Understanding How Lymph Nodes Respond to Infection May Redefine How Immune System Functions

Duke University Medical Center researchers may have solved the mystery of why lymph nodes swell when the body fights infection. Their findings may redefine how the immune system functions, they said.

Their research, published in the December 2003 issue of Nature Immunology, centered on the role of mast cells. Mast cells are immune cells that are typically found just under the skin and in the lining of the intestine and lungs and were previously associated primarily with the induction of allergic reactions. The Duke researchers report that allergic reactions are only a side effect of mast cells’ much more important role as a regulator of the body’s immune system.

“Mast cells serve as the command post for the immune system during infections,” said Soman Abraham, Ph.D., professor of pathology, associate professor of immunology and senior author of the paper. “White blood cells are sequestered within these nodes and, following proper activation, they can specifically target infectious agents and aid the host in clearing unwanted pathogens.”

Abraham said the discovery that mast cells can initiate the activation and swelling of nodes through release of specific signaling molecules points to the possible use of mast cell products for the development of vaccines designed to boost the potency of the immune response.

“Mast cells have been much maligned because of their contribution to many diseases including asthma, arthritis, Crohn’s disease and multiple sclerosis,” said Abraham. “Our research shows that mast cells play an important role in immune surveillance and defense against infectious agents.”

The human immune system comprises two components that protect it against invading pathogens. The first line of defense is the innate immune system, a quick-acting response triggered immediately when a pathogen enters the body. The innate immune response responds the same regardless of the pathogen and attacks the pathogen for the first several days until the adaptive immune response can begin its attack.

The adaptive immune system is tailored specifically to the pathogen it is attacking. Once the immune system identifies an invader, draining lymph nodes recruit infection-fighting T-cells within 24 hours. During the next week or so, the T-cells proliferate and induce B-cells to produce antibodies specific to the invader. The result is swollen lymph nodes, which are the first discernable sign that the adaptive immune system is in effect.

Previous studies by Abraham showed that mast cells trigger the body’s innate immune system by releasing a molecule called tumor necrosis factor (TNF) and recruiting infection-clearing cells called neutrophils. However, the role of mast cells in the adaptive immune system remained unknown.

To examine the role of mast cells in the adaptive immune system, the Duke researchers studied the lymph nodes of mast cell-deficient mice. When the scientists introduced bacteria into the animals, their lymph nodes did not swell. However, when the mice were injected with mast cells, their nodes did swell. Further, specific activation of mast cells in the skin induced a rapid increase in TNF in the lymph nodes and recruitment of T cells.

“We are showing that the mast cells are critically involved in both the innate and adaptive immune systems,” said Abraham. “Both are triggered with the release of TNF by the mast cells. The innate immune system, through TNF and neutrophils, attack the pathogen first, but within hours, TNF has reached the lymph nodes, triggering the adaptive immune system. Infection fighting T-cells are recruited and a specific attack on the pathogen begins. Within days, the body is producing antibodies and fighting back.”

The involvement of mast cells in the adaptive response is a major shift in the understanding of the immune system and its function, said Salvatore Pizzo, M.D., Ph.D., chairman of the department of pathology and a member of the research team.

“When you pick up a textbook two years from now that shows how the immune system functions and the way a node responds to an infectious agent, you are going to see a whole new pathway,” said Pizzo. “Mast cells are much more than just bad actors making you feel sick when you are exposed to noxious agents. They are actually major players helping you deal with these noxious agents.”

“With a clearer understanding of the adaptive immune system and the role of mast cells, comes the opportunity for new therapeutics that could improve disease protection,” said Abraham.

“It’s been known, particularly with allergy and asthma, that mast cells are involved in immune dysfunction,” he said. “But their real physiological role is triggering both the innate and adaptive immune systems. Future research needs to focus on this role. We need to continue to dissect the process and adapt some of it to improve immunity and disease protection.”

The National Institutes of Health and the Sandler Foundation for Asthma Research funded the research. Co-authors of the paper include James B. McLachlan; Justin P. Hart, Ph.D.; Christopher P. Shelburne, Ph.D.; Herman F. Staats, Ph.D.; and Michael D. Gunn, M.D., all of Duke University Medical Center.