Bruce A. Beutler and Jules A. Hoffmann
{for their discoveries regarding the activation of innate immunity}
Ralph M. Steinman
{for his discovery of the dendritic cell and its role in adaptive immunity}
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. 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.
Their work has opened up new avenues for the development of prevention and therapy against infections, cancer, and inflammatory diseases.
There are basically two types of immunity: the innate immunity and adaptive immunity. 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 killer cells that destroy infected cells.
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 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.
Jules Hoffmann made his pioneering discovery in 1996, when he investigated how fruit flies combat infections. They had access to flies with mutations in several different genes including Toll, a gene found to be involved in embryonal development. When Hoffmann infected his fruit flies with bacteria or fungi, he discovered that Toll mutants died because they could not cause effective defense. He was also able to conclude that the Toll gene was involved in sensing pathogens. 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 that involves over stimulation 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 These findings showed that mammals and fruit flies use 3 similar molecules to activate innate immunity when encountering pathogenic microorganisms. The sensors of innate immunity had finally been discovered.
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. 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.
Noble Soul That Got The Nobel Prize
On October 3, 2011, the Nobel Committee for Physiology or Medicine announced that he had received one-half of the Nobel Prize in Physiology or Medicine, for “his discovery of the dendritic cell and its role in adaptive immunity”.
However, the committee was not aware that he had died three days earlier, on September 30, from pancreatic cancer. This created a complication, since the statutes of the Nobel Foundation stipulate that the prize is not to be awarded posthumously. After deliberation, the committee decided that as the decision to award the prize “was made in good faith”, it would remain unchanged.
Steinman’s daughter said that he had joked the previous week with his family about staying alive until the prize announcement. Steinman said: “I know I have got to hold out for that. They don’t give it to you if you have passed away. I got to hold out for that.”
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.
Aravind R, Science Forum Representative
