Science and technology | Immunology

How fever helps combat disease has now been better understood

It helps recruit and direct cells of the immune system

AN ELEVATED body temperature can kill. Yet fever—which is precisely that—is a common response to infection. Clearly, extra heat has value in combating illness.

Exactly how fever works its magic is ill-understood. But research just published in Immunity by Chen Jianfeng of the Institute of Biochemistry and Cell Biology, in Shanghai, sheds light on the matter. Dr Chen’s work shows how febrile temperatures encourage a particular protein to shepherd immune-system cells to sites of infection.

That fever drives the migration of these cells towards such sites was known already. The mystery was the cause. Dr Chen wondered if molecules called heat-shock proteins might be involved. Heat-shock proteins are produced routinely in response to fever. Their job is to stabilise the structures of other proteins as temperatures climb. Dr Chen, however, considered the possibility that some of them might have a second role—that of pointing immune cells in the right direction.

To find out, he observed the heat-shock responses of mice he had made feverish by infecting them with Salmonella bacteria. He noticed that one heat-shock protein in particular, Hsp90, commonly ended up associated with immune-system cells called T-cells. Here it was linking up with a second protein, alpha-4 integrin, that is found on the surfaces of T-cells.

T-cells are produced in the thymus gland. They travel thence to the lymph nodes, where they await activation to attack intruding pathogens. Previous research has shown that alpha-4 integrins control this trafficking from thymus to lymph node, so the fact that Hsp90 interacts with them inside feverish mice led Dr Chen to take a closer look at the details.

Each Hsp90 molecule, he found, was bonding simultaneously to two alpha-4 integrin molecules. This drew the integrins closer together, creating clusters of them on the T-cells’ outer membranes. Such clustering is known to activate signalling pathways that induce T-cells to migrate—and, sure enough, when the integrins formed into large enough clusters they did drive the T-cells they were part of to migrate towards lymph nodes.

These findings suggested that Hsp90 is doing more than simply protecting proteins from heat. But, to be certain that it was as important for T-cell migration as seemed to be the case, Dr Chen chemically blocked the binding between Hsp90 and alpha-integrins in a group of infected mice. As he had predicted, the T-cells in these animals failed to move to lymph nodes in any numbers, and there was no successful immune response to the infection.

Besides helping to resolve the question of why animals develop fever in reaction to infection, Dr Chen’s research suggests ways in which the process might be regulated to a patient’s advantage. Drugs that increase Hsp90 production should promote the migration of T-cells to lymph nodes, and so aid the treatment of infections that need a larger immune response. Conversely, drugs that diminish Hsp90 production might help reduce T-cell movement in people with so-called auto-immune disorders, such as multiple sclerosis and rheumatoid arthritis, in which immune-system cells attack the body they are part of.

Dr Chen’s work also raises the question of whether medicines intended to suppress fever might be causing trouble by interfering with T-cell migration. His view is that the use of these medicaments needs to be considered in light of how Hsp90 behaves. His work shows that the heat-shock protein is produced in mice when fevers of 38.5°C or above have lasted for at least 12 hours. It then continues to be made until the temperature has gone back down again—and for a further two days thereafter. If a similar pattern pertains in people, early treatment with a fever-suppressor might, indeed, have an adverse effect. Discovering the schedule for human Hsp90-production when fever strikes is thus an important goal. With that information in hand, better deployment of antipyretic drugs should be possible.

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