B cells are an important part of the adaptive immune system, using antibodies to coordinate the T cell response to pathogens and other targets of opportunity that immune cells should attack. As is the case for all aspects of the immune system, B cell function degenerates with age. Growing numbers of what are known as age-associated B cells emerge. These are known to contribute to autoimmunity at the very least, by inappropriately rousing the immune system to attack a patient's own tissues.
What to do about this? Getting rid of the problem cells seems like a good idea. It was some years ago that researchers first demonstrated that targeted destruction of B cells can reverse measures of B cell aging in old mice. The old B cells presumably include damaged, misconfigured, and other problem cells beyond the age-associated B cells mentioned above. Depleting the B cell population triggers the aggressive generation of new B cells, and the new cells generally lack the problems of the old ones.
Does this produce an actual improvement in immune function, though? We would expect it to eliminate some autoimmune issues, and reduce the risk of occurrence going forward, but does the immune response get better? In today's open access paper, researchers demonstrate that the answer is no. This may well be for the same reason that regeneration of the thymus doesn't improve overall immune function in late life in mice and non-human primates, which is that lymph nodes degenerate to the point at which the immune system cannot effectively use the lymphatic system as a point of coordination, even when the coordinating cells have been restored and refreshed. Aging is a matter of damage in all components of any system, and while in some cases incremental benefit can be produced by fixing any one component, in others it might require more than that.
Fortunately, lymph node degeneration appears inflammatory and fibrotic in nature, features of aging that are convincingly linked to the presence of senescent cells. This dysfunction of the lymphatic system may well be something that can be addressed or pushed back sufficiently via senolytic treatments to allow incremental repairs of other components of the immune system to be individually effective. That includes replacement of B cells, removal of damaged and harmful T cell populations, regrowth of the thymus, and regeneration of the hematopoietic stem cell population. Each of those is a sizable project.
Elderly individuals are at increased risk to develop infections, which results in significant morbidity and mortality, accounting for 9% of deaths in elderly subjects. Attempts to reduce infection rates by employing vaccinations have only limited success due to the decline in immune system function. Efforts to improve vaccine efficacy by refining antigen delivery have also failed to provide the desirable immune protection. Hence, novel technologies that target the elderly patient immune system and enhance its responsiveness to vaccinations and pathogens, thereby overcoming the immunodeficiency associated with aging, are required.
Among the most promising interventions in recent years, with demonstrated rejuvenating capacity in mouse models, is the removal of "old" tissues or cells. Indeed, when applying this approach in the hematopoietic system, we have demonstrated that removal of "old" B cells reverses B-cell senescence through reactivation of B lymphopoiesis in the bone marrow (BM) of aged mice. Similar outcomes have also been reported for other tissues. Considering that senescence of the B lineage is reversible and subjected to homeostatic regulation, the current study tested whether this new paradigm can be translated to enhance immune response in elderly individuals that have been treated for B-cell malignancies by transient B-cell depletion.
We show here that B-cell depletion in both elderly mice and humans rejuvenates the peripheral B-cell compartments both phenotypically and functionally, through the induction of de novo B lymphopoiesis. However, we found that B-cell rejuvenation by itself is insufficient to significantly enhance responsiveness to vaccination in aged mice and humans and to prolong survival of old mice.
Our current findings suggest that B-cell recovery following depletion is not just a "recapturing" process, which returns B cells to the same stage they have been in before being exposed to depletion, but a rejuvenation process, in which the B-cell repertoire becomes younger both phenotypically and functionally, resulting from de novo B lymphopoiesis. This rejuvenation is observed in both aged experimental mice and in elderly humans. We proposed that B lymphopoiesis in aging is suppressed by the accumulated antigen-experienced B cells in the periphery.
These findings suggest that the in vivo immune response evoked post-B-cell depletion, at least to these stimuli, may still be suboptimal, due to concurrent, age-related impairments in other essential components of immunity. Indeed, age-related defects have been reported in T lymphocytes, dendritic cells, monocytes, and NK cells. Thus, although B-cell depletion provides a proof of principle for a rejuvenation approach in the immune system, it is insufficient to completely restore immune competence, since all other essential counterparts of cellular immunity are still "old".