Over-reactions of the immune system

1. Over-reactions of the immune system Dr Kathy Triantafilou University of Sussex School of Life Sciences

2. Reactions of the immune system • The immune system possesses recognition events that distinguish molecular components of infectious agents from those of the human body • Besides infectious agents, humans come into contact with numerous other molecules that are equally foreign but do not threaten health • These molecules are derived from plants and animals that are present in the environment where we live

3. Over-reactions • In some circumstances, molecules stimulate the adaptive immune response and the development of immunological memory • on subsequent exposures to the antigen the immune memory produces inflammation and tissue damage • The person feels ill, as though fighting an infection, when no infection exists • These over-reactions of the immune system to harmless environmental antigens are called hypersensitivity or allergic reactions

4. Gell and Coombs classification • P.G.H. Gell and R.R.A. Coombs proposed a classification system for hypersensitivity reactions: • Type I • Type II • Type III • Type IV

6. Type I hypersensitivity • Antigens (allergens) induce a humoral immune response • commonly cause by inhaled antigens (i.e. plant pollen) • This immune response results in the generation of antibody-secreting plasma cells and memory cells • The plasma cells secrete IgE • this class of antibody binds with high affinity to Fc receptors (mast cells, basophils, etc) • these IgE-coated cells are said to be sensitised

8. Degranulation • Exposure to the same allergen later cross-links the membrane bound IgE on sensitised mast cells and basophils • This causes degranulation of these cells • The pharmacologically active mediators released from the granules act on surrounding tissue causing: • vasolidation and smooth muscle contraction • either systemic or localised (depending on the extent of mediator release)

9. Components of Type I • Allergens • IgE antibodies • mast cells and basophils • IgE binding Fc receptors • IgE-mediated degranulation • receptor crosslinking • Mediators • histamine • Leukotrienes, postaglandins and cytokines

12. Allergens • IgE responses are mounted against parasites • Some persons, however have an abnormally called atopy: • hereditary pre-disposition to the development of hypersensitivity reactions • IgE regulatory defects suffered by atopic individuals allow non-parasitic antigens to stimulate inappropriate IgE production • Allergen refers specifically to non-parasitic antigens capable of stimulating type I hypersensitivity reactions

13. Allergens • Common allergens include rye grass pollen, ragweed pollen, codfish, birch pollen, timothy grass pollen, and bee venom • What makes these agents allergens? • Allergens possess diverse properties • most are small proteins (15,000-40,000) • no common chemical properties • allergenicity is a consequence of a series of interactions involving: • dose, sensitising route, genetic condition of the individual

14. IgE • The existence of a human serum factor that reacted with allergens was first demonstrated by K. Prausnitz and H. Kustner in 1921 • The response that occurs when an allergen is injected into an individual is called a P-K reaction • In the mid 1960s K. and T. Ishizaka isolated the new isotype of antibody, IgE

15. IgE • Serum levels in normal individuals are in the range of 0.1-0.4 mg/ml • IgE was found to be composed of two heavy chains and two light chains with a combined molecular weight of 190,000 • It has an additional constant region than IgG • This additional domain changes the conformation of the molecule and enables it to bind to receptors on mast cells and basophils • Half-life in the serum of 2-3 days, once bound to receptors is stable for a number of weeks

16. Mast cells and basophils • Blood basophils and tissue mast cells can bind IgE • Mast cells are found throughout the connective tissue, near blood and lymphatic vessels • skin and mucous surfaces of the respiratory and gastrointestinal track (10,000 mast cells per mm of skin) • mast cell populations in different sites differ in the types and amounts of allergic mediators they contain

17. IgE-binding Fc receptors • The activity of IgE depends on its ability to bind to a receptor specific for the Fc region of the heavy chain • Two classes of Fc receptors: • High affinity receptor (FceRI) • mast cells and basophils (40,000-90,000 receptors on a cell) • binds with 1000 fold higher affinity • Low affinity receptor (FceRII)

