Signals for war

November 16, 2005

Tags: Fink LabPloegh LabImmune System

You're packed into a crowded elevator when the woman beside you sneezes. Unsurprisingly, you keep breathing. As you step out of the elevator, vaporized particles from the sneeze make their way deep into your lungs and take hold. And so the war begins.

It's a war your body is always fighting. Microbes are everywhere, and some are out to get you. Fortunately, you're armed with multiple layers of defense, starting with your skin. But some of those microbes will find away in. And that's when they confront your immune system.

Think of the human immune system as your own army of defense, an integrated force of tissues, organs, cells and molecules that seek and destroy any cell whose membrane-or skin-looks fishy.

But there's nothing simple about this war. The enemy fights back, with tricks based on the selective pressures of Darwinian evolution. Often a few microbes with some sort of genetic variant or mutation escape detection. These gain a survival advantage and begin replicating. Now the immune system must learn to destroy these new, mutated microbes. "The very fact that you have a defense mechanism against these pathogens puts a selective pressure on them to bypass it," points out Whitehead Institute Member and immunologist Hidde Ploegh.

First responders

Suppose that the stranger in the elevator was fighting a low-grade infection caused by a virus-a small capsule of DNA (or RNA) that, on its own, has no "life" to speak of. This virus needs a home, and it's looking to pitch a tent right inside your lung.

This nano-sized capsule of viral DNA has a very specific agenda. Once it lands on a cell, it will work its way into the center of the nucleus, and like a Trojan horse, storm the genome by surprise. From that point on, the cell will do the virus's bidding. Soon it will replicate the virus, storing inside its membrane a growing mass of viral capsules. The cell will then burst apart, releasing this new batch of viruses into the tissue where they, in turn, will hunt for more cells to breed in.

But your immune system counterattacks. And it does so not as a single monolithic force, but as an entire spectrum of troops united under a single cause.

Many of these troops are ready to attack from the moment you're born. Your cough reflex, for one, is part of what scientists call your "innate immunity," immunity that's hardwired into your system, no experience required. Your mucus membranes might have also trapped the viral particle in its tracks. Other mechanisms such as fatty acid secretion and even saliva can unleash a biochemical response.

But even those viruses that get lucky and make their way into your lungs run into what's called the "complement system."

The complement system is similar to your blood clotting system, where one protein kicks off a cascade of proteins that surround and heal the wounded tissue. In the immune system response, liver-synthesized components (called serum opsonins) recognize the foreign presence and glom onto it, sending out messages to a host of different proteins that also then bind to this foreign invader and begin drilling holes in its outer shell. That viral particle in your lung is now completely disabled. Its coating has been shattered and its internal organs of nucleic acids spill out.

Or perhaps antigen-presenting cells (APCs), macrophages and dendritic cells, stumble over this virus. That scenario is likely, since these highly xenophobic cells constantly patrol the body seeking "foreigners."

Upon encountering it, APCs will eat the virus, metabolize it, and discharge it as waste.

Building a smart bomb

Or you may not be so lucky. The stranger in the elevator may have sneezed out a new strain of flu so virulent that your complement system and macrophages and dendritic cells are always one step behind it. In fact, this strain of flu has gained an evolutionary advantage over other strains for this very reason.

In a few days you'll be fully symptomatic and entirely miserable as your immune system works overtime trying to play catch-up. These cells know that unless they call in new troops with fancier weapons, they'll never win.

This newest tactical response is described by scientists as "acquired immunity." Acquired immunity is found only in vertebrates. It is an aspect of the immune system that develops only in response to a particular invader, but which then provides lifelong immunity to that invader.

"It's constructed in a more complicated manner and it takes longer to kick in, but once it does, it hits with pinpoint precision," says Ploegh. In other words, while you spend the next few days at home on the couch wrapped in a comforter watching TV and breathing vaporized water, your body is building a smart bomb.

This smart bomb is composed of two major cell types: T cells, white blood cells that originate in the thymus; and B cells, of which your bone marrow churns out approximately a billion a day.

The messengers that alert these two classes are the APCs we met earlier, which have been feasting on the invaders so heartily.

After a dendritic cell swallows an invader, it digests it into short peptides that are then loaded onto a class of proteins that shuttle them to the cell surface.

Here, the dendritic cells show off chunks of the mutilated virus to their neighbors-in particular, to T cells.

In a landmark paper in Nature, Ploegh's lab employed real-time microscopy techniques to visualize this process. The experiment yielded novel images of this occurring in living tissue. It also revealed that when a T cell recognizes the antigen on the surface of a dendritic cell, it can bolster the dendritic cell's ability to send even more antigen to the surface and thus increase the power of the signal to more T cells. As a result, the alarm is sounded loud and clear throughout your body.

Now the T cells deploy a two-fold tactic. First, they hyper-charge the innate immune system, so that production of its complement and microbial killing mechanisms goes into overdrive. Second, they signal B cells, which charge into the fray and begin producing antibodies, proteins that bind to and thus neutralize this particular virus. These B cells will begin replicating identical copies of themselves, creating a clone-filled antibody serum specially designed to crush this particular virus, and it alone.

It might take a week or so, but these antibodies have built up and amassed in your circulation, and their assault on the virus reaches its height. As they bind to the virus, this further alerts the macrophages, dendritic cells, and even the complement system to mount a larger-scale attack. Soon, the antigen and its progeny are wiped out in your body's molecular reenactment of General Custer's last battle.

