Earlier this morning, The Nobel Assembly at Karolinska Institutet has announced that this year’s Nobel Prize in Physiology or Medicine will be shared with one half jointly by American Bruce Beutler and Jules Hoffman from France and the other half by Canadian born Ralph M. Steinman from Rockefeller University in New York for their seminal discoveries in immunology. Unfortunately, Dr. Steinman, who discovered the dendritic cell, did not live to know about the prize, as he passed away just days before the announcement. Drs. Hoffmann and Beutler are well known for their research in innate immunity.
The following scientific intro, distributed by the Nobel Committee, is an interesting and important read into the history of discoveries of innate and adaptive immunology:
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 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 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.
Press release: The Nobel Prize in Physiology or Medicine 2011 …
Press release: Ralph Steinman Remains Nobel Laureate …
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