Origin and Evolution of the Immunoglobulin’s: Homologous and Variable Domains

Homologous and Variable Domains:

Among the immunoglobulin’s, certain domains of both H and L chains are homologous or constant (i.e., essentially the same from one immunoglobulin to an­other) and certain domains are variable (i.e., they are the basis of the differences among the immunoglobulin’s).

Each L chain has one variable and one constant domain; each H chain has one variable and three con­stant domains. The variable domains occur near the N-terminals of the polypeptide chains and together create an antigen-binding site that is unique to that immunoglobulin molecule. The variable domain of each light chain is designated V_L and the constant domain C_L. The variable domain of a heavy chain is designated V_H and the constant regions are called C_H1, C_H2, and C_H3.

Not all light chains have the same constant regions; instead, there are two different classes of light chains, designated kappa (k) and lambda (λ). About 40% of the amino acid positions of kappa and lambda chains are homologous; this degree of homology is similar to that exhibited by the alpha and beta chains of hemoglobin.

There are five different types of heavy chains, and these are designated y, α, λ, δ, and e. In the heavy chains, the variable region is about the same size as in the light chains but the constant region is about three times as long. Various combinations of the different light and heavy chains give rise to the five classes (or “isotypes”) of immunoglobulin’s.

The N-terminal regions of the L and H chains have different primary structures; these differences are thought to reflect the capability of different immunoglobulin’s to react with different antigens. The variable regions of the L chains (V_L) are homologous with the variable regions of the H chains (V_H). Moreover, the constant regions of the H chains (C_H1, C_H2, and C_H3) are similar to one another and are also homologous with the constant region of the L chains (C_L).

The internal homologies between various parts of the immunoglobulin’s suggest that these polypeptides, like those that form the various hemoglobin’s, have a common ancestral origin. During evolution, gene du­plications followed by separate diversification of the multiple genes probably produced all the immunoglob­ulin genes that are present today in the human genome. However, unlike the hemoglobin saga in which duplication and diversification produced the seven globin structural genes that are usually ex­ pressed, hundreds of different genes for the various regions of the L and H chains have arisen.

Basis of Immunoglobulin Diversity:

For many years, the prevailing view with regard to the proteins of a cell was that each different polypeptide chain was the product of a separate structural gene. For example, the seven expressed globin chain genes of man give rise to the seven alpha family and beta family chains, which in different combinations produce all of the hu­man hemoglobin’s.

The immunoglobulin picture is con­siderably more complex. The immune system of one individual is capable of producing more than a million different immunoglobulin’s, but this is not the conse­quence of the existence of a corresponding number of structural genes for the H and L chains.

The basis of so great an immunoglobulin diversity is the rather as­tounding finding that H and L polypeptide chains are the products of the combined contributions of several different genes; these are called the C (for constant), V (for variable), J (for joining), and D (for diversity) genes.

While several hundred different V genes are present in the genome, there are much smaller num­bers (probably less than 10) of C, J, and D genes. V, C, J, and D genes are recombined in various ways to form functional (i.e., genetically expressible) units. For example, the formation of an expressible light chain unit requires the joining of a V gene to a C gene via one of the J genes. Formation of an expressible heavy chain unit requires the joining of a V gene to a D gene and the joining of the latter complex to a J gene-C gene complex.

During embryonic development and also during an immune response, the differentiation of antibody- producing cells is accompanied by the translocation of chromosomal segments, thereby bringing the various V, J, D, and C genes together.

The diversity of immunoglobulin’s is therefore partly ex­plained by the very large number of possible combina­tions of V, J, D, and C genes. Additional diversity results from “point mutations” during the replication of the genetic material and other chromosomal phe­nomena that in a more general sense serve to increase genetic variation in all living things, not just in antibody-producing cells.