Lecture 1 Week 2

Lecture 1 Week 2

1. Respiratory infection

   • A pathogenic bacteria invades respiratory mucosa

2. Macrophages

   • Professional phagocytic cell
   • Multiple roles in host defenses
   • Present in dermis and recruited to sites of infection of inflammation
   • Ingest microbes, lyse microbes and present fragments to other immune cells (i.e. antigen presenting cell - APC)

3. Basophils and mast cells

   • Basophils
   • Mast cells = tissue form of basophil
   • Contain granules of histamine an other chemical mediators
   • Degranulate when allergens cross-link IgE molecules on surface (i.e. specific immunity)
   • Involved in acute inflammation
   • Effects on blood vessels, smooth muscles

4. How do these cells detect pathogens

   • Conserved molecular structures of microbial pathogens
   • Pathogens-associated molecular patterns (PAMPs)
   • Pattern-recognition receptors (PRRs) result in recognition of general classes of mcirobes/pathogens

5. Toll-like receptors

   • Trans-membrane receptors that recognise various PAMPs
   • TLRs 1, 2 and 4 expressed on plasma membrane
   • TLR 4 = receptor for LPS
   • TLR 3 = receptor for dsRNA

6. Acute responses: recruitment of immune cells (Neutrophil, dendritic cells, NK cells etc)

   • Inactive neutrophils are swept along by blood
   • Rolling
     • Cytokine driven induce expression of selectins
     • Neutrophils roll along endothelium, making and breaking contacts with endothelial cells
   • Adhesion
     • upon activation by inflammatory signals (e.g. complement protein c5a), binding proteins on neutrophil (integrin) and on endothelial cells are induced, arrested rolling
   • Diapedesis
     • Neutrophil move through endothelium to the site of infection

7. Neutrophils

   • Essential component of cellular innate immune system involved in killing bacteria and fungi by phagocytosis
   • Neutrophils are major cells in acute inflammation
   • Recruited to sites of infection or inflammation (short lived)
   • G-CSF and GM-CSF released by mac;s shift to left

8. Dendritic cells

   • Professional phagocytic cell
   • Act locally with antimicrobial responses (NO)
   • Promote activity by other innate immune cells -NK Cells
   • Particularly important in initiation of adaptive immune responses
   • Key cell that migrates to lymphoid tissues and present antigens to T and B cells

9. Natural killer cells

   • Can kill virus-infected cells, bacteria, parasites, fungi in tissues
   • Two types of NK Receptors: inhibitory and activating
   • Many virally-infected cells and tumor cells down regulate expression of class I MHC molecules (NK cells important preventing cancers)
   • Inhibitory receptor recognizes a self protein (Class MHC molecule) on a target cell the NK cell will not respond
   • If activating receptor binds a ligand, but inhibitory receptor does not (target cell has down regulated class I MHC proteins), NK cells kill by releasing granzyme and perforoin

10. Acute responses: phagocytosis

    • Recognition/attachment of microbes via surface receptors
    • Engulfment of microbe (phagocytosis) into phagosome/endosome
    • Killing of microbes (i.e. neutrophils)
      • Reactive oxygen species (ROS)
      • Nitric oxide

11. Complement

    • Serum proteins produced in lier
    • Majority soluble, circulating in inactive state
    • Complement activation
      • Classical triggered by antibody bound to pathogens - starts with C1q
      • Lectin triggered by repeats of polysaccharide structures
      • Alternative triggered by other foreign surface motifs - starts with C3b

12. Roles of Complement in Inflammation

    • Opsonization: C3b is important
    • Chemotaxis - complement fragments diffuse from target - stimulating cellular movement and activation
    • Target cell lysis - membrane attack complex hydrophobic 'plug' inserted into lipid membrane bilayer