Hypersensitivity reactions

PATHOGENESIS OF TYPE I, II, III & IV HYPERSENSITIVITY REACTIONS

1. Hypersensitivity REACTIONS T. SOUJANYA 16DC1T0021 PHARM. D

2. Content: Definition & types Type I: Anaphylactic (Atopic) reaction Type II: Cytotoxic (Cytolytic) reaction Type III: Immune complex mediated (Arthus) reaction Type IV: Delayed hypersensitivity (Cell-Mediated) reaction

3. Definition & types: Hypersensitivity is defined as an exaggerated or inappropriate state of normal immune response with onset of adverse effects on the body. The lesions of hypersensitivity are a form of antigen-antibody reaction. These lesions are termed as hypersensitivity reactions or immunologic tissue injury, of which 4 types are described: Type I: Anaphylactic (Atopic) reaction Type II: Cytotoxic (Cytolytic) reaction Type III: Immune complex mediated (Arthus) reaction Type IV: Delayed hypersensitivity (Cell-Mediated) reaction

4. Contd... Depending upon the rapidity, duration and type of the immune response, these 4 types of hypersensitivity reactions are grouped into: i) Immediate type ii) Delayed type Properties Immediate Delayed Type I, II, III IV Time to manifest Minutes to hours Days Mediators Antibodies T cells Route of sensitization Any route Intradermal Passive transfer with serum Possible Not possible Desensitization Easy but short lived Difficult but long lasting

5. Contd... i) IMMEDIATE TYPE: Immediate type in which on administration of antigen, the reaction occurs immediately (within seconds to minutes). Immune response in this type is mediated largely by humoral antibodies (B cell mediated). Immediate type of hypersensitivity reactions include type I, II and III. ii) DELAYED TYPE: Delayed type in which the reaction is slower in onset and develops within 24-48 hrs and the effect is prolonged. It is mediated by cellular response (T cell mediated) and it includes type IV reaction.

6. Type I: Anaphylactic (Atopic) reaction: Type I hypersensitivity is defined as a state of rapidly, developing or anaphylactic type of immune response to an antigen (i.e. allergen) to which the individual is previously sensitized (anaphylaxis is the opposite to prophylaxis). The reaction appears within minutes of exposure to antigen.

7. Etiology: Type I reaction is mediated by humoral antibodies of IgE type or reagin antibodies in response to antigen. Although definite cause for this form of immediate reaction to allergen is not known, following are the possible hypotheses: 1. Genetic basis: There is evidence that ability to respond to antigen and produce IgE are both linked to genetic basis. e.g. there is a 50% chance that a child born to both parents allergic to an antigen, may have similar allergy.

8. Contd... 2. Environmental pollutants: Another proposed hypothesis is that environmental pollutants increase mucosal permeability and thus may allow increased entry of allergen into the body, which in turn leads to raised IgE level. 3. Concomitant factors: An alternate hypothesis is that allergic response in type I reaction may be linked to simultaneous occurrence of certain viral infections of upper respiratory tract in a susceptible individual.

9. Pathogenesis: Type I reaction includes participation by B lymphocytes and plasma cells, mast cells and basophils, neutrophils and eosinophils. During the first contact of the host with the antigen, sensitization takes place. In response to initial contact with antigen, circulating B lymphocytes get activated and differentiate to form IgE-secreting plasma cells. IgE antibodies so formed bind to the Fc receptors present on the surface of mast cells and basophils, which are the main effector cells of type I reaction. Thus, these cells are now fully sensitized for the next event.

10. Contd... During the second contact with the same antigen, IgE antibodies on the surface of mast cells-basophils are so firmly bound to Fc receptors that it sets in cell damage-membrane lysis, influx of sodium & water and degranulation of mast cells-basophils. The released granules contain important chemicals and enzymes with proinflammatory properties-histamine, serotonin, vasoactive intestinal peptide (VIP), chemotactic factors of anaphylaxis for neutrophils and eosinophils, leukotrienes B 4 and D 4 , prostaglandins (thromboxane A 2 , prostaglandin D 2 and E 2 ) and platelet activating factor.

