Cell mediated immunity

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Cell mediated immunity

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Cell mediated immunity

  1. 1. CELL MEDIATED IMMUNITY Dr.T.V.Rao MDDR.T.V.RAO MD 1
  2. 2. Duality of Immune System. Cell Mediated Immunity • Involves specialized set of lymphocytes called T cells that recognize foreign antigens on the surface of cells, organisms, or tissues: • Helper T cells • Cytotoxic T cells • T cells regulate proliferation and activity of other cells of the immune system: B cells, macrophages, neutrophils, etc. • Defense against: • Bacteria and viruses that are inside host cells and are inaccessible to antibodies. • Fungi, protozoa, and helminthes • Cancer cells • Transplanted tissue DR.T.V.RAO MD 2
  3. 3. Relationship Between Cell-Mediated and Humoral ImmunityAntibody ProductionT-Dependent Antigens:• Antibody production requires assistance from T helper cells.• A macrophage cells ingest antigen and presents it to T H cell.• TH cell stimulates B cells specific for antigen to become plasma cells.• Antigens are mainly proteins on viruses, bacteria, foreign red blood cells, and hapten-carrier molecules. T-Independent Antigens:• Antibody production does not require assistance from T cells.• Antigens are mainly polysaccharides or lipopolysaccharides with repeating subunits (bacterial capsules).• Weaker immune response than for T-dependent antigens.
  4. 4. CELL MEDIATED IMMUNE RESPONSES• Primary Function Of Cell Mediated Response • Eliminate Intracellular Pathogens • Eliminate Tumor Cells• Both Ag Specific And Non-specific cells Are Involved • Ag Specific: CD8+ Cells (T C) And TH (DTH) • Non-specific: M, Neutrophils, NK• Both Specific And Non-specific Require Cytokines• Humoral And Cell Mediated Do Collaborate • Ex. M Use Abs As Receptors To Recognize Target Cells DR.T.V.RAO MD 4
  5. 5. CELL MEDIATED IMMUNITY* CMI may play a role in some harmful conditions: - Hypersensitivity reactions type IV (contact dermatitis) - Graft rejection - Autoimmune diseases* Cell mediated cytotoxicity mediated by: - T-cytotoxic cells cells - Natural killer cells - Activated macrophages DR.T.V.RAO MD 5
  6. 6. CELL MEDIATED IMMUNITY WORKS BY COMPLEX MECHANISMS LEAST UNDERSTOOD ???DR.T.V.RAO MD 6
  7. 7. CMI HELPS IN• Delayed hypersensitivity• Immunity in infections caused by Obligate and facultative intracellular parasites• Eg – Tuberculosis, Leprosy Listeriosis, Brucellosis, Fungi – Histoplasmosis, Cocccidiomysosis,Blastomycosis, Parasites – TrypanosomiasisIn transplantation immunity, Immunologioly in Transplantation, malignancy,Pathogenesis of Autoimmune diseases DR.T.V.RAO MD 7
  8. 8. IMPORTANCE OF CELL MEDIATED IMMUNITY• DiGeorge Syndrome Proves The Importance • No Thymus, No T-cell Mediated Immunity • Extracellular Infections Are Effectively Addressed • Intracellular Infections Are NOT (viruses, intracellular bacteria)• Cell Mediated Immunity Can Be Divided Into 2 Major Categories • Effectors lyse target • 2 groups of cells: CTLs (specific) and NK, M (non-specific) • Effectors which are CD4+ and mediate DTH DR.T.V.RAO MD 8
  9. 9. INDUCTION OF CELL MEDIATED IMMUNITY• Depends on Nature of Antigenic stimulus• Best developed after following infection with intracellular parasites• Live vaccines highly stimulating• Killed vaccine not very effective• But effective if contains Freund type adjuvant.DR.T.V.RAO MD 9
  10. 10. FUNCTIONS OF T CELLS• Cytotoxic T cells recognize antigen on surface of virus infected cells, tumor cells, allograft cells with MHC I and sectored Lymhokines and destroy target cells DR.T.V.RAO MD 10
  11. 11. FUNCTIONS OF T CELLS• Only T cell dependent antigens lead to development of CMI• Certain chemicals which come in contact with skin induces Delayed hypersensitivity• T Cell contain the specific receptor ( TCR )• One epitope ( Antigen ) on contact with receptor undergoes blast transformation• Leads to Clonal proliferationDR.T.V.RAO MD 11
  12. 12. FUNCTIONS OF T CELLS• The stimulated cells undergoes blast transformation, Clonal proliferation• Leads to Effectors cells and Memory cells• T cell react on presentation with MHC• Helper T cells when presented on surface of macrophages or other cells complexes with MHC II molecule – leads to release of Biological Mediators Lymhokines – activate Macrophages and kills intracellular parasites DR.T.V.RAO MD 12
