Hypersensitivity Reactions PDF

Hypersensitivity reactions George Nadăș, Professor of Immunology, [email protected] Hypersensitivity reactions  Hypersensitivity refers to excessive, undesirable (damaging, discomfort-producing and sometimes fatal) reactions produced by the normal immune system.  Hypersensitivity reactions requi...

Hypersensitivity reactions George Nadăș, Professor of Immunology, [email protected] Hypersensitivity reactions  Hypersensitivity refers to excessive, undesirable (damaging, discomfort-producing and sometimes fatal) reactions produced by the normal immune system.  Hypersensitivity reactions require a pre-sensitized (immune) state of the host. 2 Hypersensitivity reactions  The traditional classification for hypersensitivity reactions is that of Gell and Coombs and is currently the most commonly known classification system.  It divides the hypersensitivity reactions into the following 4 types:  Type I reactions (immediate hypersensitivity reactions) involve immunoglobulin E (IgE) – mediated release of histamine and other mediators from mast cells and basophils. 3 Hypersensitivity reactions  Type II reactions (cytotoxic hypersensitivity reactions) involve immunoglobulin G or immunoglobulin M antibodies bound to cell surface antigens, with subsequent complement fixation.  Type III reactions (immune-complex reactions) involve circulating antigen-antibody immune complexes that deposit in postcapillary venules, with subsequent complement fixation. 4 Hypersensitivity reactions  Type IV reactions (delayed hypersensitivity reactions, cellmediated immunity) are mediated by T cells rather than by antibodies. 5 Hypersensitivity reactions CTLs, Cytotoxic T lymphocytes; Ig, immunoglobulin 6 Hypersensitivity type I Mast cell and EosinophilMediated Hypersensitivity  Type I Hypersensitivity (T I H) also known as immediate or anaphylactic hypersensitivity are a form of acute inflammation resulting from “explosive” release of mast cell granule contents. This type of response occurs when antigens bind to IgE bound to receptors on mast cells.  Most animals exposed to environmental antigens in food and in inhaled air respond to these antigens by producing IgG or IgA antibodies, and there is no obvious clinical consequence. 7 Hypersensitivity type I Mast cell and EosinophilMediated Hypersensitivity 8 Hypersensitivity type I Mast cell and EosinophilMediated Hypersensitivity  Some animals may respond to environmental antigens by producing IgE antibodies constantly and excessively. The excessive production of IgE is called atopy and affected individuals are said to be atopic.  If both parents are atopic, most of their offspring will also be atopic and will suffer from allergies.  There is also a breed predisposition to atopy in dogs, atopic dermatitis being most commonly observed in terriers, Dalmatians and Irish setters. 9 Hypersensitivity type I The response of mast cell to antigen  When IgE binds to receptors on mast cells it has no obvious immediate effect on the cell. The mast cell is now, however primed to bind antigen.  The mast cell can reside in tissues with its attached IgE acting like a mine in a minefield.  If an antigen enters the tissue, encounters the mast cell, and links two of these bound IgE molecules, the mast cell will be triggered to suddenly release all its granule contents and inflammatory mediators into the surrounding tissue. 10 Hypersensitivity type I Vasoactive molecules  Mast cells respond to signals from damaged tissues by releasing a mixture of molecules that affect blood vessel walls (vasoactive molecules).  These include histamine, serotonin, inflammatory lipids, enzymes, cytokines and chemokines. They attach to the blood vessel receptors causing vasodilatation, and smooth muscle contraction.  Degranulated mast cells do not die but, given time, will regenerate their granules. 11 Hypersensitivity type I Eosinophil activation  Tissues undergoing T I H reactions characteristically contain large number of eosinophils. These cells are attracted to sites of mast cell degranulation, where they degranulate and release their own biologically active molecules.  The presence of eosinophils is characteristic of T I H. 12 Hypersensitivity type I Eosinophil activation  Th cells and mast cells produce molecules that stimulate the release of eosinophils into the bloodstream.  Once they reach sites of mast cell degranulation they are activated and the ability to kill parasites is enhanced – the major role of IgE mediated responses is the control of helminth parasites. 13 Hypersensitivity type I Eosinophil degranulation and mediators  Although eosinophils can phagocytose small particles, they are much more suited to extracellular destruction of large parasites since they can degranulate in the surrounding fluid.  