Intro Immune

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An introduction to immunologist- for the non-immunologist

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Intro Immune

  1. 1. Immunology for the non-immunologist
  2. 2. Introduction to the Immune System
  3. 5. Questions to be answered <ul><li>* What types of immune responses protect individuals from infections? </li></ul><ul><li>* What are the important characteristics of immunity, and what mechanisms are responsible for these characteristics? </li></ul><ul><li>* How are the cells and tissues of the immune system organized to find microbes and respond to them in ways that lead to their elimination? </li></ul>
  4. 7. <ul><li>Immune system </li></ul><ul><ul><li>Innate(Natural/native) </li></ul></ul><ul><ul><ul><li>Epithelial barriers </li></ul></ul></ul><ul><ul><ul><li>Phagocytes and NK cells </li></ul></ul></ul><ul><ul><ul><li>Complement </li></ul></ul></ul><ul><ul><ul><li>Antibodies </li></ul></ul></ul><ul><ul><li>Adaptive (specific/accquired) </li></ul></ul><ul><ul><ul><li>Humoral </li></ul></ul></ul><ul><ul><ul><li>Cell mediated </li></ul></ul></ul>
  5. 8. <ul><li>Innate- respond to structures shared by microbes </li></ul><ul><li>Adaptive- respond to specific antigens presented to lymphocytes </li></ul><ul><ul><li>Only triggered if microbes passes through innate immunity </li></ul></ul><ul><li>Innate immunity  Adaptive immunity </li></ul><ul><li>Immune response = adaptive immunity unless specified </li></ul>
  6. 9. Adaptive Immunity <ul><li>Humoral immunity </li></ul><ul><ul><li>B lymphocytes </li></ul></ul><ul><ul><ul><li>Antibodies </li></ul></ul></ul><ul><ul><ul><ul><li>Secreted into circulation and mucosal fluids </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Neutralize and eliminate microbes and toxins outside the host cells (blood/mucosal organs-GIT, resp) </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Prevents infection from getting into cells </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Cannot enter cells to kill microbes </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Recognize different types of molecules- proteins, carbohydrate, lipids </li></ul></ul></ul></ul>
  7. 10. Adaptive Immunity <ul><li>Cellular immunity </li></ul><ul><ul><li>T lymphocytes </li></ul></ul><ul><ul><ul><li>Activate phagocytes to destroy microbes </li></ul></ul></ul><ul><ul><ul><li>Kill host cell infected by microbes </li></ul></ul></ul><ul><ul><ul><li>Recognize only protein antigens </li></ul></ul></ul>
  8. 11. <ul><li>Active Immunity </li></ul><ul><ul><li>Infection </li></ul></ul><ul><ul><li>Vaccination </li></ul></ul><ul><li>Passive immunity </li></ul><ul><ul><li>Transfer of antibodies/lymphocytes from immunized individual </li></ul></ul><ul><ul><li>Active only during t ½ of antibodies/lymphocytes </li></ul></ul><ul><ul><li>Rapid immunity (before body mounts active response) </li></ul></ul>
  9. 12. <ul><li>Immune individual </li></ul><ul><ul><li>Antigen exposure </li></ul></ul><ul><li>Naïve individual </li></ul><ul><ul><li>Never have antigen exposure </li></ul></ul>
  10. 14. Properties of Adaptive Immune Responses
  11. 15. Specificity/Diversity <ul><li>Clonal selection hypothesis </li></ul><ul><ul><li>Lymphocytes specific for different Ag already present even before Ag ancounter </li></ul></ul><ul><ul><li>(diverse lymphocytes repertoire) </li></ul></ul><ul><ul><li>Each lymphocyte is made up of many different clones </li></ul></ul>
