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  1. 1. Innate immunity
  2. 2. Innate immune barriers <ul><li>Mechanical barrier </li></ul><ul><li>Oral cavity and skin: epithelial cells joined by tight junctions </li></ul><ul><li>Respiratory tract: movement of mucus by cilia </li></ul><ul><li>Chemical barrier </li></ul><ul><li>Oral, saliva, enriched in antimicrobial substances </li></ul><ul><li>Skin: fatty acids </li></ul><ul><li>Tears: lysozyme, sweat: lactic acid, gut: pepsin, low pH, </li></ul><ul><li>intestine: cryptidin, antibacterial peptides (defensins) </li></ul><ul><li>Microbiological barrier </li></ul><ul><li>Normal flora </li></ul><ul><li>Produce anti-bacterial substance </li></ul>
  3. 3. Innate immune cells and factors <ul><li>Macrophages/dendritic cells in tissues </li></ul><ul><li>phagocytosis </li></ul><ul><li>cytokines (inflammatory cytokines: TNF-  , IL-1, IL-6, IL-8,) </li></ul><ul><li>chemokines </li></ul><ul><li>function as antigen-presenting cells (facilitate adaptive immunity) </li></ul><ul><li>Toll-like receptors (TLR), the eyes of innate immunity for seeing pathogens </li></ul><ul><li>PMN </li></ul><ul><li>phagocytosis </li></ul><ul><li>cytokines </li></ul><ul><li>Natural killer cells (NK cells), confer non-specific killing of virus-infected target cells or tumor cells. </li></ul>
  4. 4. Innate immunity <ul><li>Not antigen-specific, need to be modified </li></ul><ul><li>First line of defense </li></ul><ul><li>Innate mechanisms </li></ul><ul><ul><li>Barriers </li></ul></ul><ul><ul><li>Production of cytokines, antimicrobial </li></ul></ul><ul><ul><li>peptides (defensins) by neutrophils, </li></ul></ul><ul><ul><li>macrophages and mucosal epithelium. </li></ul></ul><ul><ul><li>Defensin-  can disrupt bacterial surface membranes, and defensin-  , anti-HIV. </li></ul></ul><ul><ul><li>Monkey cells express Trim-5  protein, which confers resistance to HIV infection (human Trim-5a cannot resist to HIV) --species specific innate immunity </li></ul></ul><ul><ul><li>TLR in macrophages/DC; pattern recognition of microbial molecules; recognition results in phagocytosis, cytokine release, local inflammatory responses or facilitates innate and adaptive immune response </li></ul></ul>
  5. 5. Toll-like receptors (TLR) & pattern recognition of microbial molecules <ul><li>Toll-like receptors (TLR) are expressed in macrophages/DC. </li></ul><ul><li>TLR 1-10 are pattern recognition receptors recognizing a molecular pattern present on the surface of many microbes. </li></ul><ul><ul><li>PAMPs (Pathogen-Associated Molecular Patterns) </li></ul></ul><ul><ul><li>lipopolysaccharide (LPS) </li></ul></ul><ul><ul><li>peptidoglycan </li></ul></ul><ul><ul><li>lipoteichoic acids </li></ul></ul><ul><ul><li>mannans </li></ul></ul><ul><ul><li>bacterial DNA </li></ul></ul><ul><ul><li>glucans . </li></ul></ul><ul><li>TLR recognition results in phagocytosis, cytokine release, local inflammatory responses </li></ul><ul><li>TLR recognition induces cellular signaling and activates macrophages/DC to initiate innate & adaptive immune responses. </li></ul>
  6. 6. TLR-mediated cellular response <ul><ul><li>Ligand (LPS) binding to TLR triggers cell signaling and production of cytokines </li></ul></ul><ul><ul><li>Signaling/cytokines activates macrophages/dendritic cells (DC). </li></ul></ul><ul><ul><li>Activated macrophages/DC function better in terms of phagocytosis (innate) and presenting peptide antigens to T cells (adaptive). </li></ul></ul><ul><ul><li>Appropriate response enhances innate/adaptive immunity. </li></ul></ul><ul><ul><li>Over-activating can induce inflammation (LPS from Neisseria meningitides activate TLR-4 -> TNF  IL-1  -> septic shock). </li></ul></ul>
  7. 7. Adaptive (acquired) immunity Immunity established to adapt to infection • Learnt by experience • Confers pathogen-specific immunity • Enhanced by second exposure • Has memory • Uses cellular and humoral components • Innate immune components make it more effective Antibodies and microbe-specific T cells reflect infections to which an individual has been exposed - diagnostic for infection Immune memory is the basis for vaccine
  8. 8. Adaptive immune cells <ul><li>B cells, produce antibodies </li></ul><ul><li>CD4 T helper, produce various cytokines including interleukin-2, -4, -5 and interferon-  (IL-2, IL-4, IL-5, IFN-  ). IL-4 and IL-5 help B cells to produce antibodies) ; IL-2 help CD8 T killers,  T cells to enhance T effector function for cell-mediated immunity; IFN-  activates macrophages/dendritic cells. </li></ul><ul><li>CD8 T killer, produce cytotoxic granules (perforin, gramzyme A,B,K, granulysin), and kill virus-infected cells. </li></ul><ul><li> T cells, recognize nonpeptide antigen produced by many bacteria, produce cytokines, and exert cytotoxic activities. </li></ul><ul><li>Regulatory T cells (Treg), suppressive cells that are important for control of autoimmune diseases </li></ul><ul><li>NK T cells, express NK receptors, and T cell receptors </li></ul>
  9. 9. Features of innate and adaptive immunity yes n/a Relevance to anti-cancers or anti-autoimmune diseases yes no Utility for vaccine-induced prevention against infections/diseases n/a Yes, (monkeys resist to HIV but susceptible to SIV) Species-specific resistance to some pathogens/infections yes no Improve after the re-exposure Slow, days/weeks (but improve to act fast after 2 nd exposure) Fast, minutes Responding time after initial exposure to pathogens yes no Immune memory (faster, greater magnitude, longer lasting response after re-exposure) yes No (but TRL in macrophages show pattern recognition of some microbial molecules) Specific recognition of many different antigens adaptive immunity Innate immunity
  10. 10. Integrated question A 4-year old boy had a fever with skin rash, and quickly developed convulsions and signs of early shock. He was suspected to have Neisseria meningitides septicemia and meningitis. Which of the following is NOT TRUTH ? <ul><li>The shock occurred because the immune system over-reacted to the endotoxin LPS from Neisseria meningitides. </li></ul><ul><li>LPS was recognized by TLR-4 expressed on monocytes/macrophages/DC. </li></ul><ul><li>TLR-4 recognition of LPS led to cell signaling and production of large amounts of IL-1 and TNF-  , which contributed to the shock. </li></ul><ul><li>The boy would develop the Neisseria-specific T cell and antibody responses, which should confer him protective immunity against potential 2 nd Neisseria infection. </li></ul><ul><li>The boy would develop adaptive TLR/macrophage response, which can prevent from the over-reaction to LPS in subsequent Neisseria infection. </li></ul>