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DMS SYMPOSIUM The Immune System Casts a Widening NetScientists Tell How Body Systems Share Bag of Tricks Until recently, students who were daunted by the task of unraveling the mysteries of the nervous system had one consolation. Despite its complexity, the brain was believed to be free from the extraordinary array of immune cells that police every other organ of the body.
"We now know that the brain is a collection of genes whose activity is being regulated all the time," said Carla Schatz. Photo by Liza Green "As a graduate student, I knew that the brain was one of the most complicated systems there is," said Carla Shatz, PhD '76, at the June 7 Alumni Symposium of the Division of Medical Sciences. "But at least I wouldn't have to learn about the immune system." All that has changed, due in part to Shatz's efforts. She and her colleagues have discovered that molecules of the immune system play a role in wiring the developing brain. One of the themes of the afternoon symposium, attended by about 35 alumni, students, and faculty, was that the immune system is one that researchers in all areas of biology will have to reckon with. A Surprising ConnectionLikening the brain to the "world's most extraordinary computer," Shatz, the Nathan Marsh Pusey professor of neurobiology and chair of the department, described how its wiring is laid down in two stages. To begin, basic connections are made in a hard-wired mode, largely without outside input. Next comes a period of extensive remodeling in which local circuits are fine-tuned and reshaped. Here is where experience—how much and when particular circuits are used—will determine the overall pattern of the final product.Intrigued by the question of how experience molds the brain, Shatz and her colleagues conducted experiments in which they blocked signals from one eye of ferrets. One of their aims was to see whether the blockade turned off genes that were normally active in an area of the brain that receives input from the eye. To their surprise, the two genes that were markedly downregulated in the area were genes that are normally expressed on immune cells. When expressed on immune cells, the MHC Class I and CD3-zeta genes produce proteins that help immune cells recognize cells infected by pathogens. Shatz believes that the two proteins may be acting like recognition molecules in the brain. In making their way through the developing brain, neurons may use the signaling proteins to detect their targets. You Scratch My BackThe developing brain may have borrowed a trick from the immune system but, according to Fred Goldberg, PhD '68, the immune system appears to have co-opted one of its own.All cells face the task of getting rid of trash—damaged or used up proteins—and they do so by means of an ingenious machine, the proteasome. Over the past decade, Goldberg, HMS professor of cell biology, and his colleagues have taken apart this molecular machine and developed a representation of how it works. According to this "bite-chew" model, the proteasome processes proteins much as the mouth breaks down food—by first making a cut and then grinding the bitten-off fragment into ever smaller pieces (see Focus Sept. 17, 1999). In their studies, the researchers discovered that in response to increased levels of interferon, cells are equipped with a special version of the proteasome. This "immunoproteasome" specializes in grinding up the proteins of foreign invaders so they can be presented to the immune system as antigens. He and Jochen Beninga, then a research fellow in his lab, studied how this antigen processing works and discovered that fragments emitted by the proteasome are trimmed to the size of antigens by a specific enzyme. "So the immune system has taken over the process of protein breakdown for its own specific purpose—to monitor activity in the cytoplasm," said Goldberg. —Misia Landau |