  12. 16. Memory <ul><li>Primary immune response </li></ul><ul><ul><li>Naïve lymphocytes (immunologically inexperience) </li></ul></ul><ul><li>Secondary immune response </li></ul><ul><ul><li>Subsequent exposure to same Ag </li></ul></ul><ul><ul><li>Larger and more effective response </li></ul></ul><ul><ul><li>Occurs d/t memory lymphocytes (long lived) induced during primary response </li></ul></ul><ul><ul><li>Basis of vaccination </li></ul></ul>
  13. 18. Clonal selection/expansion <ul><li>Antigen activates lymphocytes  proliferation  clonal progeny cells specific to particular Antigen (specialized clonal expansion) </li></ul><ul><li>Infection overcomed  contraction and homeostasis </li></ul>
  14. 20. Cells of the immune system <ul><li>Lymphocytes </li></ul><ul><ul><li>Only cells that produce specific receptors for specific Ag </li></ul></ul><ul><ul><li>Key mediators of adaptive immunity </li></ul></ul><ul><ul><li>Many subtypes differentiated by (Cluster of Differentiation) </li></ul></ul><ul><ul><li>B lymphocytes </li></ul></ul><ul><ul><li>T lymphocytes </li></ul></ul><ul><ul><li>NK cells </li></ul></ul>
  15. 21. <ul><li>B lymphocytes </li></ul><ul><ul><li>Only cells capable of producing A/B </li></ul></ul><ul><ul><li>Mediate humoral immunity </li></ul></ul><ul><ul><li>A/B also expressed on membrane to recognize Ag </li></ul></ul><ul><li>T lymphocytes </li></ul><ul><ul><li>Only recognize peptide fragments that are presented via a specialized display molecule: Major Histocompatibility Complex (MHC) on specialized cells (Antigen Presenting Cells-APC) </li></ul></ul>
  16. 22. <ul><li>T lymphocytes </li></ul><ul><ul><li>CD4+ T cells  T helper </li></ul></ul><ul><ul><ul><li>Help B lymphocytes to produce A/B </li></ul></ul></ul><ul><ul><ul><li>Help phagocytes destroy ingested microbes </li></ul></ul></ul><ul><ul><li>CD4+ T cells  T regulatory </li></ul></ul><ul><ul><ul><li>Prevent/Limit immune responses </li></ul></ul></ul><ul><ul><li>CD8+ T cells  Cytotoxic T cells (CTL) </li></ul></ul><ul><ul><ul><li>Kills cells habouring intracellular microbes </li></ul></ul></ul><ul><ul><li>Natural Killer  NK cells </li></ul></ul><ul><ul><ul><li>Kills infected host cell </li></ul></ul></ul><ul><ul><ul><li>Part of innate immunity </li></ul></ul></ul><ul><ul><ul><li>Rapid action </li></ul></ul></ul>
  17. 23. <ul><li>T lymphocytes </li></ul><ul><ul><li>All produced in BM </li></ul></ul><ul><ul><ul><li>Maturation differs </li></ul></ul></ul><ul><ul><ul><ul><li>B lymphocytes  BM </li></ul></ul></ul></ul><ul><ul><ul><ul><li>T lymphocytes  Thymus </li></ul></ul></ul></ul><ul><ul><li>Maturation sites  generative lymphoid organs </li></ul></ul><ul><ul><li>After maturation  circulation  peripheral lymphoid organs  Ag surveillance </li></ul></ul><ul><ul><li>10 12 circulating lymphocytes </li></ul></ul>
  18. 24. Cells of immune system
  19. 27. <ul><li>Naïve lymphocytes  circulates to detect Ag </li></ul><ul><li>If no Ag encounter  apoptosis </li></ul><ul><li>If Ag encounter  Differentiate into effector cells </li></ul><ul><ul><li>B lymphocyte  plasma cells </li></ul></ul><ul><ul><li>T lymphocytes  Th, CTL </li></ul></ul><ul><ul><li>Effector cells  short t ½ </li></ul></ul><ul><ul><li>After infection  Memory cells (B&T lymphocytes) </li></ul></ul>
  20. 28. <ul><li>Newborn: <5% circulating lymphocytes are memory cells </li></ul><ul><li>Adult: up to 50% are memory cells </li></ul>
  21. 30. Antigen Presenting Cells <ul><li>Dendritic cells </li></ul><ul><ul><li>GIT, Skin, Resp tract </li></ul></ul><ul><ul><li>Capture Ag that manage to breach epithelium </li></ul></ul><ul><ul><li>Capture Ag  LN  present Ag to T lymphocyte </li></ul></ul><ul><li>Macrophages </li></ul><ul><ul><li>Phagocytose Ag </li></ul></ul><ul><ul><li>Present Ag to T lymphocytes </li></ul></ul><ul><li>Follicular dendritic cells (FDC) </li></ul><ul><ul><li>Germinal centers of lymphoid follicles </li></ul></ul><ul><ul><li>Present Ag to B lymphocytes only </li></ul></ul><ul><ul><li>Induce B lymphocyte differentiation </li></ul></ul>
