Notesale: Turn your study into money

Title: Hypersensitivities
Description: Hypersensitivities Hypersensitivity is an exaggerated immune response that causes damage to the individual. Immediate hypersensitivity reactions result in symptoms that manifest themselves within very short time periods after the immune stimulus. Immediate hypersensitivity reactions result from antibody-antigen reactions. Delayed-type hypersensitivity (DTH) reactions take 1-3 days to manifest themselves, and are caused by T-cell reactions. Type I hypersensitivity reactions mediated allergy and atopy (genetic tendency to develop allergic diseases). Type I hypersensitivity reactions are mediated by IgE antibodies that bind to mast cells or basophils. The foregin antigen induces cross-linking of IgE bound to mast cells and basophils, inducing the release of vasoactive mediators. These reactions include the most common responses to respiratory allergens such as pollen and dust mites, and to food allergens, such as peanuts and shellfish. Typical manifestations of type I reactions include systemic anaphylaxis and localized anaphylaxis such as hay fever, asthma, food allergies, and eczema. Type II hypersensitivity reactions (antibody-mediated hypersensitivity) results from the binding of IgG or IgM to the surface of host cells which mediates cell destruction via complement activation or antibody dependent cell-mediated cytotoxicity. For example, this is the fate of transfused red blood cells in transfusions between people differing in ABO blood types. Typical manifestations include; blood transfusion reactions, erythroblastosis fetalis, autoimmune haemolytic anaemia, acute and chronic rejection following transplantation, and graft versus host disease. Type III hypersensitivity reactions are mediated by immune complexes. In type III reactions antigen-antibody complexes are deposited on host cells or tissues and induce complement activation and an ensuing inflammatory response mediated by massive infiltration of neutrophils. Typical manifestations include; localized Arthus reactions and generalized reactions such as serum sickness, necrotizing vasculitis, glomerulonephritis, rheumatoid arthritis, and systemic lupus erythematosus. Type IV hypersensitivity reactions result from excessive and sometimes inappropriate T-cell activation. Sensitized T-cells release cytokines that activate macrophages of Tc cells, which mediate direct cellular damage. Typical manifestations include; contact dermatitis, tubercular lesions, and graft rejection. Type I hypersensitivity Allergy is defined following a response by the immune system to an otherwise innocuous antigen, a type I hypersensitivity reaction mediated by IgE. type I hypersensitivity reactions are a type of immediate hypersensitivity reaction. Common allergens associated with type I hypersensitivity include; rye grass, ragweed, timothy grass, birch tree, penicillin, sulfonamides, local anesthetics, salicylates, nuts, seafood, eggs, peas, beans, milk, bee venom, wasp venom, ant venom, cockroach calyx, dust mites, animal hair, latex, and mold spores. Individuals without allergies generate IgE antibodies only in response to parasitic infections. However, individuals who genetically are highly susceptible to allergies, a condition known as atopy, are predisposed to generate IgE antibodies against common environmental antigens. Allergens are highly soluble proteins or glycoproteins, usually with multiple epitopes. Allergens share some homology with self-proteins. Many allergens have intrinsic enzymatic activity that contributes to the allergic response, for example the production of protease. Many pathogens contin pathogen associated molecular patterns capable of interacting with receptors of the innate immune system and initiating a cascade of responses that contribute to an allergic response. Many allergens enter the host via mucosal tissues at very low concentrations, which tend to induce Th2 responses, the IL-4 and IL-13 produced by Th2 cells induce heavy-chain class switching to IgE. allergens are non-parasitic antigens capable of stimulating type I hypersensitivity reactions. Allergenicity is the potential of a material to cause sensitization and allergic reactions. IgE is present in very low levels in serum in most people in the range of 0.2-0.4 ug/ml. IgE has an additional constant region which changes the conformation of the molecule and enables it to bind to receptors on mast cells and basophils. IgE has a short half life in serum of 2-3 days, but when bound to its receptor on a granulocyte, IgE is stable for approximately three weeks. The activity of IgE depends on its ability to bind to a receptor specific for the Fc region of the heavy chain. There are two classes of Fc receptors; the high affinity receptor FcERI which is expressed on mast cells and basophils, and the low affinity receptor FcERII/ CD23 which is expressed on B cells, alveolar macrophages and eosinophils. Exposure to an allergen activates Th2 cells that stimulate B cells to proliferate, undergo heavy-chain class switching to IgE, and differentiate into IgE-secreting plasma cells and memory B cells expressing membrane IgE B-cell receptors. The secreted IgE molecules bind to IgE-specific Fc receptors (FcERI) on mast cells and blood basophils. A second exposure to the allergen leads to cross-linking of the bound IgE. IgE cross-linking induces the aggregation and migration of receptors into membrane lipid rafts, followed by phosphorylation of ITAM motifs by associated tyrosine kinase. Adaptor molecules then latch onto the phosphorylated tyrosine kinase residues and initiate signaling cascades culminating in enzyme and/or transcription factor activation. In addition, a brief increase in cyclic AMP (cAMP) levels is induced, followed by a decline, that spike in cAMP levels and increased levels of intracellular calcium are important for inducing degradation. Also phospholipase A initiates metabolism of the lipid arachidonic acid, producing inflammatory lipid mediators. FcERI signaling leads to several mast cell and basophils responses; degranulation- the fusion of vesicles containing multiple inflammatory mediators with the plasma membrane and release of their contents, synthesis of inflammatory cytokines, and conversion of arachidonic acid into leukotrienes and prostaglandins which are important lipid mediators of inflammation. These mediators cause numerous effects; smooth muscle contraction, increased vascular permeability, vasodilation, granulocyte chemotaxis, and extraversion. Effects of mast cell activation in the gastrointestinal