Gel and Coombs classification of hypersensitivities.

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1 Hypersensitivity

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3 Gel and Coombs classification of hypersensitivities.

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7 TYPE I Hypersensitivity Classic allergy Mediated by IgE attached to Mast cells. The symptoms resulting from allergic responses are known as anaphylaxis. Includes: Hay fever, asthma, eczema, bee stings, food allergies.

8 Allergy is an immune response, which is accompanied damage of own tissues.

9 Stages in development of allergy 1. Immunological stage. It covers all the changes in immune system after the penetration of an allergen into the organism, formation of antibodies or sensitized lymphocytes and their binding with the repeatedly entering allergen. 2. Pathochemical stage. Its sense is in formation of biological active substances. The stimulus to their formation is the binding of allergen to antibodies or sensitized lymphocytes at the end of immunological stage. 3. Pathophysiological stage. It is described by pathogenic action of formed mediators onto cells, organs and tissues of the organism with clinical display.

10 Allergens Allergens are nonparasite antigens that can stimulate a type I hypersensitivity response. Allergens bind to IgE and trigger degranulation of chemical mediators.

11 Classification of allergens Exogenous allergens (penetrate the organism from outside) Endogenous allergens (autoallergens - are formed in the organism).

12 Classification of allergens a) uninfectious allergens: Home dust Epidermal Pollen Food Industrial Officinal b) infectious allergens: Bacterial Fungous Viral

13 Allergens

14 Characteristics of allergens Small 15-40,000 MW proteins. Specific protein components Often enzymes. Low dose of allergen Mucosal exposure. Most allergens promote a Th2 immune.

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16 Allergens Example: Der P1 Der P1 is an enzyme allergen from the dust mite. Dermatophagoides pteronyssinus (common dust mite)

17 Der P1 Allergen Allergen is easily aerosolized and inhaled. Der P1 breaks down components of tight junctions which helps it to cross mucosa.

18 Atopy (Atopia) Atopy is the term for the genetic trait to have a predisposition for localized anaphylaxis. Atopic individuals have higher levels of IgE and eosinophils.

19 Genetic Predisposition Type I hypersensitivity Candidate polymorphic genes include: IL-4 Receptor. IL-4 cytokine (promoter region). FceRI. High affinity IgE receptor. Class II MHC (present peptides promoting Th2 response). Inflammation genes.

20 Mechanisms of allergic response Sensitization Repeated exposure to allergens initiates immune response that generates IgE isotype. Th2 cells required to provide the IL-4 required to get isotype switching to IgE.

21 Mechanisms of allergic response Sensitization The IgE can attach to Mast cells by Fc receptor, which increases the life span of the IgE. Half-life of IgE in serum is days whereas attached to FceR it is increased to months.

22 Mechanisms of allergic response Fc e receptors (FceR) FceR1 high affinity IgE receptor found on mast cells/basophils/activated eosinophils. Allergen binding to IgE attached to FceR1 triggers release of granules from cell.

23 FceRI Triggers Release of Mediators Early mediators cause immediate symptoms e.g. histamine (preformed in granules) leukotriene C4 and prostaglandin D2 are quickly made 2' mediators

24 Responsible cells of allergy: Mast cells Most important in patients with asthma Early studies implicated mast cells and histamine as part of an immediate type I hypersensitivity Provoked by allergenic and non allergenic substances Explained atopic and non-atopic asthma Explained why mast cell stabilising drugs worked

25 Responsible cells of allergy: T cells The early evidence: Eosinophil & mononuclear cells infiltrate the bronchi of asthmatics Activated T cells elevated in the peripheral blood of severe acute asthmatics Activated T cells in peripheral blood correlated with airway narrowing Bronchial CD4 lymphocyte numbers correlated with eosinophil numbers Elevated IL-5 expressing T cells in asthmatic bronchial mucosa and BAL (bronchoalveolar lavage) T cells that release IL-5 co-localise with eosinophils Eosinophils cause airway hyperresponsiveness, inflammation desquamative bronchitis, mucous hypersecretion and smooth muscle contraction IL-5 promotes differentiation and regulates the survival of eosinophils Steroid treatment associated with a decrease in IL-5 producing cells

26 Textbook scheme of allergic immunity is centred around polarised Th cells Ig isotype switch Th2 Th1 B Differentiation and development MF IgE Eosinophil Mast cell

