Chicagoan Bruce A. Beutler, MD, a 1981 graduate of The University of Chicago Pritzker School of Medicine, is one of three winners of the Nobel Prize in Physiology or Medicine for 2011. He shares the honor with Jules A. Hoffmann for their discoveries concerning the activation of innate immunity, and with Ralph M. Steinman for his discovery of the dendritic cell and its role in adaptive immunity. Unfortunately, Professor Steinman died over the weekend.
The summaries of the research provided below are taken from the Nobel Prize website.
The curved leucine-rich repeat region of toll-like receptors, represented here by TLR3. Image source: Wikipedia.
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. 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. 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.
Dendritic Cell Subsets (click to enlarge the image).
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.
References:
Dendritic Cells
Toll-like receptors (TLRs)
Nobel laureate: “I was a little bit disbelieving, so I went to Google News and saw my name there, so I knew it was real” http://goo.gl/mdv0n
Disclaimer: I am an Allergist/Immunologist and Assistant Professor of Medicine and Pediatrics at the University of Chicago.
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