Hypersensitivity 1 2023-2024 PDF

Block 1.2 (2023-2024) Hypersensitivity 1 Done by : Mawaddah Alnefaie  College of Medicine Academic Year 2022-23. Title: Hypersensitivity 1 CRN No: Male: 15569, Female: 15581 Block: Block1.2 (Infection and Immunity) Subject/Discipline: Immunology Exp...

Block 1.2 (2023-2024) Hypersensitivity 1 Done by : Mawaddah Alnefaie  College of Medicine Academic Year 2022-23. Title: Hypersensitivity 1 CRN No: Male: 15569, Female: 15581 Block: Block1.2 (Infection and Immunity) Subject/Discipline: Immunology Expert: Dr. Sayed Quadri Block Coordinator: Dr.Sayed A.Quadri  Theme 29: Allergy Abbas: Basic Immunology 6th edition Chapter 11 109. What is meant by hypersensitivity, allergy and atopy? 110. What are the four types of hypersensitivity reactions and what are the basic mechanisms of these hypersensitivity reactions? 111. Describe the type I hypersensitivity reaction and the role of IgE antibodies. 112. What are the signs of anaphylaxis? 113. What are the main clinical manifestations of immediate hypersensitivity? 114. Why are asthma, hay fever and constitutional eczema often seen together? 115. Describe how in patients with asthma the early and late allergic reactions are starting. Which cytokines are involved? Which cells infiltrate and describe the timing of the events? 116. Mention the drugs used to treat immediate hypersensitivity reactions and explain their immunological mechanism? 117. Describe the type IV hypersensitivity reaction. Explain what is contact eczema? Which immunological reactions are involved in type IV hypersensitivity? 118. Explain the principles of skin tests for diagnosis of hypersensitivity reactions. Learning Objectives Immune disorders Hypersensitivity, allergy, atopy Types of hypersensitivity reactions and basic mechanisms. Type I hypersensitivity reaction “ immune mechanism & role of IgE” Anaphylaxis Local: asthma, hay fever, eczema Early and late allergic reactions in asthma “ cytokines and cells involved” Treatment of immediate hypersensitivity reactions Immune disorders Immune response is meant to be a protection for a person against microbial infections and eliminate them. However, at certain times, an immune response would produce disease. So, these are Hypersensitivity Autoimmune called abnormal immune Disorders Disorders responses or immune disorders. When immune system response against There are different types of self-antigen immune disorders, but we will cover hypersensitivity disorders only. Immunedeficiency Disorders Hyper means increase so hypersensitivity reactions are exaggerated ( or exacerbated ) Decrease the response of immune immune response that results in system 3Ds : disease or tissue damage or sometimes death  Hypersensitivity, allergy, atopy Hypersensitivity reaction has two Hypersensitivity is an excessive, exaggerated or phases: aberrant immune response. *The first phase is the priming phase, or it is also called sensitization. It means Hypersensitivity essentially has two the first exposure to the antigen that produces a hypersensitivity reaction. So components: here the immune system is prepared to produce hypersensitivity action (not i. First priming dose “1st dose” to prime producing, just preparing)) but the reaction is not seen. immune system *The second phase is the shocking ii. Shocking dose “2nd dose” results in injurious phase. Subsequent exposure, which is consequences. called shocking dose, results in the outcome of hypersensitivity action, which is injury, tissue damage, and death. Types of hypersensitivity reactions According to time taken for the reactions and We have different methods of classification of mechanisms that cause tissue damage: hypersensitivity reactions. One method is to classify the hypersensitivity reaction in terms of time. It means how much time is required for the reaction to be seen. Immediate type “response within minutes or hours So if the reaction is to be seen within minutes or hours of exposure, we call it an immediate after exposure” hypersensitivity reaction, but if it takes days, then it is called a delayed hypersensitivity Delayed type “within days” reaction. But this is an old method we do not follow this now  TYPES OF HYPERSENSITIVITY REACTIONS Classified in 4 types on the basis of the principal Now we follow this method for immunologic mechanism that is responsible for classification tissue injury and disease. We have a qualitative term for each one of these based on immunological 1. Type I hypersensitivity characterized by mechanisms. production of IgE against environmental antigens, Type 1 is mediated by IgE; therefore, we binding of IgE to mast cells in various tissues & called it an IgE-mediated hypersensitivity reaction. release of mediators from mast cells.  