The 2011 Nobel Prize in Physiology or Medicine shall be divided, with one half jointly to Bruce A. Beutler, M.D., and Jules A. Hoffmann, Ph.D., for their discoveries concerning the activation of innate immunity and the other half to Ralph M. Steinman, M.D., for his discovery of the dendritic cell and its role in adaptive immunity.
Dr. 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 Dr. 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.
Dr. Beutler was searching for a receptor that could bind the bacterial product, lipopolysaccharide (LPS), which can cause septic shock. In 1998, Dr. 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 Dr. Hoffmann and Dr. Beutler triggered an explosion of research in innate immunity. About 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.
Dr. 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. Subsequent work by Dr. Steinman demonstrated that dendritic cells have a unique capacity to activate T cells.
Further studies by Dr. 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 toward pathogenic microorganisms while avoiding an attack on the body's own endogenous molecules.
The discoveries that are awarded the 2011 Nobel Prize 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.
Dr. Beutler was born in 1957 in Chicago. He received his M.D. 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 in La Jolla, CA.
Dr. Hoffmann was born in Echternach, Luxembourg in 1941. He studied at the University of Strasbourg in France, where he obtained his Ph.D. 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.
Dr. Steinman was born in 1943 in Montreal, where he studied biology and chemistry at McGill University. After studying medicine at Harvard Medical School in Boston, he received his M.D. in 1968. He has been affiliated with Rockefeller University since 1970, has been professor of immunology at this institution since 1988, and is also director of its Center for Immunology and Immune Diseases.