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Jude Uzonna RM 425 APOTEX Ph: 977-5659 Email: uzonna@cc.umanitoba

Immunology. Principles of the Adaptive Immunity. Jude Uzonna RM 425 APOTEX Ph: 977-5659 Email: uzonna@cc.umanitoba.ca. Why was it necessary for the immune system to evolve?. The perfect world. The real world. Review of Dr Kung’s 2 nd lecture.

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Jude Uzonna RM 425 APOTEX Ph: 977-5659 Email: uzonna@cc.umanitoba

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  1. Immunology Principles of the Adaptive Immunity Jude Uzonna RM 425 APOTEX Ph: 977-5659 Email: uzonna@cc.umanitoba.ca

  2. Why was it necessary for the immune system to evolve?

  3. The perfect world

  4. The real world

  5. Review of Dr Kung’s 2nd lecture What are the hallmarks of the innate immune system?

  6. Do you think the innate immune system needed fixing ? - Why fix it if it isn’t broken?

  7. Lecture Objectives: By the end of the Lecture, you will be able to: • Know why adaptive immune system evolved • Know the key players of adaptive immunity • Differentiate b/w cell-mediated and humoral immunity • Understand the principles of Self/non-self discrimination and its significance • Understand the concepts of immunological memory • Differentiate b/w adaptive versus innate immunity • Integrate the functions of innate and adaptive immunity

  8. Adaptive Immunity • Specific host defenses that are mediated by B and T lymphocytes following exposure to antigens, and exhibit diversity and memory.

  9. Why adaptive immunity evolved: • Shortcomings of innate immunity: • Non-specific • Similar pattern of response for all pathogens • Poor regulation • Control mechanisms are poor or lacking • Poor amplification • Response magnitude same for all insults • Lack of self discrimination • Harm to self results for lack of specificity • Short duration • No memory

  10. The enemies are different… BACTERIA -Clostridium difficile (causes antibiotic-associated colitis & diarrhea) FUNGUS -Epidermophyton floccosum (causes athlete’s foot) PARASITE - Tapeworm VIRUS- Polio

  11. ….therefore responses must be tailored for specific enemies. • Successful immune response is a huge investment!! Hence: you need to remake it: •  Faster •  Larger •  More specific •  Less damaging to self

  12. Characteristics/Hallmarks of Adaptive Immunity:

  13. Types of Adaptive Immunity • Humoral Immunity • Antibodies produced by B cells • Cell-mediated Immunity • T cells directly (cytotoxicity) or indirectly via cytokines

  14. Major Cells of Adaptive Immunity • Lymphocytes • B cells • T cells • T helper cells (Th) • Cytotoxic T cells (Tc) • Antigen presenting cells (APCs) • Dendritic cells • Macrophages • B lymphocytes

  15. T Lymphocytes • Mature in thymus • T cell receptors • MHC restriction • Class I • Nucleated cells • Necessary for CD8+ T cell activation • Class II • APCs • Necessary for CD4+ T cell activation

  16. T Lymphocytes (cont’d) • Progeny cells • T helper cells • Bear CD4 molecule • Are Class II restricted • Stimulates B and T cells (helper function) • T cytotoxic cells • Bear CD8 molecule • Are Class I restricted • Further differentiates • CTLs (killing function) • Memory T cells

  17. B Lymphocytes • Originate and mature in bone marrow • B cell receptor is membrane bound antibody • Ag binding triggers division and differentiation • Progeny • Plasma cells • Memory B cells

  18. Antigen Presenting Cells (APC) • Cells with potential to capture, process and present antigens to T cells • APCs also supply “second signal” to T cells leading to their proper activation (Proliferation, Differentiation and Effector activities) • Key to their function: • Expression of MHC I and II on surface • Ag internalization and degradation • Co-stimulatory activities

  19. Key Antigen Presenting Cells Professional Antigen Presenting Cells • Dendritic cells • Macrophages • B lymphocytes

  20. Antigen Processing (Dr Babiuk) • Chopping up of complex proteins into peptides that are recognized by T cells • Exogenous antigens: Antigens that enter the body of the organism from the outside, e.g. through inhalation, ingestion, or injection • Phagocytosis • Degradation • Ag peptide/MHC II recognized by helper (CD4+) T cells • Endogenous antigens: Antigens that are produced from within the cell as part of normal cell metabolism or when the cell is infected by bacteria or viruses • Viral or tumor induced • Complexes with Class I • Recognized by Cytotoxic (CD8+) T cells

  21. Functions of APCs • T cell selection in the thymus (only DCs) • Trap and capture antigen in the periphery • Process antigens into peptides • Storage of antigens (antigen depot) • Transport antigens to peripheral lymphoid tissues • Present antigenic peptides to T cells • Co-stimulate T cells

  22. Antigen Recognition (Dr Marshall) • Epitopes: Motifs (conformational/primary sequences) on antigens that are recognized by B and T cell • Bcells recognize epitopes (conformational) alone • T cells require MHC association (peptides) • Major molecules involved in Ag recognition • Membrane bound antibody (B cell receptor, BCR) • T cell receptor (TCR) • MHC I • MHC II