Type 2 is mediated by antibody but not IgE; it is by IgG, and the mechanism here is destroying the cells or tissues on which the antigen is detected. Therefore, we called it Type II hypersensitivity: mediated by antibodies a cytotoxic reaction or cytolytic reaction. against cell or tissue antigens resulting in cell or (if the cell is completely lysed or damaged) tissue damage. (antibody mediated cytotoxic Antigens are classified based on their reaction) physical nature : particulate antigen, which is an antigen present as part of a particle especially a cell. The other one is a soluble Type III hypersensitivity Antibodies against soluble antigen, which is present in the body fluids or plasma. antigens in blood that form antigen-antibody complexes, and deposition of these complexes in In type 3, there is a soluble antigen binding to its complementary antibody, which blood vessels in various tissues, causing produces an antigen-antibody complex inflammation and tissue injury. (immune complex that is called the immune complex. This diseases) immune complex is insoluble and tends to precipitate (settle down), so it is moving in the circulation. Wherever there are capillaries with a high flow of blood, this will make the complexes settle down in those capillary basement membranes.  Type IV hypersensitivity: reactions of T-lymphocytes This type is mediated by T lymphocytes. This is taking place specific for self antigens or microbes in tissues. (T cell– after hours. Therefore, it is a mediated diseases), delayed hypersensitivity reaction. Types I, II, III Antibody mediated and immediate Again, type 1 mediated by IgE, hypersensitivity reactions type 2 and 3 mediated by IgG, type 4 mediated by T cell Type IV cell mediated and known as delayed hypersensitivity reaction A lot of authors are using a different context; when they say immediate hypersensitivity reaction, mostly it is related to type I. Mechanisms of hypersensitivity Important information, the reactions mechanisms explained in next slides The most important cells involved in type 1 reaction are mast cells, which are located in different connective tissue and some epithelial tissue, and they have a receptor for the Fc region of IgE called Fc gamma. Mast cells contain granules (two sets of substances) that are producing the reaction; these substances are produced and stored in the mast cells before exposure to allergens (allergen means antigen that induces type 1 hypersensitivity) One of these substances is called vasoactive amines; they are amines in their chemical nature and active in blood vessels. The other substances are proteolytic enzymes like protease enzymes, which produce protein lysis. Type 1: Type 2 : The IgE is produced against Is a reaction for antigen which are antigens (allergens), then those present on the cell surface or IgE bind to the mast cells on their extracellular matrix. So, if you have surface with their Fc receptor, blood cell let’s say RBC you have and this is called mast cell antigen on RBC against which coating. So, production of IgE and antibodies are produced, those binding of IgE to mast cells take antibodies when they bind to the place in the priming dose. RBC that will lead to destruction of When you have IgE coated on the RBC ( Cytolysis ) mast cell, nothing will happen, *If antigen is a part of the cell, the but if the person is exposed to antibody binds to it and this result in: the same allergen, that will lead complement and Fc receptor- to cross-linking of IgE coated on mediated recruitment and activation the mast cell. Then, of leukocytes. degranulation will happen, which So, when antibodies bind to antigen means the mast cell releases its This will result in binding of contents and the reaction is seen. neutrophils to the RBC receptor to those antibodies or it can also activate complements. Both these events will have similar outcome : inflammation which leads to tissue damage. Opsonization and phagocytosis of the cell and therefore such cells will be damaged completely Type 3 : When the soluble antigen bind to their antibody, they will form antigen-antibody complex or immune complex. This immune complex settles down or deposits in vascular basement Type 4 : membrane and this trigger the same We have different types of cell- events. mediated immunity. One of the same two events that is CD4 mediated and CD8 mediated. neutrophils bind to immune complex. We will try to understand in next Neutrophils have Fc gamma lecture  receptors for IgG, and because the immune complexes are settled in the blood vessels wall or the basement Simple way to remember the types. of the endothelium, neutrophils are Acronym ACID not able to phagocytose the A= Allergy ( type 1 ) complex, instead, neutrophils will C= Cytotoxic or Cytolytic ( type 2 ) release the content of their granules I= Immune complex ( type 3 ) (proteases and ROS ) which leads to D= Delayed ( type 4 ) tissue damage and increase inflammation. The second one is complement activation ( the classical pathway) and the outcome is also increase inflammation. TYPE I “ Immediate” hypersensitivity reaction IgE & mast cell–mediated reaction to certain antigens that causes rapid