Feature: Innate interest
8 September 2006. By Lisa Melton, a freelance writer based in London.
Imagine a crowded train carriage. Someone sneezes, expelling disease-causing bacteria into the carriage. But not everyone is doomed to a feverish week in bed. People who have encountered the bacterium before will probably clear it within a few hours, never even realising that they were the intended victims of a microbial invasion.
But if the pathogen is one they have never come across, the experience might be quite different. The unwelcome guest activates a rough-and-ready collection of immune cells known collectively as the innate immune system (see grey box below). Although these combat the invasion, they also trigger fever, body aches, redness and swelling - the symptoms we normally associate with infection.
The human body is constantly challenged by bacteria, fungi, parasites and viruses; we inhale them, swallow them and live alongside them. It is a wonder we survive at all. One reason we do is because we possess this ancient and crucial form of defence.
Although discovered more than 120 years ago, the innate response has been one of science's backwaters. Until about seven years ago, scientists were fixated on the 'adaptive' side of the immune system, our 'acquired immunity'. This world of B cells and antibodies, T cells and cell-killing, has dominated immunology.
Things have changed. The innate immune response is turning out to be hugely important in defence, in self-inflicted damage (inflammation and autoimmune disease) and in driving acquired immunity. Many believe it could give rise to a new class of immunostimulants to boost vaccination, to crank up the body's ability to fight off tumours or to fight malaria or HIV. In contrast, drugs that tune down the innate response could be used to treat allergies and autoimmune disorders.
Key players in the innate immune response
Ancient times
One possible reason for innate immunity's neglect may be its supposed primitiveness. It is undoubtedly ancient - all sorts of organism, from flies to fish, have some kind of innate immunity. Indeed it was first discovered in starfish, by Russian immunologist Ilya Mechnikov in 1883. Poking them with thorns, he saw mobile cells surround newly introduced bacteria, engulfing and destroying them. Water fleas exposed to fungal spores mounted a similar response.
This led Mechnikov to propose his revolutionary cell-based theory of immunity, for which he won a Nobel Prize. It was Mechnikov who described the process of 'phagocytosis' ('cell-eating') as the cornerstone of the innate response.
Unlike other organisms, mammals supplement the innate immune system, always at the ready, with the adaptive response. While the innate response is swift, reacting within minutes, the adaptive response develops slowly, over days to weeks.
The two systems are complementary. Faced with an intruder, the innate immune response fires up quickly to contain the foreign element, while the relatively slow adaptive immunity gears up for a finely tuned counter-attack. Adaptive immunity is refined during the course of an infection: it adjusts until it is optimised to deal with that particular organism. It also has a 'memory'. After a particular infection has been eliminated, specially trained cells are left behind - the T and B memory cells, which are rapidly mobilised the next time the microbe attacks.
Though quick, the innate system can seem rather unsophisticated. It is less specifically targeted and causes much collateral damage to normal tissues.The burst of cytokines that accompanies the innate response not only ratchets up the immune system but produces the classic symptoms of infection, including fever, tiredness and flu-like symptoms.
Innate in the spotlight
So why has the innate immune defence come back into fashion? Of crucial importance has been the identification of a family of receptors that recognise invading organisms. These 'toll-like receptors' (TLRs) recognise patterns of molecules that are shared between different bacteria, viruses, fungi or parasites.
Their name derives from their similarity to a protein first found in the fruit fly Drosophila, known as Toll (German for 'crazy', based on the disrupted shape of Toll mutant fly embryos). In humans, a dozen TLRs have been found so far, each of which appears tobind a specific microbial motif (see pink box below).
TLRs are not exclusive to humans. Flies, worms, starfish, sea lampreys and mice have them - in fact they have been found in almost every organism examined. Even plants are bristling with TLRs, which they use to withstand fungal and viral infections. The weed Arabidopsis, for instance, has more than 200.
Innate interference
The once-neglected innate immune response has spawned a rapidly expanding range of immunotherapeutics. Vaccine research in particular is benefiting. Most vaccines depend on an adjuvant, a substance that boosts the power of a vaccine-induced immune response. Since one role of the innate system is to prime the acquired response, targeting TLRs on dendritic cells, for example, could have a significant adjuvant effect.
A similar approach could be used for the treatment of cancer. Potentially tumorous cells often have particular 'marker' proteins on their cell surface, which are recognised by receptors (e.g. the NKG2D receptor) on cells of the innate immune system. This activates natural killer cells that attack the aberrant cell. Moreover, because of the interplay between the two systems, boosting the innate response may promote both innate and acquired responses to cancer cells. This approach is currently being tested in clinical trials of melanoma and other cancers.
Several companies are investigating TLR- activating compounds as vaccine adjuvants and immunotherapies for cancer and infectious disease. Drugs such as CpG DNA that activate TLR9 are in clinical trials for metastatic melanoma and non-Hodgkin's lymphoma. And a drug that activates TLR7 and TLR8 is already on the market as treatment for genital warts and forms of skin cancer.
As well as boosting responses, agents acting on TLRs could potentially block dendritic cell activation - a possible approach to the treatment of autoimmune disorders. In mice, Californian company Dynavax has developed an inhibitor of TLR7, 8 and 9, whichit sees as a potential therapy for systemic lupus erythematosus (SLE). A TLR blocker developed by Genzyme is being tested as a treatment for ulcerative colitis and Crohn's disease.
Not surprisingly, pathogens have evolved strategies to evade innate immunity. Staphylococcus aureus, for example, secretes a protein that blocks activation of complement. Although a bacterial survival strategy, it could actually prove therapeutically useful, as an anti-inflammatory agent.
Tweaking the innate immune response could alsolead to new treatments for atherosclerosis, blockage of blood vessels by fatty deposits. For decades, researchers have seen signs of inflammation in affected artery walls, but the precise mechanisms have been unclear. It is now apparent that the innate response is critical to the development of atherosclerosis, and the key TLRs have been identified. This again suggests new ways in which the underlying inflammation could be tackled.
Finally, the innate immune system may also be involved in neurodegeneration. The culprits here appear to be microglia, the central nervous system's phagocytic cells, which can trigger a harmful inflammatory response. To emphasise the potential importance of innate immunity, a recent study found that certain polymorphisms of the TLR4 gene seemed to protect against Alzheimer's disease.
Further reading
- O'Neill LAJ. Immunity's early-warning system. Scientific American 2005;292(1):38-45.
- Meylan E et al. Intracellular pattern recognition receptors in the host response. Nature 2006;442(7098):39-44.
- Akira S et al. Pathogen recognition and innate immunity. Cell 2006;124(4):783-801.