 ANTIGENS
Properties:
Antigens- may possess: immunogenicity, antigenicity, allerogenicity,
or 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.
Haptens - 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 used 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.
In general, proteins serve
as immunogens for T cell-mediated immunity. (Recall that these proteins
must be processed into peptides and the peptides must be presented by
an APC in association with MHC proteins.
Requirements for Immunogenicity
The requirements are somewhat dependent upon the experimental conditions
(mode of immunization, organism being immunized, sensitivity of detection
methods, etc.). However, certain conditions must be met 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. A co-polymer
of glutamic acid and 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).
D. Degradability: Macromolecules that cannot be degraded and
processed by APCs are poor immunogens. For example, polymers of D-amino
acids are not immunogenic. Proteolytic enzymes can only degrade proteins
containing L-amino acids.
E. 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.
F. Method of Antigen Administration: Whether an antigen will
induce an immune response depends on the dose and the mode of administration.
Antigen can be delivered in a variety of ways: ip, sc, iv, im,
id, etc. The repsonse will vary depending upon the route chosen.
In addition, too little antigen may not stimulate a strong response,
whereas too much antigen may stimulate tolerance (specific non-responsiveness).
The use of an adjuvant can also enhance the immunogenicity of an antigen.
Adjuvants (such as Freunds) prolong the persistence of the antigen in
the body, induce a strong inflammatory response which can lead to granuloma
formation, and can stimulate lymphocyte proliferation.
T cells and B cells exhibit
fundamental differences in epitope recognition.
B cell epitopes [epitopes
recognized by membrane-bound Ig, or secreted Ig]
The binding of antigen to Ig involves weak non-covalent interactions
so there must be complementarity.
Properties of B cell epitopes:
1]Epitopes may be associated with soluble immunogens or particulate
immunogens.
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
7] 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 cell epitopes [epitopes
recognized by membrane-bound TcR only]
T cells recognize processed
peptides associated with MHC on the surface of APCs (Class II MHC) or
altered self cells (Class I MHC). In other words, T cells exhibit MHC
RESTRICTED ANTIGEN RECOGNITION
CD4+ T cells are restricted
to Class II MHC
CD8+ T cells are restricted to Class I MHC
More recent evidence suggests
that a small population of T cells may possess TcRs capable of recognizing
lipids or glycolipids. Little is known about this type of recognition
and we will restrict our discussion to peptide epitopes.
1]The binding of the TcR
to MHC + peptide represents a tri-molecular complex.
2]Only oligomeric peptides serve as epitopes. Epitopes which bind
to Class I MHC have an optimal size of 9 amino acids with a range from
8-11. Epitopes which bind to Class II MHC have an optimal size
range from 12-25 amino acids.
3) Epitopes are often internal and only exposed by processing
within APCs or target cells.
3] Antigen processing is required to generate the peptides that interact
specifically with MHC molecules.
4] T cell epitopes must have two binding regions. The region of
the peptide which binds to MHC is termed the agretope while the region
which binds to the TcR is termed the epitope.
5) Complex proteins may contain multiple, overlapping epitopes.
6 ) 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.
MITOGENS
Mitogens are agents that are able to induce cell division (mitosis)
in a high percentage of T or B cells. This proliferation is described
as polyclonal activation (as opposed to clonal expansion following the
specific encounter with a conventional immunogen). There are T
cell mitogens and B cell mitogens.
A number of common mitogens
are lectins. Lectins are proteins 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 conventional TcR-epitope or Ig-epitope
interactions.
Lectin Examples:
Con A - T cell mitogen
PHA - T cell mitogen
PWM - T and B cell mitogen
Another important mitogen
which is NOT a lectin is LPS (lipopolysaccharide). This polysaccharide
component of the outer membrane of gram - bacteria is also known as
endotoxin. LPS is a very potent 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. Many microbial pathogens (including Streptococcus
and Staphylococcus) produce toxins which function as superantigens.
The symptoms of staphylococcal food poisoning are due to the massive
T cell proliferation and cytokine secretion which occurs in the GALT
due to the presence of staphylococcal enterotoxin in food. Toxic
shock syndrome and Toxic shock-like syndrome are both due to the action
of bacterial superantigens.
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