Eosinophils degranulate as a response to IgE-coated parasites, antigenbound IgE and chemokines.  The released granules contain a mixture of inflammatory and toxic mediators including cationic proteins and peroxidase that can kill helminths and bacteria and are important mediators of tissue pathology in allergic diseases. 14 Hypersensitivity type I Clinical Type I Hypersensitivity  The clinical signs of T I H result from the excessive release of inflammatory mediators from mast cells, eosinophils and basophils.  If the rate of release of vasoactive molecules from these cells exceeds its ability to respond to the rapid changes in the vascular system, an animal will undergo acute anaphylaxis and may die. 15 Hypersensitivity type I Acute anaphylaxis  Clinical course of acute anaphylaxis is determined by organ involvement which differs among the major domestic animal species.  Many of the symptoms are a result of vasoactive molecules binding to their receptors and making smooth muscle contract in the bronchi, gastrointestinal tract, uterus, and bladder. 16 Hypersensitivity type I Acute anaphylaxis  In cattle, pigs, sheep and cats the major shock organ is the lung.  The major shock organs of horses are the lungs and the intestine.  Dogs differ from the other domestic animals in that the major shock organ is not the lung but the liver, specifically the hepatic veins. 17 Hypersensitivity type I Inhaled antigens  Inhaled antigens (allergens) provoke inflammation in the upper respiratory tract, trachea, and bronchi.  This results in fluid exudation from the nasal mucosa and tracheobronchial constriction (asthma).  Aerosolized antigens will also contact the eyes and cause conjunctivitis and intense lacrimation. 18 Hypersensitivity type I Food allergy  About 2% of ingested protein is absorbed as peptide fragments large enough to be recognized as foreign.  This antigen can travel in the blood and reach mast cells in the skin within a few minutes.  Up to 30% of skin diseases in dogs are due to allergic dermatitis.  About 10-15% of dogs with food allergies have gastrointestinal problems. 19 Hypersensitivity type I Food allergy  The skin reactions are usually papular and erythematous and may involve the feet, eyes, ears, and axile or perianal area.  The lesion is highly pruritic and tends to respond poorly to corticosteroids.  In chronic cases the skin may be hyperpigmented, lichenified, and infected, leading to a pyoderma.  The foods involved are usually protein-rich foods such as dairy products, fish, chicken, beef and eggs. 20 Hypersensitivity type I Atopic dermatitis (AD)  Is a chronic, multifactorial syndrome – chronically inflamed and itchy skin.  Very common in dogs – up to 15% are affected, but also observed in cats, horses and goats.  Has a major breed predilection: retrievers, setters, terriers, beagles, cocker spaniels, boxers, bulldogs and Shar-Peis.  Is associated to reactions to environmental allergens such as house dust mites, pollens and molds such as the yeast Malassezia pachydermatis. 21 Hypersensitivity type I Atopic dermatitis (AD)  AD etiology is complex and is unlikely to be a pure T I H.  Not all affected dogs have reised IgE levels.  Dogs commonly present with pruritus.  Chronic licking and scratching leads to hair loss, papules, scaling and crusting.  Skin lesions – ventral abdomen, inguinal and axillary regions.  Half of affected dogs – otitis externa. 22 Hypersensitivity type I Atopic dermatitis (AD) - therapy  Allergen avoidance is the best treatment.  Topical therapy such as bathing with emollient shampoos helps considerably.  Antihistamines are of limited usefulness but may be of benefit in mild cases.  Glucocorticoids (prednisolone) – rapid remission but may cause significant side effect. 23 Hypersensitivity type I Allergies to vaccines and drugs  Is more likely to occur in vaccines that employ aluminium adjuvants.  Severe allergies have been associated with the use of killed foot-andmouth disease vaccines, rabies vaccines.  Regarding drugs – most molecules are too small to be antigenic, but many can bind to host proteins – haptens.  Penicillin allergy – may be induced by therapeutic exposure or by ingestion of penicillin-contaminated milk. 24 Hypersensitivity type I Allergies to vaccines and drugs  The penicillin molecule is degraded in vivo to several compounds – they bind to proteins and provoke an immune response.  In senzitized animals – injection of penicillin ► acute systemic anaphylaxis or milder forms of allergy.  Feeding of penicillin-contaminated milk ► severe diarheea. 25 Hypersensitivity type I Allergies to parasites  Helminths preferentially stimulate IgE responses, and are commonly associated with many of the signs of allergy and anaphylaxis.  Animals with tapeworms may show respiratory distress or urticaria.  