Hi rrufff,
The thing with the Toll-like receptors is not as complicated as it might seem. Well... the fundamentals are not complicated at least. But the details are, and as usual, the devil is in the details, so work continues to work out those details. Here's the fundamentals.
The discovery of the Toll-like receptors was a huge advance in immunology, one of the 2 or 3 biggest breakthroughs in the last century. They call them "Toll-like" because the first that was discovered was Toll, but that was in flies. And for years, nobody realized that Toll had anything to do with protection against infection. Everybody thought Toll had something to do with development of fly embryos (and genes that affect fly embryo development almost always turn out to be important in human development and cancer; that's a major reason people study flies, and they are much simpler to study).
Here's the problem. When you are infected by some organism, how does the body know this? How is the presence of a germ detected?
Believe it or not, until the Toll-like receptors were discovered, nobody knew the answer to that question. Around 15 years ago, a very famous guy proposed that there are specific receptors that are activated only by molecules present on bacteria and such, but never by molecules produced in our body. But nobody knew what those receptors might be. Now we know---they are the set of about 10 distinct Toll-like receptors.
(Bacteria, viruses, etc. produce molecules that are very different from ours. Receptors can be thought of as locks, and their ligands can be thought of like keys. Only the right key will fit in a particular lock, and likewise only a specific ligand will bind to a particular receptor. With receptors and ligands, sometimes a whole set of ligands might fit a particular receptor if those ligands are very similar to one another, and that's the basis of developing drugs. It is also the basis for how the Toll-like receptors work.)
Now we know that there are other molecules that help detect particular organisms, but the Toll-like receptors seem to detect the vast majority of bacteria especially, but also most viruses, fungi, etc. Just in the past 2 months or so two other molecules were discovered (also in flies) that may well turn out to be important in detecting germs in humans, because they have certain parallels to Toll. And, no doubt, a swarm of people are onto this already, it made big news as you might imagine. One of the groups I work with are among those folks trying to find this out.
Okay, so we know now that Toll-like receptors bind almost exclusively to molecules that are found only in germs, never in people. There are important exceptions to this rule, and these exceptions are thought to be the basis of an increasing number of diseases---heart disease being just one.
What happens once the Toll-like receptors bind to their ligand? You can think of Toll-like receptors as being a kind of "smoke alarm." Now, smoke alarms don't respond to normal air and various gases and particles. But if they sense smoke or particulate matter that is derived from smoke, then they turn on an alarm. The same sort of thing happens with Toll-ike receptors. They send out certain signals to tell other parts of the body to send help, and a whole crowd of different cell types begins to swarm into the region. Sort of the body's SWAT team. They don't go away until the germs are eradicated, either. Sometimes, the germs ARE eradicated, but they stay anyway because they don't realize this fact, and that phenomena can lead to or exacerbate diseases where you have chronic inflammation (e.g., arthritis). Anyhow, the Toll-like receptors mostly sit on the surface of the cell (some are inside, located in strategic places). When the Toll-like receptors bind to their ligand, their shape gets changed slightly, and that activates a cascade of molecular events inside the cell that can be thought of like a row of dominoes----you knock the first one down, and all the rest in turn get knocked down. With Toll-like receptors, this is an oversimplification because the "wiring" is not entirely linear, and there are many ways that "wiring" from other sources influences what happens, but this is a pretty good approximation just the same.
Anyhow, at the end of this chain of events are particular genes that are turned on or off by signals triggered by Toll-like receptors. These genes are directly useful in fighting infection and in sounding the alarm to the rest of the body.
One thing we still don't understand about this system is exactly how it is tuned. For example, the body tends to tailor the magnitude of the response to the severity of the threat from the germ. Some germs are much more dangerous than others, and in those cases, the response after the body detects their presence is the equivalent of all-out war, pedal to the metal. But when the body detects the presence of other germs that are not very dangerous, this does not happen, and the defense is much more restrained. This is important, because the things that happen when the body declares war on an invader result in collateral damage. The body somehow limits the collateral damage as much as possible, but we really don't know in detail how this is accomplished (we do know some of this story). Another thing that is not clear is how the system is turned off... part of this answer is known, but part remains a mystery.
Where are Toll-like receptors located? Well, the body is pretty clever, so it positions these in strategic locations where germs are likely to be encountered, or in locations that are located in such a way that vast areas can be "screened". For example, they are found in skin cells, cells lining the gut, and in cells lining the blood vessels, also in blood cells themselves. Actually, there aren't many places in the body where Toll-like receptors are NOT found, which is a pretty smart idea. I can't think of any off the top of my head. Like I said, the body is clever, and it has a lot of backup systems. And the body long ago figured out that we are hopelessly outnumbered by germs, and we might as well get used to that fact, and also to the fact that those germs will be constantly attacking us. So.... we HAVE gotten used to that. We have adapted to what is really a hostile environment, and done so very effectively (thanks in large part to the Toll-like receptors and their attendant signaling apparatus).
So, why is it so important that we know how the body senses germs? Because the basis of many diseases involves a kind of screw-up in this system. For example, in some diseases (e.g., HIV, and bird flu) detection of the germ is inadequate, but in other diseases, things can get way out of hand, and the cure can be worse than the disease. Septic shock is an example (septic shock is usually fatal).
Another reason this is so important is because of cancer. Many people don't know this, but actually cancers are developing in numerous places in your body all the time. But they never become a problem, because there are internal ways a cell has to detect when things get screwed-up, and the cell commits suicide. In fact, quality control procedures, editing, and surveillance occurs contantly on many levels in all cells in the body, and outside of cells too. Pretty much anytime any molecule is made, it is checked for accuracy, at several points from in the manufacturing process, and often rechecked later on too. That's because the complexities of the system are such that statistically, mistakes will occur occasionally or sometimes frequently, but in many cases not even one mistake can be tolerated. So the systems demand checks, rechecks, and redundant quality control mechanisms (much the same way that mission-critical components and systems in planes must be checked and rechecked, because one mistake can be disastrous).
And the immune system is constantly patrolling the body looking for screwed-up cells that escaped the normal suicide pathway. When such cells are found, they are attacked and destroyed. And Toll-like receptors play an important role in this whole process. Now... in cancer, sometimes the cancer cells evade this whole process, and can then proliferate and become a full-blown tumor. How do they do this? We don't completely know the answer, but in just the last year or two, effects on Toll-like receptors were found to be responsible. Sometimes cancer cells can subvert the body's defense mechanisms, and instead of preventing or destroying the cancer, the tumor cells can use these same tools to PREVENT their own destruction. Again, Toll-like receptors seem to play an important role in this process, but we are only beginning to understand the details of this.
I think you can appreciate now why Toll-like receptors have made such a big splash, and why work continues rather frantically to find out more about them and how they work. Many drugs and therapies will eventually be developed that will be targeted to some aspect of Toll-like receptors and their signaling pathways, and these will likely prove extremely useful in treating or curing a very wide variety of diseases.
Sorry for being so long-winded, but I hope this helps,
T |