11. Contd... The effects of these agents are: Increased vascular permeability Smooth muscle contraction Early vasoconstriction followed by vasodilation Shock Increased gastric secretion Increased nasal and lacrimal secretions Increased migration of eosinophils and neutrophils at the site of local injury as well as their rise in blood (eosinophilia and neutrophilia).

12. Schematic representation of pathogenesis of type-I hypersensitivity reactions

13. Examples of type I reaction: 1. Systemic anaphylaxis: Administration of antisera e.g. Anti-tetanus serum (ATS). Administration of drugs e.g. Penicillin. Sting by wasp or bee. The clinical features of systemic anaphylaxis include itching, erythema, contraction of respiratory bronchioles, diarrhoea, pulmonary oedema, pulmonary haemorrhage, shock and death.

14. Contd... 2. Local anaphylaxis: Hay fever (seasonal allergic rhinitis) due to pollen sensitization of conjunctiva and nasal passages. Bronchial asthma due to allergy to inhaled allergens like house dust. Food allergy to ingested allergens like fish, cow’s milk, eggs etc. Cutaneous anaphylaxis due to contact of antigen with skin characterised by urticaria, wheal and flare. Angioedema, an autosomal dominant inherited disorder characterised by laryngeal oedema, oedema of eyelids, lips, tongue and trunk.

15. Type II: Cytotoxic (cytolytic) reaction: Type II cytotoxic reaction is defined as reactions by humoral antibodies that attack cell surface antigens on the specific cells and tissues and cause lysis of target cells. Type II reaction too appears generally within 15-30 minutes after exposure to antigen but in myasthenia gravis and thyroiditis it may appear after longer duration.

16. Etiology and pathogenesis: In general, type II reactions have participation by complement system, tissue macrophages, platelets, natural killer cells, neutrophils and eosinophils while main antibodies are IgG and IgM. Type II hypersensitivity is tissue-specific and reaction occurs after antibodies bind to tissue specific antigens, most often on blood cells. The mechanism involved is as under: The antigen on the surface of target cell (foreign cell) attracts and binds Fab portion of the antibody (IgG or IgM) forming antigen-antibody complex. The unattached Fc fragment of antibodies (IgG or IgM) forms a link between the antigen and complement.

17. Contd... The antigen-antibody binding with Fc forming a link causes activation of classical pathway of serum complement which generates activated complement component, C 3b , by splitting C 4 and C 2 by C 1 . Activated C 3b bound to the target cell acts as an opsonin and attracts phagocytes to the site of cell injury and initiates phagocytosis. Antigen-antibody complex also activates complement system and exposes membrane attack complex (MAC) that attacks and destroys the target cell.

18. Schematic representation of pathogenesis of type-II hypersensitivity reactions

19. Examples of type II reaction: 1. Cytotoxic antibodies to blood cells: Most common examples of type II reaction are on blood cells. Autoimmune haemolytic anaemia Transfusion reactions Haemolytic disease of the new-born (erythroblastic fetalis) Idiopathic thrombocytopenic purpura (ITP) Leukopenia with agranulocytosis Drug-induced cytotoxic antibodies

20. Contd... 2. Cytotoxic antibodies to tissue components: Cellular injury may be brought about by autoantibodies reacting with some components of tissue cells in certain diseases. Graves’ disease (primary hyperthyroidism) Myasthenia gravis Male sterility Type I diabetes mellitus Hyperacute rejection reaction

21. Type III: IMMUNE COMPLEX MEDIATED (ARTHUS) REACTION: These reactions result from deposition of antigen-antibody complexes on tissues, which is followed by activation of the complement system and inflammatory reaction, resulting in cell injury. The onset of type III reactions takes place about 6 hours after exposure to the antigen.

22. Etiology: Type III reaction is not tissue specific and occurs when antigen-antibody complexes fail to get removed by the body’s immune system. There can be 3 types of possible etiologic factors precipitating type III reaction: Persistence of low-grade microbial infection. Extrinsic environmental antigen. Autoimmune process.

