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.