vascular leakage and Allergy, Anaphylaxis, Atopy mucosal secretions, often followed by Each one has its own different meaning. Allergy is broadly used for any type 1 inflammation. hypersensitivity reaction, some people are using it for all types, but most often The reactions are also called Allergy, it is for type 1 Anaphylaxis, Atopy Anaphylaxis is a systemic type 1 reaction. Individuals with strong propensity to reactions Atopy is familial type 1 reaction and it is usually localized to certain tissue. are called atopic  Hay fever is a type 1 reaction characterized by increased inflammation and secretion of the nasal mucosa and we call it as allergic rhinitis. Common types of immediate reactions include Food allergies are allergies because of hay fever, food allergies, bronchial asthma and ingestion of food, that will induce type I hypersensitivity of the gastrointestinal tract, anaphylaxis. leading to increased intestinal secretion and peristalsis and this will induce diarrhea and vomiting. Allergies are the most frequent disorders of the Bronchial asthma is a type 1 reaction involving the bronchi and this is very immune system, estimating to affect 10% to 20% important type of type 1 reaction. of people. Anaphylaxis as we said is a type 1 reaction which is systemic reaction and generally when you say systemic it means that an allergen enters in the blood circulation and it Immediate hypersensitivity has a strong genetic can happen because of stings of insects then you will have events that are seen in basis so family history is a major risk factor. different part of the body. So, it is not organ- specific unlike the others. Anaphylaxis can also take place with certain food if these food are absorbed and enter systemic circulation  The initiator of type I reaction is known as allergen. Typical allergens include proteins in pollen, certain foods insect venoms, animal hair , dust mites, drugs….. Doctor said read it and you will understand it  Sequences of events in immediate IgE produced by B lymphocytes when they are exposed to IL-4 hypersensitivity reaction This IL-4 produced by T helper 2 especially T helper 2 in the follicles of lymphoid organs, we call it as TFH cell. 1) Activation of Th2 and IL-4–secreting follicular They will produce IL-4 and that IL-4 helper T cells, in response to an antigen induce B lymphocytes to switch to IgE production. Then, IgE is going to bind to mast cell, why? because the mast 2) Production of IgE antibodies cells have Fc receptor and this phase is sensitization or priming phase. 3) Binding of IgE to Fc receptors of mast cells “sensitization”. Subsequent exposure to the same allergen will lead to binding of IgE coated on the mast cells. Allergens 4) Cross-linking of the bound IgE by the re-exposure similar to what you took in humoral to allergen. immune response it has multiple epitopes and multiple IgE are bound 5) Activation of mast cells and release of mediators with different epitopes of the allergen and this is cross-linking. by degranulation “granules exocytosis This cross-linking of IgE coated mast cell will induce release of mediators of mast cells ( degranulation ) It is also given in the previous , T cells and the T helper cells, and because of IL-4 will induce IgE formation and the IgE will bind to the mast cell’s surface. This is called as IgE coating of the mast cell. Repeat exposure to allergen, will release the mediators of anaphylaxis.  TH2 secretes cytokines IL-4, IL-5 and IL-13------ stimulate B lymphocytes to switch to IgE-producing The propensity toward Th2 development to IgE production in immediate As the previous hypersensitivity has a strong genetic basis  IL-4 secreted by Tfh cells stimulates B lymphocytes switch to IgE-production. IL-5 secreted by Th2 cells promotes eosinophilic activation. IL-13 secreted by Th2 cells induce intestinal motility & excess mucus secretions. Doctor said read it and you will understand it Activation of Mast Cells and release of mediators IgE binds to high-affinity Fc receptors expressed on mast cells. binding of allergen to two or more IgE on mast cell. FcεRI are cross-linked ---- release of inflammatory mediators. As previous In hypersensitivity type 1, there are early phase response and late phase response.. The late phase because of cytokines and early phase because of the others mediators. When histamine increase permeability and vasodilation, intravascular compartment escapes or leaks to the extravascular compartment, outside the blood vessels. Then, there will be hypovolemia The blood volume will decrease and this will result in more hypotension, therefore, the person will go into hypovolemic shock ( anaphylactic shock) and the person could die. Also, it increases gastric acid secretion  Mediators released by mast cells Preformed means before the exposure 1. Preformed mediators; formed and stored in granules He focused on histamine as an i. Vasoactive amines example of vasoactive amines Histamine: The