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Hypersensitivity reactions + Type 1 HS Mahmood Sqour Ziad Al-Nasser

Wednesday,3/8/2011

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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 we said 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 the failures 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 three types 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 3 main etiological agents can be classified into 4 different types of 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, will develop 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) *contact dermatitis: a ; MycobacteriaTuberculoses is the classical delayed type of allergic example of the delayed type Hypersensitivity. reaction of the skin We have also contact dermatitis*. resulting from skin contact
with a specific allergen

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 will exaggerated 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 allergies rather than the microorganism in general.
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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 damage which 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 (HYPERSENSITIVITY reactions) urticarial lesion: Dr: This is for example urticarial lesion, you can see the erythema and the edema, all the manifestation of Type (1) HYPERSENSITIVITY reaction, erythema because of vasodilatation, edema because of the extravasation, it is itchy because of the Histamine that will be produced.

This is Type (2) HYPERSENSITIVITY reactions >>>> 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 the Ig, 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 excess zone, antigen excess zone and the zone of equivalence (when you have the ultimate proportion of antigen to antibody to form the Immune complexes). So; here 1 (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
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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 complement will be activated, calling upon macrophages and neutrophils to come to 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 one of 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

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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-mediated immunity 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 Hypersensitivity reaction (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 the allergens 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.
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 You have to differentiate between allergy and other causes or other clinical 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 and other 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 be sensitization 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. Inhaled pollens environmental. 3. Fungal spores; can induce allergies like aspergillus that occurs on walls at humid environment ,black funges that appear on walls, some people inhale these spores and become sensitized, (e.g. aspergilloses and allergic punomonitis .) 4. Feces of house dust mite, insect venoms, and some people are allergic to bees venoms 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 to reverse the condition and increase the blood pressure; By giving the magic drug for this which is epinephrine adrenalin, catecholamines, this is a life saving drug acts as alpha and beta adrenergic stimulant; it increases the blood pressure, stoppage of the loosing of plasma out of endothelial lining, and the blood pressure starts to go up and losing will stop here, so its a life saving drug. Maybe fatal allergy 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 then bronchodilatation 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, coexisting 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 have mast 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, IgE mediated, 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 depends where the antigen is going to stimulate which one of Toll-like receptors!!! E.g. if Toll-like receptor 2 is stimulated then the pathway will go to Thelper(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 that will 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 Thelper(2) pathway and the intermediate is GATA3. Also IL-4 will be produced, and T-helper(2) activation here is going to suppress the Thelper(1) (negative feedback to T-helper(1)). Not just that!! If we need to suppress this type of reaction then the Treg cells (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 Thelper(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 IL4 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 can suppress 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 the allergen 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 will be 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-5 stimulate 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 bronchioles inside. they dont have histamine compared 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 antibodies sensitization, other activation agents. - You could stimulate Mast Cells not by just the IgE antibodies, there are drugs 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 that Basophils 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 Thepler(2). And the signal comes from macrophages and which Tolllike 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. Positive feedback, 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 suppressor lymphokines. - 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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