tract include increased fluid extraversion and increased peristalsis, resulting in expulsion of gastrointestinal tract contents through vomiting and/or diarrhea. Effects of mast cell activation on the airways include decreased diameter and increased mucus secretion resulting in congestion of airways and swelling and mucus secretion in nasal passages. Effects of mast cells activation on blood vessels include increased blood flow and increased permeability, resulting in increased fluid in tissues causing increased flow of lymph to lymph nodes, increased cells and proteins in tissues and increased effector response in tissues. Mast cells are most common near epithelial surfaces. Mast cell activation can also result in skin wheal and flare, nasal discharge, sneezing, and conjunctivitis. Binding of IgE to its low affinity FcERII receptor helps to regulate IgE responses, transports IgE across the intestinal epithelium, and induces inflammatory cytokine production by macrophages. Primary mediators are preformed and stored in granules prior to cell activation, examples of primary mediators include; histamine, proteases, eosinophil chemotactic factor, neutrophil chemotactic factor, and heparin. Secondary mediators are either synthesized after target cell activation or released by the breakdown of membrane phospholipids during the degranulation process, examples of secondary mediators include; platelet activating factor, leukotrienes, prostaglandins, bradykinin, cytokines and chemokines. Histamine, which is formed by decarboxylation of the amino acid histidine, is a major component of mast cell granules, accounting for 10% of granule weight. Its biological effects are observed within minutes of mast cell activation. One released from mast cells, histamine binds to one of four different histamine receptors, designated H1, H2, H3, and H4. binding of histamine to the H1 receptor induces contraction of intestinal and bronchial smooth muscles, increased vascular permeability of venules, and increased mucus secretion. Interaction of histamine with H2 receptors increases vascular permeability due to contraction of endothelial cells, and vasodilation by relaxing the smooth muscle of blood vessels, stimulates exocrine secretory glands, and increases the release of acid in the stomach. Binding of histamine to H2 receptors on mast cells and basophi;s decreased/suppresses degradation, thus, histamine exerts negative feedback on the further release of mediators. The H4 receptor mediates chemotaxis of mast cells. H3 is less involved in type I hypersensitivity reactions. Histamine may be used in the treatment of immune and inflammatory disorders. Mast cells, basophils, and eosinophils secrete cytokines, including IL-4, IL-5, IL-8, IL-9, IL-13, GM-CSF and TNF alpha. These cytokines alter the local microenvironment and lead to the recruitment and activation of inflammatory cells. IL-4 and IL-13 stimulate a Th2 response and thus increase IgE production by B cells. IL-5 recruits and activates eosinophils. IL-8 activates neutrophils, monocytes, mast cells, and basophils to the site of the hypersensitive response. IL-9 increases the number and activity of mast cells. TNF-alpha contributes to shock in systemic anaphylaxis. GM-CSF stimulates the production and activation of myeloid cells. Leukotrienes and prostaglandins are secondary mediators. These mediators require a longer time period for their biological effects to become apparent in comparison to primary mediators such as histamine. Their effects are longer lived and more pronounced than those of primary mediators. The effects of leukotrienes and prostaglandins include increased vascular permeability, vasodilation platelet aggregation, and contraction of pulmonary smooth muscles. Systemic anaphylaxis is the most severe type of allergic response. Anaphylaxis is a systemic, often fatal state that occurs within minutes of exposure to an allergen. It is usually initiated by an allergen introduced directly into the bloodstream or absorbed into the circulation from the gut or skin. Symptoms of anaphylaxis include a drop in blood pressure leading to anaphylactic shock, followed by contraction of smooth muscles leading to defection, urination and bronchiolar constriction causing labored respiration. This can lead to asphyxiation and death. These symptoms are due to rapid and wide-spread IE antibody-mediated degranulation of mast cells and basophils and the systemic effects of their contents. A wide range of allergens has been shown to trigger this reaction in susceptible humans, including the venom from bee, wasp, hornet, and anti stings; drugs such as penicillin, insulin, and antitoxins; foods such as seafood, and nuts; and latex. Epinephrine is the drug of choice for treating systemic anaphylactic reactions. Epinephrine counteracts the effects of mediators such as histamine and leukotrienes, relaxing the smooth muscles of airways and reducing vascular permeability. Epinephrine also improves cardiac output, which is necessary to prevent vascular collapse during anaphylactic reaction. In localized hypersensitivity reactions, the effects are limited to a specific target site in a tissue or organ, often occurring at the epithelial surfaces first exposed ott allergens. These localized allergic reactions include; allergic rhinitis (hay fever), asthma, atopic dermatitis (eczema), urticaria (hives), angioedema (deep tissue swelling), and food allergens. Food allergens are a common type of atopy. The most common food allergens for children are found in cow’s milk, egg, peanuts, tree nuts, soy, wheat, fish, and shellfish. Among adults, nuts, fish, and shellfish are the predominant culprits. Most major food allergens are water soluble glycoproteins that are relatively stable to heat, acid, and proteases and therefore, are digested slowly. Some food allergens are capable of acting directly as adjuvants and promoting a Th2 response and IgE production in susceptible individuals. Allergen cross-linking of IgE on mast cells along the upper or lower gastrointestinal tract can induce localized smooth muscle contraction and vasodilation, resulting in such symptoms as; nausea, abdominal pain, vomiting, and/or diarrhoea. Some individuals also have oral hypersensitivity, leading to tingling and angioedema of the lips, palate, and thoat. Some individuals may develop hives when a food allergen is carried to sensitized mast cells in the skin. Basophils play a role in acute food allergy symptoms. Asthma is an example of a localized hypersensitivity reaction. Allergic asthma is triggered by activation and degranulation