Missing molecules could hold key to reduced immunity in the aged

By Lorraine Cichowski and Andras Szakal

RICHMOND, Va. – It's commonly accepted by health experts that our immune system slowly loses its ability to fight disease and sickness as we age. That's one reason doctors urge flu shots for those 65 years and older.

It's less clear, however, which cellular changes in the body cause the aging immune system to make fewer, less-potent antibodies to fight viruses and diseases -- even after receiving a vaccine, such as a flu shot.

A team of immunologists at Virginia Commonwealth University has one possible answer. The researchers have discovered a decline in the numbers of a critical molecule on the surface of follicular dendritic cells (FDCs) in older individuals and linked that molecule shortage to immune deficiency.

The finding, published in the October issue of the European Journal of Immunology, is an important step in unlocking the secrets of the immune system, particularly in the aged.

"We have known for some time that immunization becomes less effective in people 65 years and older," said Andras K. Szakal, Ph.D., professor of anatomy and immunobiology at VCU and lead investigator on the study. "The older person is more likely to produce low-affinity antibodies, not the abundance of high-affinity antibodies produced by healthy young people.  Even after a flu shot, for example, many elderly are unable to produce high quantities of antibodies.

"Now we are beginning to be able to point to this molecule on FDCs as one culprit in causing a bottleneck situation that reduces antibody production in the aged." 

Follicular dendritic cells (FDCs) play a central role in the immune system in helping white blood cells produce antibody responses to antigens that help people fight viruses and diseases. Higher production of antibodies leads to increased resistance to microbes and disease. 

Dr. Szakal and his VCU colleagues - John G. Tew, Ph.D., professor of microbiology, and research associate Yuksel Aydar, Ph.D. - studied the interaction of FDCs and the two types of white blood cells - B cells and T cells - in young and old mice, looking for cellular changes that affect the immune system with age. Their research found that, in older individuals, shortages of the molecule known as the FcgRII receptor on the surface of FDCs prevent FDCs from fulfilling their role in the antibody-production process, resulting in lower amounts of antibodies produced and less disease-resistance in the aged.

"The significant role of FDCs is to trap immune complexes - the combination of antigens and antibodies," Szakal said. "The FDCs then present these immune complexes to B cells, activating the B cells to start processing the antigen. With the help of T cells, the B cells then make antibodies.

"When you look at old mice, we find that the FDCs are not able to efficiently trap the antigen-antibody complexes or to stimulate the B cells.  At least one of the reasons is that, in old FDCs, FcgRII receptors are scarce. That's a problem because FDCs rely on these FcgRII molecules to bind the tails of the antibody in the immune complex.  Fewer FcgRII molecules on the FDCs mean that immune complexes are left exposed.  Because B cells also have FcgRII receptors, the exposed immune complexes will bind to the B cell FcgRII, sending a message to the B cells to halt antibody production.  When the B cells can't be stimulated, they die."

The role of the FcgRII receptor on the surface of FDCs was identified by Dr. Tew in June 2000. 

Szakal emphasizes that the scarcity of FcgRII receptor molecules is a significant concern - but not the only problem in the elderly. In addition to a shortage of FcgRII, older individuals have fewer CD21L molecules on their follicular dendritic cells.  The shortages of both molecules could help explain why the influenza vaccine and other vaccinations tend to be less effective at preventing the flu and other diseases in the elderly than in younger people

The Centers for Disease Control estimates that a flu shot generally will prevent illness in 70 percent to 90 percent of healthy adults under 65 years old. A CDC trial found that the effectiveness in preventing upper respiratory tract infections drops to 58 percent in those aged 60 and older and lower in those over 70 years old. CDC said the effectiveness of a flu shot for preventing flu-related illness is 30 percent to 40 percent for elderly in nursing homes.

Szakal said future research will investigate ways to replace the missing molecules on follicular dendritic cells so that the FDCs can perform their intended function in the immune system. He said certain proteins called cytokines that are produced by B cells and T cells may one day form the basis of an injection that older people could get to reverse the problem of the lost molecules on FDCs.