Lecture 1 Week 5

Lecture 1 Week 5

1. Cell-mediated effector mechanisms

   • The elimination of microbes that have invaded tissue spaces and cells
   • This is accomplished by T cells and phagocytes

2. T helper cells (CD4+) help for macrophages

   • Cytokine release (IFN-gamma) to macrophages resulting in destruction of ingested microbes
   • Initiation: Dendritic cell presents antigen/MHC Class II complex to naive T cell (lymph node)
   • Activated Th cell clonally expands differentiates into Th1 cell and migrates to sites of antigen
   • Th cell interacts with macrophage displaying antigen/MHC complex and releases IFN-gamma
   • Result: macrophage is activated to kill ingested microbe (stimulates macrophages to increase phagocytosis)

3. Dendritic cell will present antigen/MHC complex to naive T cell in lymph node (co-stimulation with IFN-gamma)

   • Activate Th Cell will clonally expand and differentiate
   • Migration to sites of antigen/inflammation infection
   • Th cell then interacts with macrophages displaying antigen/MHC Complex releases IFN - gamma
   • Macrophage activated to kill ingested microbe (stimulation of phagocytosis)

4. Th help for macrophages

   • Cell interaction with macrophages at sites of infection; binding via antigen/MHC Complex and TCR and co-stimulatory molecules; releases IFN-gamma
   • Macrophage activated by Th cell up-regulates reactive oxygen species (ROS), nitric oxide (NO) and co-stimulatory molecules, microbe killing, increased phagocytosis, increased APC function

5. T helper cells; Help for B cells

   • Function: cytokine release: IFN-gamma or IL-4 to B cells presenting antigen on MHC Class II
   • Activation of naive T cell in lymph nodes
   • Clonally expansion and differentiation, migrate close to the lymph node follicle
   • Provide cognate help to B cell; co-stimulation (CD4 ligand/receptor), release IFN-gamma or IL-4
   • Activation of B cell; clonal expansion (formation of germinal centre), Ig class switching and affinity maturation, development plasma/memory B cells

6. T helper cytokine profiles

   • Th1 response
     • Release INF-gamma, IL-2
     • Increased macrophage killing of bacteria; B cells class switching (INF-gamma = IgG and IgA)
   • Th2 response
     • Promote eosinophil activity (IL-5); macrophage activity (IL-4, -13, B cell class switching = IgG, IgA and IgE
     • Release IL-4, IL-5, IL-10 and IL-13

7. T cytotoxic cells (CD8+) CTL

   • CTL eliminate intraceullar microbes by killing infected cells
   • Dendritic cell presents viral antigen/MHC Class I complex to naive CD8+ T cells in lymph node
   • Activated CTL clonally expand, differentiate, migrate through vascular supply to infected tissues
   • Killing of cells displaying viral peptid/MHC Class I complex (granzyme/perforin; Fas ligand)

8. CTL killing of infected cell by Fas ligand/receptor induction

   • Activated CTLs also express Fas ligand on their plasma membrane
   • Fas ligand binds to Fas receptor (death receptor) on some infected cells (ie. if expressed)
   • initiates intracellular apoptotic cascade

9. Humoral effector mechanisms: principle role

   • Elimination of extracellular microbes and microbial toxins
   • Accomplished by antibodies secreted by B cells

10. Antibody-mediated effector mechanisms

    • Opsonisation (deposition/coating)
    • Phagocytosis
    • complement fixing (classical)
    • Cell-mediated cytotoxicity
    • Neutralisation
      • of microbes and toxins

11. Antibody-mediated phagocytosis

    • Professional phagocytes (i.e. macs) have Fc receptor on their cell membranes which binds Fc portion of antibodies
    • Non-specific i.e. mac will bind any antibodies
    • An example of adaptive immune enhancement of phagocytosis (microbial particles/toxins)

12. Antibody-dependent cell-mediated cytotoxicity

    • NK cells can use FC-gamma-RIII to bind clustered IgG on surface of pathogens
    • FC-gamma- RIII cannot bind to monomeric IgG ciculation
    • NK cells can lyse cells coated with antibody (i.e. infections or autoimmunity)

13. Antibody-mediated activation of complement

    • Fc portion of antibodies (i.e. IgG and IgM have binidng sites for C1q which initiates the Classical pathway of complement activation
    • Unbound form of IgM does not bind C1q
    • Bound IgM has Fc portions available for binding
    • Soluble (unbound) IgG does not have 2 Fc regions

14. Antibody neutralisation

    • Antibody blocks binding of microbes and infection of cell
      • Prevention of microbial infection of cells
      • Antibody binds to specific site that is used by microbe to gain entry to a cell
    • Antibody blocks infection of adjacent cells
      • binding of antibody to the specific site involved with cell entry will prevent spread of new extracellular microbes
    • Antibody blocks binding of toxin to cellular receptor
      • products of microbes can also contain antigenic sites resulting in antibody production
      • Antibody can block active sites on toxins

15. Specifc effector functions of antibodies: neonatal immunity

    • Neonates and newborns lack adaptive immune responses
    • IgG antibodies cross placenta from the maternal blood and IgG and IgA contained within breast milk
    • Pathogenic antibodies can also be transferred (i.e. Graves disease)

16. Specific effector functions of antibodies: passive transfer of pathogen antibodies

    • Autoimmune thryrotoxicosis (Graves Disease). Antibodies (maternal) against thyroid gland are IgG class
    • IgG antibodies cross placenta from the maternal blood
    • Pathogenic effect on fetus and during first months of infant life

17. Effector functions of antibodies at specific anatomical sites: Gastrointestinal Tract

    • IgA is dominant Ig in seromucous secretions
      • Saliva
      • Colostrum
      • Milk
      • tracheobronchial secretions
    • Genitourinary secretions
    • Secretory IgA mainly dimeric associated with secretory J chain
    • B Cells is specialised lymphoid tissues (GI tract - Peyers patch) produce IgA for mucosal/intestinal effector functions