of mast cells, with subsequent release of inflammatory mediators, contraction of the bronchial smooth muscles, mucus secretion, and swelling of the tissues surrounding the airway all contribute to bronchoconstriction and airway obstruction. With chronic asthma, over time more serious changes occur in the airway passages, including damage to the epithelial layers, thickened basement membrane, increases in mucus-producing cells and accumulation of inflammatory cells (neutrophils, eosinophils, mast cells, and lymphocytes). Intrinsic asthma is induced by exercise or cold, independently of allergen stimulation. The most common localized hypersensitivity reaction is allergic rhinitis or hay fever, symptoms results from the inhalation of common airborne allergens (pollens, dust, animal dander, mold spores) which are recognized by IgE antibodies bound to sensitized mast cells in the conjunctiva and nasal mucosa. Allergen cross-linking of the receptor bound to IgE induces the release of histamine and other mediators from tissue mast cells, which then cause vasodilation, increased capillary permeability, and production of secretions in the eyes, nasal passages, and respiratory tract. Tearing, runny nose, sneezing, and coughing are symptoms. Allergic rhinitis affects 15-50% of the global population. The prevalence of allergic rhinitis is increasing due to; increasing airborne pollutants, rising dust mite populations, poor ventilation in buildings, increased time spent indoors, dietary factors changes in gut indeginous microflora, and increasingly sedentary lifestyles. Allergic rhinitis is associated with asthma. Family history of atopy is associated with progression of either allergic rhinitis or asthma to allergic rhinitis and asthma. Atopic dermatitis (allergic eczema) is an allergic inflammatory disease of skin. Atopic dermatitis is frequently associated with a family of atopy. It is observed most frequently in young children, often developed during infancy. Serum IgE levels are usually elevated. The affected individual develops rash, erythematous skin eruptions that can fill with pus if there is an accompanying bacterial infection, the skin lesions contain Th2 cells and an increased number of eosinophils. The hygiene hypothesis proposes that exposure to some pathogens during infancy and childhood benefits individuals by stimulating immune responses other than the tpe 2 responses that induce IgE responses and allergies. There is some evidence that while the immune system of newborns may be biased in the Th2 direction by the uterine environment, that bias diminishes during the first few months of life in nonallergic individuals, but becomes stronger in allergic children. The skewing of responses away from Th2 responses appears to occur as children become exposed to childhood infectiousness reflecting either the induction of Th1 responses or the suppression of Th2 responses by Treg cells. In westernized countries, where microbial infections are reduced as a result of sanitation, vaccinations, antibiotics and less exposure to farm animals, a child's immune system may be less likely to undergo the exposure to infections that would otherwise reorient it away from Th2 responses. An alternate hypothesis suggests that the increase in allergy is due to the failure to microbially modulate immune responses in childhood. Early exposure to a variety of infections educates the immune system. Environmental factors (including air pollution, exposure to farm animals and their bacteria, and diet) and genetics both influence susceptibility to allergies. Among genes that have variants associated with predisposition to allergies and asthma are genes that affect the integrity of the epithelial barrier, cytokines and chemokines, proteins controlling regulatory T cells, transcription factors, and receptors and signaling proteins. IgE-mediated immediate hypersensitivity is commonly assessed by skin testing, an inexpensive and relatively safe diagnostic approach that allows screening of a wide range of antigens at once. Small amounts of potential allergens are introduced at specific skin sites, either by intradermal injection or by dropping onto a site of a superficial scratch. Thirty minutes later, the sites are reexamined. Redness and swelling (the result of local mast cell degranulation) indicate an allergic response. Less commonly, serum levels of either total or allergen specific IgE may be measured using ELISA or western blot technologies. Treatment for allergies always begins with measures to avoid exposure to allergens. Allergic reactions can be treated with pharmacological inhibitors of cellular and tissue responses and inflammation, including antihistamines, leukotriene inhibitors, and corticosteroids. An anti-IgE-antibody also can be effective, though expensive and difficult to administer. Antihistamines are used in the treatment of allergic rhinitis. These drugs inhibit histamine activity by binding and blocking histamine receptors on target cells. Immunotherapeutic approaches include attempts to desentize allergic individuals by exposing them to increasing levels of their allergen. Immunotherapy by injection or sublingual administration of airborne allergens has been successful in preventing allergic rhinitis. Clinical trials are underway to desensitize children with food allergies by feeding increasing doses of allergen, which might work by inducing regulatory T cells and Th1 cells instead of Th2 cells, and the production of IgG4 instead of IfE antibodies. Type II hypersensitivity Transfusion reactions are an example of type II hypersensitivity. Transfusion reactions are caused by antibodies that bind to A, B or H carbohydrate antigens, which are expressed on the surface of red blood cells. individuals with different blood types express different carbohydrate antigens. They are tolerant to their own antigens, but generate antibodies against the antigen that they do not express. All individuals express antigen H, so no antibodies are generated to this carbohydrate. Transfusion across differences in other blood-group antigens stimulating production of IgG antibodies, which cause delayed and less severe reactions. Haemolytic disease of the newborn is caused by type II reactions. Haemolytic disease of the newborn is caused by maternal antibody reaction to the Rh antigen, which can happen if the mother of Rh negative and the father is Rh positive. As red blood cells from a fetus enter the maternal circulation during pregnancy and birth, the mother will develop Rh antibodies that can cause haemolytic disease in subsequent pregnancies. This