Immune System


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Immune System

  1. 1. Immune System • Dispersed throughout the body • Protects against infection and cancer • Tightly regulated, self- limited and promptly terminated • Lack of regulation could lead to inadequate response and failure to protect Failure to regulate Beginnings of immunology • Edward Jenner-1796 Cowpox vaccine • Robert Koch-19th century-microorganisms • Louis Pateur-1880s-vaccines for chicken cholera and rabies • Emil von Behring & Shibasaburo Kitasato- 1890 Antibodies • Elie Metchnikoff-Macrophages
  2. 2. Fig. 1.2 The eradication of smallpox by vaccination Components of the immune system Objectives: 1. Organization of the immune system 2. Origin of cells of the immune system 3. Central/peripheral lymphoid systems 4. Pattern recognition 5. Antigen presentation
  3. 3. Organization of the lymphoid system • Lymphoid system is organized into: • Central/primary lymphoid organs • Peripheral/secondary lymphoid organs. • The central lymphoid organ: consists of thymus and bone marrow where T cells and B cells undergo maturation respectively • The peripheral lymphoid organs: Designed to trap Ag Allow initiation of adaptive immune response Sustain re-circulating lymphocytes Fig. 1.7 The distribution of lymphoid tissues in the body
  4. 4. All cells in the blood originate from a common precursor Pluripotent hematopoietic stem cell: Common myeloid progenitor gives raise to: Erythrocyte progenitor: Platelets Red blood cells Granulocyte/macrophage progenitor Neutrophils Eosinophils Basophils Macrophages Mast cells Dendritic cells Common lymphoid progenitor gives raise to: T lymphocytes B lymphocytes Fig. 1.3 All the cellular elements of blood, including the lymphocytes of the adaptive immune system, arise from hematopoietic stem cells
  5. 5. Fig. 1.4 Myeloid cells in innate and adaptive immunity Fig. 1.5 Lymphocytes are mostly small and inactive cells
  6. 6. Fig. 1.6 Natural killer cells Properties of lymphocytes • Resting B and T cells have large nuclei with very little cytoplasm • Upon Ag encounter lymphocytes proliferate and differentiate. • They mount specific immune responses against virtually all foreign Ags • They recognize Ags through cell surface receptors. • B cells have membrane immunoglobulins, which serve as BCRs • T cell antigenic receptors are called T cell receptors (TCRs) • BCR and TCR are structurally related but are distinct • NK cells lack Ag receptor-therefore, are part of the innate immune system.
  7. 7. Fig. 2.2 Pathogens infect the body through a variety of routes Fig. 1.8 Organization of a lymph node
  8. 8. Fig. 1.9 Organization of the lymphoid tissues of the spleen Fig. 1.10 Organization of typical gut-associated lymphoid tissue
  9. 9. Fig. 1.11 Circulating lymphocytes encounter antigen in peripheral lymphoid organs Fig. 2.1 The response to an initial infection occurs in three phases
  10. 10. Innate Immunity • Physical barriers • Chemical barriers • Phagocytosis • Complement activation • Receptors of the innate system • Induction of innate immunity • Cytokines and chemokines • NK cells • IgM antibodies Fig. 2.3 An infection and the response to it can be divided into a series of stages
  11. 11. Fig. 2.4 Surface epithelia provide mechanical, chemical, and microbiological barriers to infection Fig. 2.6 Bactericidal agents produced or released by phagocytes on the ingestion of microorganisms
  12. 12. Fig. 1.12 Bacterial infection triggers an inflammatory response Fig. 1.13 Dendritic cells initiate adaptive immune responses
  13. 13. Summary • Immune system is dispersed in the body • All cells arise from a common precursor • Different cells have specialized functions • Some provide 1st line of defense • Others provide memory function for recall • Cell-cell interactions required for response • Soluble mediators play a key role Lecture-II: Objectives • Receptors of the innate immune system • Induced innate responses: Cytokines and Chemokines • Summary of Innate immunity • Adaptive immune responses • Clonal selection • Antibody structure
  14. 14. Receptors of the innate immune system • They are pattern recognition molecules • Expressed by all cells of a particular type • Recognize broad classes of pathogens • Examples include: • Macrophage mannose receptor • Mannan binding lectin • CD-14/TLRs-involved in signaling Fig. 2.27 The characteristics of receptors of the innate and adaptive immune systems are compared
