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MICROBIOLOGY AND IMMUNOLOGY MOBILE  -  IMMUNOLOGY CHAPTER FIVE

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.

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.

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