Bruce A. Beutler, Jules A. Hoffmann en Ralph M.Steinman zijn de
Opening new avenues
Het Nobel Comité zegt over de winnaars en hunbetekenis:
‘Scientists have long been searching for the gatekeepers of theimmune response by which man and other animals defend themselvesagainst attack by bacteria and other microorganisms. Bruce Beutlerand Jules Hoffmann discovered receptor proteins that can recognizesuch microorganisms and activate innate immunity, the first step inthe body’s immune response. Ralph Steinman discovered the dendriticcells of the immune system and their unique capacity to activateand regulate adaptive immunity, the later stage of the immuneresponse during which microorganisms are cleared from the body.
The discoveries of the three Nobel Laureates have revealed howthe innate and adaptive phases of the immune response are activatedand thereby provided novel insights into disease mechanisms. Theirwork has opened up new avenues for the development of preventionand therapy against infections, cancer, and inflammatorydiseases.
Two lines of defense in the immune system
We live in a dangerous world. Pathogenic microorganisms(bacteria, virus, fungi, and parasites) threaten us continuouslybut we are equipped with powerful defense mechanisms (please seeimage below). The first line of defense, innate immunity, candestroy invading microorganisms and trigger inflammation thatcontributes to blocking their assault.
If microorganisms break through this defense line, adaptiveimmunity is called into action. With its T and B cells, it producesantibodies and killer cells that destroy infected cells. Aftersuccessfully combating the infectious assault, our adaptive immunesystem maintains an immunologic memory that allows a more rapid andpowerful mobilization of defense forces next time the samemicroorganism attacks.
These two defense lines of the immune system provide goodprotection against infections but they also pose a risk. If theactivation threshold is too low, or if endogenous molecules canactivate the system, inflammatory disease may follow.
The components of the immune system have been identified step bystep during the 20th century. Thanks to a series ofdiscoveries awarded the Nobel Prize, we know, for instance, howantibodies are constructed and how T cells recognize foreignsubstances. However, until the work of Beutler, Hoffmann andSteinman, the mechanisms triggering the activation of innateimmunity and mediating the communication between innate andadaptive immunity remained enigmatic.
Discovering the sensors of innate immunity
Jules Hoffmann made his pioneering discovery in1996, when he and his co-workers investigated how fruit fliescombat infections. They had access to flies with mutations inseveral different genes including Toll, a gene previously found tobe involved in embryonal development by
Bruce Beutler was searching for a receptor thatcould bind the bacterial product, lipopolysaccharide (LPS), whichcan cause septic shock, a life threatening condition that involvesoverstimulation of the immune system. In 1998, Beutler and hiscolleagues discovered that mice resistant to LPS had a mutation ina gene that was quite similar to the Toll gene of the fruit fly.This Toll-like receptor (TLR) turned out to be the elusive LPSreceptor. When it binds LPS, signals are activated that causeinflammation and, when LPS doses are excessive, septic shock. Thesefindings showed that mammals and fruit flies use similar moleculesto activate innate immunity when encountering pathogenicmicroorganisms. The sensors of innate immunity had finally beendiscovered.
The discoveries of Hoffmann and Beutler triggered an explosionof research in innate immunity. Around a dozen different TLRs havenow been identified in humans and mice. Each one of them recognizescertain types of molecules common in microorganisms. Individualswith certain mutations in these receptors carry an increased riskof infections while other genetic variants of TLR are associatedwith an increased risk for chronic inflammatory diseases.
A new cell type that controls adaptiveimmunity
Ralph Steinman discovered, in 1973, a new cell type that hecalled the dendritic cell. He speculated that it could be importantin the immune system and went on to test whether dendritic cellscould activate T cells, a cell type that has a key role in adaptiveimmunity and develops an immunologic memory against many differentsubstances. In cell culture experiments, he showed that thepresence of dendritic cells resulted in vivid responses of T cellsto such substances. These findings were initially met withskepticism but subsequent work by Steinman demonstrated thatdendritic cells have a unique capacity to activate T cells.
Further studies by Steinman and other scientists went on toaddress the question of how the adaptive immune system decideswhether or not it should be activated when encountering varioussubstances. Signals arising from the innate immune response andsensed by dendritic cells were shown to control T cell activation.This makes it possible for the immune system to react towardspathogenic microorganisms while avoiding an attack on the body’sown endogenous molecules.
From fundamental research to medical use
The discoveries that are awarded the 2011 Nobel Prize haveprovided novel insights into the activation and regulation of ourimmune system. They have made possible the development of newmethods for preventing and treating disease, for instance withimproved vaccines against infections and in attempts to stimulatethe immune system to attack tumors. These discoveries also help usunderstand why the immune system can attack our own tissues, thusproviding 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 andworked as a scientist at Rockefeller University in New York and theUniversity of Texas in Dallas, where he discovered the LPSreceptor. Since 2000 he has been professor of genetics andimmunology 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 inFrance, where he obtained his PhD in 1969. After postdoctoraltraining at the University of Marburg, Germany, he returned toStrasbourg, where he headed a research laboratory from 1974 to2009. He has also served as director of the Institute for MolecularCell Biology in Strasbourg and during 2007-2008 as President of theFrench National Academy of Sciences.
Ralph M. Steinman was born in 1943 in Montreal,Canada, where he studied biology and chemistry at McGillUniversity. After studying medicine at Harvard Medical School inBoston, MA, USA, he received his MD in 1968. He has been affiliatedwith Rockefeller University in New York since 1970, has beenprofessor of immunology at this institution since 1988, and is alsodirector of its Center for Immunology and Immune Diseases.
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