  15. 15. Fig. 2.5 Phagocytes bear several different receptors that recognize microbial components and induce phagocytosis Fig. 2.28 Mannan-binding lectin (MLB) binds to patterns of carbohydrate groups in the correct spatial orientation
  16. 16. Fig. 2.29 Bacterial lipopolysaccharide signals through the Toll-like receptor TLR-4 to activate the transcription factor NFκB Fig. 2.30 Bacterial LPS induces changes in Langerhans’ cells, stimulating them to migrate and initiate adaptive immunity to infection by activating CD4 T cells
  17. 17. Induced Innate responses • Pathogens induce macrophage activation • They produce cytokines and chemokines • Different molecules have different effects • Local effects: cell activation/recruitment • Systemic effects: Fever, shock, mobilize metabolites, acute-phase protein prodn • Follows initial innate immune response • Lacks memory and is not long lasting
  18. 18. Fig. 2.31 Important cytokines secreted by microphages in response to bacterial products include IL-1, IL-6, IL-8, IL-12 and TNF-α
  19. 19. Fig. 2.33 Properties of selected chemokines Fig. 2.36 Neutrophils leave the blood and migrate to sites of infection in a multistep process mediated through adhesive interactions that are regulated by macrophage-derived cytokines and chemokines
  20. 20. Inflammation • Inflammation: Heat, Pain, Redness and Swelling • Reflect effects of inflammatory mediators on blood vessels • Results in increased blood flow • Results in increased permiability • Leakage of fluid from blood vessels and tissues causes edema • Leukocytes migrate into the site through endothelial wall • Initially neutrophils-the principal cells that engulf and destroy bacteria appear • Later in the process monocytes migrate and differentiate into macrophages • Further down in the process lymphocytes might be involved • This increases lymph flow into the lymph node • Lymph brings Ag into the lymph node where it is trapped • Activates adaptive immune system via dendritic cells Fig. 2.31 Important cytokines secreted by microphages in response to bacterial products include IL-1, IL-6, IL-8, IL-12 and TNF-α
  21. 21. Fig. 2.38 The cytokines TNF-α, IL-1, and IL-6 have a wide spectrum of biological activities that help to coordinate the body’s responses to infection Fig. 2.40 Interferons are antiviral proteins produced by cells in response to viral infection
  22. 22. Fig. 2.41 Natural killer cells (NK cells) are an early component of the host response to virus infection Fig. 2.42 Possible mechanisms by which NK cells distinguish infected from uninfected cells
  23. 23. Fig. 2.43 CD5 B cells might be important in the response to carbohydrate antigens such as bacterial polysaccharides Summary • Physical, Chemical and Mechanical barriers provide the first line of defense • Cells of the innate immune system are rapidly deployed and can clear infections • Sometimes they cannot completely clear infection • Cells of the innate immune system are involved in activating adaptive immune system • This is facilitated through Ag presentation and cytokine production • Adaptive immune system is more versatile but there is 4-7 day delay in deployment • Therefore, cells of the innate immune system play a critical role in host defense
  24. 24. Summary: Innate immune system-2 • Phagocytic cells recognize patterns on microbes • Macrophages engulf bacteria, which in turn induce cytokines • Cytokines are proteins that affect cells that express their cognate receptor • Macrophages also release chemokines • Chemokines attract neutrophils and monocytes from blood • Inflammation is initiated by Chemokines • Inflammation can also be initiated by activation of complement Adaptive Immunity • Activated upon exposure to a pathogen/Ag • Requires help from the innate immune system • Depends on clonal selection from a repertoire of lymphocytes with diverse Ag specificity • Ag specific lymphocytes proliferate/differentiate into effector cells and eliminate pathogens • Generates memory cells that allow rapid effective response to re-infection
