How immune cells reshape DNA to make better antibodies
The immune system learns from every infection it encounters. That ability depends on a process in which immune cells deliberately mutate their own DNA to produce increasingly effective antibodies. New research reveals how the three-dimensional structure of the cell nucleus controls where this happens.
B cells are the immune cells that produce antibodies. To continuously improve those antibodies, the cell introduces targeted mutations into a specific stretch of its DNA, a process called somatic hypermutation (SHM). How the cell decides which part of the DNA gets mutated and which does not has long been unclear. The researchers report in Science that the three-dimensional organisation of DNA in the nucleus is the key: a mechanism called loop extrusion brings the target region into contact with the mutation machinery.
A switch inside the nucleus
Loop extrusion is a process in which proteins pull DNA through themselves like a loop, bringing distant sections of the genome into close proximity. This mechanism regulates gene activity across many cell types. In B cells, it also determines where the mutation system operates. Without correct loop extrusion, somatic hypermutation becomes less precise, potentially reducing antibody quality.
The study is primarily immunological, but has broader relevance. Loop extrusion and its associated proteins (cohesin and CTCF) are also involved in DNA repair and in how the genome changes during aging. Disruptions in this system have been linked to cancer and to age-related decline of the immune system.
Aging of the immune system
An aging immune system produces less effective antibodies. Whether disrupted loop extrusion contributes to that decline in older people has not yet been investigated. But this finding provides a concrete molecular hook for asking that question. For longevity science, understanding how B cells maintain (or lose) their learning capacity with age is a relevant direction.
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