18. High affinity receptor (FceRI) • The high affinity receptor contains four polypeptide chains: • an a, a b chain and two identical g chains • Displays immunoglobulin-fold structure, and thus belongs to the immunoglobulin superfamily • The a chain binds the IgE molecules • The b chain spans the membrane four times and is thought to link the a to the g homodimer • The g chains contain ITAMS similar to CD3

20. Low affinity receptor (FceRII) • The low affinity receptor (CD23) is specific for the CH3/CH3 domain of IgE • It has a lower affinity for IgE • Allergen crosslinkage of IgE bound to FceRII has been shown to activate B cells, alveolar macrophages and eosinophils • When this receptor is blocked, IgE secretion by B cells is diminished • A soluble form of the receptor exists that has been shown to enhance IgE production by B cells • Sensitised individuals have higher levels of CD23

22. Receptor crosslinkage • IgE-mediated degranulation begins when an allergen crosslinks IgE that is bound to the Fc receptor on a mast cell or basophil • the binding of IgE to FceRI has no effect on the target cell • It is only after the allergen crosslinks the fixed IgE-receptor complex that degranulation begins • monovalent antigens can not crosslink and thus can not trigger degranulation

24. Intracellular events leading to degranulation • The cytoplasmic domains of the b and g chains of the FceRI are associated with protein tyrosine kinases (PTKs) • Crosslinking of the receptor results in the phosphorylation of tyrosines within the PTKs • Within 15 sec after crosslinking, methylation of various membrane phospholipids is observed, resulting in the formation of Ca2+ channels • An increase in Ca2+ channels reaches a peak within 2 min

26. Ca2+ channels • The Ca2+ increase eventually leads to the formation of arachidonic acid which is converted into two classes of mediators: • postaglandins • leukotrienes • The increase of Ca2+ also promotes the assembly of microtubules and the contraction of microfilaments (necessary for the movement of granules to the cell surface)

27. Mediators • The manifestation of the type I hypersensitivity reactions are related to the biological effects of the mediators released from the granules • The mediators can be classified as: • primary mediators • produced before degranulation (histamine, proteases, eosinophil chemotactic factor, neutrophil chemotactic factor and heparin) • secondary mediators • after degranulation (platelet activating factor, leukotrienes, postaglandins, cytokines

28. Histamine • Is formed by decarboxylation of the amino acid histidine • Histidine is a major component of mast cell ganules, accounting for 10% of the granule weight • Once released, it binds to specific receptors on various target cells • Three types of histamine receptors have been identified: H1, H2, and H3 • binding to the receptors induces contraction of intestinal and bronchial smooth muscles, increased permeability of venules, and increased mucus secretion

29. Leukotrienes and postaglandins • Secondary mediators which are not formed until the mast cell goes through degranulation, and enzymatic breakdown of membrane phospholipids • Longer time for the biological effects to become apparent • Their effects are more pronounced and longer lived than histamine

30. Leukotrienes bronchoconstriction increased vascular permeability mucus production 1000x more potent as bronchoconstrictors than histamine prolonged bronchospasm and buildup of mucus (asthmatics) Postaglandins bronchoconstriction Leukotrienes and postaglandins

31. Cytokines • Cytokines released from mast cells and eosinophils contribute to the clinical manifestation of type I hypersensitivity • Human mast cells secrete IL-4, IL-5, IL-6 and TNF-a • These cytokines alter the local environment leading to the recruitment of inflammatory cells • IL-4 increases IgE production by B-cells • IL-5 is important in the recruitment of eosinophils • TNF-a contribute towards the shock in anaphylaxis

33. Consequences of type I • Systemic anaphylaxis • Localised anaphylaxis • Allergic Rhinitis • Asthma • Food allergies • Atopic dermatitis

