Adaptive Immunity: Specific Defenses of the Host

Immunity

  • Innate immunity: Defenses against any pathogen.
  • Adaptive immunity: Induced resistance to a specific pathogen.
    • Aka--learned immunity, acquired immunity, humoral immunity.

Development of Adaptive Immunity

  • A “complete” immune system only found in vertebrate animals.
  • Portions found in simpler animals.

Dual Nature of Adaptive Immunity

  • T and B cells develop from stem cells in red bone marrow.
  • Cellular immunity: Due to T cells. T cells mature in the thymus.
  • Humoral immunity: B cells mature in the bone marrow (Chickens: Bursa of Fabricius), and is due to antibodies.

Antibodies and Antigens

  • Antibody (Ab): A protein produced in response to an antigen (Ag), capable of combining with that antigen. Also called an immunoglobulin.
  • Antigen (Ag): A substance that causes the body to produce specific antibodies or sensitized T cells.
  • Antibodies (Ab) interact with epitopes or antigenic determinants.
  • Antigens have minimum size and structural requirements.
  • Proteins make excellent antigens.
  • Hapten: Small or poor antigen is combined with carrier molecules and elicits antibody production (e.g., Penicillin).

The Nature of Antibodies

  • Globular proteins called immunoglobulins.
  • 5 classes of immunoglobulins.
  • Produced by B-cells.
  • Can be cell-associated or secreted.
  • Antigen specific.
  • Basic structure of 2 heavy and 2 light polypeptides.
  • Differ in location found, when produced, and number of antigen-binding sites (valence).
  • Classes of antibodies differ in Fc region.
  • Fab region highly variable.
  • “V” region is variable in sequence.
  • “C” region is constant in sequence.

Antibody Diversity

  • Each B cell (or each clone of B cells) produces one specific antibody.
  • Each human can synthesize more than 100 million different kinds of antibodies.
  • The light chain consists of 3 parts: V, J, and C.
  • The germ line DNA has about 200 (?) variable genes designated V (e.g., V1, V2, V3…….Vn).
  • The germ line has 1 constant region (C) for each class of antibody.
  • The germ line DNA has 4 joining genes designated J, e.g. J1, J2, etc.
  • During differentiation in the bone marrow, different combinations of a V gene, a J gene, and a C gene come together forming the final gene for the light chain.
  • 200 \times 4 \times 1 = 800 combinations (at least).
  • Light chain combinations times heavy chain combinations: 800 \times 4800 = almost 4 million combinations.
  • Each combination produces one specific antibody.
  • Lymphocytes use only about 400 to 500 genes to code for millions of abs.
  • By rearranging genes (and by mutations), millions of combinations are possible.
  • The rearrangements all occur before birth.
  • Any combinations that react to “self” are eliminated prior to birth or undergo anergy later on.
  • Even with these combinations, hypermutation in the V regions increases diversity even into adulthood!

IgD Antibodies

  • Monomer.
  • 0.2% of serum Abs.
  • In blood, in lymph, and on naive B cells.
  • On B cells, initiate immune response.
  • Half-life = 3 days.

IgM Antibodies

  • Pentamer.
  • 5–10% of serum Abs.
  • Fix complement.
  • In blood, in lymph, and on B cells.
  • Agglutinates microbes; first Ab produced in response to infection.
  • Half-life = 5 days.

IgG Antibodies

  • Monomer.
  • 80% of serum Abs.
  • Fix complement.
  • In blood, lymph, and intestine.
  • Cross placenta.
  • Enhance phagocytosis; neutralize toxins and viruses; protects fetus and newborn.
  • Half-life = 23 days.

IgA Antibodies

  • Dimer.
  • 10–15% of serum Abs.
  • In secretions.
  • Mucosal protection.
  • Half-life = 6 days.

IgE Antibodies

  • Monomer.
  • 0.002% of serum Abs.
  • On mast cells, on basophils, and in blood.
  • Allergic reactions; lysis (?) of parasitic worms.
  • Half-life = 2 days.

Activation of B Cells

  • Major histocompatibility complex (MHC) expressed on mammalian cells.
  • T-dependent antigens: Ag presented with (self) MHC to TH cell. TH cell produces cytokines that activate the B cell.
  • T-independent antigens: Stimulate the B cell to make Abs.

Activation of B Cells-T cell Independent

  • Polysaccharide (T-independent antigen) Usually a "pattern" molecule.

Clonal Selection (Clonal Expansion)

  • Stem cells differentiate into mature B cells, each bearing surface immunoglobulins against a specific antigen.
  • B cell III complexes with its specific antigen and proliferates.
  • Some B cells proliferate into long-lived memory cells, which at a later date can be stimulated to become antibody-producing plasma cells.
  • Other B cells proliferate into antibody-producing plasma cells.
  • Plasma cells secrete antibodies into circulation.

Elimination of “self” immunity

  • Prior to birth:
    • Activated B-cells and/or T-cells undergo apoptosis.
    • Clonal deletion instead of expansion.
  • Clonal expansion begins following birth.
  • After birth:
    • Lymphocytes undergo clonal anergy. Interaction of receptors with antigen in the absence of other markers of inflammation causes down-regulation of secreted antibody.
    • Lymphocytes (T and B) become dormant.
    • Occasionally fails giving rise to autoimmune disorders such as Multiple Sclerosis.

