Signals for war
Your immune system is an army on full alert.
How does it recognize the enemy when it's under attack?
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.
| "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. |
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.
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