Immunoglobulin

Aka: Immunoglobulin, Antibody, Fragment Antigen Binding, Immunoglobulin Fab Fragment, Fragment Crystallizable, Immunoglobulin Fc Fragment, Ligand, Humoral Immunity, Immunoglobulin Constant Region, Immunoglobulin Variable Region, Immunoglobulin Heavy Chain, Immunoglobulin Light Chain, Immunoglobulin J-Chain, Clonal Selection Theory, Isotype, Allotope, Idiotype

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II. Definitions

  1. Fragment Antigen Binding (Fab)
    1. Antibody region that recognizes and binds Antigens
  2. Fragment Crystallizable (Fc)
    1. Antibody region that interacts with Immune System components
    2. Endogenous Fc triggers Natural Killer Cells and complement cascade
    3. Synthetic monoclonal antibodies may bind Fc to toxins or radioisotopes in Chemotherapy
  3. Ligand
    1. Molecule that binds to a specific receptor
  4. Humoral Immunity
    1. Humoral Immunity (i.e. B-Cells and antibodies) targets extracellular pathogens
    2. Part of Adaptive Immunity (learned Immunity) in combination with cellular Immunity (T-Cell function)
  5. Isotype
    1. Individual Antibody groups (Immunoglobulin A, E, G, M and D)
  6. Allotope
    1. Isotype (Immunoglobulin A, E, G, M and D) variation specific to an individual
    2. Functionally insignificant changes in Antibody structure that differentiates Isotypes from one individual to another
  7. Idiotype
    1. Antigen receptor types found on Lymphocytes
    2. B Cell Idiotypes are identical to their corresponding antibodies
    3. T Cell Idiotypes vary considerably from their B Cell counterparts, but still respond to the same Antigen

III. Physiology: B-Cells

  1. Derivation
    1. Fetal Liver
    2. Bone Marrow Pluripotent Stem Cells
  2. Peripheral Migration to Secondary Lymphoid Tissue
    1. Spleen
    2. Lymph Nodes
    3. Peyer's Patches (Small Bowel)
  3. Clonal Selection Theory
    1. Immature Lymphocytes are generated from hematopoietic stem cells
      1. Surface covered in wide variety of Antigen receptors (surface antibodies) prior to sensitization
      2. Variable region of surface antibodies contain many permutations (10^12) of heavy and light chains
    2. Lymphocytes mature into inactive Lymphocytes
      1. Lymphocytes differentiate to inactive Lymphocytes, each ready to respond to a limited set of Antigens
      2. Antibodies that recognize self Antigens are inactivate and destroyed (including during fetal development)
        1. Self Tolerance is critical to preventing Autoimmune Disease
    3. Foreign Antigen is encountered
      1. B-Lymphocyte is activated and multiple clones of the reacting Lymphocyte are made
      2. Each B-Lymphocyte produces a variety of slightly different antibodies against an Antigen
        1. Contrast with identical monoclonal antibodies produced in the lab, and by lymphocytic tumors
    4. Resources
      1. Clonal Selection (Wikipedia)
        1. https://en.wikipedia.org/wiki/Clonal_selection
      2. Generation of Antibody Diversity (Molecular Biology of the Cell)
        1. https://www.ncbi.nlm.nih.gov/books/NBK26860/
  4. Activation
    1. Images
      1. BCellActivation.jpg
    2. Recognition
      1. Antigen binds B-Lymphocyte Surface Receptor (BCR)
        1. Protein Antigens
          1. Primary response (IgM mediated after 5-10 days)
          2. Secondary response (highly specific, IgG mediated after another 1-3 days)
            1. More specific response via T-Helper-mediated B-memory cell proliferation
        2. CarbohydrateAntigens
          1. Limited secondary response due to lack of T-Cell (and related B-memory cell) involvement
          2. Associated with less potent and shorter duration immune response (compared with Protein)
      2. BCR binding activates B-Lymphocyte
        1. T-Cell Independent Antigen (e.g. inert Antigens) alone activate B-Cells
        2. T-Cell Dependent Antigen (e.g. Microbes) require added stmulus (e.g. T Cells)
          1. Phagocytes (e.g. Macrophages) identify foreign Antigen and release Interleukin-1 (IL-1)
          2. Interleukin-1 (IL-1) stimulates T-Helper Cells
          3. T-Helper Cells release Cytokines that promote B Cell Proliferation and Differentiation
    3. B-Cell Proliferation
      1. Activated Lymphocytes proliferate
    4. B-Cell Differentiation
      1. Plasma Cells (Antibody producing cells)
        1. Survive for days to weeks in Lymph Nodes and Spleen, producing antibodies, and without replicating
      2. Memory Cells
        1. Formed in germinal centers of Lymphoid Tissue and then distribute to peripheral circulation
        2. Remain in B-Lymphocyte pool ready to respond to the same Antigen in future
        3. Future Antigen response is known as secondary immune response