can be prevented by several approaches to eliminate fetal red blood cells or the maternal antibodies. Similar immunization of mother against A and B blood group antigens of the fetus may also occur, blood group antigen antibodies cause less severe hemolytic disease of the newborn. Drug induced haemolytic anaemia is another example of a type II hypersensitivity reaction. Certain antibiotics, eg. penicillin, cephalosporins, and streptomycin, as well as other drugs, including ibuprofen and naproxen, can adsorb nonspecifically to proteins on red blood cells membranes, forming a drug protein complex. Income patients, such drug protein complexes induce the formation of antibodies, these antibodies then bind to the adsorbed drug on the red blood cells, inducing complement mediated lysis, and thus preogressive anemia. When the drug is withdrawn, the haemolytic anaemia disappears. Type III hypersensitivity The reaction of antibodies with antigen generates immune complexes. In general, the antigen-antibody complexes facilitate the clearance of antigen by phagocytic cells and red blood cells. In some cases, however, the presence of large numbers and networks of immune complexes can lead to tissue damaging type III hypersensitivity reactions. The magnitude of the reaction depends on the levels and size of immune complexes, their distribution within the body, and the ability of the phagocytic system to clear the complexes and thus minimize the tissue damage. Failure to clear immune complexes may also result from peculiarities of the antigen itself, or disorders in phagocytic machinery. The deposition of immune complexes in the blood vessels or tissues initiates reactions that result in the recruitment of complement components and neutrophils to the site, with resultant tissue injury. Uncleared immune complexes can induce granulation of mast cells and inflammation, and can be deposited in tissues and capillary beds where they induce mpoe innate immune activity, blood vessel inflammation (vasculitis), and tissue damage, such as glomerulonephritis in the kidneys, or arthritis in the joints. If antibodies are present, a single bolus of the antigen may produce immune complexes that may be cleared without problems, but repeated exposure, eg. injection with antibodies from a different species, can cause serum, typically mild and characterised by skin rashes, joint stiffness and fever. Chronic exposure to immune complexes against auto-antigens can lead to chronic type III hypersensitivity reactions and tissue damage. Arthus reactions are examples of immune complex hypersensitivity reactions and can be induced by insect bites, as well as by inhalation of fungal or animal protein in individuals with antibodies to those antigens. Deposition of immune complexes in blood vessels can cause local and sometimes severe inflammation of blood vessels in the skin and other tissues. Type IV hypersensitivity Type IV hypersensitivity, commonly referred to as delayed type hypersensitivity, is the only hypersensitivity category that is purely cell mediated rather than antibody mediated. The hallmarks of a type IV reaction are its initiation by T cells, the delay required for the reaction to develop, and the recruitment of macrophages as the primary cellular component of the infiltrate that surrounds the site of inflammation. The presence of a type III reaction can be measured experimentally by injecting antigen intradermally into an animal and observing whether a characteristic skin lesion develops days later at the injection site. A positive skin test reaction indicates that the individual has a population of sensitized Th1 cells specific for the test antigen. For example, to determine whether an individual has been exposed to M.tuberculosis, purified protein derivative from the cell wall of this mycobacterium is injected intradermally. Development of a red, slightly swollen, firm lesion at the site between 48 and 72 hours later indicates previous exposure. Contact dermatitis is a type IV hypersensitivity response. Contact dermatitis occurs when a reactive chemical compound contacts the skin and binds chemically to skin proteins. Peptides with the modified amino acid residues are presented to T cells in the context of appropriate MHC antigens. The reactive chemical may be a pharmaceutical, a component of a cosmetic or a hair dye, an industrial chemical such as formaldehyde or turpentine, an artificial hapten such as fluorodinitrobenzene, a metal ion such as nickel, or the active compound from poison ivy, poison oak, and related plants. A good example is the contact dermatitis induced by the toxins found in plants in the genus Toxicodendron including poison play and poison ivy. The toxins, a family of related alkyl catechols, are known collectively as urushiol. Urushiol activates DTH-inducing Th1 cells, CD8+ cells, and Th17 cells. After oxidation in the body, urushiol binds covalently to skin proteins, which can be taken up by skin dendritic cells and carried to the draining lymph nodes, where they can be degraded into peptides, presented bound to MHC class II proteins,, and induce the formation of Th1 cells. These sentized effector cells can go back to the skin and release chemokines that recruit leukocytes to the site and cytokines, such as IFN-gamma and TNF-alpha, that activate macrophages to release inflammatory cytokines, lytic enzymes, and reactive oxygen species that cause tissue damage. Urushiol can also enter cells where it can bind to cytoplasmic proteins that may be degraded into peptides that enter the endoplasmic reticulum and bind to MHC class I. CD8+ T cells can be activated by the modified peptides bound to MHC class I and form effector cytotoxic T lymphocytes, which in the skin can be activated by skin cells expressing MHC class I with the urushiol-bound peptides to either kill those skin cells or release cytokines including IFN-gamma, a major macrophage activator. Th17 cells generate DTH responses to urushiol. Human CD1a expressed by skin langerhans dendritic cells binds urushiol and that complex activates Th17 cells. These T cells secrete proinflammatory cytokines IL-17 and IL-22, which recruit and activate neutrophils and macrophages which release inflammatory and tissue damaging mediators. In the sensitization phase of a type IV reaction, T cells are activated by antigen-presenting cells. The T cells are primarily of the Th1 subtypes, but can also be Th17, Th2 and CD8+ cells. In the effector phase of a type IV reaction, sensitized T cells are reactivated by an antigen-presenting cell, which produces cytokines that activate macrophages.