Cytokines = Cell to Cell Messengers

  • Examples of cytokines: interleukin-1 (IL-1), IL-2, IL-12, and more; interferons; tumor necrosis factor (TNF); colony-stimulating factor; Chemokines/chemotaxins.
  • Cells of the immune system communicate with each other by cytokines.
  • Lymphokine--A cytokine produced by a lymphocyte.
  • Interleukin--A cytokine that communicates only between leukocytes.

Activation of B Cells

  • During clonal selection, B cells differentiate into:
    • Antibody-producing plasma cells (First IgM, Seroconvert to IgG, or IgA, or IgE).
    • Memory cells (Persist in lymphatic tissue at least 30 years in humans).
  • Clonal deletion eliminates harmful B cells (Mainly occurs during fetal development, Self-reacting B-cells eliminated).

The Results of Ag-Ab Binding

  • Agglutination: Reduces number of infectious units to be dealt with.
  • Opsonization: Coating antigen with antibody enhances phagocytosis.
  • Neutralization: Blocks adhesion of bacteria and viruses to mucosa and attachment of toxin.
  • Activation of complement: Causes inflammation and cell lysis.
  • Antibody-dependent cell-mediated cytotoxicity: Antibodies attached to target cell cause destruction by macrophages, eosinophils, and NK cells.

T Cells and Cellular Immunity

  • T cells mature in the thymus (originate in bone marrow).
  • Thymic selection eliminates many immature T cells.
  • T cells respond to Ag by T-cell receptors (TCRs).
  • T cells require antigen-presenting cells (APCs).
  • APC’s are concentrated in lymphatic tissues but also in peripheral tissues as well.
  • Pathogens entering the gastrointestinal or respiratory tracts pass through M (microfold) cells over Peyer’s patches, which contain APCs.

T Helper Cells

  • CD4+ or TH cells.
  • TCRs recognize Ags and MHC II on APC.
  • Toll-like receptor (TLR) can be a costimulatory signal on APC and TH.
  • TH cells proceed through clonal expansion.
  • TH cells produce cytokines and differentiate into:
    • TH1.
    • TH2.
    • Memory cells.
  • The balance between the TH1 to TH2 responses depends on host and antigen-related factors.
  • TH1 produces IFN-g, which activates cells related to cell-mediated immunity such as macrophages.
  • TH2 activate B cells to produce antibodies.

T Cytotoxic Cells

  • CD8+ or TC cells.
  • Target host cells that are expressing antigens.
  • Activated into cytotoxic T lymphocytes (CTLs).
  • CTLs recognize Ag + MHC I.
  • Induce apoptosis in target cell.
  • CTL releases perforin and granzymes.
  • An effective response versus intracellular pathogens (viruses).

T Regulatory Cells

  • Treg cells (aka inhibitory T-cells).
  • CD4 and CD25 on surface.
  • Secrete anti-inflammatory cytokines.
  • Down-regulate immune response over time.
  • Suppress immune response to “self” antigens.

Antigen-Presenting Cells

  • Digest antigen.
  • Ag fragments on APC surface with MHC.
  • B cells.
  • Dendritic cells.
  • Activated macrophages.

Natural Killer (NK) Cells

  • Granular lymphocytes destroy cells that don’t express MHC I (foreign cells).
  • Kill virus-infected and tumor cells.
  • Attack parasites.
  • MHC class I on almost all cells.
  • MHC class II on immune cells.

Antibody Dependent Cell-Mediated Cytoxicity (ADCC)

  • Organisms, such as many parasites, that are too large for ingestion by phagocytic cells must be attacked externally.

HUMORAL (ANTIBODY-MEDIATED) IMMUNE SYSTEM

  • Control of freely circulating pathogens.
  • A B cell binds to the antigen for which it is specific.
  • A T-dependent B cell requires cooperation with a Tч cell. B cell proliferates and some progeny become plasma cells or memory cells.
  • The B cell, often with stimulation from a helper T cell, differentiates into a plasma cell.
  • Cytokines transform B cells into antibody-providing plasma cells.
  • Plasma cells proliferate and produce antibodies against the antigen.
  • Memory cell
  • Some T and B cells differentiate into memory cells that respond rapidly to any secondary encounter with an antigen

CELLULAR (CELL-MEDIATED) IMMUNE SYSTEM

  • Control of intracellular pathogens
  • Exposure to antigen.
  • Intracellular antigens expressed on the surface of a cell infected by a virus, bacterium, or parasite. (Also may be expressed on surface of an APC.)
  • A T cell binds to MHC-antigen complexes on the surface of the infected cell, activating the T cell (with its cytokine receptors).
  • Activation of macrophage (enhanced phagocytic activity).
  • Cytotoxic T lymphocyte
  • CD8 T cell becomes cytotoxic T lymphocyte (CTL) able to induce apoptosis of target cell

Immunological Memory

  • Antibody titer is the amount of Ab in serum.
  • Primary response occurs after initial contact with Ag.
  • Secondary (memory or anamnestic) response occurs after second exposure.

Types of Adaptive Immunity

  • Naturally acquired active immunity (Resulting from infection).
  • Naturally acquired passive immunity (Transplacental or via colostrum).
  • Artificially acquired active immunity (Injection of Ag - vaccination).
  • Artificially acquired passive immunity (Injection of Ab).

Terminology of Adaptive Immunity

  • Serology: The study of reactions between antibodies and antigens.
  • Antiserum: The generic term for serum because it contains Ab.
  • Globulins: Serum proteins.
  • Immunoglobulins: Antibodies.
  • Gamma (g) globulin: Serum fraction containing Ab.