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PORTUGUES IMMUNOLOGY - CHAPTER THREE
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Gene Mayer, Ph.D
SEARCH Emertius Professor of Pathology, Microbiology and Immunology
University of South Carolina
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DEFINITIONS
TEACHING OBJECTIVES
Immunogen
To compare and contrast A substance that induces a specific immune response.
immunogen, antigen and
hapten Antigen (Ag)
A substance that reacts with the products of a specific immune response.
To describe the factors
influencing Hapten
immunogenicity A substance that is non-immunogenic but which can react with the products of a specific
immune response. Haptens are small molecules which could never induce an immune
To define the chemical response when administered by themselves but which can when coupled to a carrier molecule.
nature of immunogens Free haptens, however, can react with products of the immune response after such products
have been elicited. Haptens have the property of antigenicity but not immunogenicity.
To compare the
structures of T- Epitope or Antigenic Determinant
independent and T- That portion of an antigen that combines with the products of a specific immune response.
dependent antigens
Antibody (Ab)
To introduce the concept A specific protein which is produced in response to an immunogen and which reacts with an
of hapten-carrier antigen.
conjugates and to
describe their structure
To characterize antigenic FACTORS INFLUENCING IMMUNOGENICITY
determinants
Contribution of the Immunogen
To introduce the concept
of superantigens Foreignness
The immune system normally discriminates between self and non-self such that
only foreign molecules are immunogenic.
Size
There is not absolute size above which a substance will be immunogenic. However,
in general, the larger the molecule the more immunogenic it is likely to be.
Chemical Composition
In general, the more complex the substance is chemically the more immunogenic it
will be. The antigenic determinants are created by the primary sequence of
residues in the polymer and/or by the secondary, tertiary or quaternary structure of
the molecule.
Physical form
In general particulate antigens are more immunogenic than soluble ones and
denatured antigens more immunogenic than the native form.
Degradability
Antigens that are easily phagocytosed are generally more immunogenic. This is
because for most antigens (T-dependant antigens, see below) the development of
an immune response requires that the antigen be phagocytosed, processed and
presented to helper T cells by an antigen presenting cell (APC).
Contribution of the Biological System
Genetic Factors
Some substances are immunogenic in one species but not in another. Similarly,
some substances are immunogenic in one individual but not in others (i.e.
responders and non-responders). The species or individuals may lack or have
altered genes that code for the receptors for antigen on B cells and T cells or they
may not have the appropriate genes needed for the APC to present antigen to the
helper T cells.
KEY WORDS Age
Age can also influence immunogenicity. Usually the very young and the very old
Immunogen have a diminished ability to mount and immune response in response to an
Antigen immunogen.
Hapten
Epitope Method of Administration
Antigenic determinant
Dose
Antibody
T-independent antigen The dose of administration of an immunogen can influence its immunogenicity.
T-dependent antigen There is a dose of antigen above or below which the immune response will not be
Hapten-carrier conjugate optimal.
Native determinant
Route
Haptenic determinant Generally the subcutaneous route is better than the intravenous or intragastric
Superantigen routes. The route of antigen administration can also alter the nature of the
response
Adjuvants
Substances that can enhance the immune response to an immunogen are called
adjuvants. The use of adjuvants, however, is often hampered by undesirable side
effects such as fever and inflammation.
CHEMICAL NATURE OF IMMUNOGENS
Proteins
The vast majority of immunogens are proteins. These may be pure proteins or they may be
glycoproteins or lipoproteins. In general, proteins are usually very good immunogens.
Polysaccharides
Pure polysaccharides and lipopolysaccharides are good immunogens.
Nucleic Acids
Nucleic acids are usually poorly immunogenic. However, they may become immunogenic
Figure 1a
when single stranded or when complexed with proteins.
Immunogenicity of
biological molecules Lipids
In general lipids are non-immunogenic, although they may be haptens.
See figure 1a.
TYPES OF ANTIGENS
T-independent Antigens
T-independent antigens are antigens which can directly stimulate the B cells to produce
antibody without the requirement for T cell help In general, polysaccharides are T-independent
Figure 1b antigens. The responses to these antigens differ from the responses to other antigens.
In an antigen, the same
antigenic determinant Properties of T-independent antigens
repeated many times
Polymeric structure
These antigens are characterized by the same antigenic determinant
repeated many times as illustrated in Figure 1b.
Polyclonal activation of B cells
Many of these antigens can activate B cell clones specific for other
antigens (polyclonal activation). T-independent antigens can be
subdivided into Type 1 and Type 2 based on their ability to polyclonally
activate B cells. Type 1 T-independent antigens are polyclonal activators
while Type 2 are not.
Resistance to degradation
T-independent antigens are generally more resistant to degradation and
thus they persist for longer periods of time and continue to stimulate
the immune system.
T-dependent Antigens
T-dependent antigens are those that do not directly stimulate the production of antibody
without the help of T cells. Proteins are T-dependent antigens. Structurally these antigens are
characterized by a few copies of many different antigenic determinants as illustrated in the
Figure 2.
Figure 2
T-dependent antigens are
characterized by a few
copies of many different
antigenic determinants HAPTEN-CARRIER CONJUGATES
Definition
Hapten-carrier conjugates are immunogenic molecules to which haptens have been covalently
attached. The immunogenic molecule is called the carrier.
