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 Nü
sslein-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 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 Jolla, USA.
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.
Key publications:
Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos
E, Silva M, Galanos C, Freudenberg M, Ricciardi-Castagnoli P, Layton B,
Beutler B. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice:
Mutations in Tlr4 gene. Science 1998;282:2085-2088.
Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA. The
dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the
potent antifungal response in drosophila adults. Cell 1996;86:973-983.
Steinman RM, Cohn ZA. Identification of a novel cell type in peripheral
lymphoid organs of mice. J Exp Med 1973;137:1142-1162.
Steinman RM, Witmer MD. Lymphoid dendritic cells are potent stimulators of
the primary mixed leukocyte reaction in mice. Proc Natl Acad Sci USA 1978;75
:5132-5136.
Schuler G, Steinman RM. Murine epidermal Langerhans cells mature into potent
immunostimulatory dendritic cells in vitro. J Exp Med 1985;161:526-546.
