Bruce Beutler, of the US, Jules Hoffmann from France and Ralph Steinman from Canada
The Nobel Prize in Physiology or Medicine 2011
shall be divided, with one half jointly to
Bruce A. Beutler and Jules A. Hoffmann
for their discoveries concerning the activation of innate immunity
and the other half to
Ralph M. Steinman
for his discovery of the dendritic cell and its role in adaptive immunity
Summary
This year's Nobel Laureates have revolutionized our understanding of
the immune system by discovering key principles for its activation.
Scientists have long been searching for the gatekeepers of the immune
response by which man and other animals defend themselves against
attack by bacteria and other microorganisms. Bruce Beutler and Jules
Hoffmann discovered receptor proteins that can recognize such
microorganisms and activate innate immunity, the first step in the
body's immune response. Ralph Steinman discovered the dendritic cells of
the immune system and their unique capacity to activate and regulate
adaptive immunity, the later stage of the immune response during which
microorganisms are cleared from the body.
The discoveries of the three Nobel Laureates have revealed how the
innate and adaptive phases of the immune response are activated and
thereby provided novel insights into disease mechanisms. Their work has
opened up new avenues for the development of prevention and therapy
against infections, cancer, and inflammatory diseases.
Two lines of defense in the immune system
We live in a dangerous world. Pathogenic microorganisms (bacteria,
virus, fungi, and parasites) threaten us continuously but we are
equipped with powerful defense mechanisms (please see image below). The
first line of defense, innate immunity, can destroy invading
microorganisms and trigger inflammation that contributes to blocking
their assault. If microorganisms break through this defense line,
adaptive immunity is called into action. With its T and B cells, it
produces antibodies and killer cells that destroy infected cells. After
successfully combating the infectious assault, our adaptive immune
system maintains an immunologic memory that allows a more rapid and
powerful mobilization of defense forces next time the same microorganism
attacks. These two defense lines of the immune system provide good
protection against infections but they also pose a risk. If the
activation threshold is too low, or if endogenous molecules can activate
the system, inflammatory disease may follow.
The components of the immune system have been identified step by step during the 20th century.
Thanks to a series of discoveries awarded the Nobel Prize, we know, for
instance, how antibodies are constructed and how T cells recognize
foreign substances. However, until the work of Beutler, Hoffmann and
Steinman, the mechanisms triggering the activation of innate immunity
and mediating the communication between innate and adaptive immunity
remained enigmatic.
Discovering the sensors of innate immunity
Jules Hoffmann made his pioneering discovery in
1996, when he and his co-workers investigated how fruit flies combat
infections. They had access to flies with mutations in several different
genes including Toll, a gene previously found to be involved in
embryonal development by Christiane Nüsslein-Volhard
(Nobel Prize 1995). When Hoffmann infected his fruit flies with
bacteria or fungi, he discovered that Toll mutants died because they
could not mount an effective defense. He was also able to conclude that
the product of the Toll gene was involved in sensing pathogenic
microorganisms and Toll activation was needed for successful defense
against them.
Bruce Beutler was searching for a receptor that
could bind the bacterial product, lipopolysaccharide (LPS), which can
cause septic shock, a life threatening condition that involves
overstimulation of the immune system. In 1998, Beutler and his
colleagues discovered that mice resistant to LPS had a mutation in a
gene that was quite similar to the Toll gene of the fruit fly. This
Toll-like receptor (TLR) turned out to be the elusive LPS receptor. When
it binds LPS, signals are activated that cause inflammation and, when
LPS doses are excessive, septic shock. These findings showed that
mammals and fruit flies use similar molecules to activate innate
immunity when encountering pathogenic microorganisms. The sensors of
innate immunity had finally been discovered.
The discoveries of Hoffmann and Beutler triggered an explosion of
research in innate immunity. Around a dozen different TLRs have now been
identified in humans and mice. Each one of them recognizes certain
types of molecules common in microorganisms. Individuals with certain
mutations in these receptors carry an increased risk of infections while
other genetic variants of TLR are associated with an increased risk for
chronic inflammatory diseases.
A new cell type that controls adaptive immunity
Ralph Steinman discovered, in 1973, a new cell type that he called
the dendritic cell. He speculated that it could be important in the
immune system and went on to test whether dendritic cells could activate
T cells, a cell type that has a key role in adaptive immunity and
develops an immunologic memory against many different substances. In
cell culture experiments, he showed that the presence of dendritic cells
resulted in vivid responses of T cells to such substances. These
findings were initially met with skepticism but subsequent work by
Steinman demonstrated that dendritic cells have a unique capacity to
activate T cells.
Further studies by Steinman and other scientists went on to address
the question of how the adaptive immune system decides whether or not it
should be activated when encountering various substances. Signals
arising from the innate immune response and sensed by dendritic cells
were shown to control T cell activation. This makes it possible for the
immune system to react towards pathogenic microorganisms while avoiding
an attack on the body's own endogenous molecules.
From fundamental research to medical use
The discoveries that are awarded the 2011 Nobel Prize have provided
novel insights into the activation and regulation of our immune system.
They have made possible the development of new methods for preventing
and treating disease, for instance with improved vaccines against
infections and in attempts to stimulate the immune system to attack
tumors. These discoveries also help us understand why the immune system
can attack our own tissues, thus providing clues for novel treatment of
inflammatory diseases.
Bruce A. Beutler was born in 1957 in Chicago, USA.
He received his MD from the University of Chicago in 1981 and has
worked as a scientist at Rockefeller University in New York, at UT
Southwestern Medical Center in Dallas, where he discovered the LPS
receptor, and the Scripps Research Institute in La Jolla, CA. Very
recently, he rejoined the University of Texas Southwestern Medical
Center in Dallas as professor in its Center for the Genetics of Host
Defense.
Jules A. Hoffmann was born in Echternach, Luxembourg
in 1941. He studied at the University of Strasbourg in France, where he
obtained his PhD in 1969. After postdoctoral training at the University
of Marburg, Germany, he returned to Strasbourg, where he headed a
research laboratory from 1974 to 2009. He has also served as director of
the Institute for Molecular Cell Biology in Strasbourg and during
2007-2008 as President of the French National Academy of Sciences.
Ralph M. Steinman was born in 1943 in Montreal,
Canada, where he studied biology and chemistry at McGill University.
After studying medicine at Harvard Medical School in Boston, MA, USA,
he received his MD in 1968. He was affiliated with Rockefeller
University in New York since 1970, where he was professor of immunology
from 1988. Sadly, Ralph Steinman passed away before the news of his
Nobel Prize reached him.