Anaphylaxis may be provoked by rupture of a hydatid cyst or blood transfusion from a dog infected with Dirofilaria to a sensitized animal. 26 Hypersensitivity type I Allergies to parasites  Allergies are also commonly associated with exposure to arthropod antigens but also to venom.  Anaphylaxis can occur in cattle infested with the warble fly Hipoderma bovis.  Allergic reactions appear also to antigens represented by saliva of various insects: black flies, mosquitoes and even mange. 27 Ty p e I I H y p e r s e n s i t i v i t y Red cell antigens and AntibodyMediated Hypersensitivity  Red blood cells, like nucleated cells, have many characteristic cell surface molecules that can act as antigens.  If blood is transfused from one animal to another, genetically different individual, the red cell antigens will stimulate an antibody response.  These antibodies will cause the rapid elimination of the transfused red cells. 28 Ty p e I I H y p e r s e n s i t i v i t y Red cell antigens and AntibodyMediated Hypersensitivity  The elimination of the RBCs is a result of intravascular hemolysis by complement and of extravascular destruction through opsonization and removal by the mononuclear phagocyte system.  Cell destruction by antibodies in this way is classified as a Type II Hypersensitivity reaction. 29 Ty p e I I H y p e r s e n s i t i v i t y Blood groups  The antigens expressed on the surface of RBCs are called blood group antigens or erythrocyte antigens (EAs).  A, B and 0 antigens were for the first time introduced by Landsteiner in 1900.  He observed that on the surface of RBCs exist two different antigens (A and B agglutinogens) while in serum exist natural antibodies against these agglutinogens (α and β agglutinin). 30 Ty p e I I H y p e r s e n s i t i v i t y Blood groups  According to the A, B and 0 antigenic system, human can be classified in 4 distinct groups:  Group I or 0: no agglutinogen but with α and β agglutinin;  Group II or A: agglutinogen A and agglutinin β;  Group III or B: agglutinogen B and agglutinin α;  Group IV or AB: agglutinogen A and B but no agglutinin. 31 Ty p e I I H y p e r s e n s i t i v i t y Blood transfusions and incompatible transfusions  Blood is easily transfused from one animal to another. If the recipient possesses antibodies (usually of the IgM class) to donor red cell antigens, they will be attacked immediately.  The rapid destruction of large numbers of foreign RBCs can lead to serious illness, a T II H reaction.  The severity of transfusion reactions varies from a mild febrile response to death and depends on the amount of incompatible blood transfused. 32 Ty p e I I H y p e r s e n s i t i v i t y Blood transfusions and incompatible transfusions  The most severe reaction occur when large amounts of incompatible blood are transfused to a sensitized recipient.  This result in complement activation, massive hemolysis that releases large amounts of free hemoglobin, resulting in hemoglobinemia and hemoglobinuria.  Large number of lysed red cells may trigger blood clotting and disseminated intravascular coagulation. 33 Ty p e I I H y p e r s e n s i t i v i t y Blood transfusions and incompatible transfusions  Complement activation  anaphylatoxin release, mast cell degranulation, and release of vasoactive molecules and cytokines.  Transfusion reactions can be prevented by prior testing of the recipient for antibodies against the donor’s RBCs.  Donor RBCs 2-4% in saline are mixed with recipient serum and incubated at 37°C for 15-30 minutes.  If the RBCs are lysed or agglutinated by the recipients serum, than no transfusion should be attempted with those cells. 34 Ty p e I I I H y p e r s e n s i t i v i t y Immune-Complexes and NeutrophilMediated Hypersensitivity  Acute inflammation can be triggered by the presence of immune complexes (IC) in tissues.  IC formed by the combination of antibodies with antigen activate complement.  When these immune complexes are deposited in tissues, they generate chemotactic peptides that attract neutrophils that release oxidants and enzymes into tissues causing acute inflammation and tissue destruction.  Lesions generated in this way are classified as T III or immune complexmediated hypersensitivity reactions. 35 Ty p e I I I H y p e r s e n s i t i v i t y Classification of T III H  Two major forms of T III H reactions are recognized: - One form includes local reactions that occur when immune complexes form within tissues - The second – generalized form results when large quantities of immune complexes form within the blood stream This can occur, for example, when an antigen is administrated intravenously to an immune recipient. 36 Ty p e I I I H y p e r s e n s i t i v i t y Local T III H reactions  If an antigen is injected subcutaneously into an animal that already has precipitating antibodies (most probably IgG type), than acute inflammation will develop at the injection site.  