34. Systemic anaphylaxis • A shock-like (often fatal), whose onset occurs within minutes of a type I hypersensitivity reaction • This was the reaction observed by Portier and Richet • Caused by venom from bee, wasp, hornet and ant stings; drugs such as penicillin, insulin and antitoxins, seafood and nuts • Epinephrine is the choice of drug for anaphylaxis (counteracts the effects of mediators by relaxing the smooth muscle, and reducing vascular permeability

35. Localised anaphylaxis • The reaction is limited to a specific target tissue or organ • Often involving epithelial surfaces at the site of allergen entry • The tendency to manifest localised anaphylactic reactions is inherited and is called atopy • atopic allergies afflict about 20% of the population

36. Asthma • Common localised anaphylaxis is asthma • There are two types of asthma: • allergic asthma • airborne or blood-borne allergens, such as pollen, dust, fumes, insect products or viral antigens trigger an asthmatic attack • intrinsic asthma • induced by exercise, cold, independently of allergen stimulation

37. Asthma • Like hay fever, asthma is triggered by degranulation of mast cells with release of mediators • Instead of occurring in the nasal mucosa, the reaction develops in the lower respiratory tract • The resulting contraction of the bronchial smooth muscles leads to bronchoconstriction • Airway edema, mucus secretion, and inflammation contribute to the bronchial constriction and to airway obstruction

38. Asthmatic response • The asthmatic response can be divided into: • early response • occurs within minutes of allergen exposure and primarily involves histamine, leukotrienes and postaglandin • bronchoconstriction, vasolidation, and some build-up of mucus • late response • occurs hours later • involves IL-4, IL-5, IL-16, TNF-a, eosinophil chemotactic factor (ECF) and platelet activating factor (PAF)

39. The overall effects is to increase endothelial cell adhesion as well as recruit inflammatory cells into the bronchial tissue • the inflammatory cells are capable of causing significant tissue damage • this lead to the occlusion of the bronchial lumen with mucus, proteins and cellular debris, thickening the basement of the epithelium and hypertrophy of the bronchial smooth muscles

40. Food allergies • Various foods can cause localised anaphylaxis in allergic individuals • allergen crosslinking of IgE on mast cells along the upper and lower gastrointestinal track can induce localised smooth muscle contractions and vasolidation • this leads to symptoms such as vomiting and diarrhea

41. Atopic dermatitis • Atopic dermatitis (allergic eczema) is an inflammatory disease of skin that is frequently associated with a family history of atopy • The disease is observed more frequently in young children • Serum IgE levels are often elevated • The allergic individual develops skin eruptions that are erythematous • The skin lesions have Th2 cells and an increased number of eosinophils

42. Late-Phase reaction • As the reaction begins to subside, mediators released during the course of the reaction often induce a localised inflammatory response, called the late-phase reaction • It develops 4-6 hours after the type I reaction and persists for 1-2 days • Characterised by infiltration of neutrophils, eosinophils, macrophages, lymphocytes and basophils • Mediated by cytokines such as TNF-a, IL-1, IL-3, IL-5

44. Detection of type I • Skin testing • Small amounts of potential antigens are introduced at specific skin sites either by intradermal injection or by superficial scratching • a number of tests can be applied to the site on the forearm or back • If the person is allergic, local mast cells degranulate and the release of histamine produces a wheal and flare within 30 min

45. Advantages inexpensive large number of allergens tested Disadvantages sometimes sensitises the allergic individual to new allergens rarely induces systemic anaphylactic shock a few manifest a late-phase reaction Skin test

47. Detection of type I • Another method is to determine serum levels of IgE • Using the radioimmunosorbent test (RIST) • Patient’s serum is reacting with agarose beads or paper disks coated with rabbit anti-IgE

50. Therapy of type I • Identify the offending allergen and avoid contact if possible • removal of house pets, dust-control measures, or avoidance of offending food • elimination of inhalant allergens (such as pollen) is impossible • immunotherapy with repeated injections of increasing doses of allergens (hyposensitization) has been known to reduce the severity of type I