The Nobel Assembly at the
Swedish Karolinska Institutet today decided that the 2011 Nobel Prize in Physiology or
Medicine should be divided, with one half jointly to Bruce A. Beutler, an
American and Jules A. Hoffmann, a Luxembourger, for their discoveries concerning the
activation of innate immunity and the other half to Ralph M. Steinman, a
Canadian, for his discovery of the
dendritic cell and its role in adaptive immunity.
Reuters reports that
Canadian-born Ralph Steinman, 68, had been treating himself with a
groundbreaking therapy based on his own research into the body's immune system
but died on Friday after a four-year battle with pancreatic cancer. His
colleagues at Rockefeller University in New York called it a "bittersweet"
This year´s Nobel Laureates have
revolutionized our understanding of the immune system by discovering key
principles for its activation.
The Nobel Assembly said 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
Two lines of defense in
the immune system
The Nobel Assembly said 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 figures on page 5). 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
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
A new cell type that
controls adaptive immunity
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
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 worked as a
scientist at Rockefeller University in New York and the University of Texas
in Dallas, where he discovered the LPS receptor. Since 2000 he has been
professor of genetics and immunology at The Scripps Research Institute, La
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 has been affiliated with
Rockefeller University in New York since 1970, has been professor of
immunology at this institution since 1988, and is also director of its
Center for Immunology and Immune Diseases.