27 Responsible cells of allergy: T cells Wider analysis of cytokines in atopy showed that T cells that expressed elevated levels of IL-5, also expressed IL-4 - a profile typical of Th2 cells IL-3 Growth of progenitor haemopoeitic cells GM-CSF Myelopoiesis. IL-4 IL-5 IL-10 TGF- B cell activation and growth IgE isotype switch. Induction of MHC class II. Macrophage inhibition Eosinophil growth IL-6 B cell growth Acute phase protein release Inhibits macrophage activation Inhibits Th1 cells Inhibits macrophage activation Th2

28 Allergic immune responses are much like any other immune response and involves the same regulators Non self protein from allergen or pathogen Barrier: Skin, gut, lung, eye, nose etc Inflammation inc. MIP-1a, MCP-1 MIP-1 Activation and migration of dendritic cells to site of inflammation

29 More information than is provided by the antigen is exchanged between the DC and T cell DC have a profound influence on the properties of the T cell that develops

30 Early entry of DC to the lymph node Mempel, T.R et al Nature 427: , DCs strategically cluster around HEV 18hr after entering the LN 2. Distribution of Ag-loaded DCs and T cells is ordered 4-5hr after T cells are injected

31 Signals 1, 2 and 3 Signal 1 antigen & antigen receptor DC Th Signal 2 B7 - CD28 Costimulation Signals 1 & 2 activate T cells to proliferation and effector function But what tunes the response to Th1 or Th2? Signal 3 - pathogen polarised DC

32 Polarised DC subsets Signal 1 DC Th Signal 2 Signal 3 Th polarising signal Integration of signals from pathogen/allergen and the extracellular milieu polarise the DC to produce qualitatively different signals 3 The properties of the allergen, or allergen carrier influences the DC to drive the development of appropriate Th cells

33 Type 1 and 2 DC Polarising PAMPS + + T Type 1 PAMPS bind to PRR CD80/CD86 Class II CD40 + Th1 polarising factor IL-12 Th2 polarising factor CCL2 (MCP-1) Type 2 PAMPS bind to PRR

34 T cell help to B cells IL-4 and IL-13 B Th Th Y Antigen CD40 CD40 Ligand

35 Mediators of Type I Hypersensitivity Primary Mediators Pre-formed mediators in granules Histamine Cytokines TNF-a, IL-1, IL-6. Chemoattractants for Neutrophils and Eosinophils. Enzymes tryptase, chymase, cathepsin. Changes in connective tissue matrix, tissue breakdown.

36 Mediators of Type I Hypersensitivity Immediate effects Histamine Constriction of smooth muscles. Bronchiole constriction = wheezing. Constriction of intestine = cramps-diarrhea. Vasodilation with increased fluid into tissues causing increased swelling or fluid in mucosa. Activates enzymes for tissue breakdown. Leukotrienes Prostaglandins

37 Type I Hypersensitivity Secondary mediators Mediators formed after activation Leukotrienes Prostaglandins Th2 cytokines- IL-4, IL-5, IL-13, GM-CSF

38 Continuation of sensitization cycle Mast cells control the immediate response. Eosinophils and neutrophils drive late or chronic response. More IgE production further driven by activated Mast cells, basophils, eosinophils.

39 Localized anaphylaxis Target organ responds to direct contact with allergen. Digestive tract contact results in vomiting, cramping, diarrhea. Skin sensitivity usually become inflamed resulting in itching. Airway sensitivity results in sneezing and rhinitis OR wheezing and asthma.

40 Systemic anaphylaxis Systemic vasodilation and smooth muscle contraction leading to severe bronchiole constriction, edema, and shock. Similar to systemic inflammation.

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43 Anaphylactic shock Anaphylactic shock develops as severe complication. Spasm of smooth muscles of internal organs with clinical manifestation of bronchospasm (cough, expiratory dyspnea), spasm of gastro-intestinal tract muscles (spastic pain in the whole abdomen, nausea, vomiting, diarrhea), spasm of uterus in women (pain below abdomen) are observed. Spastic phenomena are worsened by edemas of mucous covers of internal organs, during the edema of larynx the picture of asphyxia may develop. The arterial pressure sharply is decreased, the heart insufficiency, ischemia of brain, paralysis develop danger for the life of the patient appears.

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45 Treatment for Type I Effect of allergy shots Allergen Specific Antibodies Change in amount of each isotype from more IgE to more IgG.

