Antigens-May possess: immunogenicity, antigenicity, allerogenicity, and tolerogenicity
Immunogenicity - Property that allows a substance to induce a detectable immune response (humoral or cellular) when introduced into an animal. Such substances are termed Immunogens.
Antigenicity - Property that allows a substance to combine specifically with antibodies or TcR , whether or not they are immunogenic. Therefore, all immunogens are antigens but not all antigens are immunogens.
Allerogenicity- Property that allows a substnace to induce an allergic response. Such substances are termed allergens.
Tolerogenicity- Property that allows a substance to induce specific immunologic non-responsiveness in either the humoral or cell-mediated branch. Such substances are termed tolerogens.
Low-molecular weight compounds including many drugs and antibiotics, are non-immunogenic but when coupled to immunogenic proteins, the resulting conjugates stimulate the production of antibodies which can bind to the low-molecular weight component. Such molecules are termed haptens.
Epitope - the part of an antigen that combines with a specific antibody or T cell receptor. Previous term was antigenic determinant.
Immunogens For the induction of humoral immunity (antibody response), the most potent immunogens are macromolecular proteins or glycoproteins, but polysaccharides, synthetic peptides, and other synthetic polymers such as polyvinylpyrrolidone are immunogenic under appropriate conditions. Pure nucleic acids or lipids are not immunogenic but antibodies which react with them can be induced by immunization with nucleoproteins or lipoproteins.
Only proteins serve as immunogens for cell-mediated immunity. (Remember, these proteins must be processed and presented by an APC in association with MHC.
Requirements for Immunogenicity
Somewhat dependent upon the experimental conditions (mode of immunization, organism being immunized, sensitivity of detection methods, etc.). However, certain conditions must be satisfied in order for a molecule to be immunogenic.
A. Foreignness: Rabbit albumin not immunogenic in another rabbit but would be immunogenic in a mouse.
B. Molecular Size: Certain minimum size is required for immunogenicity. The most potent immunogens are macromolecular proteins with molecular weights greater than 100,000. Substances <1000 are not usually immunogenic.
C. Chemical Complexity: Homopolymers consisting of repeating units of a single amino acid are poor immunogens regardless of their size. Co-polymers of 2 or 3 amino acids may be good immunogens. CO-polymer of glutamic acid an lysine must be 30-40,000 to be immunogenic
Add tyrosine - reduce size limitation to 10-20,000
Add tyrosine and phenylalanine and reduce to, 4000
-- In general, immunogenicity increases with structural complexity.
Aromatic amino acids contribute more to immunogenicity than non-aromatic (ex: tyrosine or phenylalanine). All four levels of protein structure (1o, 2o, 3o, & 4o) influence immunogenicity.
D. Degradability: Macromolecules that cannot be degraded and processed by APCs are poor immunogens. Polymers of D-amino acids are not immunogenic. Proteolytic enzymes can only degrade proteins containing L-amino acids.
D. Genetic constitution of the Animal: Immune response is under genetic control. Individuals differ in their ability to respond to immunogens. Animal may not have an appropriate Ig, may not have an appropriate TcR, or may not have an appropriate MHC.
E. Method of Antigen Administration: Whether an antigen will induce an immune response depends on the dose and the mode of administration. Too little may not stimulate a strong response, too much may stimulate tolerance.
Lymphocytes do not interact with or recognize an entire immunogen, instead, lymphocytes recognize discrete sites on the macromolecule called epitopes or antigenic determinants.
T cells and B cells exhibit fundamental differences in antigen recognition. Much of this information has been determined with the aid of the technique of epitope mapping (critical to vaccine development).
B cell epitopes
The binding of antigen to Ig involves weak non-covalent interactions so there must be complementarity.
Properties of B cell epitopes:
1]Soluble antigens
2]epitopes tend to be accessible and on the exposed surface of the immunogen
3]Epitopes generally contain hydrophilic amino acids
4]Often the epitopes are found where the molecule bends or where there is a high degree of segmental mobility [atomic mobility]
5]The epitope may consist of either sequential or non-sequential amino acids. If non-sequential, the 3D conformation of the epitope if vital.
6] Complex proteins contain multiple overlapping epitopes
The size of a B cell epitope is determined by the size of the antigen binding site on the antibody molecule. Conformationally determined epitopes tend to require a larger epitope. Smaller ligands (carbohydrates, peptides, haptens, etc.) tend to fit within a deep concave pocket or crevice. Larger globuluar antigens tend to interact with Ig across a large planar face. Protrusions on the antigen binding site would be complementary with depressions on the epitope and vice versa. This type of interaction is obviously highly dependent upon the 3D conformation of the globular antigen.
T cells
Recognize processed peptides associated with MHC on the surface of APCs (Class II MHC) or altered self cells (Class I MHC). MHC RESTRICTED ANTIGEN RECOGNITION
CD4+ T cells are restricted to Class II MHC
CD8+ T cells are restricted to Class I MHC
1]The binding of the TcR to MHC + peptide represents a tri-molecular complex
2]Only oligomeric peptides serve as epitopes
3] Antigen processing is required to generate the peptides that interact specifically with MHC molecules.
4] T cell antigens often contain amphipathic peptides [amphipathic peptides contain both a hydrophilic and hydrophobic region]. The hydrophobic region serves as the agretope while the hydrophilic region serves as the epitope.
5]Immunodominant T cell epitopes are determined by the set of MHC molecules which are expressed by an individual.
Experimentally it has been demonstrated that there is a correlation between the ability of a peptide to bind to a particular MHC molecule and the T cell response to that peptide.
Haptens - Small molecules [small size and minimal valency] that of themselves do not induce the production of antibody, but are capable of reacting with antibody. In terms we have previously introduced they are antigenic but not immunogenic. When the hapten is conjugated to a carrier (a large immunogenic molecule such as a protein) the animal responds by producing antibodies to both the hapten and the carrier.
Many biologically important substances, including drugs, peptide hormones, and steroid hormones can function as haptens. By making hapten-carrier complexes it has been possible to produce anti-hapten-specific antibody that can then be used to measure the presence of these substances in the body. Home pregnancy test HCG- presence or absence
MITOGENS
Mitogens are agents that are able to induce cell division in a high percentage of T or B cells. There are T cell mitogens and B cell mitogens. polyclonal activators
A number of common mitogens are lectins. Lectins are molecules which bind to specific carbohydrate groups (moieties). They bind to glycoproteins on the surface of the lymphocytes and cause activation. Important...they do not act via the TcR or the Ig
Con A - T cell mitogen
PHA - T cell mitogen
PWM - T and B cell mitogen
LPS (lipopolysaccharide) is not a lectin but it does function as a mitogen for B cells.
SUPERANTIGENS
among the most potent T cell mitogens known
Bind differently to the TcR and MHC so a large # of T cells are activated. In some cases as many as 1/5 T cells may be activated to proliferate and to secrete cytokines.
See figure in text for nature of interaction of superantigen + TCR and MHC
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Lecture 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29