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 INFECTIOUS DISEASE

BACTERIOLOGY IMMUNOLOGY MYCOLOGY PARASITOLOGY VIROLOGY

VIDEO LECTURE



IMMUNOLOGY - CHAPTER  FIVE 

THE STRUCTURE AND FUNCTION OF IMMUNOGLOBULINS - ANTIBODIES 

Isotypes, Allotypes and Idiotypes 

Dr Gene Mayer
 

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Logo image Jeffrey Nelson, Rush University, Chicago, Illinois  and The MicrobeLibrary
Last major update July 2010
READING
Male et al. Immunology
7th edition  pp 79-80
Murray, et al. Medical Microbiology
5th edition,  pp 110-113

 

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.

typ-1.jpg (88283 bytes)   Figure 1  Location of isotype determinants

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.

 

 

typ-2.jpg (96323 bytes)   Figure 2 Immunoglobulin allotypes

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.

 

   

Table 1 Human allotypes

Chain

Domain

Allotype

Amino Acid

Position

IgG1

CH1

G1m(f) = (3)

Arg

214

CH1

G1m(z) = (17)

Lys

 

 

CH1

G1m(a) = (1)

Arg, Asp, Glu, Leu

355-358

κ light chain

CL

Km(1)

Val, Leu

153, 191

CL

Km(3)

Ala, Val

153,191

Adapted from Stites et al., Basic and Clin. Immunol., 3rd Ed., Table 7-8

 

 

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.

 Km(1)/Km(3)  X   Km(1)/Km(1)

Km(1)/Km(1)  and  Km(1)/Km(3)

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

 

 

GM1(1)

G1m(17)

_____________|______________________________________|______________

214

 355-358

 

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

 

typ-3.jpg (75523 bytes)   Figure  3 Immunoglobulin 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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