Hypersensitivity Classification and Mechanisms PDF

# Hypersensitivity ## Classification and Mechanisms of Hypersensitivity There are four types of hypersensitivity that are commonly recognized: - Type I Hypersensitivity Reaction (Immediate or Anaphylactic Hypersensitivity) - Type II Hypersensitivity Reaction (Cytotoxic or cytolytic reaction) - Type...

# Hypersensitivity ## Classification and Mechanisms of Hypersensitivity There are four types of hypersensitivity that are commonly recognized: - Type I Hypersensitivity Reaction (Immediate or Anaphylactic Hypersensitivity) - Type II Hypersensitivity Reaction (Cytotoxic or cytolytic reaction) - Type III Hypersensitivity Reaction (Immune-complex mediated) - Type IV Hypersensitivity Reaction (Delayed Type Hypersensitivity or T cell mediated) ## Type I Hypersensitivity Reaction ### Mechanism - Type I hypersensitivity begins with entry of a substance, called an **allergen**, which triggers an allergic reaction in the body. The allergen may be a wide variety of materials such as: - plant pollen - certain foods - bee venom - serum - proteins - a drug, such as penicillin - The reaction occurs within minutes of re-exposure to the antigen. ### Steps 1. The allergen is taken up by antigen-presenting cells, digested and fragments are presented to T helper 2 (TH2) cells. (Genetic predisposition is an important determinant). 2. TH2 cells secrete Interleukins 4, 5, 13 which activate B cells to secrete IgE antibodies. 3. IgE antibodies enter the circulation and each antibody attaches by its Fc fragment to the surface of mast cells and basophils and the Fab fragments point outward from the cell. 4. Once IgE antibodies attach to mast cells and basophils, the individual becomes sensitized. 5. Sensitization usually requires a minimum of one week, during which time millions of IgE molecules are synthesized and attach to thousands of mast cells and basophils. 6. On subsequent exposure to the same allergen, the allergen molecules bind to the Fab ends of IgE antibodies cross-linking them (Fig 9-1). This crosslinking triggers degranulation of mast cells in tissues and basophils and in blood. 7. Degranulation releases physiological mediators such as: - histamine - leukotrienes - heparin - prostaglandins - platelet-activating factor (PAF) - eosinophil chemotactic factor of anaphylaxis (ECF-A) - proteolytic enzymes 8. These mediators trigger smooth muscle contractions, vasodilatation, and increased vascular permeability, increased mucus secretion, and stimulation of nerve endings leading to itching and pain. 9. Mast cells also secrete cytokines (TNF -a, IL3, 4, 5, 13) stimulating recruitment of leukocytes mainly eosinophils, neutrophils and TH2 cells, producing the late-phase reactions (several hours after exposure to antigen). ### Late Phase reactions Eosinophils and neutrophils secrete proteases causing tissue damage and TH2 cells secrete more cytokines that exacerbate the reaction. ### Clinical Presentations: - As mast cells accumulate in respiratory passages, intestinal walls, and the skin, type I reactions are often most pronounced in these tissues. Anaphylaxis can be divided into systemic and localized reactions. ### Systemic Anaphylaxis - If an allergen enters the blood for the second time (after an initial phase of sensitization), it will cross link preformed IgE on mast cells and basophils with degranulation and immediate release of mediators. - This will result in a systemic reaction characterized by edema in many tissues, fall in blood pressure due to vasodilatation, respiratory distress and urticarial rash (raised areas of itchy skin). - The condition might be fatal within a few minutes. ### Localized anaphylaxis (Atopy) - Airborne allergens such as plant pollen, fungal spores, animal hair and dander, house dust, mites cause: - degranulation of mast cells within the mucous membranes of the eye resulting in red, itchy, tearing eyes, - increased mucus secretion; inflammation of upper airways, sinuses lead to congested nasal passages, coughing, and sneezing (allergic rhinitis, sinusitis (hay fever), - degranulation of mast cells located within the lower respiratory tract. - The patient suffers from symptoms of bronchial asthma (difficulty in breathing and wheezy chest) due to: - Smooth muscle contraction. - Vasodilatation with increased vascular permeability and mucus secretion lead to narrowing of the walls of the bronchi. - The alveoli become over-distended and filled with fluid and mucus. - Food or drug allergens affecting the gastrointestinal tract may produce local reactions in the form of abdominal