1. TYPE III & IV HYPERSENSITIVITY REACTION 1 Hypersensitivity reaction

2. Outline  Introduction.  Type III hypersensitivity reaction. - General mechanisem of action 1-Systemic Immune Complex Disease 2-Local Immune Complex Disease - Summary  TypeVI hypersensitivity reaction. - Variants of type IV hypersensitivity reactions - Mechanisem of action 2 Hypersensitivity reaction

3. Type III hypersensitivity reaction Sensitization phase IgM and IgG bind to soluble Ag which lead to immune comlex formation Soluble Ag-Ab complex that are large in size are cleared from circulation by phagocyte cell (liver and spleen) 3 Hypersensitivity reaction

4. However Circulation Ag-Ab immune complexe formed in excess (chronic infection) and are Small in size escape clearance 4 Hypersensitivity reaction Type III hypersensitivity reaction

5. Title Larger aggregates fix complement and are readily cleared from the circulation by the mononuclear phagocytic system. The small complexes that form at antigen excess, however, tend to deposit in blood vessel walls. There they can ligate Fc receptors on leukocytes, leading to leukocyte activation and tissue injury. 5 Hypersensitivity reaction

6. Effectors phase They are then deposited in capillary walls either:  Locally at site Ag entry  Systematically in blood vessels and various tissue. Ag-Ab complex stimulate complement activation causing tissue damage (Type III) 6 Hypersensitivity reaction Type III hypersensitivity reaction

7. Factors that determine whether immune complex formation will lead to tissue deposition and disease: *Size of immune complexes and functional status of the mononuclear phagocyte system 1. large complexes in antibody excess are rapidly removed from circulation by mononuclear phagocyte system (harmless) 2. Pathogenic complexes are small or intermediate (formed in antigen excess), which bind less avidly to phagocytic cells  circulate longer 7 Hypersensitivity reaction Type III hypersensitivity reaction

8. 8 Hypersensitivity reaction Type III hypersensitivity reaction

9. Immune complex-mediated diseases can be  generalized  immune complexes are formed in circulation and deposited in many organs  localized  deposited to particular organs, such as kidney (glomerulonephritis), joints (arthritis), or small blood vessels of skin 9 Hypersensitivity reaction Type III hypersensitivity reaction

10. Systemic Immune Complex Disease 10 Hypersensitivity reaction Type III hypersensitivity reaction

11. Pathogenesis of systemic immune complex disease divided into three phases: 1.) formation of antigen-antibody complexes in circulation - initiated by introduction of an antigen, a protein, and interaction with immunocompetent cells  formation of antibodies which are secreted into blood  they react with antigen still present in the circulation to form antigen-antibody complexes 2.) deposition of the immune complexes in various tissues 3.) an inflammatory reaction at the sites of immune complex deposition 11 Hypersensitivity reaction Type III hypersensitivity reaction Systemic Immune Complex Disease

12. Two types of antigens cause immune complex – mediated injury 1) antigen may be exogenous (foreign protein, bacterium, or virus) 2) individual can produce antibody against self- components (endogenous antigens); antigen compounds of one’s own cells/tissues such as nuclear antigens, immunoglobulin or tumour antigens. 12 Hypersensitivity reaction Type III hypersensitivity reaction

13. Systemic Immune Complex Disease serum sickness - patients with diphtheria infection treated with serum from horses immunized with diphtheria toxin - patients develop arthritis, skin rash, fever - patients made antibodies to horse serum proteins  antibodies formed complexes with injected proteins, and disease was due to antibodies or immune complexes 13 Hypersensitivity reaction Type III hypersensitivity reaction

14. hypersensitivity Reactions Type IV (T-Cell Mediated)

15. Type IV hypersensitivity Reactions (T-Cell Mediated)  It is also known as cell mediated or delayed type hypersensitivity.  Type IV hypersensitivity reactions are mediated by immune cells (T cell), not antibodies that develops in response to antigen challenge in a previously sensitized individual.  In contrast with immediate hypersensitivity, the DTH reaction is delayed for 48-72 hours, which is the time it takes for effector T cells to be recruited to the site of antigen challenge and to be activated to secrete cytokines.  The delayed hypersensitivity reactions lesions mainly contain monocytes and T cells

16. Type IV hypersensitivity Reactions Two types of T cell reactions are capable of causing tissue injury and disease: (1) Cytokine-mediated inflammation: -In which the cytokines are produced mainly by CD4+ T cells. -CD4+ T cells of the TH1 and TH17 subsets secrete cytokines, which recruit and activate other cells, especially macrophages, and these are the major effector cells of injury. (2) Direct cell cytotoxicity: -Mediated by CD8+ T cells -In which cytotoxic CD8+ T cells are responsible for tissue damage.

