In aging, B- cell regeneration is regulated by communication between peripheral B cells and progenitors in the bone marrow. Loss of B lymphocyte regeneration in the bone marrow (BM) is an immunological hallmark of advanced age, which impairs the replenishment of peripheral B-cell subsets and results in impaired humoral responses, contributing to immune system dysfunction associated with aging.
A better understanding of the mechanism behind this loss may suggest ways to restore immune competence and promote healthy aging. A team of scientists from the Technion-Israel Institute of Technology found a way to reverse the process of natural aging of immune system cells, and potentially make the elderly far more resistant to infections like COVID-19.
They identified the molecular pathway that the human body uses to create B cells, which the immune system uses to identify and produce antibodies against new pathogens. Typically, our body stops making as many B cells later in life, but suppressing a particular hormone can trigger production, theoretically giving an older person’s immune system the same robustness it had earlier in life, according to the research published in the journal Blood.
B cells are produced in bone marrow and then travel through the blood to lymph nodes and the spleen, where they wait for pathogens to enter and then attack them. They are constantly replenished by new ones sent from the bone marrow, creating a state of homeostasis, in which the total number of B cells in the bone marrow and outside remains constant. However, B cells do not just disappear. They turn into memory B cells so that if the body is exposed to a previous pathogen, the individual will not get sick or will have mild symptoms of the disease. This is because the immune response will be fast and robust, and it will eliminate the pathogen, often without the individual knowing he or she had been exposed to it. And, unlike B cells, memory cells are long-lived.
In order to find a way to trick the body into making new B cells, the researchers probed one of the ways that the body naturally replenishes its supply. As part of the treatment for some medical conditions, such as lupus, lymphoma and multiple sclerosis, patients undergo B cell depletion, meaning a significant amount of memory B cells is removed from their bodies.
Examining older patients who underwent this procedure, the group found that their immune systems rejuvenated, and their bodies could produce new B cells again. An effect similar to B cell depletion can be produced by inhibiting one of the hormones in the signaling pathway that suppresses the production of new B cells.
They found that tumor necrosis factor alpha (TNFα), which is highly produced by peripheral B cells in aging, stimulates the production of insulin-like growth factor-binding protein 1 (IGFBP-1), which binds to insulin-like growth factor 1 in the circulation, restraining its activity in promoting B-cells generation in the bone marrow. After B-cells are depleted in aged humans and mice, TNFα decreases, resulting in increased IGF-1 and reactivation of B-cells generation (lymphopoiesis).
Perturbation in this circuit by administration of IGF1 to old mice or anti-TNFα antibodies to human patients restored B-lymphopoiesis in the bone marrow. Hence, the researchers suggest that in both human and mouse aging, peripheral B-cells use this mechanism to repress B-cell generation.
The researchers hope to turn that hormonal trick found into a new rejuvenating treatment for the elderly and immunocompromised.
Reem Dowery, et al. Peripheral B-cells repress B-cell regeneration in aging through a TNFα/IGFBP-1/IGF1 immune-endocrine axis. Blood 2021; blood.2021012428. doi: https://doi.org/10.1182/blood.2021012428.