Title: Hypersensitivities
Description: Hypersensitivities Hypersensitivity is an exaggerated immune response that causes damage to the individual. Immediate hypersensitivity reactions result in symptoms that manifest themselves within very short time periods after the immune stimulus. Immediate hypersensitivity reactions result from antibody-antigen reactions. Delayed-type hypersensitivity (DTH) reactions take 1-3 days to manifest themselves, and are caused by T-cell reactions. Type I hypersensitivity reactions mediated allergy and atopy (genetic tendency to develop allergic diseases). Type I hypersensitivity reactions are mediated by IgE antibodies that bind to mast cells or basophils. The foregin antigen induces cross-linking of IgE bound to mast cells and basophils, inducing the release of vasoactive mediators. These reactions include the most common responses to respiratory allergens such as pollen and dust mites, and to food allergens, such as peanuts and shellfish. Typical manifestations of type I reactions include systemic anaphylaxis and localized anaphylaxis such as hay fever, asthma, food allergies, and eczema. Type II hypersensitivity reactions (antibody-mediated hypersensitivity) results from the binding of IgG or IgM to the surface of host cells which mediates cell destruction via complement activation or antibody dependent cell-mediated cytotoxicity. For example, this is the fate of transfused red blood cells in transfusions between people differing in ABO blood types. Typical manifestations include; blood transfusion reactions, erythroblastosis fetalis, autoimmune haemolytic anaemia, acute and chronic rejection following transplantation, and graft versus host disease. Type III hypersensitivity reactions are mediated by immune complexes. In type III reactions antigen-antibody complexes are deposited on host cells or tissues and induce complement activation and an ensuing inflammatory response mediated by massive infiltration of neutrophils. Typical manifestations include; localized Arthus reactions and generalized reactions such as serum sickness, necrotizing vasculitis, glomerulonephritis, rheumatoid arthritis, and systemic lupus erythematosus. Type IV hypersensitivity reactions result from excessive and sometimes inappropriate T-cell activation. Sensitized T-cells release cytokines that activate macrophages of Tc cells, which mediate direct cellular damage. Typical manifestations include; contact dermatitis, tubercular lesions, and graft rejection. Type I hypersensitivity Allergy is defined following a response by the immune system to an otherwise innocuous antigen, a type I hypersensitivity reaction mediated by IgE. type I hypersensitivity reactions are a type of immediate hypersensitivity reaction. Common allergens associated with type I hypersensitivity include; rye grass, ragweed, timothy grass, birch tree, penicillin, sulfonamides, local anesthetics, salicylates, nuts, seafood, eggs, peas, beans, milk, bee venom, wasp venom, ant venom, cockroach calyx, dust mites, animal hair, latex, and mold spores. Individuals without allergies generate IgE antibodies only in response to parasitic infections. However, individuals who genetically are highly susceptible to allergies, a condition known as atopy, are predisposed to generate IgE antibodies against common environmental antigens. Allergens are highly soluble proteins or glycoproteins, usually with multiple epitopes. Allergens share some homology with self-proteins. Many allergens have intrinsic enzymatic activity that contributes to the allergic response, for example the production of protease. Many pathogens contin pathogen associated molecular patterns capable of interacting with receptors of the innate immune system and initiating a cascade of responses that contribute to an allergic response. Many allergens enter the host via mucosal tissues at very low concentrations, which tend to induce Th2 responses, the IL-4 and IL-13 produced by Th2 cells induce heavy-chain class switching to IgE. allergens are non-parasitic antigens capable of stimulating type I hypersensitivity reactions. Allergenicity is the potential of a material to cause sensitization and allergic reactions. IgE is present in very low levels in serum in most people in the range of 0.2-0.4 ug/ml. IgE has an additional constant region which changes the conformation of the molecule and enables it to bind to receptors on mast cells and basophils. IgE has a short half life in serum of 2-3 days, but when bound to its receptor on a granulocyte, IgE is stable for approximately three weeks. The activity of IgE depends on its ability to bind to a receptor specific for the Fc region of the heavy chain. There are two classes of Fc receptors; the high affinity receptor FcERI which is expressed on mast cells and basophils, and the low affinity receptor FcERII/ CD23 which is expressed on B cells, alveolar macrophages and eosinophils. Exposure to an allergen activates Th2 cells that stimulate B cells to proliferate, undergo heavy-chain class switching to IgE, and differentiate into IgE-secreting plasma cells and memory B cells expressing membrane IgE B-cell receptors. The secreted IgE molecules bind to IgE-specific Fc receptors (FcERI) on mast cells and blood basophils. A second exposure to the allergen leads to cross-linking of the bound IgE. IgE cross-linking induces the aggregation and migration of receptors into membrane lipid rafts, followed by phosphorylation of ITAM motifs by associated tyrosine kinase. Adaptor molecules then latch onto the phosphorylated tyrosine kinase residues and initiate signaling cascades culminating in enzyme and/or transcription factor activation. In addition, a brief increase in cyclic AMP (cAMP) levels is induced, followed by a decline, that spike in cAMP levels and increased levels of intracellular calcium are important for inducing degradation. Also phospholipase A initiates metabolism of the lipid arachidonic acid, producing inflammatory lipid mediators. FcERI signaling leads to several mast cell and basophils responses; degranulation- the fusion of vesicles containing multiple inflammatory mediators with the plasma membrane and release of their contents, synthesis of inflammatory cytokines, and conversion of arachidonic acid into leukotrienes and prostaglandins which are important lipid mediators of inflammation. These mediators cause numerous effects; smooth muscle contraction, increased vascular permeability, vasodilation, granulocyte chemotaxis, and extraversion. Effects of mast cell activation in the gastrointestinal tract include