46 TYPE II Hypersensitivity Antibody mediated cytotoxicity Blood Transfusion reactions Innocuous antigens on red blood cells. EXAMPLE: ABO blood group antigens A and B carbohydrate antigens

47 TYPE II Hemolytic disease of newborn Rh factor incompatibility Rh + baby born to Rh - mother first time fine. 2nd time can have abs to Rh from 1st pregnancy. Ab crosses placenta and baby kills its own red blood cells. Treat mother with antibody to Rh antigen right after birth and mother never makes its own immune response.

48 TYPE II Rh factor incompatibility

49 TYPE III Antigen antibody immune complexes. Immune Complex Disease (IgG mediated) Large amount of antigen and antibodies form complexes in blood. If not eliminated can deposit in capillaries or joints and trigger inflammation.

50 TYPE III Immune Complexes PMNs and macrophages bind to immune complexes via FcR and phagocytize the complexes. BUT If unable to phagocytize the immune complexes can cause inflammation via C activation ---> C3a C4a, C5a and "frustrated phagocytes".

51 TYPE III Immune Complex Disease Localized disease Deposited in joints causing local inflammation = arthritis. Deposited in kidneys = glomerulonephritis.

52 TYPE III Immune Complex Disease Serum sickness from large amounts of antigen such as injection of foreign serum. Serum sickness is usually transient immune complex disease with removal of antigen source.

53 Type IV DTH Delayed type hypersensitivity (DTH) DTH is a type of immune response classified by Th1 and macrophage activation that results in tissue damage. DTH can be the result of Chronic infection or Exposure to some antigens.

54 Delayed type hypersensitivity Th1 cells and macrophages DTH response is from: Th1 cells release cytokines to activate macrophages causing inflammation and tissue damage. Continued macrophage activation can cause chronic inflammation resulting in tissue lesions, scarring, and granuloma formation. Delayed is relative because DTH response arise hours after exposure rather than within minutes.

55 Stages of Type IV DTH Sensitization stage Memory Th1 cells against DTH antigens are generated by dendritic cells during the sensitization stage. These Th1 cells can activate macrophages and trigger inflammatory response.

56 Stages of Type IV DTH Effector stage Secondary contact yields what we call DTH. Th1 memory cells are activated and produce cytokines. IFN-g, TNF-a, and TNF- which cause tissue destruction, inflammation. IL-2 that activates T cells and CTLs. Chemokines- for macrophage recruitment. IL-3, GM-CSF for increased monocyte/macrophage

57 Stages of Type IV DTH Effector stage Secondary exposure to antigen Inflamed area becomes red and fluid filled can form lesion. From tissue damage there is activation of clotting cascades and tissue repair. Continued exposure to antigen can cause chronic inflammation and result in granuloma formation.

58 Drug reactions can be any Type of Hypersensitivity

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71 Immune mechanisms Activation of Th-1 increases formation of IL-2, it stimulates the secretion of IgM, IgG, IgGA by B-cells and switch on cellular mechanism of immunity. Activation of Th-2 leads IL-4 to changing of synthesis of IgE by B-cells to proliferation of fat cells and through IL-5 to increase and proliferation of eosinophiles.

72 Immunological stage IgE and IgG4 are formed as an answer to penetrated allergen into the organism. They get fixed on the mast cells and basophiles of blood. These cells have on their surface Fc receptors for immune globulin. The state of sensitization of the organism appears. If the same allergen again gets into the organism or it still stays in the organism after the first penetration, connection of antigen with IgE-antibodies occurs. The same thing is observed with IgG4. They bind with their receptors on basophiles, macrophages, eosinophiles, thrombocytes. Depending on the quantity of IgE-antibodies connected to antigen, quantity of antigen can observe either inhibition of the cell activity or its activation and transfer to the pathochemical stage.

73 Cellular mechanisms of allergy

74 Pathological/chemical stage Activation of the mast cells and basophile leads to releasing of different mediators. Some mediators are in the cell in ready form and easily are secreted (histamine, serotonin, eosinophiles chemotaxic factors). Some mediators are formed after stimulation of the cell (leukotriens, thrombocyte activating factors). This mediators act on vessels and targetcells, including in the development of allergic reaction eosinophiles, thrombocytes and other cells. As a result eosinophiles, neutrophiles, which start also to release mediators phospholipase D, histaminase, leukotriens and others.