  23. The Clonal Selection of Lymphocytes

  24. The Two-Signal Requirement for Lymphocyte Activation • Requirements: Two signals • Signal 1: specific recognition of antigen • TCR-Peptide-MHC • BCR-Native antigen • Signal 2: Non-specific • Microbial-induced molecules on/from APC • Microbial molecule (LPS, CpG etc) • Signal 1 alone leads of unresponsiveness • Anergy, Deletion, Apoptosis

  25. Phases of Adaptive Immune Response

  26. MHC Restriction: • T cell receptors recognize antigenic peptide/MHC complexes • CD4+ T cells: restricted by class II • CD8+ T cells: restricted by class I

  27. Self/non-Self Discrimination • Property of the adaptive immune system to mount specific/targeted responses to foreign antigens without responding to self • Achieved by early and continuous presence of self-antigens • Important for self tolerance and control of autoimmunity

  28. Danger vs non-Danger model • Immune system does not discriminate b/w self and non-self • Only interested in responding to dangers elicited via recognition of danger signals • What makes an antigen dangerous??

  29. Key Differences b/w Self/non-Self and Danger model • Only foreign antigens can elicit immune response (self/nonself) vs.Even self Ag can elicit response if they become dangerous • Keep looking for “foreigners” vs. ignore everybody and only respond if threatened • Police vs Fire fighters

  30. T cell selection/education:

  31. Shaping T Cell Repertoire by Positive and Negative Selection

  32. T cell development: Overview of the big picture • 1. Developing T cells generate wide diversity of novel receptors • 2. Each interacts with surrounding cells that express “self” MHC • 3. Receptors on maturing T cells may: • - not bind MHC (are not “positively” selected) • - bind very strongly (are not negatively selected; to protect against autoimmunity) • Cells that are both positively and negatively selected are exported to the periphery • 99% of all maturing stem cells in the thymus die.

  33. B lymphocytes - development

  34. B cell development: Overview Stem cell  B cell in Bone marrow (primary organ) Two key goals for the system: * Generate multiple Ag specific receptors (1 per cell) Enzymes that join Ab gene components together to get a functional Ab gene are error prone: introduction of random variability * Delete self reactive B cells generated by accident

  35. B cells also undergo selection • Positive and negative selection in Bone marrow • Selection is not MHC molecule-dependent • Binding affinity and avidity more important Is it really necessary for B cells to undergo positive and negative selection?

  36. Self Tolerance: • Ability to remain “tolerant” to self while retaining the capacity to mount response to non-self. • Self/non-self discrimination with in-built fail-safe mechanisms are key

  37. Significance of Self/non-self discrimination (Tolerance): • Prevention of autoimmunity • Scarce resources are all directed against “potential” enemies • What is the price for self/non-self discrimination? • Why do we develop autoimmune diseases anyway?

  38. Cell-mediated Immunity • Conferred via T lymphocyte activities (i.e. immunity can be transferred by T cells) • Cell dependent • Modulates humoral immunity • Cytotoxic T cells

  39. CD4+ T cells: CD4+ T helper cell differentiation

  40. Key Differences b/w Th1 and Th2 cells

  41. Th2 Effector functions of Th1 and Th2 helper T cells Th1

  42. Th17 Cells • IL-17-producing CD4+ T helper cells • Secrete IL-17, IL17F, IL-21 and IL-22 • IL-17 and Il-21 receptor is ubiquitously expressed • Differentiation factors: TGF- plus IL-6 or IL-21 • IL-23 is stabilization factor for Th17 cells • Utilizes transcription factors STAT3, RORt and ROR) • Master regulator of inflammatory responses

  43. Differentiation of Th17 cells

  44. Take home review: * Natural and Inducible Regulatory T cells * Factors that influence Regulatory T cell differentiation

  45. CD8+ T cells Mechanism of Cytotoxic T cell effector functions

  46. Humoral Immunity • Conferred via serum (cell-free) • Antibody dependent • Antibody functions • Enhanced elimination • Neutralization • C fixation/lysis

  47. B cells • B cells produce antibodies (also known as immunoglobulins) • B cell receptor: Antibody • Receptor is membrane bound (usually IgM, IgD) • Unlike for T cells, the B cell receptor: • Recognize native (intact) protein • Can be secreted, sometimes at high concentration. • There are 5 main families (isotypes/classes) of Ab • IgM, IgG, IgA, IgD, IgE

  48. Ab isotypes (Classes) • IgM • First produced in primary responses • 2nd most common serum Ab • Opsonization, activates complement, neutralizing Ab • IgG • Dominates memory (20) responses in serum • Highest concentration in serum • Opsonization, activates complement, neutralizing Ab • Transplacental transfer; hence important for fetal immunity and immunopathologies

  49. Ab isotypes (continued) • IgA • Major Ab at mucosal surfaces • In colostrum, tears, GI and respiratory secretions • Opsonization, activates complement, neutralizing Ab • IgD • Who knows? • IgE • Parasite defense; mediate immediate type hypersensitivity reactions • ~10,000x lower levels than IgG, even in allergic individuals

  50. Effector mechanisms of humoral immunity • Neutralization: binding to toxins or pathogens block their interaction with target cell receptors • Antibody-dependent cytolysis: binding of Ab couples pathogen to a cell with capacity to destroy that pathogen • Opsonization: Ab-coated particles are easier and more “palatable” for phagocytes to ingest • Complement activation: Leads to release of inflammatory mediators, deposition of opsonins and direct lysis of microbes

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