increased fluid extraversion and increased peristalsis, resulting in expulsion of gastrointestinal tract contents through vomiting and/or diarrhea. Effects of mast cell activation on the airways include decreased diameter and increased mucus secretion resulting in congestion of airways and swelling and mucus secretion in nasal passages. Effects of mast cells activation on blood vessels include increased blood flow and increased permeability, resulting in increased fluid in tissues causing increased flow of lymph to lymph nodes, increased cells and proteins in tissues and increased effector response in tissues. Mast cells are most common near epithelial surfaces. Mast cell activation can also result in skin wheal and flare, nasal discharge, sneezing, and conjunctivitis. Binding of IgE to its low affinity FcERII receptor helps to regulate IgE responses, transports IgE across the intestinal epithelium, and induces inflammatory cytokine production by macrophages. Primary mediators are preformed and stored in granules prior to cell activation, examples of primary mediators include; histamine, proteases, eosinophil chemotactic factor, neutrophil chemotactic factor, and heparin. Secondary mediators are either synthesized after target cell activation or released by the breakdown of membrane phospholipids during the degranulation process, examples of secondary mediators include; platelet activating factor, leukotrienes, prostaglandins, bradykinin, cytokines and chemokines. Histamine, which is formed by decarboxylation of the amino acid histidine, is a major component of mast cell granules, accounting for 10% of granule weight. Its biological effects are observed within minutes of mast cell activation. One released from mast cells, histamine binds to one of four different histamine receptors, designated H1, H2, H3, and H4. binding of histamine to the H1 receptor induces contraction of intestinal and bronchial smooth muscles, increased vascular permeability of venules, and increased mucus secretion. Interaction of histamine with H2 receptors increases vascular permeability due to contraction of endothelial cells, and vasodilation by relaxing the smooth muscle of blood vessels, stimulates exocrine secretory glands, and increases the release of acid in the stomach. Binding of histamine to H2 receptors on mast cells and basophi;s decreased/suppresses degradation, thus, histamine exerts negative feedback on the further release of mediators. The H4 receptor mediates chemotaxis of mast cells. H3 is less involved in type I hypersensitivity reactions. Histamine may be used in the treatment of immune and inflammatory disorders. Mast cells, basophils, and eosinophils secrete cytokines, including IL-4, IL-5, IL-8, IL-9, IL-13, GM-CSF and TNF alpha. These cytokines alter the local microenvironment and lead to the recruitment and activation of inflammatory cells. IL-4 and IL-13 stimulate a Th2 response and thus increase IgE production by B cells. IL-5 recruits and activates eosinophils. IL-8 activates neutrophils, monocytes, mast cells, and basophils to the site of the hypersensitive response. IL-9 increases the number and activity of mast cells. TNF-alpha contributes to shock in systemic anaphylaxis. GM-CSF stimulates the production and activation of myeloid cells. Leukotrienes and prostaglandins are secondary mediators. These mediators require a longer time period for their biological effects to become apparent in comparison to primary mediators such as histamine. Their effects are longer lived and more pronounced than those of primary mediators. The effects of leukotrienes and prostaglandins include increased vascular permeability, vasodilation platelet aggregation, and contraction of pulmonary smooth muscles. Systemic anaphylaxis is the most severe type of allergic response. Anaphylaxis is a systemic, often fatal state that occurs within minutes of exposure to an allergen. It is usually initiated by an allergen introduced directly into the bloodstream or absorbed into the circulation from the gut or skin. Symptoms of anaphylaxis include a drop in blood pressure leading to anaphylactic shock, followed by contraction of smooth muscles leading to defection, urination and bronchiolar constriction causing labored respiration. This can lead to asphyxiation and death. These symptoms are due to rapid and wide-spread IE antibody-mediated degranulation of mast cells and basophils and the systemic effects of their contents. A wide range of allergens has been shown to trigger this reaction in susceptible humans, including the venom from bee, wasp, hornet, and anti stings; drugs such as penicillin, insulin, and antitoxins; foods such as seafood, and nuts; and latex. Epinephrine is the drug of choice for treating systemic anaphylactic reactions. Epinephrine counteracts the effects of mediators such as histamine and leukotrienes, relaxing the smooth muscles of airways and reducing vascular permeability. Epinephrine also improves cardiac output, which is necessary to prevent vascular collapse during anaphylactic reaction. In localized hypersensitivity reactions, the effects are limited to a specific target site in a tissue or organ, often occurring at the epithelial surfaces first exposed ott allergens. These localized allergic reactions include; allergic rhinitis (hay fever), asthma, atopic dermatitis (eczema), urticaria (hives), angioedema (deep tissue swelling), and food allergens. Food allergens are a common type of atopy. The most common food allergens for children are found in cow’s milk, egg, peanuts, tree nuts, soy, wheat, fish, and shellfish. Among adults, nuts, fish, and shellfish are the predominant culprits. Most major food allergens are water soluble glycoproteins that are relatively stable to heat, acid, and proteases and therefore, are digested slowly. Some food allergens are capable of acting directly as adjuvants and promoting a Th2 response and IgE production in susceptible individuals. Allergen cross-linking of IgE on mast cells along the upper or lower gastrointestinal tract can induce localized smooth muscle contraction and vasodilation, resulting in such symptoms as; nausea, abdominal pain, vomiting, and/or diarrhoea. Some individuals also have oral hypersensitivity, leading to tingling and angioedema of the lips, palate, and thoat. Some individuals may develop hives when a food allergen is carried to sensitized mast cells in the skin. Basophils play a role in acute food allergy symptoms. Asthma is an example of a localized hypersensitivity reaction. Allergic asthma is triggered by activation and degranulation of mast cells, with