75 Pathophysiological stage Under influence of mediators permeability of vessels and chemotaxis of neutrophiles and eosinophiles are increased, that leads to development of inflammatory reaction. The increase of permeability of vessels promotes the exit of fluid, immunoglobulins and complement into tissues. By means of mediators and also through the IgE-antibodies, the cytotoxic effect of macrophages is activated, secretion of enzymes, prostaglandins and leukotriens, thrombocyte activating factor is stimulated. The released mediators cause also damaging action onto cells and connective tissue structures. Bronchospasm develops in respiratory organs. These effects clinically are manifested by attacks of bronchial asthma, rhinitis, conjunctivitis, nettle-rash, skin itch, diarrhea.

76 Cytotoxic type of allergic reactions Immunological stage. It is called cytotoxic because the antibodies that developed to antigen of the cell bind to cells and cause their damage or even lysis (cytolytic action).

77 Pathochemical stage. The main mediator of cytotoxicity is the activated enzymes of complement. Pathophysiological stage. The damage of the cell with antigen properties may be caused by three factors: a) due to activation of complement, the components of which damage the cell membrane; b) due to activation of phagocytosis of the cells with fixed antibodies; c) due to activation of T-lymphocytes, natural killers.

78 Immune complex type Immunological stage. Many exogenous and endogenous antigens participate in formation of immune complexes. Among them officinal preparations (penicillin, sulfanilamides,), antitoxic vaccines, allogen gamma-globulins, food product (milk, egg, white), inhalation allergen (home dust, fungi). In case of penetration of soluble antigen into the organism IgG and IgM antibodies are formed. These antibodies can cause the formation of precipitate and connection to antigen. Immune complex can be formed in tissues or in blood flow. Patochemical stage. Under the influence of immune complexes the next mediators are formed: fragments C3a, C5a, C4a of the complement, lyzosomal enzymes of phagocytes

79 Immune complex type Pathophysiological stage. Usually immune complexes are placed on vessels of kidneys, inflammation, and exudation (glomerulonephritis) develops, in case if the complexes are placed in the lungs alveolitis appears, in skin dermatitis. The inflammation may lead to formation of ulcers, hemorrhages, thrombosis is possible in the vessels. This type of allergic reactions is main in development of serum sick, some autoallergic diseases (rheumatoid arthritis, systemic red lupus erythematosus). In case of activation of complement anaphylactic shock, bronchial asthma may develop.

80 Allergic reactions of delayed type Immunological stage. The cellular mechanism of immunity is usually activated in case of intracellular localization of the antigen (mycobacterium, brucella, histoplasma etc.) or when cells are antigen themselves. It may be microbes, fungi and their spores, which get into the organism from the outside. The cells of own tissues also may acquire the auto allergen properties. This mechanism may take place as a response to formation of complex allergens, in case of including haptens into proteins, for example, in case of contact dermatitis, which appears during the contact of the skin with different medicinal, industrious and other allergens.

81 Mechanisms of delayed type allergy

82 Pathophysiological stage Lymphokines (lymphotoxin, interferon) shows cytotoxic action and decrease activity of cell. Damaging action in allergic reaction of delayed type may develop in several ways: a) direct cytotoxic action of sensitized T-lymphocytes on target-cells, which acquired autoallergen properties; b) cytotoxic activity of T-lymphocytes, mediated by lymphotoxin; c) releasing of lysosome enzyme, which damage tissue structures during phagocytosis.

83 Inflammation is associated to immune reaction due to action of mediators is component of allergic reaction of delayed-type. Nevertheless inflammation is factor of damage of organs function.

84 Allergic inflammation

85 Skin reaction onto allergen

86 Prevention of allergy. Hyposensitization. Prophylaxis of an allergic disease depends on its character and group of the allergens. It directs to preventing of penetration of given allergen into the organism and influence of different irritating factors on the one. If sensitization has occurred and allergic diseases has started the next measures are appropriated.

87 1. Suppression of antibodies and sensitized lymphocytes production by means of immune depressants, ionizing radiation, cytostatics, specific lymphocyte vaccines and monoclonal antibodies. 2. Specific desensitization by Bezredka. Desensitization is provided by little doses of the antigen, which do not cause severe reactions. The doses are introduced repeatedly after certain intervals of time, during which produced mediators get inactivated in the organism. The main dose of the antigen is introduced after antibodies binding. This method is effective in introduction of foreign medical vaccines. 3. Inactivation of biological active substances. For this purpose antihistamine preparations, inhibitors of proteolytic enzymes etc.