B-lymphocytes rearrange their V, D, and J gene segments to create diverse antibodies. T-lymphocytes, however, only rearrange their T-cell receptor genes. Consequently, in T-cells, the immunoglobulin genes remain in their original, unrearranged "germline" state.

• Immunotherapy medications often utilize fragments of a monoclonal immunoglobulin rather than the full immunoglobulin; because fragments are smaller, they typically have better tissue penetration and pharmacokinetics. Fab fragments contain a variable domain and the first constant region from a heavy and light chain; because they do not contain an Fc receptor, Fab fragments cannot trigger cell killing via complement or phagocytosis.
• IgG, IgA, and IgD also have a hinge region between the Fab and the Fc fragments. The hinge region is rich in cysteine and proline amino acids, which provide significant flexibility to the immunoglobulin and allow greater movement of the Fab fragment arms. Fab fragments with long hinge regions are better able to reach multiple epitopes on an antigen; this increases immunoglobulin avidity because avidity is directly proportional to the number of Fab-antigen interactions. However, long hinge regions are more susceptible to destruction by bacterial proteases (eg, IgA protease).

Immunoglobulin types

• IgM
  • Blood group antibodies
• IgG
  • The only immunoglobulin that can cross the placenta and thus conveys transient passive immunity to the child
  • Neutralization of viruses and bacterial toxins, preventing the virus from entering host cells.
• IgA
  • Found especially on mucosal surfaces and in bodily fluids like saliva, mucus, tears and breast milk
  • Prevents binding of pathogens to mucous membranes of host cells

Antibody-dependent cell-mediated cytotoxicity (ADCC)

• Definition: an immune response in which Fc receptor-bearing immune effector cells (e.g., NK cells, eosinophils) bind to and lyse target cells that have specific antibodies attached to their surface antigens (pathogen or tumor-derived)
• Characteristics
  • Allows innate immune cells to recognize pathogens that do not express pathogen-associated molecular patterns (PAMPs)
  • Part of the immune response to parasites
• Effector cells
  • NK cells (most common): interact with IgG-coated target cells and subsequently release cytotoxic substances (perforins, granzymes)
  • Eosinophils: interact with IgE-coated helminths and subsequently release major basic proteins and other cytotoxic substances
  • Other: monocytes, macrophages, neutrophils
• Mechanism
  • Binding of antibodies (e.g., IgG or IgE) produced by B-cells to antigens on target cells (e.g., tumor cells, viruses, or parasites)
  • Recognition and binding of the Fc portion of bound IgG or IgE by Fc receptors expressed on the surface of effector cells (e.g., CD16 Fc receptors on NK cells)
  • Activation of signaling pathways in the effector cell (e.g., NK cell), leading to cytotoxic granule release
  • Destruction of the target cell (e.g., via the perforin/granzyme cell death pathway)
• Clinical significance: monoclonal antibody therapy