17. Type IV hypersensitivity Reactions 1)Cytokine-mediated inflammation : 1-Naive CD4+ T lymphocytes recognize peptide antigens of self or microbial proteins in association with class II MHC molecules on the surface of DCs or macrophages that have processed the antigens. 2-Then CD4+ T cells are activated and differentiate into TH1 and TH17 effector cells. (If the DCs produce IL-12, the naive T cells differentiate into effector cells of the TH1 type, If the APCs produce IL-1, IL-6, or IL-23 instead of IL-12, the CD4+ cells develop into TH17 effectors)

18. Type IV hypersensitivity Reactions 3-Subsequent exposure to the antigen the previously generated effector cells are recruited to the site of antigen exposure and results in the secretion of cytokines. 4-The TH1 cells secrete IFN-γ, which is the most potent macrophage- activating cytokine known. 5-Macrophages produce substances that cause tissue damage and promote fibrosis, and TH17 secrete IL-17 and other cytokines recruit leukocytes especially macrophages, thus promoting inflammation.

19. Cytokine-mediated inflammation

20. Type IV hypersensitivity Reactions 2)T cell–mediated cytotoxicity : 1- CD8+ CTLs specific for an antigen recognize cells expressing the target antigen and kill these cells. 2- Class I MHC molecules bind to intracellular peptide antigens and present the peptides to CD8+ T lymphocytes, stimulating the differentiation of these T cells into effector cells called CTLs. 3-The principal mechanism of killing by CTLs is dependent on the perforin–granzyme system. 4-These enzymes induce apoptotic death of the target cells. 5-CD8+ T cells may also secrete IFN-γ and contribute to cytokine-mediated inflammation, but less so than CD4+ cells

21. T cell–mediated cytotoxicity

23. Sensitization phase

24. Type IV hypersensitivity Reactions Cont. phases : 2- Effector phase: This occurs following re-exposure to antigen and activation of the memory Th1 cells IFN γ, from activated Th1 cells, promotes differentiation of monocytes to macrophages, and activates mature macrophages to kill intracellular organisms. In addition, activated macrophages secrete products including IL-1 and TNF, that stimulate processes producing inflammatory mediators that cause bystander tissue injury.

25. Effector phase: IFN γ, secreted by activated Th1 cells, is a potent activator of tissue macrophages Activated macrophages secrete cytokines (e.g., IL-1 and TNF) and chemokines that activate adhesion molecules on the endothelium and circulating leukocytes Neutrophils phagocytose antigen and secrete inflammatory mediators that cause local tissue damage

26. Type IV hypersensitivity Reactions  Examples : 1.Contact hypersensitivity 2.Granulomatous hypersensitivity 3.The tuberculin test

27. Contact Hypersensitivity is usually caused by haptens that combine with proteins (particularly the amino acid lysine) in the skin of some people to produce an immune response. Reactions to poison ivy, cosmetics, and the metals in jewelry (especially nickel ) are familiar examples of these allergies.

28. Contact Hypersensitivity

29. Granulomatous hypersensitivity It usually results from the persistence within macrophages of intracellular microorganisms, which are able to resist macrophage killing or particles that the cell is unable to destroy. This leads to chronic stimulation of T cells and the release of cytokines. The process results in the formation of epithelioid cell granulomas with a central collection of epithelioid cells,giant cells and macrophages surrounded by lymphocytes. Granulomas occur with chronic infections such as tuberculosis or with foreign particulate agents such as talc and silica.

30. Granulomatous hypersensitivity

31. The tuberculin test The test is used to determine whether an individual has been infected with the causative agent of tuberculosis, Mycobacterium tuberculosis. (A previously infected individual would harbor reactive T cells in the blood.)

32. The Mechanism of Tuberculin Test

33. 33 Hypersensitivity reaction