Once the fighting ends, your body retains the history of this battle. Memory is stored in the form of a rich supply of cloned antibodies that bear the signature of that virus, so plentiful that if it were ever to enter you again, it wouldn't stand a chance.

Shape shifters

Unfortunately, the tale of immunity doesn't end here.

"Viruses and bacteria have been around a lot longer than vertebrates," says Whitehead Member and pathogenesis expert Gerald Fink. "If there's one thing that they've learned how to do, it's to survive."

Some flu strains, like certain varieties of the much feared avian flu, have evolved to such a virulent degree that our fully deployed T and B cells only get the upper hand in a small percentage of cases. Even more frightening, other viruses such as malaria and HIV manage to mutate when they're inside the host, so by the time the acquired immune functions have polished off a strain, a new one has evolved.

Yet another breed of microbes also plays havoc with our immune system: fungus. This threatens transplant or chemotherapy patients who are taking drugs to temporarily subdue their immune systems. If they're unlucky, they contract a pathogenic hospital-borne fungal microbe.

This microbe knows a few tricks. It can actually alter its outer coating-its skin-so that the few active immune cells will pass right by. The fungus then latches on to tissue, morphs into long finger-like filaments, and causes organ damage. Drugs that target these fungal microbes are particularly brutal on the patient, since fungal cells-unlike bacteria or viruses-are very similar to mammalian cells. As a result, the drugs will damage many healthy cells as well, causing collateral damage that can at times prove fatal.

Kevin Verstrepen, a postdoctoral researcher in Fink's lab, has discovered a genetic mechanism that enables fungal microbes to disguise themselves so readily.

In a recent Nature Genetics paper, he described how these microbes can dramatically alter their appearance in one cell division, and then change back. The results can be deadly.

Imagine you are immunocompromised and an infection has taken hold. Your immune system attempts a defense with what little strength it retains. Then one fungal cell divides in half moments before it's attacked. The new daughter cell looks nothing like her mother, but she's just as deadly. She passes immune cells unnoticed.

"Unfortunately, so far we've been unable to develop vaccines against certain pathogens," says Ploegh. "Flu, HIV, malaria and pathogenic fungi have an evolutionary range that makes them-for now-impossible to wipe out with a single shot."

Polio, on the other hand, also has a range of "shapes" that it can assume, but they're limited enough so that a single injection can take care of them all.

Inside the black box

Some of Fink's early work in yeast genetics has been spun off to Microbia in Cambridge, Massachusetts, created by several of his former postdoctoral researchers. Other biotechs also are hammering away at these thorny problems.

But what we know about the epic battles between pathogens and our immune systems is vastly greater than our ability to act on such knowledge. And there is still much more we don't yet know.

For instance, although we understand much about autoimmunity-in which our immune system turns on us and attacks healthy cells-we actually don't understand what exactly triggers autoimmune diseases or why this process doesn't occur more frequently.

And while we know that immune cells recognize invaders by their skin, and we know what happens after they recognize these invaders, the precise mechanisms by which these cells actually "see" each other are still hidden in a biological black box.

"We don't know the full range of molecules that our immune cells can recognize," says Robert Wheeler, a postdoctoral researcher in the Fink lab. "And we don't understand how these cells create the unique signal of 'Here is a flu virus, attack!' versus 'Here is a Candida albicans, attack!' We know that it happens, but we don't know how." Says Fink, "This is one of biology's greatest unanswered questions."


Attack and counterattack

Our immune cells are brilliant-unfortunately, so are viruses.

Before your body can fight invaders, it must first ID them. Whitehead Member Hidde Ploegh has been investigating this poorly understood process for over two decades. He studies how a particular class of cells called antigen-presenting cells (APCs) shows off chunks of these invaders to the rest of the immune system-after they've swallowed and eaten them.

In a paper published in Nature in 2002, Ploegh demonstrated how a class of APCs called dendritic cells shoot chunks of these invaders over to T cells through a network of long tubes that spring out almost like harpoons. The dendritic cells also appear to hand-pick certain T cells to receive these goods, enabling the immune system to design a tailor-made response. Ploegh captured this process on video using time-lapse microscopy, creating a short movie of the immune system gearing up for a fight.

But as Ploegh showed in a second, 2004 Nature paper, viruses can often undermine these cells, at times ingeniously. Most of our cells deal with waste, such as misshapen proteins, by directing them into the cell's waste-disposal machinery. Certain viruses, however, trick our immune cells into treating key immune proteins (the very same proteins that shuttle antigen fragments to the cell surface) as waste, thus dumping them into the cellular trash bin. Ploegh and his colleagues identified the intermediary molecule that directs proteins into this bin, a discovery that illuminates both a healthy cellular process and a viral tactic.

Written by David Cameron.

This article first appeared in the Fall 2005 issue of Paradigm magazine.


Communications and Public Affairs
Phone: 617-258-6851

Whitehead Institute is a world-renowned non-profit research institution dedicated to improving human health through basic biomedical research.
Wholly independent in its governance, finances, and research programs, Whitehead shares a close affiliation with Massachusetts Institute of Technology
through its faculty, who hold joint MIT appointments.

© Whitehead Institute for Biomedical Research              455 Main Street          Cambridge, MA 02142