This is called an Arthus reaction and it starts as a red, edematous swelling and, if severe – tissue destruction.  Is observed neutrophil adherence to vascular endothelium, followed by the mononuclear cells, becoming predominant. 37 Ty p e I I I H y p e r s e n s i t i v i t y Local T III H reactions  The IC act on two major cell types: mast cells and neutrophils.  IC formed binds to mast cells and triggers the release of vasoactive molecules. Among the molecules released by mast cells are neutrophil chemotactic factor and proteases that activate complement that generate chemotactic factor C5a.  Neutrophils attracted by C5a emigrate from the blood vessels, phagocytosing IC.  Enzymes released by neutrophils make mast cells degranulate resulting inflammation, edema and hemorrhage characteristic of the Arthus reaction. 38 Ty p e I I I H y p e r s e n s i t i v i t y Staphylococcal hypersensitivity  Staphylococcal hypersensitivity is a pruritic pustular dermatitis of dogs.  Skin testing with staphylococcal antigens suggest that types I, III and IV hypersensitivity may be involved.  The histological findings of neutrophilic dermal vasculitis suggest that the type III reaction may predominate in some cases. 39 Ty p e I V H y p e r s e n s i t i v i t y T-cell mediated  Certain antigens when injected into the skin of sensitized animals cause slowly developing inflammation at the injection site.  Delayed hypersensitivity reactions are classified as type IV hypersensitivity reactions and result from the interactions among the injected antigen, antigen presenting cells, and T cells. 40 Ty p e I V H y p e r s e n s i t i v i t y T-cell mediated  Delayed hypersensitivity reactions can be considered to be specialized forms of inflammation directed against antigens that are resistant to elimination by conventional acute inflammatory processes.  An example of delayed hypersensitivity reaction is the tuberculin response, which is the skin reaction in an animal with tuberculosis that results from an intradermal injection of tuberculin. 41 Ty p e I V H y p e r s e n s i t i v i t y T-cell mediated  Tuberculin is the name given to extracts of Mycobacterium tuberculosis, M. bovis, or M. avium used to skin-test animals for the purpose of identifying those suffering from tuberculosis.  The most important is purified protein derivate (PPD) tuberculin, which is prepared by growing organisms in synthetic medium, killing them with steam and filtering.  PPD tuberculin is a poorly defined complex antigen mixture. 42 Ty p e I V H y p e r s e n s i t i v i t y T-cell mediated  When tuberculin is injected into the skin of a normal healthy animal there is no apparent response.   But if injected to an animal infected with mycobacteria, a delayed hypersensitivity response occurs.  Following intradermal injection into a sensitized animal, a red, indurated (hard) swelling develops at the injection site. 43 Ty p e I V H y p e r s e n s i t i v i t y T-cell mediated  The inflammation begins between 12 and 24 hours, reaches its greatest intensity by 24 to 72 hours.  In very severe reactions, tissue destruction and necrosis may occur at the injection site.  Histological examination of the lesion shows that it is infiltrated with mononuclear cells (lymphocytes, macrophages). 44 Ty p e I V H y p e r s e n s i t i v i t y T-cell mediated  The tuberculin reaction is a hypersensitivity reaction mediated by T cells.   When an animal is invaded by M. tuberculosis, the antigen is readily phagocytosed by macrophages.  Some of this mycobacterial antigen triggers a Th cell-mediated response and generates memory cells. These memory cells can respond to mycobacterial antigen entering any route, even many years after the exposure. 45 Ty p e I V H y p e r s e n s i t i v i t y T-cell mediated  When tuberculin is injected intradermally, it is taken up by Langerhans cells, which migrate to the draining lymph node.  Here they present antigen to memory T cells that respond by generating Th effector cells.  The circulating Th cells recognize the antigen when they encounter it in the skin and accumulate around the antigen deposit, within 12 hours. 46 Ty p e I V H y p e r s e n s i t i v i t y T-cell mediated  There are no B cells in the lesion. T cells, macrophages and basophils are attracted in the lesion due to released mediators – IFN-γ, IL-2, and IL-6, chemokines, resulting in local inflammation.  Some of the tissue damage may be due to the release of proteases and oxidants from the activated macrophages.  The macrophages ingest and eventually destroy the injected antigen. 47 Hypersensitivity reactions ©2024 Ross University School of Veterinary Medicine. All rights reserved.