IV. Physiology: Immunoglobulin

  1. Images
    1. idAntibody.jpg
  2. Immunoglobulins (or antibodies) are Y-Shaped Glycoproteins generated by Plasma Cells
  3. Immunoglobulin is composed of a 4 chain monomeric structure
    1. Two heavy chains (identical)
      1. Five heavy chain classes: M, D, E, A, and G1-4
    2. Two light chains (identical)
      1. Two light chain classes: kappa and lambda
  4. Immunoglobulin stem (Fc) is composed of 2 identical heavy chains
  5. Two Immunoglobulin Arms emanate from the stem
    1. Each arm is composed of 2 heavy chains and 2 light chains
    2. The end of each arm contains an Antigen binding site (Fab)
  6. Immunoglobulins have 2 forms
    1. Membrane bound Immunoglobulins (on surface of B-Cell)
    2. Secretory Immunoglobulin (unbound, free-floating)
      1. Monomeric antibodies exist as single Antibody molecules (IgE or IgG)
      2. Multimeric antibodies exist as multiple joined antibodies (IgA or IgM)
        1. Connected with J Chains
    3. Antibodies
      1. Immunoglobulin (Ig)

V. Types: Immunoglobulins (Isotypes)

  1. Immunoglobulin G (IgG and subclasses IgG1-4)
    1. Monomer with Molecular weight 160,000 dalton
    2. Accounts for 75% of all Antibody
    3. Serum Half-Life of 23 days
    4. Responsible for long lasting Immunity (secondary immune response) and Type 2 Hypersensitivity
  2. Immunoglobulin A (IgA and subclasses IgA1, IgA2)
    1. Dimer (2 Antibody molecules) when secretory Ig with Molecular weight 350,000 dalton
    2. Accounts for 10-15% of all Antibody
    3. Serum half life of 6 days
    4. Present in body secretions (e.g. tears, Saliva, milk) and responsible for mucosal Immunity
  3. Immunoglobulin M (IgM)
    1. Pentamer (5 Antibody molecules) when secretory Ig with Molecular weight 900,000 dalton
    2. Responsible for early, primary Antibody response and potent complement activator
  4. Immunoglobulin E (IgE)
    1. Long stem (Fc) monomeric Antibody with Molecular weight 180,000 dalton
    2. Fc region is bound to Eosinophils, Basophils and Mast Cells
    3. Serum Half-Life of 2.5 days
    4. Reacts to allergans (Type 1 Hypersensitivity) and Parasitic Infections
  5. Immunoglobulin D (IgD)
    1. Monomer with Molecular weight 160,000 dalton
    2. Serum half life of 3 days
    3. Membrane bound surface Antibody on B Lymphocytes

VI. References

  1. Bakerman (1984) ABCs of Interpretive Lab Data, p. 392
  2. Mahmoudi (2014) Immunology Made Ridiculously Simple, MedMaster, Miami, FL
  3. Guyton and Hall (2006) Medical Physiology, p. 419-50

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