By Dr Ananya Mandal, MD
All microbes trigger an antibody response. Due to diversity in microbes, the antibody needs to adopt variations to allow their interactions with many different antigens.
Human, for example, generate about 10 billion different antibodies. Each of these is specific for distinct epitope of an antigen. Since each of the antibodies are different for each of the antigens, the body needs to be capable for generating these proteins.
The genes coding for these diverse range of immunoglobulins however are limited and do not number similar to the variety of antibodies. To create the variety of antibodies thus the body adopts complex mechanisms from the relatively small number of antibody genes.
Variation of domains
Each of the genes for the antibodies are located on specific location (loci) on the chromosomes. The locus for antibodies is a relatively large segment. There are several distinct genes for each domain of the antibody. There is a locus for the heavy chain genes that is found on chromosome 14 and a locus for lambda and kappa light chain genes that is found on chromosomes 22 and 2 respectively in humans.
One of these regions is called the variable domain. This is present in each heavy and light chain of every antibody, but can differ in different antibodies generated from distinct B cells.
The variable domains are located on three loops known as hypervariable regions (HV-1, HV-2 and HV-3). These are also called complementarity determining regions (CDR1, CDR2 and CDR3). The loci for the heavy chains has around 65 different variable domain genes. These differ in their CDRs. When combined, these genes can yield a large variety of combinations for antibodies by permutation and combination.
The recombination of these genes is called ''V(D)J recombination''. This means generation of distinctly different antibodies due to different variable domains on the antibodies. The variable region of each immunoglobulin heavy or light chain is encoded in several pieces on the genes. These are called variable (V), diversity (D) and joining (J) segments.
Isotypes are called class switching. Once the B cells are activated they produce different classes of antibody (IgA, IgE, or IgG). When the heavy chain gene locus undergoes a phenomenon called class switch recombination (CSR), it leads to formation of isotypes. This process results in an immunoglobulin gene that encodes an antibody of a different isotype.
The plasma cells switch from producing IgM to IgG or to another immunoglobulin class. The switch involves a change in the H chain constant domains (CH). In this there is usually no alteration in the L chain or in the variable portion of the H chain and thus there is no change in antigen-binding specificity.
Variability due to hypermutation
When the antigen binds to the antibody and activates the B cells, they rapidly proliferate and each of these cells contains DNA for antibody formation. The genes coding for the antibodies in these B cells undergo high rate of point mutation or point changes in genetic codes for antibodies. This is called ''somatic hypermutation'' (SHM).
Each SHM results in one nucleotide change per variable gene with each cell division. This mutation leads to formation of a variety of antibodies specific for the antigen. While some of the generated antibodies are weak, some have a stronger affinity for the antigen. Those B cells that produce these strong antibodies as a result of the mutations are preserved and proliferated while the others die off.
Reviewed by April Cashin-Garbutt, BA Hons (Cantab)