Our immune system has the incredible capability to generate antibodies against nearly any offender or invader they encounter. It's been estimated that B cells, which produce antibodies, and capable of creating 1012 different antibody molecules. Since B cells use genes to make antibodies, how are they able to make many more antibodies than there are genes? It does so by using portions or segments of genes, and mixing them up to make new combinations of sequences. This process is also not always the same in different animals.
Researchers have now used a mouse model to show that B cells can also utilize changes in the genomic structure to produce diverse types of antibodies. DNA is a large molecule, and changes it how it is folded or compacted can bring very distant parts of the genome into close proximity. This means that virtually any sequence in the genome might be accessible to B cells during antibody production, and as pieces of different genes are brought together, very different antibodies can be made.
This work showed that in each different, young B cell, the genome was found to be folding the same Igh (immunoglobulin heavy chain complex) gene in very different ways, showing that genes can be combined in nearly infinite ways. This gene encodes for the heavy chain portion of antibodies, or immunoglobulins. The findings have been published in Cell Reports.
This work may also help us understand how and why immune system function declines with age, and leads to a reduction in the creation of diverse antibodies.
"We wanted to understand the mechanisms behind antibody variety. One way the cell achieves this is cutting and pasting from a suite of options for the antibody genes, but the puzzling thing is genes that are far away from the location of this event are used just as often as ones close by, so there must be some way of bringing everything together and making sure that everything needed is at hand," noted study leader Dr. Anne Corcoran, senior group leader at the Babraham Institute.
In this study, the researchers used high-resolution techniques to analyze how chromosomes were interacting and next generation sequencing to understand how the genome was configured in B cells. This illustrated how the genome was looped and structured, and where various points of contact between different regions of DNA were located.
This study also revealed gene associations that promote specific aspects of B cell development. The researchers suggested that the points of contact among chromosomes could help ensure that genes are expressed in the right ways while B cells are developing.
This type of chromosomal interaction may also be important to other types of cells, the investigators noted.
As we get older, antibody diversity declines, and the distant parts of the genome are utilized in antibody production less often. The aspects of DNA folding outlined in this study might become less efficient over time. Now, the researchers want to know more about how DNA is folded in older B cells. These findings also have to be confirmed in humans.
Sources: Babraham Institute, Cell Reports