Two immune proteins found in the brains of mice help the brain develop and may play key roles in triggering developmental disorders like dyslexia and neurodegenerative disorders like Parkinson's disease, according to a Harvard Medical School study reported in [the 15 December issue of] Science.
Although neuroscientists have recently found evidence that the brain is subject to immune surveillance, the Harvard researchers were surprised to discover the mouse brain also produces its own immune molecules, the proteins Class I MHC and CD3-zeta. In the immune system, the two proteins act as part of a lock and key system to recognize and rid the body of foreign invaders. In the brain, they may be part of a signaling system that recognizes and eliminates inappropriate neural connections.
"What we find surprising and important about the results is that we found a novel use by neurons for molecules previously thought only to be the domain of the immune system," said Carla Shatz, Nathan Marsh Pusey professor of neurobiology at HMS and lead author of the study. "What are these immune molecules doing in the brain? The results of the studies imply they are being used by neurons to accomplish the normal business of neurons during development and synaptic plasticity."
While the brain's early neural connections are determined by genetic instructions, the refashioning that occurs during development-and in learning-is a product of both genes and the brain's own activity. The research by Shatz and her team suggests the two immune proteins play a role in the activity-dependent remodeling of the brain. The immune proteins have been found not only in the hippocampus, the region of the brain associated with learning, and the lateral geniculate nucleus, the visual area of the brain, but also in many other regions of the brain in mice.
The researchers found that mutant mice lacking either of the two immune proteins failed to undergo normal development in the geniculate nucleus. Normally, projections from the eye form a small tidy patch in the region, but in the mutants, the connections created a larger and fuzzier profile, presumably because cells in the area lacked the molecular mechanism for getting rid of the unneeded connections. "We think Class I MHC acts like an anti-glue," said Shatz. The mutant mice also experienced abnormal functioning in the hippocampus, the region of the brain associated with learning. In normal mice, production of Class I MHC is especially high in primary sensory areas of the brain-those areas that are thought to function abnormally in people with dyslexia. Further studies are expected to show if the mutant mice also have problems processing sensory information.
Though the evidence is still preliminary, the research could help clarify the neurobiological dimensions of dyslexia. Preliminary studies by British researchers of families with dyslexia suggest that some of them carry genetic defects on chromosome 6-in the same region of the chromosome that carries the Class I MHC genes. "It's very speculative at this point, but it remains certainly a possibility that this could in some way be related to their dyslexia," Shatz said.
The widespread presence of MHC Class I in the brain prompts another speculation: that neurodegenerative diseases such as Parkinson's and multiple sclerosis may be the result of a misguided attack by immune cells on Class I MHC-bearing neurons. "The idea that neurons would normally be expressing Class I MHC might help explain why certain neurons die or are attacked," Shatz said. "MHC Class I-bearing neurons could be the target for an abnormal immune response. I think that people need to start thinking about that." (From Science press release.)
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- Huh GS, Boulanger LM, Du H, Riquelme PA, Brotz TM, Shatz CJ. Functional requirement for class I MHC in CNS development and plasticity. Science. 2000 Dec 15;290(5499):2155-9. PubMed.