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Immediate Hypersensitivity Type I Samah Abu-Ghannam Ziad Al-Nasser Thursday, 4/8/2011

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 2040% 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 to develop 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.

It was noticed that there is a polymorphism in IL4 that is produced & in Fc receptor one (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 of Mycobacterium 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 be acting 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 suppress Th2, actually we can also use drugs, those which will activate macrophages and so switch 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 )

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 IgE cross-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 of mucous, 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 is mediated 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 the problem here is in the vasoactive amines produced by mast cells, so we can use mast

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 lining preventing 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 relieving the 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), the heart 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 not that 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

Avoidance

Of 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 an IgG or IgE 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:

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 to be 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

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:

Medications like morphine could induce these urticarial lesions, we call it cholinergic urticaria*. Change of heat. For example, after taking a cold shower, urticaria or bronchial asthmatic attack could be developed.

- Following an exercise, running. * Cholinergic urticaria: is a subcategory of physical urticaria 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 a disease 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

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 where lymphocytes 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 physiology if its controlled. We talked before about the antiidiotypic antibodies and the B1 cells which produce the natural antibodies; these autoantibodies 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 modify certain antigens in us, so they will be recognized as foreign and the body would turn against itself.

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 for example. 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 antiDNA 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) and Hashimoto'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

that are present according to blood groups. When we have blood group O, we have anti-A and anti-B. When we have blood group A, we have anti-B. Those are natural antibodies that develop maybe in response to normal flora, for example. To sum up: When talking about autoimmune diseases, we have antibodies or T cells against self tissues; and this process could be normal. Auto-antibodies are against auto-antigens. Very important to remember that! The 1st antibodies to be produced -for the normal physiological function- are of low affinity, while the ones causing the disease are more specific and of high affinity. During B cell development, this is when the central tolerance is going to take place. When we talked about B cell development, we said if the immature B cell receptor recognizes a self antigen, its going to be edited. If this editing was successful, the B cell will go as a nave cell to the secondary lymphoid organs; if it fails, then this B cell could react against self antigens. B1 cells produce natural antibodies with low affinity for self antigens but NEVER high affinity binding. Natural antibodies clear bacteria by complement activation. They form the isohemagglutinins, and they clear cellular debris and damaged cells. Auto-reactive T cells bind to MHC antigens in the thymus gland (central tolerance). ALL the previous points were regarding the NORMAL physiology.

The initiation of autoimmune disease: We have auto-antibodies or auto-reactive T cells causing damage through type II, III, or IV hypersensitivity reaction. Autoimmune diseases are NEVER acute. They are always chronic and very difficult to treat; we use immune suppressive drugs as well see.

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 has to 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 having auto-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 of auto-reactive T cells cause the disease; NOT autoantibodies!]
3. Autoimmune diseases are linked to MHC genes; exactly like those of the specific antigens.

[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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