cramps, pain, diarrhea and vomiting or may be absorbed in the blood, reaching the skin, producing an urticarial reaction or the lung participating in an asthmatic attack. ## Diagnosis: ### Allergy skin test: - Performed to determine the causative allergens involved in hypersensitivity reaction. - The skin test can be applied to an individual's forearm or back. - The test allergens include grasses, molds, common tree, plant, and weed pollens, cat and animal dander, foods, and other common substances that people encounter. - Each allergen is applied by pricking the skin with a separate sterile lancet containing a drop of the allergen (skin prick test). - It takes about 15 to 20 minutes for possible reactions to develop. - Positive reactions appear as small circles of inflammation (wheal and flare reactions), which itch and look like mosquito bites. - Based on the wheal size, allergen sensitivity can be assessed as a mild, moderate, or severe reaction. ### Allergy blood tests: - Measurement of total serum IgE by radioimmunoassay tests (high level is detected in some allergic individuals). - Specific IgE (specific against certain different allergens) levels could be also measured by radioallergosorbent assay. (Fig 9-2) ## Management: 1. Identifying and avoiding the allergen (if possible) is the most effective way of preventing an allergic reaction. 2. Drugs: relieve symptoms or prevent the release of the chemical mediators that cause the allergies. - Epinephrine relaxes smooth muscles, constricts blood vessels and may be lifesaving in anaphylaxis. - Antihistaminic block the binding of histamine to histamine receptors on target cells. - Corticosteroids reduce inflammation associated with allergies. - Mast cell stabilizers sodium cromoglycate inhibits mast cell degranulation. 3. Allergen specific immunotherapy (Desensitization): Fig 9-3 - It is recommended when medications fail to control allergy symptoms. It is done by repeated subcutaneous administration of small doses of allergens, called desensitization or allergen-specific immunotherapy. As a result of this treatment, specific IgE levels decrease and IgG titers often rise, This treatment may work by: - Changing the T cell response away from Th2 dominance or - Changing the antibody response away from IgE, (by stimulating the production of IgG antibodies rather than IgE). The circulating IgG antibodies can then act to capture and neutralize allergens before they have time to react with mast cell bound IgE. - Inducing tolerance in allergen-specific T cells, or by stimulating regulatory T cells (Tregs). ## Type II Hypersensitivity Reaction ### Mechanism - This type of hypersensitivity occurs when antibodies (IgM or IgG) react with antigen on the surface of a cell resulting in cell lysis. The antigens may be endogenous or exogenous molecules as drug metabolite adsorbed onto cell membrane. ### Mechanisms of tissue damage: - Antibodies can cause tissue damage by 3 main mechanisms (Fig 9-4): - Antibodies act as opsonins enhancing phagocytosis of the cell. - Antibody dependent cell-mediated cytotoxicity (ADCC): In this process, The Fc region of antibodies bind to Fc receptors on NK, macrophages or neutrophils and promote killing of the cells by release of perforins and granzymes. - Activation of complement - C3 b is an opsonin enhancing phagocytosis. - C5b678 complex attacks the cell membrane creating pores and enhancing cell lysis. - Possible binding to normal cellular receptors and interference with their function. For instance, antibodies specific for the thyroid stimulating hormone receptor or the acetylcholine receptor cause functional abnormalities that lead to Graves' disease and myasthenia gravis, respectively. ### Clinical Presentations: - Alloimmune Hemolysis: - Incompatibility in ABO system: - Antigens of ABO on red blood cells are allogenic i.e differ from person to person. Transfusion of an incompatible blood group is the commonest cause of serious blood transfusion reactions. - For example, an A-positive individual possesses natural antibodies against B-positive cells (anti-B IgM). If B-positive cells are transfused, they will be rapidly hemolysed by pre-existing antibodies and complement activation. - Hemolytic disease of the newborn: (Fig 9-5) - Red blood cells carry an antigen called Rhesus factor (Rh factor or D antigen). - If a rhesus-negative woman (D negative) carries a Rhesus-positive fetus, (D positive), fetal cells leak into the maternal circulation and sensitize the mother to produce antibodies. This occurs most often at the birth of the first child. - The antibodies