1. Hypersensitivity Cell mediated immunity Lecture by professor. M.Boychenko

2. HYPERSENSITIVY Hypersensitivity describes an immune response which occurs in an exaggerated form The hypersensitivity reactions were classified by Gell and Coombs,according to the speed of the reaction and the immune mechanisms involved

3. HYPERSENSITIVY Such reaction occurs after the second contact with a specific antigen (allergen) The first contact is necessary because it induces sensitization to that allergen

4. Type I (immediate) (anaphylactic)hypersensitivity Allergy, originally meaning altered reactivity on a second contact with an antigen, now means type I hypersensitivity. Theses reactions are mediated by IgE, and indicate a Th2-type response It develops within minutes of exposure to antigen, and is dependent on the activation of must cells and the release of mediators of acute inflammation

5. Mast cells bind IgE via their Fc receptors,and when antigen crosslinks the IgE, the mast cells degranulate,releasing vasoactive amines, which produce acute inflammation.Prostoglandins and leukotrienes, produced by arachidonic acid metabolism, contribute to a delayed component of the reaction which develops hours after the original exposure to antigen

7. The clinical manifestation of Type I Type I can appear in: Eczema, rhinitis,conjuctivitis,astma,atopy Major manifestation of anaphylaxis occur when large amounts of mediators are suddenly released as a result of massive dose of antigen abruptly combing with IgE on many must cells

8. Desensitization can prevent systemic anaphylaxis Desensitization involves the administration of very small amount of antigen at 15 minute intervals

9. Type II hypersensitivity Type II is caused by antibody to cell surface antigens. These antibodies can sensitize the cell for antibody-dependent cytotoxic attack by K cells or for complement- mediated lysis

11. Haemolytic disease of the newborn If Rhesus –negative mothers carry Rhesus-positive children,the mother becomes sensitized by fetal red cells entering her circulation at birth and antibodies to fetal red cells are formed.This antibodies cross the placenta and destroy fetal red cells

12. Haemolytic disease of the newborn Prohylaxis is the administration of anti-Rhesus antibody to Rhesus- negative mothers immediately after they have delivered a Rhesus- positive child, in order to destroy the Rh+ cells,preventing sensitizing the mother

13. Type II hypersensitivity manifestation Drugs(penicillin) can attach to surface proteins on red blood cells and initiate antibody formation. Such autoimmune antibodies (IgG) then interact with the cell surface causing haemolysis

14. Type III hypersensitivity (immune-complex-mediated) Type III results from the deposition of immune complexes in blood vessel walls and tissues. Complexes can activate platelets and basophils via Fc receptors, to release vasoactive amines which cause endothelial cell retraction and increased vascular permeability, leading to complex deposition.

15. Type III hypersensitivity Complexes also activate complement, releasing C3a and C5a, both of which activate basophils. Complexes also attract macrophages which release reactive oxygen causing local tissue damage. Complexes tend to deposit at sites of high pressure, filtration, particularly the kidney

17. Immune complex diseases Serum sickness is a type III reaction which occurs in individuals injected with foreign serum. Antibodies are made to the serum antigens and there is massive immune complex formation, producing arthritis and nephritis

18. Immune complex diseases Arthus reaction is skin reaction seen as an area of redness and swelling which is maximal 5-6 hours after itradermal injection of antigen. It is caused by IgG binding to the injected antigen and triggering inflammation by type III mechanism

19. Type IV (delayed) hypersensitivity Type IV arises more than 24 hours after encounter with the antigen and is mediated by antigen-sensitized CD4 T cells,which release cytokines, attracting macrophages to the site and activating them.

20. Type IV (delayed) hypersensitivity The macrophages produce tissue damage which may develop into chronic granulomatous reactions if the antigen persists. This type is seen in skin contact reactions and in the the response to some chronic pathogens Mtuberculosis

22. Granulomatous reaction It develops where there is a persistent stimulus which macrophages cannot eliminate.

23. Granulomatous reaction The lesion consists of a palisade of epithelioid cells and macrophages surrounding the infectious agent, which is in turn surrounded by a cuff of lymphocytes

24. Contact hypersensitivity It produces an eczematous skin reaction in sensitized humans, which is maximal 48 hours after contact with allergen. Allergens attach to normal body protein and modify them. Langerhans’ cells pick up these antigens and present them to T cells in local lymph nodes

25. Contact hypersensitivity Sensitized T cells migrate into skin site, producing the reaction with mononuclear cell infiltration and oedema

26. Cell mediated immunity (CMI) CMI is directed (targeted) against: 1.protozoa 2.fungi 3.virus infected cells 4.bacteria,that are intracelullar parasites: Mycobacterium,Brucella,Yersinia,Salmon ella,Francisella 5.tumor cells and transplantant tissue

27. The TH1 subset predominantly involved in CMI,releasing: 1.IL-2, INF- gamma 2.GM-CSF 3.TNF Macrophages,CD8,NK Promoter of cellular inflammation Directly toxic to alert cells

28. CMI is triggered when Antigen-presenting cells (APC) display an antigenic determinant in association with the class II proteins. APC may bee: 1.dendritic cells 2.macrophages 3.B-lymphocytes

29. CMI effectors cells After recognition of antigenic determinants Th1 cell lock them onto their surface.This stimulates the releasing of interleukins by the Th1 and transformation of T lymphocytes into effectors cells that provide the actual protection. There are: 1. Cytotoxic T-cells and 2. Lymphokine-producing cells

30. CD8 subset Direct cytotoxity kills: 1. Virus infected cells 2.tumor cells 3.foreign tissue CD8 attach to their target cells and destroy them by membrane disruption and lysis. They bind only when they both recognize antigen determinant and class I protein

31. DTH cells They do not damage their cellular targets directly. They mediate their effect by releasing lymphokines The effect of the most lymphokines is to enhance the activity of nonspecific protective mechanism, especially the phagocytes macrophage system

32. DTH cell lymphokines 1.Macrophage chemotactic factor 2.Macrophage activating factor 3.Migration inhibition factor 1.Attracts macrophages to region of high lymphocyte concentration 2.Enhances phagocytosis, including intracellular parasites 3.Reduces the mobility of macrophages,accumul ating them surround the activated T cells e

33. DTH cell lymphokines 4.Lymphotoxi n TNF 5.Immune interferon 4.Nonspecifically destroys potentially pathogenic cell 5.Aids the arrest of infection by increasing the cytotoxity of T cells e

35. Null cells Null cells are lymphocytes that are neither T nor B cells They do not require previous exposure to an antigen They participate in protection from : Viral infection, tumors in response to lymphokines by inserting a pore-forming protein into membrane of abnormal cells

36. Null cells Natural killer (NK) Anti tumor activity of NK is enhanced by lymphokines: IL-2,INF-gamma Killer (K) cells Possess receptor for Fc tail of antibody and react with antibody-coated cell causing it to lyse (antibody-dependent cell-mediated cytotoxity)