Structure
Structurally these conjugates are characterized by having native antigenic determinants of the
Figure 3 carrier as well as new determinants created by the hapten (haptenic determinants) as
Hapten-carrier illustrated in the Figure 3. The actual determinant created by the hapten consists of the hapten
conjugates have native and a few of the adjacent residues, although the antibody produced to the determinant will
antigenic determinants also react with free hapten. In such conjugates the type of carrier determines whether the
of the carrier as well as response will be T-independent or T-dependent.
new determinants of the
hapten
ANTIGENIC DETERMINANTS
Determinants recognized by B cells
Composition
Antigenic determinants recognized by B cells and the antibodies secreted by B cells
are created by the primary sequence of residues in the polymer (linear or sequence
determinants) and/or by the secondary, tertiary or quaternary structure of the
Figure 4 molecule (conformational determinants).
Antigenic determinants
Size
are usually limited to
those portions of the In general antigenic determinants are small and are limited to approximately 4-8
residues. (amino acids and or sugars). The combining site of an antibody will
antigen that are
accommodate an antigenic determinant of approximately 4-8 residues.
accessible to antibodies
shown in black for this
Number
iron-containing protein
Although, in theory, each 4-8 residues can constitute a separate antigenic
determinant, in practice, the number of antigenic determinants per antigen is much
lower than what would theoretically be possible. Usually the antigenic determinants
are limited to those portions of the antigen that are accessible to antibodies as
illustrated in the Figure 4 (antigenic determinants are indicated in black).
Determinants recognized by T cells
Composition
Antigenic determinants recognized by T cells are created by the primary sequence
of amino acids in proteins. T cells do not recognize polysaccharide or nucleic acid
antigens. This is why polysaccharides are generally T-independent antigens and
proteins are generally T-dependent antigens. The determinants need not be located
on the exposed surface of the antigen since recognition of the determinant by T
cells requires that the antigen be proteolytically degraded into smaller peptides.
Free peptides are not recognized by T cells, rather the peptides associate with
molecules coded for by the major histocompatibility complex (MHC) and it is the
complex of MHC molecules + peptide that is recognized by T cells.
Size
In general antigenic determinants are small and are limited to approximately 8-15
amino acids.
Number
Although, in theory, each 8-15 residues can constitute a separate antigenic
determinant, in practice, the number of antigenic determinants per antigen is much
less than what would theoretically be possible. The antigenic determinants are
limited to those portions of the antigen that can bind to MHC molecules. This is
why there can by differences in the responses of different individuals.
SUPERANTIGENS
When the immune system encounters a conventional T-dependent antigen, only a small fraction (1 in 104
-105) of the T cell population is able to recognize the antigen and become activated
(monoclonal/oligoclonal response). However, there are some antigens which polyclonally activate a large
fraction of the T cells (up to 25%). These antigens are called superantigens (Figure 5).
Examples of superantigens include: Staphylococcal enterotoxins (food poisoning), Staphylococcal toxic
shock toxin (toxic shock syndrome), Staphylococcal exfoliating toxins (scalded skin syndrome) and
Streptococcal pyrogenic exotoxins (shock). Although the bacterial superantigens are the best studied
there are superantigens associated with viruses and other microorganisms as well.
The diseases associated with exposure to superantigens are, in part, due to hyper activation of the
immune system and subsequent release of biologically active cytokines by activated T cells.
DETERMINANTS RECOGNIZED BY THE INNATE IMMUNE SYSTEM
Determinants recognized by components of the innate (nonspecific) immune system differ from those
recognized by the adaptive (specific) immune system. Antibodies, and the B and T cell receptors
recognize discrete determinants and demonstrate a high degree of specificity, enabling the adaptive
immune system to recognize and react to a particular pathogen. In contrast, components of the innate
immune system recognize broad molecular patterns found in pathogens but not in the host. Thus, they
lack a high degree of specificity seen in the adaptive immune system. The broad molecular patterns
recognized by the innate immune system have been called PAMPS (pathogen associated molecular
patterns) and the receptors for PAMPS are called PRRs (pattern recognition receptors). A particular PRR
can recognize a molecular pattern that may be present on a number of different pathogens enabling the
receptor to recognize a variety of different pathogens. Examples of some PAMPs and PRRs are illustrated
in Table1.
Table 1 Examples of pathogen associated molecular patterns and their receptors
Figure 5 Biological Consequence
PAMP PRR
Superantigens activate a of Interaction
large fraction of T cells in
contrast to conventional Microbial cell wall Opsonization,
Complement
T-dependent antigens components Complement activation
Mannose-containing Opsonization
Mannose-binding protein
carbohydrates Complement activation
Polyanions Scavenger receptors Phagocytosis
Lipoproteins of Gram +
Macrophage activation,
bacteria TLR-2 (Toll-like receptor
secretion of inflammatory
Yeast cell wall 2)
cytokines
components
Production of interferon
Double stranded RNA TLR-3
(antiviral)
Macrophage activation,
LPS (lipopolysaccharide of
TLR-4 secretion of inflammatory
Gram negative bacteria)
cytokines
Macrophage activation,
Flagellin (bacterial flagella) TLR-5 secretion of inflammatory
cytokines
U-rich Single stranded viral Production of interferon
TLR-7
RNA (antiviral)
Macrophage activation,
CpG containing DNA TLR-9 secretion of inflammatory
cytokines
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