatalallergy to nuts

( ) and antibiotics, many people are allergic to nuts.

2) Asthma, Reversible airway obstruction in the bronchi, when you

give adrenaline, the beta receptor will be stimulated and thenbronchodilatation will take place, we could use in bronchial asthma

the salbutamol which is the beta 2 receptor stimulant, so we will have

bronchodilatation.

3) Rhinitis, The airways discharge, sneezing, nasal obstruction, co-

existing with allergic conjunctivitis, he will have red eyes and they will

be itchy and he will sneeze also and so on.

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4) Urticaria, short live itchy edema of the cutaneous tissues, the

lesions are identical to that induced by prick testing, the urticaria that

occurs in response to many allergens or to cold or heat or exercise.

Just u will be getting skin Type (1) of reaction.

5) Angioedema, short live non itchy edema, subcutaneous tissues,

swelling of the lips for example, and food allergy can be manifestated

with that.

6) Eczema, chronic itchy inflammation of the skin, some cases are

caused by food allergy as well.

What happens ??

So simply what happens in Type (1) hypersensitivity reaction, we havemast cells that have IgE antibody receptor, so if u have a history of

atopy then you respond to certain allergen, and those allergens

produce IgE antibodies, so these IgE antibodies will bind to Fc

receptor 1, Fc Receptor 1 epsilon, so it binds through the Fc portion.

Now as u can see the mast cell sensitize, and when u get exposed to

allergen again cross linking will take place between the IgE antibodies

and degarnulation is going to take place.

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So here the signal will pass through, and degarnulation will take place

and these granules are the vasoactive amines (prostaglandins,

histamine , leuktriens, heparin) and all the inflammatory mediators.

This the mechanism of Type (1) Hypersensitivity reaction, IgEmediated, its T-helper(2) stimulation, IL-4 & IL-5 also is going to be

involved. And if you remember how T-helper(2) can be stimulated and

GATA3 (transcription factor that will be produced as well).

- So what really determines to go into T-helper(1) or T-helper(2)??- It is the APC (antigen presenting cell), and what really going to

stimulate the APC??

Here e.g., the T precursor for T-helper(1) or T-helper(2) , it dependswhere the antigen is going to stimulate whichone of Toll-like

receptors!!!

E.g. if Toll-like receptor 2 is stimulated then the pathway will go to T-

helper(2) as you can see.

If e.g. Toll-like receptor 9 is stimulated then it will go to T-bet pathway

, and then T-bet as precursor expression or transcription factors thatwill lead to production of interferon gamma and IL-12 which will make

the differentiation into T-helper(1). So T-bet intermediate and then

the Inteferon gamma. Inteferon gamma will suppress the T-Helper(2).

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While if Toll-Like receptor 2 is stimulated then it will take into T-

helper(2) pathway and the intermediate is GATA3. Also IL-4 will be

produced, and T-helper(2) activation here is going to suppress the T-

helper(1) (negative feedback to T-helper(1)).

Not just that!! If we need to suppress this type of reaction then the T-

regcells (T-regulatory cells) is going to be activated and the T-reg

cells is going to produce the TGF-B (transforming growth factor-beta)

that suppresses the T-Helper(2). As well as IL-10 which will also do the

suppression.

Also we have IL-13 btw, that can help in going in the direction of T-

helper(2).

- IL-12, IL-18, can go to T-helper(1).- IL-4, IL-5 and IL-13 can go into T-helper(2).

So as you see here the T-helper(2) is going to be activated, then the

intermediate stage GATA3 and then T-helper(2) and then of course IL-

4 and IL-5 is going to be produced and then IgE antibody, and

eosinophils will be called.

So the reaction has to be controlled and the T-reg cansuppress this

type of reaction. And Ill tell u more about T-reg involvement when we

do the Desensitization, we notice that when we do the

desensitization, two types of mechanism take place, when we inject

the antigen subcutaneously we stimulate the T-helper 1 and it will

suppress the T-helper(2), and makes IgG antibodies.

So the IgG antibodies are specific and are going to neutralize theallergen when it passes our body the second time, IgE antibody will

NOT be produced.

And the same thing here is going to activate the T-reg which going to

suppress the T-helper(2), so these simply the mechanisms of

desensitization that we are going to talk about.

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So by understanding how the pathway is going to move in the

direction of IgE antibody then you can block it by the desensitization

mechanisms.

When T-helper(2) is activated then you willbe calling upon eosinophils to come into

the area, Interleukin4 (IL-4) is going to

make isotype switching to the IgE

antibodies and suppress T-helper(1).

- IL-10 switch off the macrophages. IL-5stimulate eosinophils maturation, And

those will be responsible in the late-phase

response. Eotaxin attracts eosinophils and

T-helper(2) cells to the site of

inflammation. So Eotaxin as a chemotactic

factor will bring the eosinophils into the

area. So Eotaxin and IL-5.

* Degarnulating cells here or the Mast Cells are of two types that I

want u to remember: 1)Mast cells that Present in the skin.

2)Mast cells that Present in the bronchiolesinside. they dont have

histaminecompared to ones thats present in the skin. Thats why

when you have bronchial asthma, it doesnt work as like to give

Antihistamine compared if u had allergy to the skin where

Antihistamines will work much much better.

Then the Dr went to slide #20 (Degranulation cells) and started

[Reading from slides]

Mast cells, tissues resistant, Fc epsilon receptor(1), IgE antibodiessensitization, other activation agents.

- You could stimulate Mast Cells not by just the IgE antibodies, there aredrugs that could do that like morphine, also exercise, and cold can do

so. All of these can activate and degranulate the mast cells.

Eosinophiles, attracted to site, Eotaxin, IL5, IL-13.

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Basophils act exactly the same of Mast Cells. The difference is thatBasophils are present in the circulation. While Mast cells in tissues,

they are fixed in a way.

Antibody IgE, class switching by IL-4, T-helper(2), skin, prick test,ELISA. i.e., if I want to see if Im sensitized or not; I can do the prick

test to skin, or I can measure the IgE antibody. And you know that the

concentration of the IgE antibodies is the lowest among the

immunoglobulins. So if you notice that their concentration starts to

arise and those specific for certain allergens then u can make the

diagnosis of Type1 Hypersensitivity reaction.

T-hepler(2), we should know what really activates T-hepler(1) or T-hepler(2). And the signal comes from macrophages and which Toll-like receptor or warning signal is going to be activated. Suppresses

each others; when T-hepler(1) activated it suppreses T-helper(2) and

vice versa.

And remember the intermediate stages:

T-helper(1) ; T-bet that going to give Interferone gamma .

T-helper(2) ; GATA3 that will give IL-4, IL-5 and IL-13. Positivefeedback, I mean those they are going to activate more of B

cells to produce IgE antibodies .

- T-reg cells, they produce IL-10 & TGF-B, and those are suppressorlymphokines.

- The APCs (Antigen Presenting Cells)role is extremely important, the

binding to Toll-like receptor 2 leads to GATA3 and T-helper(2)

activation, IL-12 and Interferone gamma for the T-bet.

.. """"....

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-..