We know that antigens that are proteins act as potent antigens and can induce the immune system. Similarly if you think about antibodies, they are glycoproteins so logically they also should be able to induce our immune system. Interesting, isn’t it? There are specific regions on antibodies which can induce the immune system. These regions on antibodies are called antigenic determinants.
These
antigenic determinants fall under three categories: 1. Isotype, 2. Allotype and
3. Idiotype.
1.
Isotype: Iso = Same
Definition: Isotype antigenic determinants characterize the classes and subclasses of heavy chain and types and subtypes of light chains.
For
example, in humans there are 5 different types of antibodies; IgM, IgA, IgG,
IgE and IgD based on the class of heavy chain they have (µ, α, γ, ε and δ
respectively). That means we have specific set of genes which codes for these
heavy chains. So there are specific sequences on constant regions of heavy and
light chain (κ and λ) which decides what class or subclass of antibody it is.
It
is called isotype (iso = same) because all members of a given species expresses
all the isotypes in the serum.
For example, all immunologically normal individuals will have all five types of
antibodies present in their serum i.e. IgM, IgA, IgG, IgE and IgD.
Therefore,
different species inherits different constant regions genes and thus expresses
different isotypes.
So
if take antibodies from one species and inject it in
another speciesit would result in anti-isotypic antibody production.
Location: Constant
region of heavy chain and light chain.
Observed: In
all the individuals of a species (immunologically normal individuals).
Importance: To
measure Ig levels,
To check for immunodeficiency,
In detection of B cell tumors.
2.
Allotype: Allo = Different
Definition: Allotype
antigenic determinants are specified by the allelic forms of the Ig genes.
Although
all the members of a species inherit the same set of Ig genes, there would be
multiple alleles present for these genes which code for different amino acids.
That means the amino acid sequence for the same antibody heavy chain would be
slightly different in you than in me.
So
if we take antibodies from one member of the species and
inject it into another member of the same species it will
result in production of antibodies against allotypic determinants.
Location: Constant
region of heavy chain and light chain
Observed: During
blood transfusion
During pregnancy
Importance: Monitoring
bone marrow grafts
Paternity testing
Forensic
3.
Idiotype: Idio = Own or Peculiar
Definition: Idiotypes
are the unique antigenic determinants present on variable heavy chain and
variable light region of individual antibody molecules.
When
we encounter any Ag, the variable region of our Ab recognizes the Ag and our B
cells produce specific antibodies (during affinity maturation by somatic
hypermutaion) against that particular Ag. So when we encounter an Ag, our B cell
makes very specific or peculiar Abs against it.
Let’s
say for example, I encounter two different antigens i.e. Ag a and Ag b and
produce IgG1 against both. In this case the idiotypic determinants for the IgG1
against Ag a will be different than IgG1 against Ag b.
Location: Variable
region of heavy chain and light chain.
Observed: When
we inject antibodies from a donor who is genetically identical to a
recipient, it induces production of anti-idiotypic antibodies. In
genetically identical twins the isotype and allotype will be the same
but the idiotype will be different.
Importance: Treatment
of B cell tumors
Vaccines
THE STRUCTURE AND
FUNCTION OF IMMUNOGLOBULINS - ANTIBODIES
Isotypes, Allotypes and Idiotypes
I. ISOTYPES
A. Definition
Isotypes are antigenic
determinants that characterize classes and subclasses of heavy chains and types
and subtypes of light chains.
If human IgM is injected into a rabbit the rabbit will recognize antigenic
determinants on the heavy chain and light chain and make antibodies to them. If
that antiserum is absorbed with human IgG the antibodies to the light chain
determinants and any determinants in common between human IgM and IgG will be
removed and the resulting antiserum will be react only with human IgM. Indeed,
the antibodies will only react with the constant region of the μ chain.
Antibodies to the variable region are rare perhaps because only a few copies of
each different variable region are represented in the IgM and thus effective
immunization does not occur. The determinants that are recognized by such
antibodies are called isotypic determinants and the antibodies to those
determinants are called anti-isotypic antibodies. Each class, subclass, type
and subtype of immunoglobulin has its unique set of isotypic determinants.
B. Location
Heavy chain isotypes are
found on the Fc portion of the constant region of the molecule while light
chain isotypes are found in the constant region. The location of isotypic
determinants is illustrated in Figure 1.
