The Origins of Antibody Diversity
Have you ever wondered how the human can body recognize and fight off a huge number of antigenic structures despite our relatively small genome size? You’re not alone. The immune system is an amazingly complex and wonderful system that never fails to amaze even the most experienced researchers. If you want to understand the origins of antibody diversity and how the body produces an extremely diversified antibody repertoire, here are some things you need to know.
Origins of Antibody Diversity
While the formal study of antibodies began in 1890, as German physiologist Emil von Behring and Japanese physician and bacteriologist Kitasato Shibasaburo formulated the theory of humoral immunity, it wasn’t until the early 1960s that American biologist Gerald Edelman discovered that antibodies are made up of disulfide bond-linked heavy chains and light chains.
During the same period, British biochemist and Nobel laureate Rodney Porter characterized the antibody-binding (Fab) and antibody tail (Fc) regions of IgG. Other antibody isotopes were also identified during the period.
There are two major theories on the origin of antibody diversity: the germline theory and the somatic diversification theory.
According to the germline theory, each individual antibody variable region structure is encoded in a separate germline gene. It also claimed that the antibody or immunoglobulin repertoire is largely inherited. Upon review, however, the scientific community ruled that this theory is not applicable in humans and mice, but appears to happen in Elasmobranchs.
On the other hand, the somatic diversification theory maintains that the genes that give rise to antibodies are generated as the inherited genes undergo extensive somatic alteration during the individual’s lifetime. While this theory was proven to be partly true, since somatic hypermutation is now widely established, the other features of antibody diversity like somatic gene rearrangement and isotype switching warrant further explanation.
Aside from these two major theories, there are other theories proposing that antibody diversity is brought about by completely different mechanisms, like when two or more genes interact to form an immunoglobulin variable region.
The Generation of Antibody Diversity
The immune system uses two approaches in recognizing and attacking pathogens: innate immunity and adaptive immunity.
The innate immunity system employs general pathogen recognition systems (monocytes, macrophages, mast cells, dendritic cells, B1 cells, granulocytes, and innate lymphoid cells) which, though largely non-specific, are capable of immediately attacking invading pathogens. Alternatively, the adaptive immunity system, which is largely based on B-cells and T-cells, needs to be activated by the antigen before it can do its job.
So, how exactly does the immune system produce a diversified immunoglobulin repertoire capable of recognizing almost every conceivable antigenic structure?
The body does not need to be exposed to an antigen to produce antibodies. In fact, it can make more than 1012 different antibody molecules on its own (preimmune antibody repertoire). In this stage, antibody diversity is effected through:
- The combination of VL and VJ chains to build a functional light chain, and VH, DH and JH chains to build a functional heavy chain.
- The V(D)J recombination process as additional nucleotides are added between the gene segments of the heavy and light chains.
- Allelic exclusions
- B-cell receptor editing
- VH-VL pairing
The antibody repertoire also experiences an exponential increase after repeated exposure to an antigen. When this happens, the B-cells produce antibodies with higher affinity through a process known as affinity maturation, a phenomenon that is largely attributed to the large accumulation of point mutations in the heavy and light chains of the V-region coding sequence. The process is also called somatic hypermutation since the spontaneous mutation rate is about a million times greater compared to the other genes.
Antibody diversification is also achieved through class-switch recombination (CSR) or isotype switching, a biological mechanism that alters the type of immunoglobulin a B-cell produces (e.g. IgM to IgG). In the process, the constant region of the heavy chain is altered while its variable region remains unchanged. In effect, the antigen specificity does not change, but the antibody gains the ability to interact with different effector molecules.