  13. 13. T Cells and Cell Mediated ImmunityCellular Components of Immunity:• T cells are key cellular component of immunity.• T cells have an antigen receptor that recognizes and reacts to a specific antigen (T cell receptor).• T cell receptor only recognize antigens combined with major histocompatibility (MHC) proteins on the surface of cells. • MHC Class I: Found on all cells. • MHC Class II: Found on phagocytes.• Clonal selection increases number of T cells. DR.T.V.RAO MD 13
  14. 14. BROAD VIEW ON CYTOKINES• Cytokines are a category of signalling proteins and glycoproteins that, like hormones and neurotransmitters, are used extensively in cellular communicationDR.T.V.RAO MD 14
  15. 15. T CELLS ONLY RECOGNIZE ANTIGEN ASSOCIATED WITH MHC MOLECULES ON CELL SURFACES
  16. 16. CENTRAL ROLE OF HELPER T CELLS
  17. 17. CYTOKINES• Cytokines have been classed as Lymhokines, interleukins, and chemokines, based on their presumed function, cell of secretion, or target of action. Because cytokines are characterised by considerable redundancy and pleiotropic, such distinctions, allowing for exceptions, are obsolete.DR.T.V.RAO MD 17
  18. 18. DEFINITIONS• Lymhokines Biologically active substance released by activated T Lymphocytes• Monokines – Substances secreted by Monocytes and Macrophages• Interleukins – Produces by lymphocytes which exert a regulatory effect on other cells• All above grouped under cytokines DR.T.V.RAO MD 18
  19. 19. DEFINITIONS• Autocrine, if the cytokine acts on the cell that secretes it.• Paracrine, if the target is restricted to the immediate vicinity of a cytokines secretion.• Endocrine, if the cytokine diffuses to distant regions of the body (carried by blood or plasma).• It seems to be a paradox that cytokines binding to antibodies have a stronger immune effect than the cytokine alone. This may lead to lower therapeutic doses.DR.T.V.RAO MD 19
  20. 20. WHAT ARE CYTOKINES• They are peptide mediators, intracellular messengers, which regulate immunological, inflammatory and reparative host cell responses• They are potent hormones Active even at Fetomolar concentrations produced by widely distributed cells ( Lymphocytes, Macrophages, Platelets, and Fibroblasts.DR.T.V.RAO MD 20
  21. 21. CYTOKINES WORK ON MULTIPLE LINEAGESDR.T.V.RAO MD 21
  22. 22. CYTOKINES HAVE• Paracrine effect – acts locally – near the producing cells• Having pleotrophic effects – Multiple effects on growth and differentiation of various cell types. DR.T.V.RAO MD 22
  23. 23. IMPORTANT CYTOKINES• Interleukin I 1979• Interleukin I divided into Alpha and Beta• IL1 is secreted by Macrophages, Monocytes other nucleated cells.• Stimulated by Antigens, Toxins, Injury, Inflammation,• Inhibited by• Cyclosporins,Corticosteiods,Prostaglandins DR.T.V.RAO MD 23
  24. 24. HOW CTLS KILL• Phases In CTL Killing • Conjugate formation • LFA-1 (CTL) binds ICAMs (Target) • LFA-1 changes to high avidity if Ag Is Recognized • Activated LFA-1 persists for 5-10 mins • Membrane attack • Requires Ca 2+ and energy • Granules release Perforins (65 kDa) and Granzymes (serine proteases) at the junctional space • Perforins polymerize forming cylindrical pores (5-20 nm), Ca 2+ is needed • Granzymes enter target cell • Granzyme B can enter thru mannose-6-phosphate receptor in a vesicle • DNA fragmentation • CTL dissociation • Target cell destruction • Apoptotic death within a few hours DR.T.V.RAO MD 24
  25. 25. FUNCTIONS OF INTERLEUKIN 1• IL1 stimulates T cells and Produces IL2 and other Lymhokines• Helps B cell proliferation• Synthesizes Antibodies• Helps Neutrophils in Chemo taxis• Promotes Phagocytosis• Promotes Metabolic Physiological and inflammatory responses by action on Bone marrowDR.T.V.RAO MD 25
  26. 26. IL1 INITIATES FEVER• IL1 is crucial in promoting fever and called as Pyrogens.• With the help of Tumor Necrosis factor causes hematological changes in Septicemias, Shock and bacterial meningitisDR.T.V.RAO MD 26
  27. 27. OTHER INTERLEUKINS• Interleukins 2 Modulates the immune response• Major activator of T and B Lymphocytes• Stimulates cytotoxic T cells and Natural Killer cells.• Interleukin 3 Stimulates multilineage cells of the Hematopoietic system.DR.T.V.RAO MD 27
  28. 28. OTHER INTERLEUKINS• Interleukin 4 Acts as a Growth factor for T Lymphocytes• Interleukin 5 Causes the proliferation of activated B Lymphocytes• Interleukin 6 Produced by Stimulated B and T Lymphocytes Induces the production of Immunoglobulin synthesis Stimulates the Hepatocytes, nerve cells,Hematopoetic cellsDR.T.V.RAO MD 28
  29. 29. INHIBITORY CYTOKINES• Some cytokines are predominantly inhibitory. For example, IL-10 and IL-13 inhibit inflammatory cytokine production by macrophages.DR.T.V.RAO MD 29
