As Bodies Age, Disease-Fighting Cells Lose Punch

New research on cells that produce disease-fighting antibodies helps explain why people succumb more easily to infectious diseases as they grow older. Researchers at National Jewish Medical and Research Center and the University of Colorado Denver (UCHSC) report in the May 15 issue of The Journal of Immunology that, as mice age, they must rely increasingly on B cells that developed during previous infections with other pathogens.

"In most cases, the 'antigen-experienced' B cells do not fight new disease-causing organisms as effectively as do naïve B cells, which are responding to an infection for the first time," said John Cambier, PhD, co-author of the paper and Chairman of the Integrated Department of Immunology at National Jewish and UCHSC.

B cells secrete antibodies, which bind to and neutralize foreign particles in the body. Antibodies secreted by antigen-experienced B cells were made to fight a previous pathogen and generally do not bind strongly to the current one. Naïve B cells can mount a more potent defense because they custom-tailor their antibodies to the current pathogen, allowing the antibodies to bind it strongly.

"As occurs in many parts of the aging mind and body, the immune system becomes less responsive to new challenges," said Cambier.

Most immunology researchers have believed that elderly people are less capable of fighting infection because their failing T cells no longer effectively orchestrate the cellular immune response. Although T cells do appear to play a role, Cambier and his colleagues believed there was more to the story.

Their current paper started with a basic paradox. Older mice, and humans, produce fewer and fewer new B cells. Yet, B-cell levels remain high in elderly people and mice. Cambier and his colleagues hypothesized that older mice maintain high B-cell levels by stockpiling antigen-experienced B cells. Exposure to foreign pathogens helps them live longer than naive B cells, which usually die after five to six weeks if they do not encounter a pathogen.

Cambier and his colleagues closely examined the B cells in mice less than 3 months of age and mice older than 22 months. That is roughly equivalent to studying B cells from a teenager and from a 75-year-old person. They used a number of cell characteristics, including cell-surface receptors and antibody expression, to distinguish antigen-experienced B cells from naive ones. One kind of naive B cell, called a follicular cell, decreased from an average of 70% of the B-cell population in young mice to 32% in older mice. In another analysis, results indicated that only about 5% of the B cells in young mice were antigen-experienced, but they accounted for 76% of the B cells in older mice.

"These numbers are averages," said co-author Sarah Johnson. "The B cell populations of individual mice varied, with some retaining large numbers of naive B cells and other carrying almost none. The mice with many naive B cells would presumably be better at fighting off infections."

In a follow up to these findings, Cambier and his colleagues have transplanted hematopoietic stem cells from young mice into old mice. Initial results suggest that the transplantation restores the B cell population to a younger, more naïve and adaptable profile.