formed are of the IgG class and are able to cross the placenta in subsequent pregnancies. These antibodies will react with fetal red blood cells and lead to their destruction. - The fetal circulatory system rapidly releases immature red blood cells (erythroblasts) to replace the lysed blood cells, but these cells are also destroyed. The result may be stillbirth or, in a less extreme form, a baby with jaundice. ### Diagnosis: - Coombs' test: (see practical) ### Treatment: - For the newborn exchange transfusion, a technique that replaces baby red cells with donor rhesus negative cells. Exchange transfusion could be carried in utero. - For the mother: Anti D antibodies are given to the mother within 72 hours after first delivery of a Rh-positive baby to neutralize any fetal red blood cells that escaped to the mother's blood during delivery before stimulating the mother's immune system. - Autoimmune Hemolytic Anemia, Thrombocytopenia or Granulocytopenia: - Autoantibodies to the patient's own antigens on red blood cells, platelets or granulocytes are produced. - This might occur as a part of an autoimmune disease or may be elicited by drug administration with reaction of a drug metabolite (hapten) to protein antigen on the surface of a cell (carrier). - Antibodies are cytotoxic for the cell-drug complex as in hemolytic anemia associated with administration of penicillin. ### Other Syndromes: - Rheumatic fever: antistreptococcal antibodies cross react with an antigen in the heart muscle. - Good pasture's syndrome: IgG autoantibodies bind noncollagenous protein in basement membranes of kidney glomeruli and lung alveoli leading to destruction of the lung and kidney. - Graft rejection: Type II hypersensitivity may play a role in rejection of grafts. - Diseases due to affection of cell receptors: The antibodies may bind to normal cellular receptors and interfere with their function. The antibody-receptor interaction may be either: stimulatory, eg Grave's disease or inhibitory e.g. Myasthenia gravis. ### Diagnostic tests: - Detection of circulating antibodies against tissues involved in the disease by ELISA. - Detection of antibody and complement in the lesion (biopsy) by immunofluorescence. ### Treatment: - Anti-inflammatory, immunosuppressive agents and other symptomatic treatment. ## Type III Hypersensitivity Reaction ### Mechanism: - Type III hypersensitivity involves the formation of immune complexes (antigens, antibodies and activated complement). - The antigen may be exogenous (chronic bacterial, viral or parasitic infections), or endogenous self-antigens. - Antibodies involved mostly belong to the IgG class. - Formed immune complexes are normally removed from the circulation by phagocytes, but in the presence of large amounts, the immune system fails to eliminate them. - Excess complexes will pass between endothelial cells of blood vessels especially those in the skin, joints and kidneys and are deposited there causing tissue damage. ### The major mechanism of tissue injury (fig 9-6) in immune complex diseases is: - Inflammation within the walls of blood vessels, resulting from complement activation and binding of leukocyte Fc receptors to the antibodies in the deposited complexes. - Immune complexes and inflammatory mediators cause platelets aggregation with micro thrombi formation leading to local ischemia. ### Clinical presentations: - Serum sickness - It follows intravenous injection of foreign serum into humans as in plasma transfusion. - IgG antibodies are formed against the foreign serum proteins and large amounts of soluble immune complexes are produced. - The complexes are deposited mainly in small arteries of skin, kidney and joints causing vasculitis, nephritis, and arthritis. - Symptoms appear a week after the first injection of serum and more rapidly with each repeated injection. - The Arthus reaction - It is observed in patients who are exposed to repeated subcutaneous injections of an antigen e.g. insulin or penicillin injections or after rabies vaccination. - Injected antigens cannot diffuse out rapidly. - Circulating antibodies rapidly bind to the injected antigen and form immune complexes that are deposited in the walls of the small arteries at the injection site. This deposition gives rise to a local cutaneous vasculitis and necrosis. - Farmer's lung is a hypersensitivity pneumonitis (also called extrinsic allergic alveolitis) that occurs due to deposition of immune complexes in the lung after repeated inhalation of mold spores or pigeon feces. ### Microbial diseases complicated by immune complex formation: - Bacterial: Glomerulonephritis that follows streptococcal diseases appears to be a consequences of immune complex formation in the kidneys. - Viral: Chronic viral hepatitis infections are associated with immune complex formation. - Autoimmune disorders with formation of antibodies against self-antigens as rheumatoid arthritis and systemic lupus erythematosus. ### Diagnosis: - In serum: complement component C3 may fall to a very low level during the acute response and can be detected by single radial immunodiffusion. - In tissues biopsies: immune complexes are detected by immunofluorescence using fluorescein- labelled anti-C3, or anti IgG or IgM. ### Treatment: - Corticosteroids to limit inflammation and its injurious consequences. - In severe cases, plasmapheresis is used to reduce levels of circulating immune complex. ## Type IV Hypersensitivity Reaction ### Mechanism: - Type IV hypersensitivity reactions result from the interaction of macrophages and T cells and does not involve antibody. - CD4+ helper T cells recognize antigen in a complex with type 2 major histocompatibility complex. The antigen-presenting cells in this case are macrophages which secrete many cytokines leading to proliferation of further CD4+ T cells and tissue damage. CD8+ cytotoxic T cells may recognize antigens in association type 1 major histocompatibility complex with direct cytotoxicity (Fig 9-7). ### Clinical presentations: - Granulomatous diseases: - Infection with intracellular bacteria e.g tuberculosis and leprosy leads to delayed hypersensitivity reaction with formation of a granuloma. - Chronic antigenic stimulation of macrophages by surviving intracellular bacteria invites T lymphocytes. - Continuous release of cytokines from sensitized T lymphocytes, lead to accumulation of large number of macrophages releasing cytokines. - Macrophages fuse to form multinucleated cells or show signs of activation (large elongated nuclei and pinker cytoplasm). - Morphologically, collection of macrophages, lymphocytes and fibroblasts are called a Granuloma. - Granulomas represent an attempt of the body to wall off a site of persistent infection, but it is also associated with severe functional impairment caused by tissue necrosis and fibrosis. ### Skin tests based on delayed hypersensitivity e.g. - Tuberculin test for tuberculosis. - A purified protein derivative (PPD) of Mycobacterium tuberculosis is applied to the skin by intradermal injection (the Monteux test). - Macrophages and dendritic cells at the site of injection uptake the purified protein derivative. Dendritic cells migrate to the draining lymph nodes presenting antigen to T lymphocytes. If this individual is previously exposed to that antigen, sensitized T lymphocytes will migrate to the site of antigen; secrete cytokines inviting more lymphocytes and macrophages with vasodilatation producing an area of induration & erythema. (Fig.9-8) - A positive result indicates previous exposure to antigens due to: - subclinical previous exposure to the organisms, - clinical disease or - Vaccination. ### Contact Dermatitis - It is a delayed type of hypersensitivity reaction produced by direct contact of the skin with foreign low molecular weight substances (haptens) as certain hair dyes, cosmetics, and nickel jewelry, soap, skin ointments and poison ivy. - These materials are capable of binding to proteins in the skin (carrier proteins) forming new antigens. These antigens are presented by Langerhans cells (antigen presenting cells in the skin) to CD4+ Th cells leading to their sensitization and activation and their recruitment to the skin together with macrophages. ### CD8+ T-lymphocytes via MHC class I molecule can also induce the contact hypersensitivity response. - The reaction is characterized by a mononuclear infiltrate peaking at 12-15 hours accompanied by redness, edema and itchy vesicle formation (eczematous oozing lesions). - Identifying the causative substance is carried by: A skin patch test by applying a sample of the suspected substance to the skin and leaving it in place for 24 to 48 hours. Appearance of an inflammatory eczema at the site will help identifying the source of the allergy. ### Autoimmune diseases - Many organ-specific autoimmune diseases are caused by activation of autoreactive T cells by self-antigens, leading to cytokine release and inflammation. This is believed to be the major mechanism underlying rheumatoid arthritis, multiple sclerosis, type 1 diabetes, psoriasis and other autoimmune diseases. ### Graft rejection - Type IV hypersensitivity may play a role in acute and chronic graft rejection.