Immunopharmacology

• Introduction-- Immune System

  • Defenses against antigenic insults:

    • Innate immune system

    • Adaptive immune system

• Innate Immune System

  • Physical (skin)

  • Biochemical (e.g. complement, lysozyme)

  • Cellular (e.g. macrophages, neutrophils)

  • When the barrier is disrupted, bacterial destruction may occur by:

    1. Lysozyme enzyme activity causes peptidoglycan cell wall component cleavage; also:

    2. Split products from complement activation

       • Complement components: enhance macrophage and neutrophil phagocytosis by:

         • Acting as opsonins (C3b)

         • Attracting immunocytes to inflammatory sites (C3a, C5a)

         • Promoting bacterial lysis -- membrane attack complex generation

• Adaptive Immune System

  • The adaptive immune system comes into play if the innate immune system has not managed the infection adequately.

  • Characteristics of the adaptive immune system

    1. Specific responses to a variety managements

    2. Discriminate between foreign ("nonself") and "self", i.e. host antigens

    3. Exhibits "memory"; initiates an aggressive response to previously encountered antigen

  • Effectors of humoral immunity: antibodies

  • Effectors of cell mediated immunity: activated lymphocytes

  • Specific Immunity:-- requirements

    1. Antigen presenting cells (APCs)

       • Langerhans cells

       • B lymphocytes

       • Dendritic cells

       • Macrophages

    2. APCs digest antigens (enzymatically) producing peptides that:

       • Interact with T cell lymphocyte receptors (TCR) in association with class I and class II major histocompatibility complex proteins (MHC proteins)

       • T cell lymphocyte activation-- additional molecular dependencies:

         •  CD₄ on helper T cells

         •  CD₈ on cytotoxic T cells

         •  LFA-1(lymphocyte functional antigen) and CD₂ on both helper and cytotoxic T cells

         •  Co-stimulatory molecules (B7.1 and B7.2) by cognate receptors on APCs

  • Lymphocyte selection

    • Thymic lymphocyte that bind to "self"-- eliminated by apotosis (negative selection)

    • Thymic lymphocytes that respond to foreign antigens in the presence of "self" MHC: retained (positive selection) and distributed to peripheral sites, available for later activation (after interacting with MHC-presented peptides):

      • Lymph node

      • Spleen

      • Peripheral blood

      • Musosa-associated lymphoid tissue

  • Subsets of T helper lymphocytes:  discrimination based on cytokine secretion, after activation

    • TH1:  Cell-mediated Immunity

      • TH1:  Cell-mediated Immunity Produces interferon-g (IFNg) Produces interleukin-2 (IL-2) Produces tumor necrosis factor-b (TNFb) Induces cell-mediated immunity by activation of: Cytotoxic T cells (CTL) Natural killer (NK) cells Macrophages IL-10 (from TH2 cells) down regulates TH1 activity

      •  

        T Helper Function

        "Function of T helper cells:  Antigen-presenting cells (APCs) present antigen on their Class II MHC molecules (MHC2).  Helper T cells recognize these, with the help of their expression of CD4 co-receptor (CD4+).  The activation of a resting helper T cell causes it to release cytokines and other stimulatory signals (green arrows) that stimulate the activity of macrophages, killer T cells and B cells, the latter producing antibodies." Figure:  Haggstrom M  T helper cell function: http://en.wikipedia.org/wiki/File:Lymphocyte_activation_simple.png Figure Legend:  http://en.wikipedia.org/wiki/Immune_system

      • Produces interferon-g (IFNg)

      • Produces interleukin-2 (IL-2)

      • Produces tumor necrosis factor-b (TNFb)

      • Induces cell-mediated immunity by activation of:

        •  Cytotoxic T cells (CTL)

        •  Natural killer (NK) cells

        •  Macrophages

    • TH2 :Humoral Immunity

      • Produces (interleukins) IL-4, IL-5, IL-6 which in turn causes:

        • B-cell proliferation

        • Differentiation into antibody secreting plasma cells

  • T helper lymphocytes:  mutual regulation

    • TH2 cells produce IL-10: inhibits TH1 cytokine production (down-regulates MHC expression by APCs)

    • TH1 interferon-g: inhibits TH2 cell proliferation

  • Other down-regulation/suppression factors (in some tissues)

    • Iransforming growth factor-b (TGF-b)

      • Down-regulates lymphocyte proliferation

    • Prostaglandin E2: down-regulates immune response

  • T helper lymphocytes: phenotype selection based on antigenic challenge

    • Extracellular bacteria: TH2 cytokine release

    • Intracellular organisms (e.g. Mycobacterium): TH1 cytokine release

Cytotoxic Consequences of Immune System Activation

• Activated cytotoxic T cells (recognize processed peptides presented by virus-infected cells/tumor cells)

  • Induce target cell death by:

    • Perforin

    • Lytic granule enzymes ("granzymes")

    • Fas-Fas ligand (Fas-Fasl) apotosis pathway

    • Nitric oxide (may be released): inhibits cell enzymes

• Viral Antigen Presentation (by virus-infected cells):

  • Nonapeptide fragments in the group of class 1 MHC molecules

• MHC molecules

  • Class I MHC molecules: presenting fragments of cellular antigens (virus/tumor antigens)--after Golgi apparatus processing

  • Class II MHC molecules: presenting antigen fragments from:

    • Internalized/enzymatically digested foreign antigens

• Natural Killer Cells: (NK): (CD16+, CD56+, CD57+):  possible role in tumor rejection/viral immunity; in vivo role uncertain

  • NK cells: large granular lymphocytes

    • Azurophilic cytoplasmic granules

    • Surface immunoglobulin negative

    • FC receptor-positive

    • Probably separate lymphoid cell lineage

  •  NK cells: main precursor of lymphokine activated killer (LAK.)cells

    • LAK cells:

      • Stimulated by IL-2 (high concentration)

      • Referred to as (promiscuous killers) because:

        •  Kill across MHC barriers

        •  Kill target cells not expressing MHC

B lymphocytes:  Humoral Immunity

• The cells of the immune system that make antibodies to invading pathogens such as viruses.  They form memory cells that remember the same pathogen for faster antibody production in future infections. Figure attribution:  Hazmat2- http://en.wikipedia.org/wiki/File:Original_antigenic_sin.svg Legend:  http://en.wikipedia.org/wiki/B_cell

• Self-reactive B lymphocytes clonally deleted in the bone marrow

• B-cell clones specific for foreign antigens -- retained/expanded

• B-cell specificities due to:

  • Immunoglobulin gene rearrangement

  • These determinations occur prior to antigen exposure

    • Antigen specificity: T cells:  genetically determined; derive from T-cell receptors

• Sequence following Antigen binding to B-cell membrane immunoglobulin (IgM or IgD)

  1. Antigen endocytosed, processed, presented to CD4+ T helper cells

  2. T helper cells then stimulated to produce IL-4 and IL-5

  3. Interleukins IL-4 and IL-5 stimulate:

     •  B-cells proliferation

     •  B-cell differentiation into memory B cells

     •  Antibody secreting plasma cells

  4. Primary antibody response: IgM-class immunoglobulins

     • Later antigenic stimulation leads to a "booster" response associated with:

       • Class switching (isotype switching) to produce IgG, IgA, IgD antibodies with various effector functions

       • Evolution over time:

         •  Increased affinity; more efficient antigen binding

         •  Antibodies activates opsonins to enhance phagocytosis, cellular cytotoxicity, and by activating complement promotes the inflammatory response which leads to bacterial lysis.