414/514 Immunology Principles 415/515 Immunology Principles and Practice

Antigens

Antigens are molecules that interact specifically with antigen-specific immune response molecules ... antibodies, B cell receptors (BCRs), T cell receptors (TCRs) or Antigen-presenting cell receptors (ACRs) ... via antigenic determinants

• Antigenic determinants, or epitopes, are the portions of antigen molecules that physically interact with paratopes (combining sites) of immune response molecules and therefore actually "determine" antigen specificity
• Types of epitopes:
  • Linear epitopes
    • continuous and found in polysaccharides as well as in both native (nondenatured) and denatured proteins, especially fibrillar proteins
    • specificity depends upon primary sequence
    • typical size is 5-6 subunits in length
  • Conformational epitopes
    • discontinuous (involve multiple subunits, often located far apart in the primary sequence of the antigen molecule) and are thus found only in native (globular) proteins
    • specificity depends upon conformation, or three-dimensional shape, which is a combination of tertiary and quaternary structure ... supported by primary and secondary structure, of course
    • typical size is hard to pinpoint, but sequences of up to 16 amino acids in certain protein antigens have been shown to interact with their complementary paratope
• Incomplete antigens have antigenic determinants, but cannot induce immune responses because they lack one or more of the important attributes (described below) needed for this function (one example of an incomplete antigen is a hapten, which is an artificial monovalent epitope)

Immunogens are complete antigens because, in addition to being able to interact with specific immune response molecules,they can also induce immune responses ... due to the function of several interrelated attributes or factors

• Immunogenicity is determined by these factors:
  • Foreignness is essential to immunogenicity because self-responsive cells are eliminated during lymphocyte ontogeny, leaving only cells that respond to non-self, so-called "foreign" epitopes
  • Molecular size (high molecular weight) is essential to immunogenicity because larger molecules are:
    • More complex and therefore more likely to contain more than one foreign epitope
    • Engulfed and processed more readily than smaller molecules of the same composition
      • Protein immunogens must be processed and presented to trigger T cell responses
      • Antigen molecule concentration must be reduced greatly by the immune system if immune responses are to occur (so the immune system cells are not "swamped-out" by too many molecules)
  • Composition and chemical complexity
    • Composition is important in determining whether a response will occur or not:
      • Proteins are generally the most potent immunogens
      • Polysaccharides run a distant second
      • Nucleic acids and lipids are not immunogenic unless attached to immunogenic proteins or polysaccharides
    • Chemical complexity is important because more complex molecules are more likely to:
      • contain more than one (foreign) epitope that can be recognized by lymphocyte receptors
      • be engulfed and processed more readily than simple (small) molecules ... the more complex the immunogen, the smaller it can be and still induce an immune response (important for proteins)
  • Processing and presentation susceptibility is important because:
    • T cell recognition of antigen requires its processing and presentation by antigen-presenting cells (APCs)
    • removal of excess antigen (generally the job of phagocytic cells) is often necessary to prevent tolerance, in which development of an immune response is prevented, sometimes due to the presence of too many immunogen molecules
• Immune responses, although dependent upon immunogenicity factors, are also influenced by a number of attributes of the responding animal ... some of which are:
  • Genotype of the responding animal
    • Immunogenicity factor studies performed with synthetic immunogens indicated that certain molecules could induce immune responses in some strains of experimental animals but not in others ... thus indicating that genetic factors are important in determining immune responsiveness
    • Major histocompatibility complex (MHC) molecules are the gene products responsible for this variability in immune responsiveness in most cases ... because these MHC molecules function as antigen-presenting cell receptors (ACRs)
    • ACRs form complexes with fragments of immunogen molecules in responsive animals, but not in non-responsive animals (and to an intermediate degree in animals that respond poorly to an immunogen)
    • Genotype controls immune responsiveness by determining the structure of ACRs present on immune cells, which determines whether or not (or to what degree, for intermediate levels of responsiveness) they can bind immunogen fragments ... thus determining whether or not they can respond to an immunogen
  • Immunogen dosage and route of administration
    • Dosage
      • High doses of immunogen may cause a lack of responsiveness referred to as tolerance because they "swamp-out" the immune system
      • Intermediate doses of immunogen are generally the best immune response inducers
      • Low doses of immunogen may not induce immune responses because they:
        • constitute too few molecules to adequately stimulate enough cells to yield an immune response ... or
        • induce tolerance
    • Route of immunogen administration influences which cells (and how many of them) are stimulated, thus having a profound influence on the nature and intensity of the immune response induced
      • Parenteral administration:
        • Intravenous (iv) and intraperitoneal (ip) injections stimulate immune cells in the spleen first
        • Intradermal (id), subcutaneous (cs) and intramuscular (im) injections stimulate immune cells in the lymph node that "drains" the site of injection first
      • Non-parenteral (enteric = ingestion) administration:
        • Preferred route for intestinal parasite immunogens
        • Frequenly induces B cell tolerance rather than an immune response
  • Adjuvants are immune response enhancers that function by causing one or more of these effects:
    • Prolonged persistence of immunogen molecules at the site of injection
    • Enhancement of co-stimulatory signals
    • Induction of granuloma formation
    • Stimulation of lymphocyte proliferation in a non-specific manner

Interaction of immunogen with immune cell receptors is considered further on the Antigen Receptors and on the Antigen Interactions web pages

Interaction of antigen with antibody is considered further on the Antigen Interactions web page