immune system - innate

• Immunis

  Latin meaning exempt, so if you recover, you will never get it again
• Thucydides 430BC - Athens Plague. Only recovered people nurse the sick
• 15th Century - China/Aztecs: Inhaled crusts of smallpox to provide protection
• Jenner 18th C: Cowpox can provide immunity against smallpox
• Pasteur 19th C: Attenuated rabies virus used as a vaccine
• 1980: Smallpox eradicated by vaccination
• 2011 Nobel prize: ½ for Discovery of innate immune activation (PRRs), ½ to Ralph Steinman for discovering Dendritic Cells
• What is the Immune System?

  • Lymphatic system
  • Blood
  • Bone Marrow
  • Thymus
  • Lymph nodes
  • Spleen
  • Antibodies
  • cytokines
  • complement
• How do we fight infection?

  • Stop pathogen entering
  • If it enters, flush it out, kill it, control it
  • Once you've defeated it, remember it
• Mechanical barriers to stop pathogens entering

  • Skin
  • Tight Junctions
  • Mucosal surfaces
• Immunity requires both innate (inherent) and adaptive (learned) immune responses
• The innate immune system consists of Mechanical and Physiological barriers
• Innate Immune Cells

  • Granulocytes: Neutrophils, Eosinophils, Mast Cells, Basophils
  • Phagocytes: Neutrophils, Macrophages, Dendritic cells
  • Lymphocytes: Innate Lymphoid Cells (ILCs), Natural Killer cells
• Phagocytes

  Cells that eat
• Neutrophil produce Extracellular Traps
• Granulocytes

  • Neutrophils
  • Eosinophils
  • Mast Cells
  • Basophils
• The four signs of inflammation: Heat (Calor), Redness (Rubor), Swelling (Tumor), Pain (Dolor)
• In addition to local inflammatory response there is also a systemic response: Fever, Leukocytosis, Acute phase protein production by the liver
• Complement system

  A group of serum proteins in the blood that performs a critical defence against pathogens, especially extracellular bacteria
• Complement proteins can be grouped into 7 functional categories

  • Initiators
  • Enzymes (convertases)
  • Opsonins
  • Anaphylatoxins
  • Membrane attack proteins
  • Complement receptors on phagocytes or neutrophils
  • Regulatory proteins
• Pathogen Associated Molecular Patterns (PAMPs)

  Molecules from pathogens detected by the innate immune system
• Pattern Recognition Receptors (PRRs)


  Receptors on innate immune cells that detect PAMPs
• Phagocytosis

  1. Bacteria have Pathogen associated molecular patterns (PAMPs)

  2. Phagocytes have Pattern Recognition Receptors (PRRs)

  3. Bacterium becomes attached to pseudopodia

  4. Bacterium is ingested forming phagosome

  5. Phagosome fuses with lysosome

  6. Bacterium is killed and digested by lysosomal enzymes & reactive oxygen species

  7. Digestion products are released from cell
• Killing mechanisms after phagocytosis

  • Oxygen-dependent killing: Oxidative burst, Superoxide and other toxic oxidants are generated
  • Oxygen-independent killing: Lysozyme, Defensins
• Skin act as a mechanical barrier: dead cells bacteria. Skin contains sebaceous glands which produce fatty acids, lactic acid and low pH (3-5). The skin is dry so prevents bacterial growth
• Tight junction: stop ignested antigens passing into body
• Mucosal surfaces: provide a slippery surface which allows cilia to beat them way as mucus traps microorganisms.
• Physiological barriers

  pH and environment: low pH in stomach, normal commensal microbiate

  chemical mediators
• Chemical mediators:

  • anti-microbial peptides: defensins damage pathogens
  • anti-microbial proteins: lysozyme in tears and saliva
  • cytokines: interferens induce anti-viral state in cells
  • complement: MAC lyses bacteria
• How can parasite evade the innate immune response?

  hook on to avoid being flushed

  burrow straight through skin

  too big to be phagocytosed
• Stages of inflammation:

  1. tissue damage and bacteria cause resident sentinel cells to release chemoattractant and vasoactive factors that trigger a local increase in blood flow and capillary permeability.
  2. Permeable capillaries allow an influx of fluid (exudate) and cells
  3. neutriphils and other phagocytes migrate to site of inflammation (chemotaxis)
  4. phagocytes and antibacterial substances destroy bacteria
• Stages of the local inflammatory response:

  1. chemokine release: CXCL8/IL-8 release from damage endothelial cells and TNF-a release from macrophages help to recruit neutrophils and allow migration from blood. Histamine released from mast cell lead to vasodilation and increased blood vessel permeability
  2. activation of clotting and complement cascades
  3. neutrophils secrete chemokines to recuit monocytes from blood
  4. phagocytosis
  5. macrophages migrate into tissue and secrete IL-1 and TNF-a to recruit lymphocytes, monocytes and neutrophils
• what does the systemic acute-phase response include?

  fever, leukocytosis, acute phase protein
• What is acute phase proteins?

  C-reactive protein (CRP): binds to microbes, activates complement proteins to aid phagocytosis, type-1 interferons, IL-6, CXCL8
• Complement: initiators, enzymes, opsonins, anaphylatoxins, membrane attack proteins, complement receptors, regulatory proteins
• Initiators bind pathogens components or antibodies
• enzyme (convertase)
• Opsonins promote phagocytosis
• anaphylatoxin cause inflammation
• membrane attack proteins lyse pathogens