C. Occurrence
Isotypes are found in
ALL NORMAL individuals in the species. The prefix Iso means same in all members
of the species. Some individuals with immunodeficiencies may lack one or more
isotypes but normal individuals have all isotypes.
D. Importance
Antibodies to isotypes
are used for the quantitation of Ig classes and subclasses in various diseases,
in the characterization of B cell leukemia and in the diagnosis of various
immunodeficiency diseases.
II. ALLOTYPES
A. Definition
Allotypes are antigenic
determinants specified by allelic forms of the Ig genes.
Allotypes represent
slight differences in the amino acid sequences of heavy or light chains of
different individuals. Even a single amino acid difference can give rise to an
allotypic determinant, although in many cases there are several amino acid
substitutions that have occurred.
Allotypic differences
are detected by using antibodies directed against allotypic determinants. These
antibodies can be prepared by injecting the Ig from one person into another. In
practice however we obtain anti-allotype antisera from women who have had
multiple pregnancies or from people who have received blood transfusions or
from some patients with rheumatoid arthritis.
B. Location
In man the allotypic
differences are localized to the constant region of the heavy and light chains
as illustrated in the Figure 2.
C. Occurrence
Individual allotypes are
found in individual members of a species. All allotypes are not found in all
members of the species. The prefix Allo means different in individuals of a
species
D. Human Ig Allotypes
Nomenclature - Human Ig
allotypes are named on the basis of the heavy or light chain on which it is
located. Thus, an allotype on a Gamma 1 heavy chain is given the name: G1m(3).
An allotype on a Kappa light chain is given the name: Km(1). Table 1 lists some
human allotypes.
E. Genetics
1. Codominant autosomal
genes - Allotypes that
represent amino acid substitutions at the same position in a heavy or light
chain (eg. G1m(3) and G1m(17) or Km(1) and Km(3) are inherited as
codominant autosomal genes. e.g.
|
Km(1)/Km(3) X
Km(1)/Km(1) |
|
|
|
Km(1)/Km(1) and
Km(1)/Km(3) |
2. Allelic Exclusion - Although in a
heterozygote both alleles are expressed, any individual Ig molecule will only
have one allotype. This is because an individual B cell can only expresses one
allele. This is called allelic exclusion. Allotypes that represent amino acid
substitutions at different locations in a molecule (eg. G1m(1) and
G1m(17)) can be found on the same molecule.
eg. In a G1m(1,17)
individual both allotypes can be on the same heavy chain
|
GM1(1) |
G1m(17) |
|
_____________|______________________________________|______________ |
|
|
214 |
355-358 |
F. Importance
1. Monitoring bone
marrow grafts - Bone marrow grafts that produce a different allotype from the
recipient can be used to monitor the graft.
2. Forensic medicine - Km and Gm
allotypes are detectable in blood stains and semen and are useful in forensic
medicine.
3. Paternity testing - The
immunoglobulin allotypes are one of the characteristics used in legal cases
involving paternity.
III. IDIOTYPES
(Id)
A. Definition - Unique antigenic
determinants present on individual antibody molecules or on molecules of
identical specificity.
Identical specificity
means that all antibodies molecules have the exact same hypervariable regions.
Antigenic determinants
created by the combining site of an antibody are called idiotypes and
the antibodies elicited to the idiotypes are called anti-Id antibodies.
Idiotypes are the antigenic determinants created by the hypervariable regions
of an antibody and the anti-idiotypic antibodies are those directed against the
hypervariable regions of an antibody.
To understand what
idiotypes are, it is helpful to understand how they are detected.
|
DNP-BSA |
|
Strain A |
|
anti-DNP Ab |
|
|
||||
|
Antibody against the combining site of anti-DNP Ab |
|
Strain A |
|
purified anti-DNP Ab |
|
An antigen, in this case the hapten dinitrophenol, is
injected into a mouse and antibodies (against DNP) are elicited. This
antibody can be purified to homogeneity and injected into another mouse of
the same strain. Most epitopes on the antibody will be seen by the second
mouse's immune system as "self"; however, the epitopes that form
the binding site to DNP (idiotopes - this is a term that is not often used
and frequently is used interchangeably with idiotype) will be seen as foreign
since the second mouse has not been injected with DNP-BSA. The second mouse
will raise antibodies only against the idiotopes of the purified anti-DNP
antibody. These are therefore anti-idiotypic antibodies Antigenic determinants created by
the hypervariable region of an antibody are idiotypes |
||||
B. Location
Idiotypes are localized
on the Fab fragment of the Ig molecules as illustrated in Figure 3.
