Human antibodies are Y shaped, tetrapeptide glycoproteins made by two heavy chains and two light chains that are bound together by disulfide bonds. Like any other proteins, antibodies can act as an antigen, if injected to different species or hosts. For example, if antibodies from humans are injected into mice, mice will recognize these antibodies are foreign proteins (antigens) and will form antibodies against human antibodies (i.e. anti-human antibodies).
It is observed that the entire immunoglobulin is not immunogenic but it contains antigenic determinants at specific sites. Based on the location of those antigenic determinants, immunoglobulins are divided into, isotypes, allotypes, and idiotypes.
Each antibody has only one type of (γ, or α, or μ, or ε, or δ) heavy chain and one type of (k or λ) light chain. The structural differences in the constant region of a heavy chain or light chain determine immunoglobulin (Ig) class and sub-class, types and subtypes within a species. These constant region determinants are called isotypic determinants or isotypes.
Formation of anti-isotypic antibody
All members of a species carry the same constant-region genes (including multiple alleles) so when an antibody from one species is injected into another species, the isotypic determinants will be recognized as foreign, forming anti-isotypic antibody.
Although all members of a species inherit the same set of isotype genes, multiple alleles exist for some of the genes. These alleles encode subtle amino acid differences. Products of allelic forms of the same gene will have slightly different amino acid sequences in the constant regions, which are known as allotypic determinants. The sum of the individual allotypic determinants displayed by an antibody determines its allotype.
Allotypes in human
Allotypes have been characterized for all four IgG subclasses, IgA2 subclass, and Kappa light chain. They are designated by the class and subclass followed by the allele number.
- Gamma-chain allotypes (also known as Gm markers): So far at least 25 different Gm allotypes have been identified e.g. G1m(1), G2m(23), G3m (11), G4m(4a).
- IgA2 subclass has 2 allotypes designated as A2m(1) and A2m(2).
- Kappa (κ) light chain has 3 allotypes, designated Km(1), Km(2), and Km(3).
Each of these allotypic determinants represents differences in one to four amino acids that are encoded by different alleles.
Formation of anti-allotypic antibodies
Antibody to allotypic determinants can be produced by injecting antibodies from one member of a species into another member of the same species who carries different allotypic determinants. Sometimes, a pregnant mother can produce antibodies to paternal allotypic determinants present on the fetal immunoglobulin. Anti-allotype antibodies may also be developed following blood transfusion.
VH and VL domains of an antibody constitute an antigen-binding site. To recognize the vast array of antigens that a human can encounter in its lifetime, this variable region has different structural conformation owing to the presence of different amino acids. There are millions of such antibodies in the human body specific for each antigen.
These unique amino acid sequences present in the VH and VL domains of a given antibody also serves as a set of antigenic determinants. Each individual antigenic determinant of the variable region is referred to as an idiotope. Each antibody will present multiple idiotopes; the sum of the individual idiotopes is called the idiotype of the antibody.
Formation of anti-idiotype antibodies
A single clone of plasma cells produces immunoglobulin molecules with identical variable-region sequences i.e., they all have the same idiotype. When antibodies having no or minimal variation in their isotypes and allotypes are injected into a genetically identical person, anti-idiotype antibodies will be formed.
References and further readings
- Cellular and Molecular Immunology, 9th Edition
- Kuby Immunology, 8th Edition
- Roitt’s Essential Immunology, 13th Edition