INFECTIOUS DISEASE

IMMUNOLOGY - CHAPTER  FIVE 

THE STRUCTURE AND FUNCTION OF IMMUNOGLOBULINS - ANTIBODIES 

Isotypes, Allotypes and Idiotypes 

Gene Mayer, Ph.D
Emertius Professor of Pathology, Microbiology and Immunology
University of South Carolina
 

TEACHING OBJECTIVES

To explain the structural basis for immunoglobulin isotypes, allotypes and idiotypes

To describe some of the uses of isotypes, allotypes and idiotypes

KEY WORDS
Isotype
Allotype
Idiotype
Codominant alleles
Allelic exclusion

ISOTYPES

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.

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.

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.

Importance
Antibodies to isotypes are used for the quantitation of immunoglobulin classes and subclasses in various diseases, in the characterization of B cell leukemia and in the diagnosis of various immunodeficiency diseases.

 

ALLOTYPES

Definition
Allotypes are antigenic determinants specified by allelic forms of the immunoglobulin 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 immunoglobulin 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.

Location
In humans, the allotypic differences are localized to the constant region of the heavy and light chains as illustrated in the Figure 2.

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

Human Immunoglobulin Allotypes

Nomenclature
Human immunoglobulin 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.

Genetics

Co-dominant 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 co-dominant autosomal genes. e.g.

Allelic Exclusion
Although, in a heterozygote, both alleles are expressed, any individual immunoglobulin molecule will only have one allotype. This is because an individual B cell can only express one allele. This is called allelic exclusion. Allotypes that represent amino acid substitutions at different locations in a molecule (e.g. G1m(1) and G1m(17)) can be found on the same molecule.

E.g. In a G1m(1,17) individual both allotypes can be on the same heavy chain

Importance

• Monitoring bone marrow grafts
  Bone marrow grafts that produce a different allotype from the recipient can be used to monitor the graft.
   

• Forensic medicine
  Km and Gm allotypes are detectable in blood stains and semen and are useful in forensic medicine.
   

• Paternity testing
  The immunoglobulin allotypes are one of the characteristics used in legal cases involving paternity.

 

IDIOTYPES (Id)

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

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.

Importance

• V region marker -
  Idiotypes are a useful marker for a particular variable region.
   

• Regulation of immune responses
  There is evidence that immune responses may be regulated by anti-Id antibodies directed against our own Id's.
   

• 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.

Anti-idiotype vaccines

 

• 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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