subsequent release of inflammatory mediators, contraction of the bronchial smooth muscles, mucus secretion, and swelling of the tissues surrounding the airway all contribute to bronchoconstriction and airway obstruction. With chronic asthma, over time more serious changes occur in the airway passages, including damage to the epithelial layers, thickened basement membrane, increases in mucus-producing cells and accumulation of inflammatory cells (neutrophils, eosinophils, mast cells, and lymphocytes). Intrinsic asthma is induced by exercise or cold, independently of allergen stimulation. The most common localized hypersensitivity reaction is allergic rhinitis or hay fever, symptoms results from the inhalation of common airborne allergens (pollens, dust, animal dander, mold spores) which are recognized by IgE antibodies bound to sensitized mast cells in the conjunctiva and nasal mucosa. Allergen cross-linking of the receptor bound to IgE induces the release of histamine and other mediators from tissue mast cells, which then cause vasodilation, increased capillary permeability, and production of secretions in the eyes, nasal passages, and respiratory tract. Tearing, runny nose, sneezing, and coughing are symptoms. Allergic rhinitis affects 15-50% of the global population. The prevalence of allergic rhinitis is increasing due to; increasing airborne pollutants, rising dust mite populations, poor ventilation in buildings, increased time spent indoors, dietary factors changes in gut indeginous microflora, and increasingly sedentary lifestyles. Allergic rhinitis is associated with asthma. Family history of atopy is associated with progression of either allergic rhinitis or asthma to allergic rhinitis and asthma. Atopic dermatitis (allergic eczema) is an allergic inflammatory disease of skin. Atopic dermatitis is frequently associated with a family of atopy. It is observed most frequently in young children, often developed during infancy. Serum IgE levels are usually elevated. The affected individual develops rash, erythematous skin eruptions that can fill with pus if there is an accompanying bacterial infection, the skin lesions contain Th2 cells and an increased number of eosinophils. The hygiene hypothesis proposes that exposure to some pathogens during infancy and childhood benefits individuals by stimulating immune responses other than the tpe 2 responses that induce IgE responses and allergies. There is some evidence that while the immune system of newborns may be biased in the Th2 direction by the uterine environment, that bias diminishes during the first few months of life in nonallergic individuals, but becomes stronger in allergic children. The skewing of responses away from Th2 responses appears to occur as children become exposed to childhood infectiousness reflecting either the induction of Th1 responses or the suppression of Th2 responses by Treg cells. In westernized countries, where microbial infections are reduced as a result of sanitation, vaccinations, antibiotics and less exposure to farm animals, a child's immune system may be less likely to undergo the exposure to infections that would otherwise reorient it away from Th2 responses. An alternate hypothesis suggests that the increase in allergy is due to the failure to microbially modulate immune responses in childhood. Early exposure to a variety of infections educates the immune system. Environmental factors (including air pollution, exposure to farm animals and their bacteria, and diet) and genetics both influence susceptibility to allergies. Among genes that have variants associated with predisposition to allergies and asthma are genes that affect the integrity of the epithelial barrier, cytokines and chemokines, proteins controlling regulatory T cells, transcription factors, and receptors and signaling proteins. IgE-mediated immediate hypersensitivity is commonly assessed by skin testing, an inexpensive and relatively safe diagnostic approach that allows screening of a wide range of antigens at once. Small amounts of potential allergens are introduced at specific skin sites, either by intradermal injection or by dropping onto a site of a superficial scratch. Thirty minutes later, the sites are reexamined. Redness and swelling (the result of local mast cell degranulation) indicate an allergic response. Less commonly, serum levels of either total or allergen specific IgE may be measured using ELISA or western blot technologies. Treatment for allergies always begins with measures to avoid exposure to allergens. Allergic reactions can be treated with pharmacological inhibitors of cellular and tissue responses and inflammation, including antihistamines, leukotriene inhibitors, and corticosteroids. An anti-IgE-antibody also can be effective, though expensive and difficult to administer. Antihistamines are used in the treatment of allergic rhinitis. These drugs inhibit histamine activity by binding and blocking histamine receptors on target cells. Immunotherapeutic approaches include attempts to desentize allergic individuals by exposing them to increasing levels of their allergen. Immunotherapy by injection or sublingual administration of airborne allergens has been successful in preventing allergic rhinitis. Clinical trials are underway to desensitize children with food allergies by feeding increasing doses of allergen, which might work by inducing regulatory T cells and Th1 cells instead of Th2 cells, and the production of IgG4 instead of IfE antibodies. Type II hypersensitivity Transfusion reactions are an example of type II hypersensitivity. Transfusion reactions are caused by antibodies that bind to A, B or H carbohydrate antigens, which are expressed on the surface of red blood cells. individuals with different blood types express different carbohydrate antigens. They are tolerant to their own antigens, but generate antibodies against the antigen that they do not express. All individuals express antigen H, so no antibodies are generated to this carbohydrate. Transfusion across differences in other blood-group antigens stimulating production of IgG antibodies, which cause delayed and less severe reactions. Haemolytic disease of the newborn is caused by type II reactions. Haemolytic disease of the newborn is caused by maternal antibody reaction to the Rh antigen, which can happen if the mother of Rh negative and the father is Rh positive. As red blood cells from a fetus enter the maternal circulation during pregnancy and birth, the mother will develop Rh antibodies that can cause haemolytic disease in subsequent pregnancies. This can be