  25. 25. Clonal selection • Clonal Selection is the Central Principal of Adaptive Immunity: • T cells are selected in thymus • B cells are selected in BM • When cells encounter self-antigens- • clonal deletion occurs. • This is known as negative selection. • When cells are positively selected • it is called clonal selection Fig. 1.14 Clonal selection
  26. 26. Fig. 1.15 The four basic principles of clonal selection Structure of antibody • Antibody (Ab) consists of two regions • Constant region - can only take 4 or 5 distinct forms • Variable region - can take infinite variety that can bind to a vast variety of Ags • Abs have two fold axis of symmetry • Consist of two identical heavy and light chains • Both heavy and light chains have variable and constant regions • Variable regions of H & L chains combine to form Ag binding site • Immunoglobulins act as Ag receptors on B cells
  27. 27. Fig. 1.16 Schematic structure of an antibody molecule Fig. 1.17 Antibodies are made up of four protein chains
  28. 28. Antibody diversity • Antigenic (Ag) receptors with infinite range of specificities are encoded by a finite number of genes • Variable regions are inherited as sets of gene segments • Through DNA recombination a complete region in encoded • Once a productive rearrangement has occurred, further rearrangement in prohibited • Gene rearrangement has 3 important consequences: • Vast diversity is generated with very few genes • Each cell expresses unique receptor specificity • All progeny inherit the same gene Fig. 1.18 The diversity of lymphocyte antigen receptors is generated by somatic gene rearrangements
  29. 29. Fig. 1.20 The course of a typical antibody response Fig. 1.21 Two signals are required for lymphocyte activation
  30. 30. Fig. 1.19 Transmission electron micrographs of lymphocytes at various stages of activation to become effector cells Fig. 1.22 The professional antigen-presenting cells
  31. 31. Fig. 1.23 the major pathogen types confronting the immune system and some of the diseases that they cause Fig. 1.24 Antibodies can participate in host defense against extracellular pathogens in three main ways
  32. 32. Fig. 1.25 Mechanism of host defense against intracellular infection by viruses Fig. 1.26 Mechanism of host defense against intracellular infection by mycobacteria
  33. 33. Fig. 1.27 MHC molecules on the cell surface display peptide fragments of antigens T cell activation • T cells do not recognize soluble antigens • Antigenic peptides are presented with MHC proteins • MHC class-I is expressed on all cells • MHC class-II is expressed on APCs • Class-1/peptide-activate CD8+ T cells • Class-II/peptide-activate CD4+ T cells • 1st signal- Peptide/MHC interaction with TCR • 2nd signal- B7 binding to CD28 • T cells are down modulated by CTLA-4 • T cells are eliminated by AICD
  34. 34. Fig. 1.28 MHC class I molecules present antigen derived from proteins in the cytosol Fig. 1.29 MHC class II molecules present antigen originating in intracellular vesicles
  35. 35. Fig. 1.30 Cytotoxic T cells recognize antigen presented by MHC class I molecules and kill the cell Fig. 1.31 TH1 helper T cells recognize the antigen presented by MHC class II molecules
  36. 36. DCs induce immune response and tolerance Adapted from Immunology Letters 2004 Regulatory T cells • They are CD4+CD25+ cells • Begin appearing 3 days after birth • Appear when double +ve cells become single +ve cells • High affinity for self-peptide might be necessary for thymic selection • Factors that determine +ve vs -ve selection of T cells not known • The selection appears at the thymic cortical epithelium through interactions with MHC/peptide complex • Co-receptor interactions are required: • CD28-CD80/86 • CD40-CD154 • Mice lacking these molecules have defective CD4+CD25+ cells • Whether they are not selected or not maintained in the periphery is not known
  37. 37. Fig. 1.32 Immune responses can be beneficial or harmful depending on the nature of the antigen Fig. 1.33 Successful vaccination campaigns
  38. 38. Summary • Early after infection the innate immune system provides protection • Later in infection the adaptive immune system provides protection • Innate immune system helps activate the adaptive immune system • Adaptive immune response can be either antibody mediated or T cell mediated • T cell responses can be mediated by: • Th1 CD4-delayed type hypersensitivity • Th2 CD4-Antibody production • CD8-Cytotoxic T cell response