  30. 30. ANTIBODY DEPENDENT CELL MEDIATED CYTOTOXICITY (ADCC)• Cells Capable of Cytotoxicity Express Fc Receptors• Antibody Binds Target Cell, Cytotoxic Cells Bind Fc Portion Of Ab• Antibody Provides The Specificity• Examples Of Cells Capable Of ADCC • M, NK, Neutrophils, eosinophils• Killing Of Target Is Accomplished • Thru perforin, granzyme (NK, Eosinophils) • TNF (M, NK) • Lytic enzymes (M, Neutrophils, Eosinophils, NK) DR.T.V.RAO MD 30
  31. 31. DR.T.V.RAO MD 31
  32. 32. INTERFERONS• Primarily identified as Antiviral agents• Now classified as Cytokines• Interferons play an important role in the first line of defence against viral infections. They are part of the non-specific immune system and are induced at an early stage in viral infection – before the specific immune system has had time to respond..DR.T.V.RAO MD 32
  33. 33. DYNAMICS OF INTERFERONS• Interferons are made by cells in response to an appropriate stimulus, and are released into the surrounding medium; they then bind to receptors on target cells and induce transcription of approximately 20-30 genes in the target cells, and this results in an anti- viral state in the target cells.DR.T.V.RAO MD 33
  34. 34. CLASSIFICATION OF INTERFERONS• There are three classes of Interferons: Alpha, Beta and Gamma. Interferon Alpha and Beta are produced by many cell typesDR.T.V.RAO MD 34
  35. 35. FUNCTIONS OF INTERFERONS• Interferons are within the cytokine family of proteins. Interferons are especially important because they enhance the immune system’s ability to recognize foreign invaders, enabling the system as a whole to function more effectivelyDR.T.V.RAO MD 35
  36. 36. TYPES OF INTERFERONS• Interferon-alpha (leukocyte interferon) is produced by virus-infected leukocytes, etc• Interferon-beta (fibroblast interferon) is produced by virus-infected fibroblasts, or virus-infected epithelial cells.• Interferon-gamma (immune interferon) is produced by certain activated T-cells and NK cells.• Interferon-gamma is made in response to antigen (including viral antigens) or mitogen stimulation of lymphocytes. DR.T.V.RAO MD 36
  37. 37. INTERFERON GAMA• Interferon-Gamma is involved in the regulation of immune response throughout the body. Interferon-Gamma is the signalling protein that gets the immune system as a whole ready for attack and fine tunes it to quickly and effectively get rid of foreign and unwanted intrudersDR.T.V.RAO MD 37
  38. 38. USES OF INTERFERONS• Interferon-gamma has been used to treat a variety of disease in which macrophage activation might play an important role in recovery, eg. lepromatous leprosy, leishmaniasis, toxoplasmosis. Since interferons have anti- proliferative effects, they have also been used to treat certain tumours such as melanoma and Kaposi’s sarcoma.DR.T.V.RAO MD 38
  39. 39. THEORIES OF IMMUNE RESPONSE• Several theories are considered1 Direct template theory2 Indirect template theory3 Natural selection theory4 Clonal selection theoryDR.T.V.RAO MD 39
  40. 40. JERNE’S NETWORK HYPOTHESIS• It explains the mechanism of antibody response• The variable region of an immunoglobulin molecule carrying the antigen combining site is different in different antibodies• The distinct Aminoacid sequence at antigen combing site and the adjacent parts of the variable regions are termed as idiotype• Produce antiidotypic antibodies• Which in turn produce antibodies to them DR.T.V.RAO MD 40
  41. 41. WHAT IS CLONAL SELECTION THEORY• Burnet proposed the theory 1957• The theory emphasizes the immunological specificity to cellular level In this theory the cell are formed by somatic mutation, the cells that react with self antigens are eliminated and called as Forbidden clones. Their persistence in later life leads to Autoimmune processDR.T.V.RAO MD 41
  42. 42. NOBEL PRIZE WINNING THEORY• Which in turn produce antibodies to them• Forms a idiotype network• The above process controls the amount of antibodies• The above theory by Niels K.Jerne was awarded Nobel Prize for Medicine in 1984 DR.T.V.RAO MD 42
  43. 43. DR.T.V.RAO MD 43
  44. 44. RECENT THEORIES• Now genetic basis of antibody diversity is identified.• The recent theory of Split genes explains many unknown mechanisms• The theory says the information occurs in discontinuous stretches of DNA, each coding for separate regions of the antibody moleculeDR.T.V.RAO MD 44
  45. 45. • Programme created by Dr.T.V.Rao MD for Medical and Paramedical Students in the Developing World • Email • doctortvrao@gmail.comDR.T.V.RAO MD 45

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