Specifically, they are localized at or near the hypervariable regions of the
heavy and light chains. In many instances the actual antigenic determinant
(i.e. idiotype) may include some of the framework residues near the
hypervariable region. Idiotypes are usually determinants created by both heavy
and light chain HVR's although sometimes isolated heavy and light chains will
express the idiotype.
C. Importance
1. V region marker - Idiotypes are a useful
marker for a particular variable region.
2. Regulation of immune
responses - there is
evidence that immune responses may be regulated by anti-Id antibodies directed
against our own Id's.
3. Vaccines - In some cases
anti-idiotypic antibodies actually stimulate B cells to make antibody and thus
they can be used as a vaccine. This approach is being tried to immunize against
highly dangerous pathogens that cannot be safely used as a vaccine.
4. Treatment of B cell
tumors - Anti-idiotypic
antibodies directed against an idiotype on malignant B cells can be used to
kill the cells. Killing occurs because of complement fixation or because toxic
molecules are attached to the antibodies.
Some
of the categories of epitopes of the antibody molecule are : 1. Isotypic
determinants 2. Allotypic determinants 3. Idiotypic determinants.
Antibodies
are glycoproteins and have high molecular weight. Hence the antibodies also act
as immunogens and induce antibody production.
ADVERTISEMENTS:
The
antibodies formed against antibodies are called antiantibodies.
The
epitopes (or antigenic determinants) of the antibody molecule are described in
three categories:
1. Isotypic
determinant:
The
prefix ‘Iso’ means same in all members of the same species. Isotypic determinant
is present in the constant region of the heavy chain. Isotypic determinant is
characteristic for a particular species and is present in all members of the
same species.
Therefore
all individuals of the same species have the same isotype. But the isotypic
determinants between different species are not the same. Consequently, when an
antibody from one species is injected into another species, the injected
antibodies are recognized as foreign, resulting in the induction of antibodies
(anti-antibodies) against the isotypic determinants of the injected antibodies.
The antiantibodies react with isotypic determinants in the constant region of
the injected antibodies.
2. Allotypic
determinants:
The
prefix ‘Alio’ means that different in individuals of the same species. As
explained above, all the individuals of the same species have identical set of
isotypic determinants (and genes coding for isotypic determinants). Yet, within
a species multiple alleles exist for certain isotypic genes; consequently, some
members within the same species have different antigenic determinants called
allotypic determinants.
Therefore
injection of antibodies from one animal to another animal of the same species
induces antiantibodies (anti-allotypic antibodies) formation against the
allotypic determinants of the injected antibodies, provided that the two
animals differ in their allotypic determinants. Genes in the constant region of
immunoglobulin code the allotypic determinants. In humans allotypic
determinants are found in the four IgG subclasses, IgA2 subclass, and k light
chain.
i.
The allotype of IgG are called Gm markers. They are designated by class,
subclass and allele number [e.g. Glm (1), G2m (23)]
ii.
The allotypes of IgA2 are called A2m [e.g. A2m (1), A2m (2)].
iii.
K light chain allotypes are designated Km markers (e.g. Km (l), Km(2), and
Km(3)
3.
Idiotypic determinant:
Antigen-binding
site in antibody molecule is formed by the amino acids of the VH and
VLchains. The amino acids of the antigen binding site also act as
immunogen. The antigenic determinants of the VH and VL region
are called idiotypic determinants or idiotopes. One antibody molecule has many
idiotopes in the antigen-binding site. The sum of the individual idiotopes in
an antibody molecule is called the idiotype of the antibody. The idiotopes are
further designated alpha, beta, and gamma idiotopes.
i.
Alpha idiotope lie outside the antigen-binding site of hyper-variable region.
iii.
Beta idiotope lie close to the antigen binding site of hyper- variable region.
iii.
Gamma idiotope is formed by the amino acids of the antigen binding site.
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