other example of vasoactive amine is 5-hydroxytryptamine or it causes increased vascular permeability and is called serotonin which is not having a prominent role in type 1, vasodilation. but it is also involved.Also, it is a stimulates the transient contraction of bronchial and mediator in the different synaptic nerve. intestinal smooth muscles. Effect of histamine transient for a ii. Proteases cause tissue damage. short time  Arachidonic acid is a precursor of two important biological active groups : prostaglandin through a pathway called as cyclo-oxygenase ( Cox pathway ) Mediators released by mast cells pathway and also leukotrines through lipo-oxegenase pathway ( lox pathway ) The leukotriens have a sustained effect of smooth 2. Mediators formed after allergen muscle contraction, so they produce smooth muscle contraction for a long time binding to IgE on mast cells.(Arachidonic acid metabolites or Lipid mediators). NSAIDs like aspirin and ibuprofen are prostaglandin synthesis inhibitors, so all these used as anti- i. Prostaglandins: causes vascular inflammatory because prostaglandin is an important dilation, mediator of inflammation, so here in hypersensitivity reaction also prostaglandin is involved but NSAIDs are ii. Leukotrienes: stimulate prolonged not recommended in treatment ( contraindicated ) because if you block Cox pathway and reduce bronchial smooth muscle prostaglandin synthesis all the available arachidonic acid will be directed for production leukotrine and it is contraction. more stronger in smooth muscle contraction. For example in bronchial asthma, NSAIDs are contraindicated so you should not give it to the patient because you will exaggerate the symptoms and the patient may die due to intense bronchospasm. So we can reduce inflammation by corticosteroids Mediators released by mast cells 3. Cytokines. Mast cell–derived TNF and IL-4 promote neutrophil- and eosinophil recruitment. Cytokines are other group of mediators of anaphylaxis, which are produced in the Chemokines produced by mast cells and later part. epithelial cells contribute to leukocyte Persistent inflammation after several recruitment hours of exposure to allergen in case of bronchial asthma or hay fever is due to Eosinophils and neutrophils release release of cytokines proteases, which cause tissue damage.  Anaphylaxis The systemic form of type I hypersensitivity Anaphylaxis is also seen because of iatrogenic reasons. Common allergen are drugs e.g. penicillin, bee Iatrogenic means physician induced or stings and ingested shellfish or nuts some treatment that cause a disease About signs and symptoms, in airway basically there is laryngeal edema ( edema of larynx ), therefore, the person will feel choking ( Not able to breathe or to swallow because of the intense edema) For breathing: person with anaphylaxis may wheeze ( wheezing is a musical type of sound that you hear when the bronchi The gastrointestinal tract, abdominal pain, and vomiting because of smooth muscle contraction of the intestine. So, there is an increased intestinal motility. Atopy The local form of type I hypersensitivity. The manifestation depend on the site of reaction. It is familial and not emergency. Bronchial asthma in the bronchial tree, rhinitis We have different types based on or hay fever in nose, eczema in skin, the organ involved. conjunctivitis in eye. Conjunctivitis : exposure to certain allergens of the conjunctiva will lead to conjunctivitis and will increased conjunctival secretions or tears. Pollen is a small particles that are produced by plants and released in the air There is seasonal allergic rhinitis happens during seasons of plants blooming Especially by dust mite ( an insect thar is not seen with naked eyes )  Bronchial asthma Form of respiratory allergy due to stimulation of bronchial mast cells by inhalant allergens to release mediators. Mediators: Early Vasoactive amines……… transient smooth m. contraction Late leukotrienes ……….. Prolonged smooth m. contraction …….. Airway obstruction late phase reaction by cytokines “TNF, IL4, IL13”: large no. of eosinophils in mucosa, excessive mucus , hypertrophied and hyperactive bronchial smooth ms. Some Asthma cases are not associated with IgE. Asthma may be triggered by cold or exercise. References Basic Immunology: Functions and Disorders of the Immune System [Abul K. Abbas MBBS, Andrew H. H. Lichtman MD PhD, Shiv Pillai MBBS PhD]  QUIZ Q1/Which of the following mediators is responsible for Q3/ In immediate hypersensitivity reaction, Wich the late phase reaction in type 1 hypersensitivity? one of cytokine stimulate increase mucus secretion? A. Cytokines A. IL-10 B. Histamine B. IL-13 C. Prostaglandin C. IL-17 D. Serotonin D. IL-23 Q2/ Which of the following drugs is mast cell stabilizer? Q4/ What of the following is not preformed? A. Cromolyn Na A. Heparin B. Diphynhyramine B. Histamine C. Loratadine C. Prostaglandin D. Amoxicillin D. Serotonin 1/A – 2/A - 3/B – 4/C Good luck !