Lecture 5-6

• Functions of the Immune system:

  1. Neutralize or destroy pathogens
  2. Help resolve tissue injury
• The 5 cardinal signs of inflammation are: pain, heat, redness, swelling, and loss of function.
• Innate Immunity:

  1. Non-specific
  2. Immediate response
• Adaptive Immunity:

  1. Specific
  2. Slow response
  3. Memory persists
• Innate Immunity incudes: epithelial barrier, phagocytes, dendritic cells, complement, and NK cells
• Adaptive Immunity includes: B-cells, T-cells, and antibodies.
• functions of the epithelial barrier:

  • Mucous production by goblet cells creates a physical barrier
  • Specialized cells secrete antimicrobial peptides to sterilize the microenvironment
• functions of the complement system:

  • Formation of the MAC (C5b,C6, C7, C8, C9)
  • Opsinization (C3b)
  • Chemotaxis (C3a, C4a, C5a)
  • Functional complexes with Abs
• The 3 non cellular defense systems are: kinin system, coagulation cascade, and complement system
• Professional phagocytes have receptors for opsonins, which can be found on Antibodies and Complement proteins.
• Innate immune receptors are known as pattern recognition receptors (PRRs), and the most common ones are known as PAMPs.
• PAMPs are usually repetitive structural elements of pathogens that are recognized by the immune system
• PAMPs:

  • Produced by microbes, not host cells.
  • Are essential for viability of the microbes and therefore cannot be mutated to escape detection.
  • Shared by entire classes of pathogens
• Host factors may also activate innate immune receptors, known as DAMPs (Death associated molecular patterns)
• the first responders are phagocytes:

  1. Activation of Mast cells
  2. Neutrophil Recruitment
  3. Activation of Macrophages
  4. Dendritic Cells – antigen presentation
• neutrophils are phagocytes with a wide range of innate immune receptors, and can release antimicrobial agents such as ROS, cathepsin G and defensins
• neutrophils can undergo NETosis, which are traps for pathogens.
• NETs can cause: cell damage, inflammation, vaso-occulsion, tumor growth, formation of autoantibody, cytokine degradation.
• macrophages can be made in the bone marrow, yolk sac and liver.
• macrophage functions:

  • antimicrobial actions
  • antigen presentation
  • antigen/antibody uptake
  • wound healing
  • phagocytosis
  • bone reabsorption
• dendritic cells:

  1. Derived from monocytes
  2. Carry antigens to LN
  3. Present antigens to T cells via MHC Class II
  4. Maintain tolerance to self antigens
  5. Most efficient APC
• steps of antigen presentation:

  1. antigen enters dendritic cell
  2. enzyme inside cell breaks antigen into pieces
  3. antigen pieces bind to MHC protein inside the ER
  4. the MHC-antigen complex is transported to the cell surface via the Golgi
  5. the MHC protein presents the antigen on the surface of the cell membrane
• There are two MHC molecules, Class I and Class II. Class II are specific to APCs and Class I are expressed on all nucleated cells.
• In humans, HLA class I and II genes are located on chromosome 6.
• The HLA genes are polygenic and highly polymorphic. Only identical twins have the same HLA genes.
• most innate lymphoid cells are derived from myeloid progenitor cells, except NK cells which are from lymphoid progenitor cells.
• natural killer cells are large Innate lymphoid cells with cytotoxic functions, which are important for clearing virus infected cells and tumor cells.
• Killing mechanisms of NK cells: Induction of apoptosis (Granzyme and Perforins) and Fas ligand
• NK cells attack host cells that have escaped immune surveillance.
• NK cells have inhibitory receptors and activating receptors.

  They will lyse the cell if: activating receptor and no inhibitory, or more activating than inhibitory.

  they won't lyse the cell if: inhibitory and no activating, or more inhibitory than activating.
• More Innate lymphoid cells that respond to specific pathogens and respond by releasing specific groups of cytokines:

  • ILC1: respond to intracellular pathogens
  • ILC2: respond to parasites
  • ILC3: respond to extracellular bacteria and fungi
• adaptive immunes come from lymphoid progenitor cells.
• How is the T cell receptor repertoire generated?

  VJ recombination and Random nucleotide insertions
• MHC class I molecules bind to CD8 T-cells and MHC class II molecules bind CD4 T-cells.
• stem cell -> pre B-cell -> B-cell (first step in bone marrow and second in the bone marrow)

  stem cell -> pre T-cell -> T-cell (first step in bone marrow and second in the thymus)

  then, both mature cells go to the lymph node.
• T cells that recognize self MHC with too high avidity are deleted in the thymus.
• In peripheral tissues CD4+ T cells will further mature into different subtypes depending on the cytokine and TF profiles.
• B cells bind to Surface Immunoglobulin or B cell receptor.
• B cells encounter antigens and become activated in Lymph nodes.
• Consequences of B cell activation:

  • If B cells have low affinity for antigen they will be eliminated by apoptosis
  • Increased affinity for antigen by hypermutation of the variable region of the B cell receptor via AID
  • T cell dependent activation.