  22. 31. <ul><li>Granulocytes, macrophages </li></ul><ul><ul><li>Innate/Adaptive immunity </li></ul></ul>
  23. 32. Tissues of the Immune System <ul><li>Generative(Primary/Central) lymphoid organs </li></ul><ul><ul><li>BM  B cells maturation </li></ul></ul><ul><ul><li>Thymus  T cells maturation </li></ul></ul><ul><li>Peripheral (Secondary) lymphoid organs </li></ul><ul><ul><li>LN </li></ul></ul><ul><ul><li>Spleen </li></ul></ul><ul><ul><li>Mucosal/ cutaneous immune systems </li></ul></ul><ul><ul><ul><li>Peyer’s patches, Waldeyer’s ring </li></ul></ul></ul><ul><ul><ul><li>To optimize APC-Lymphocyte interaction </li></ul></ul></ul>
  24. 33. Lymph nodes <ul><li>Lymphoid tissue located along lymphatic channels </li></ul><ul><li>Fluid from epithelia, connective tissue, parencyma organs  Lymph  LN </li></ul><ul><li>Ensure APC able to present Ag to lymphocytes </li></ul><ul><li>Enable APC in LN to sample Ag </li></ul>
  25. 34. Lymph nodes <ul><li>B cells  concentrated in follicles </li></ul><ul><ul><li>Cortex of LN </li></ul></ul><ul><ul><li>Germinal center present if recent exposure to Ag </li></ul></ul><ul><ul><li>Contains follicular dendritic cells (FDC) </li></ul></ul><ul><li>T cells  paracortex </li></ul><ul><ul><li>Adjacent to follicle </li></ul></ul><ul><ul><li>Contains dendritic cells </li></ul></ul>
  26. 35. Tissue of Immune System
  27. 37. Spleen <ul><li>Detect blood borne Ag </li></ul><ul><li>Blood enters spleen through network of channels (sinusoids)  Ag trapped by dendritic cells/macrophages in spleen </li></ul><ul><li>T cells concentrated in periarteriolar lymphoid sheaths (PALS) </li></ul><ul><li>B cells concentrated in follicles </li></ul>
  28. 39. Why do cells concentrate at specific sites <ul><li>Chemoattractants (chemokines secreted by FDCs, naïve T cells expressed CCR7) </li></ul><ul><li>Once naïve cells are activated, they change their expression of chemokine receptors and take on a new role </li></ul>
  29. 40. Lymphocyte circulation and migration into tissues <ul><li>Discussion focused on LN & T cells </li></ul><ul><li>Unsure- </li></ul><ul><ul><li>B cell circulation </li></ul></ul><ul><ul><li>Splenic circulation/other lymphoid tissues </li></ul></ul><ul><ul><ul><li>Spleen- no HEVs </li></ul></ul></ul><ul><ul><ul><li>General pattern of migration ?similar to LN </li></ul></ul></ul><ul><li>Matters most for T cells </li></ul><ul><li>B cells produce A/B which can circulate to targets. </li></ul><ul><ul><ul><li>Effector B cells remain in LN </li></ul></ul></ul>
  30. 41. <ul><li>Naïve T cells enters LN via specialized post-capillary venules (High Endothelial Venules-HEVs) </li></ul><ul><li>Naïve T cells express L-selectin (involved in cell-cell adhesion)  binds to carbohydrate ligands on HEVs  migrate through HEVs to specific sites in response to chemokine secretion  moves around LN  scans APCs searching for Ag  Ag recognized  forms stable conjugates with APCs  T cell activation </li></ul>
  31. 42. <ul><li>Random events </li></ul><ul><li>Most T cells circulates through some LN at least once daily </li></ul><ul><li>Likelihood of correct T cells finding its Ag is increased in peripheral lymphoid organs d/t this Ag/T cells concentration </li></ul><ul><li>After T cell activation  reduce expression of adhesion molecules and certain chemokine recpetors  increase expression of other chemokine (sphingosine-1-PO4)  Migrates out of LN into blood circulation  Infected site </li></ul>