prevented by several approaches to eliminate fetal red blood cells or the maternal antibodies. Similar immunization of mother against A and B blood group antigens of the fetus may also occur, blood group antigen antibodies cause less severe hemolytic disease of the newborn. Drug induced haemolytic anaemia is another example of a type II hypersensitivity reaction. Certain antibiotics, eg. penicillin, cephalosporins, and streptomycin, as well as other drugs, including ibuprofen and naproxen, can adsorb nonspecifically to proteins on red blood cells membranes, forming a drug protein complex. Income patients, such drug protein complexes induce the formation of antibodies, these antibodies then bind to the adsorbed drug on the red blood cells, inducing complement mediated lysis, and thus preogressive anemia. When the drug is withdrawn, the haemolytic anaemia disappears. Type III hypersensitivity The reaction of antibodies with antigen generates immune complexes. In general, the antigen-antibody complexes facilitate the clearance of antigen by phagocytic cells and red blood cells. In some cases, however, the presence of large numbers and networks of immune complexes can lead to tissue damaging type III hypersensitivity reactions. The magnitude of the reaction depends on the levels and size of immune complexes, their distribution within the body, and the ability of the phagocytic system to clear the complexes and thus minimize the tissue damage. Failure to clear immune complexes may also result from peculiarities of the antigen itself, or disorders in phagocytic machinery. The deposition of immune complexes in the blood vessels or tissues initiates reactions that result in the recruitment of complement components and neutrophils to the site, with resultant tissue injury. Uncleared immune complexes can induce granulation of mast cells and inflammation, and can be deposited in tissues and capillary beds where they induce mpoe innate immune activity, blood vessel inflammation (vasculitis), and tissue damage, such as glomerulonephritis in the kidneys, or arthritis in the joints. If antibodies are present, a single bolus of the antigen may produce immune complexes that may be cleared without problems, but repeated exposure, eg. injection with antibodies from a different species, can cause serum, typically mild and characterised by skin rashes, joint stiffness and fever. Chronic exposure to immune complexes against auto-antigens can lead to chronic type III hypersensitivity reactions and tissue damage. Arthus reactions are examples of immune complex hypersensitivity reactions and can be induced by insect bites, as well as by inhalation of fungal or animal protein in individuals with antibodies to those antigens. Deposition of immune complexes in blood vessels can cause local and sometimes severe inflammation of blood vessels in the skin and other tissues. Type IV hypersensitivity Type IV hypersensitivity, commonly referred to as delayed type hypersensitivity, is the only hypersensitivity category that is purely cell mediated rather than antibody mediated. The hallmarks of a type IV reaction are its initiation by T cells, the delay required for the reaction to develop, and the recruitment of macrophages as the primary cellular component of the infiltrate that surrounds the site of inflammation. The presence of a type III reaction can be measured experimentally by injecting antigen intradermally into an animal and observing whether a characteristic skin lesion develops days later at the injection site. A positive skin test reaction indicates that the individual has a population of sensitized Th1 cells specific for the test antigen. For example, to determine whether an individual has been exposed to M.tuberculosis, purified protein derivative from the cell wall of this mycobacterium is injected intradermally. Development of a red, slightly swollen, firm lesion at the site between 48 and 72 hours later indicates previous exposure. Contact dermatitis is a type IV hypersensitivity response. Contact dermatitis occurs when a reactive chemical compound contacts the skin and binds chemically to skin proteins. Peptides with the modified amino acid residues are presented to T cells in the context of appropriate MHC antigens. The reactive chemical may be a pharmaceutical, a component of a cosmetic or a hair dye, an industrial chemical such as formaldehyde or turpentine, an artificial hapten such as fluorodinitrobenzene, a metal ion such as nickel, or the active compound from poison ivy, poison oak, and related plants. A good example is the contact dermatitis induced by the toxins found in plants in the genus Toxicodendron including poison play and poison ivy. The toxins, a family of related alkyl catechols, are known collectively as urushiol. Urushiol activates DTH-inducing Th1 cells, CD8+ cells, and Th17 cells. After oxidation in the body, urushiol binds covalently to skin proteins, which can be taken up by skin dendritic cells and carried to the draining lymph nodes, where they can be degraded into peptides, presented bound to MHC class II proteins,, and induce the formation of Th1 cells. These sentized effector cells can go back to the skin and release chemokines that recruit leukocytes to the site and cytokines, such as IFN-gamma and TNF-alpha, that activate macrophages to release inflammatory cytokines, lytic enzymes, and reactive oxygen species that cause tissue damage. Urushiol can also enter cells where it can bind to cytoplasmic proteins that may be degraded into peptides that enter the endoplasmic reticulum and bind to MHC class I. CD8+ T cells can be activated by the modified peptides bound to MHC class I and form effector cytotoxic T lymphocytes, which in the skin can be activated by skin cells expressing MHC class I with the urushiol-bound peptides to either kill those skin cells or release cytokines including IFN-gamma, a major macrophage activator. Th17 cells generate DTH responses to urushiol. Human CD1a expressed by skin langerhans dendritic cells binds urushiol and that complex activates Th17 cells. These T cells secrete proinflammatory cytokines IL-17 and IL-22, which recruit and activate neutrophils and macrophages which release inflammatory and tissue damaging mediators. In the sensitization phase of a type IV reaction, T cells are activated by antigen-presenting cells. The T cells are primarily of the Th1 subtypes, but can also be Th17, Th2 and CD8+ cells. In the effector phase of a type IV reaction, sensitized T cells are reactivated by an antigen-presenting cell, which produces cytokines that activate macrophages.