23. Contd… 1. Persistence of low-grade microbial infection: A low grade infection with bacteria or viruses stimulates a weak antibody response. Persistence of infection (antigen) and corresponding weak antibody response leads to chronic antigen-antibody complex formation. Since these complexes fail to get eliminated from body fluids, they are instead deposited in tissues. e.g. in blood vessel wall, glomeruli, joint tissues etc.

24. Contd… 2. Extrinsic environmental antigens: Exogenous antigens may be inhaled into the lungs. e.g. antigens derived from moulds, plants or animals. The inhaled antigen combines with antibody in the alveolar fluid and forms antigen-antibody complex which is deposited in the alveolar walls.

25. Contd… 3. Autoimmune process: Another sequence in type III reaction can be formation of autoantibodies against own tissue (self antigen) forming autoantibody-self antigen complex. Such self antigens can be circulating ( e.g. IgA) or tissue derived ( e.g. DNA). Immune complexes containing both components from body’s own system can thus be deposited in tissues.

26. Pathogenesis: Type II and type III reactions have antigen-antibody complex formation but the two can be distinguished – antigen in type II is tissue specific while in type III is not so; moreover the mechanism of cell injury in type II is direct but in type III it is by deposition of antigen-antibody complex on tissues and subsequent sequence of cell injury takes place. Type III reaction has participation by IgG and IgM antibodies, neutrophils, mast cells and complement. The sequence of underlying mechanism is as under:

27. Contd… Immune complexes are formed by interaction of soluble antibody and soluble or insoluble antigen. Immune complexes which fail to get removed from body fluid get deposited into tissues. F C component of antibody links with complement and activates classical pathway of complement resulting in formation of C 3a , C 5a and membrane attack complex. C 3a stimulates release of histamine

28. Contd… C 3a stimulates release of histamine from mast cells and its resultant effects of increased vascular permeability and oedema. C 5a releases proinflammatory mediators and chemotactic agents for neutrophils. Accumulated neutrophils and macrophages in the tissue release in tissue destruction.

29. Schematic representation of pathogenesis of type-III hypersensitivity reactions

30. Examples of type iii reaction: Immune complex glomerulonephritis Goodpasture syndrome Systemic lupus erythematosus (SLE) Rheumatoid arthritis Farmer’s lung Polyarteritis nodosa and Wegener’s granulomatosis Henoch- Schoenlein purpura Drug induced vasculitis

31. Type iv: delayed hypersensitivity (cell-mediated) reaction: Type IV or delayed hypersensitivity reaction is tissue injury by cell mediated immune response without formation of antibodies (contrary to type I, II and III) but is instead a slow and prolonged response of specifically-sensitized T lymphocytes. The reaction occurs about 24 hours after exposure to antigen and the effect is prolonged which may last up to 14 days.

32. Etiology & pathogenesis: Type IV reaction involves role of mast cells and basophils, macrophages and CD8+ T cells. Briefly, the mechanism of type IV reaction is as under: The antigen is recognized by CD8+ T cells (cytotoxic T cells) and is processed by antigen presenting cells (APCs). Antigen-presenting cells migrate to the lymph node where antigen is presented to helper T cells (CD4+ T cells).

33. Contd… Hepler T cells release cytokines that stimulate T cell proliferation and active macrophages. Activated T cells and macrophages release proinflammatory mediators and cause cell destruction.

34. Schematic representation of pathogenesis of type-IV hypersensitivity reactions

35. Examples of type iv reaction: Type IV reaction can explain tissue injury in following common examples: Mycobacterial infection (e.g. tuberculosis, leprosy) Virally infected cells Malignant cells in the body Organ transplantation (e.g. graft versus host reaction, transplant rejection)

36. Comparison of hypersensitivity reactions: TYPE I TYPE II TYPE III TYPE IV Antigen Exogenous Cell surface Soluble Tissue & organ Antibody IgE IgG, IgM IgG, IgM None Reaction time 15-30 minutes Minutes to hours 3-8 hours 48-72 hours Transfer Antibody Antibody Antibody T cells Conditions Hay fever, allergy & asthma Erythroblastic fetalis and Goodpasture’s syndrome SLE, serum sickness Tuberculin test, poison ivy etc.

37. references/bibliography: Text book of pathology by Harsh Mohan Hypersensitivity reactions- brainkart.com