  32. 44. Summary of immune response <ul><li>Innate Immunity </li></ul><ul><ul><li>Epithelia </li></ul></ul><ul><ul><ul><li>Physical and functional barrier </li></ul></ul></ul><ul><ul><ul><li>Natural anti-microbial agents </li></ul></ul></ul><ul><ul><li>Microbes able to traverse epithelia,  2 nd defense mechanism </li></ul></ul><ul><ul><ul><li>Phagocytes (macrophages/neutrophils) </li></ul></ul></ul><ul><ul><ul><ul><li>Ingest microbes into vesicles </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Cytokine secretion  adaptive immunity </li></ul></ul></ul></ul>
  33. 45. <ul><ul><ul><li>NK cells </li></ul></ul></ul><ul><ul><ul><ul><li>kills virus infected cells </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Produce macrophage activating cytokine interferon γ (IFN-γ) </li></ul></ul></ul></ul><ul><ul><ul><li>Complement  coat (opsonize) microbe </li></ul></ul></ul>
  34. 46. <ul><li>Adaptive immunity </li></ul><ul><ul><li>3 main strategies </li></ul></ul><ul><ul><ul><li>Antibody secretion  promote ingestion and destruction by phagocytes </li></ul></ul></ul><ul><ul><ul><li>T h  Enhance phagocytosis </li></ul></ul></ul><ul><ul><ul><li>CTLs  destroys cells infected by microbes that are inassessible to A/B </li></ul></ul></ul><ul><ul><li>Antigen capture and display </li></ul></ul><ul><ul><ul><li>Naïve T cells (MHC associated TCR)- Peptide sequences </li></ul></ul></ul><ul><ul><ul><li>B cells- Peptide/non peptide sequences </li></ul></ul></ul><ul><ul><ul><li>Complement activation </li></ul></ul></ul>
  35. 47. <ul><li>Cell mediated immunity </li></ul><ul><ul><li>T cell stimulation  effector T cells </li></ul></ul><ul><ul><ul><li>Th </li></ul></ul></ul><ul><ul><ul><ul><li>Cytokine production and expression of cell surface molecules </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Bind to B cells  A/B production </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Bind to Macrophages  stimulate phagocytosis </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Recruit/Activate neutrophils </li></ul></ul></ul></ul></ul><ul><ul><ul><li>CTLs </li></ul></ul></ul><ul><ul><ul><ul><li>Kills cells in cytoplasm </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Also kills bacteria phagocytosed but escape killing by macrophages </li></ul></ul></ul></ul>
  36. 48. <ul><li>Humoral Immunity </li></ul><ul><ul><li>Full response requires Th </li></ul></ul><ul><ul><li>B cells ingest protein Ag  degrade them  display to Th  activate B cells </li></ul></ul><ul><ul><li>Polysaccharide and lipids stimulate IgM </li></ul></ul><ul><ul><li>Protein Ag stimulates Th  induce B cells to produce IgG, A, E </li></ul></ul><ul><ul><li>Production of different A/B with different Fx but with same specificity  heavy chain class (isotype) switching </li></ul></ul>
  37. 49. <ul><li>Th stimulate A/B with higher and higher affinity towards Ag  Affinity maturation </li></ul><ul><li>How humoral response combat infection </li></ul><ul><ul><li>A/B binds microbes  neutralizing </li></ul></ul><ul><ul><li>A/B coats microbes (opsonize)  Phagocytosis </li></ul></ul><ul><ul><li>A/B activates complement </li></ul></ul><ul><ul><ul><li>Complement stimulates phagocytosis </li></ul></ul></ul>
  38. 50. <ul><li>Immune contraction and homeostasis </li></ul><ul><ul><li>Effector lymphocyte undergoes apoptosis after elimination of microbe </li></ul></ul><ul><ul><li>Return of immune system to basal resting state (homeostasis) </li></ul></ul><ul><ul><li>B & T memory cells </li></ul></ul><ul><ul><ul><li>More rapid and effective immune response </li></ul></ul></ul>

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