Immunogenicity is determined, in part, by four properties of
the immunogen: its foreignness, molecular size, chemical composition and
complexity, and ability to be processed and presented with an MHC molecule on
the surface of an antigen-presenting cell or altered self-cell.
FOREIGNNESS
In order to elicit an immune response, a molecule must be
recognized as nonself by the biological system. The capacity to recognize
nonself is accompanied by tolerance of self, a specific unresponsiveness to
self antigens. Much of the ability to tolerate self antigens arises during
lymphocyte development, during which immature lymphocytes are exposed to
self-components. Antigens that have not been exposed to immature lymphocytes
during this critical period may be later recognized as nonself, or foreign, by
the immune system. When an antigen is introduced into an organism, the degree
of its immunogenicity depends on the degree of its foreignness. Generally, the
greater the phylogenetic distance between two species, the greater the
structural (and therefore the antigenic) disparity between them. For example,
the common experimental antigen bovine serum albumin (BSA) is not immunogenic
when injectedinto a cow but is strongly immunogenic when injected into a
rabbit. Moreover, BSA would be expected to exhibit greater immunogenicity in a
chicken than in a goat, which is more closely related to bovines. There are
some exceptions to this rule. Some macromolecules (e.g., collagen and
cytochrome c) have been highly conserved throughout evolution and therefore
display very little immunogenicity across diverse species lines. Conversely,
some self-components (e.g., corneal tissue and sperm) are effectively
sequestered from the immune system, so that if these tissues are injected even
into the animal from which they originated, they will function as immunogens.
MOLECULAR SIZE
There is a correlation between the size of a macromolecule
and its immunogenicity. The most active immunogens tend to have a molecular
mass of 100,000 daltons (Da). Generally, substances with a molecular mass less
than 5000–10,000 Da are poor immunogens, although a few substances with a
molecular mass less than 1000 Da have proven to be immunogenic.
CHEMICAL COMPOSITION AND HETEROGENEITY
Size and foreignness are not, by themselves, sufficient to
make a molecule immunogenic; other properties are needed as well. For example,
synthetic homopolymers (polymers composed of a single amino acid or sugar) tend
to lack immunogenicity regardless of their size. Studies have shown that
copolymers composed of different amino acids or sugars are usually more
immunogenic than homopolymers of their constituents. These studies show that
chemical complexity contributes to immunogenicity. In this regard it is notable
that all four levels of protein organization—primary, secondary, tertiary, and
quaternary—contribute to the structural complexity of a protein and hence
affect its immunogenicity (Figure 3-1).
LIPIDS AS ANTIGENS
Appropriately presented lipoidal antigens can induce B- and
T-cell responses. For the stimulation of B-cell responses, lipids are used as
haptens and attached to suitable carrier molecules such as the proteins keyhole
limpet hemocyanin (KLH) or bovine serum albumin (BSA). By immunizing with these
lipid-protein conjugates it is possible to obtain antibodies that are highly
specific for the target lipids. Using this approach, antibodies have been
raised against a wide variety of lipid molecules including steroids, complex
fatty-acid derivatives, and fat-soluble vitamins such as vitamin E. Such
antibodies are of considerable practical importance since many clinical assays
for the presence and amounts of medically important lipids are antibody-based.
For example, a determination of the levels of a complex group of lipids known
as leukotrienes can be useful in evaluating asthma patients. Prednisone, an
immunosuppressive steroid, is often given as part of the effort to prevent the
rejection of a transplanted organ. The achievement and maintenance of adequate
blood levels of this and other immunosuppressive drugs is important to a
successful outcome of transplantation, and antibody-based immunoassays are
routinely used to make these evaluations. The extraordinary sensitivity and
specificity of assays based on the use of anti-lipid antibodies is illustrated
by Table 3-2, which shows the specificity of an antibody raised against
leukotriene C4. This antibody allows the detection of as little as 16–32
picograms per ml of leukotriene C4. Because it has little or no reactivity with
similar compounds, such as leukotriene D4 or leukotriene E4, it can be used to
assay leukotriene C4 in samples that contain this compound and a variety of
other structurally related lipids.
T cells recognize peptides derived from protein antigens
when they are presented as peptide-MHC complexes. However, some lipids can also
be recognized by T cells. Lipoidalcompounds such as glycolipids and some
phospholipids can be recognized by T-cell receptors when presented as complexes
with molecules that are very much like MHC molecules. These lipid-presenting
molecules are members of the CD1 family (see Chapter 8) and are close
structural relatives of class I MHC molecules. The lipid molecules recognized
by the CD1–T-cell receptor system all appear to share the common feature of a
hydrophobic portion and a hydrophilic head group. The hydrophobic portion is a
long-chain fatty acid or alcohol and the hydrophilic head group is composed of
highly polar groups that often contain carbohydrates. Recognition of lipids is
a part of the immune response to some pathogens, and T cells that recognize
lipids arising from Mycobacterium tuberculosis and Mycobacterium leprae, which
respectively cause tuberculosis and leprosy, have been isolated from humans
infected by these mycobacteria.
SUSCEPTIBILITY TO ANTIGEN PROCESSING AND PRESENTATION
The development of both humoral and cell-mediated immune
responses requires interaction of T cells with antigen that has been processed
and presented together with MHC molecules. Large, insoluble macromolecules
generally are more immunogenic than small, soluble ones because the larger
molecules are more readily phagocytosed and processed. Macromolecules that
cannot be degraded and presented with MHC molecules are poor immunogens. This
can be illustrated with polymers of D-amino acids, which are stereoisomers of
the naturally occurring L-amino acids. Because the degradative enzymes within
antigen-presenting cells can degrade only proteins containing L-amino acids,
polymers of D-amino acids cannot be processed and thus are poor immunogens.
Source : Richard A. Goldsby, Thomas J. Kindt, And Barbara A. Osborne. 2000. KUBY IMMUNOLOGY 4th Edition. New York. W. H. FREEMAN AND COMPANY. Page 58 - 60.
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