T Cells May Check in with Their Neighbors

Bacteria use so-called quorum sensing to know when to turn on their virulence genes, holding off until they have reached a critical mass. Scientists at the Massachusetts Institute of Technology have proposed that T cells, too, operate via a quorum-sensing mechanism, and that the mechanism allows the immune system to avoid autoimmune attacks. T-cell editing deletes many autoimmune T cells before they take up patrol in the bloodstream, but with the sheer number of T cells that comprise a functional immune system, some autoreactive T cells will inevitably make it through any screening process. The authors hope that their model, which for the time being has no direct experimental support, will lead to studies to test it, and ultimately, "a deeper understanding of how the immune system is able to be both responsive to pathogen and tolerant of self." Their work appeared in the July 1, 2013, issue of the Proceedings of the National Academy of Sciences.

Brain Gene Therapy via Cerebrospinal Fluid

Researchers at the Spanish Universitat Autonoma de Barcelona have shown that it may be possible to treat lysosomal storage disorders via gene therapy administered to the cerebrospinal fluid. Lysosomal storage diseases are a group of metabolic disorders that impair the functioning of the lysosome, a cellular recycling center where cell components are metabolized for reuse. Lysosomal storage disorders affecting the central nervous system are currently untreatable due to the challenges of getting replacement enzymes, which are used to treat those lysosomal storage disorders that affect other organs, across the blood-brain barrier. In their work, the authors showed that when they injected a viral vector containing sulfamidase, the replacement enzyme for Mucopolysaccharidosis Type IIIA, into the cerebrospinal fluid of mice with the disease, enzymatic activity increased "throughout the brain and in serum, leading to whole body correction of GAG accumulation and lysosomal pathology, normalization of behavioral deficits, and prolonged survival." Experiments in dogs also showed that the enzyme spread throughout the body. The authors concluded that administering gene therapy to the cerebrospinal fluid might be useful for treating lysosomal storage disorders that affect the brain. Their work appeared in the July 1, 2013, online edition of the Journal of Clinical Investigation.

Not Just Bacteria are Sensitive to ROS

One theory, albeit a contested one, is that antibiotics work by increasing bacterial sensitivity to reactive oxygen species (ROS). Now, researchers from Boston University have provided evidence that some of their toxicity, especially during long-term use, may stem from the fact that they have the same effect on host cells. In their experiments, the authors showed that at doses used to treat infections, several classes of antibiotics produced mitochondrial damage via ROS overproduction in mammalian cells, and that such damage could be prevented by co-treatment with an antioxidant. "This work," the authors said, "highlights the role of antibiotics in the production of oxidative tissue damage in mammalian cells and presents strategies to mitigate or prevent the resulting damage, with the goal of improving the safety of antibiotic treatment in people." They published their findings in the July 3, 2013, issue of Science Translational Medicine.

Structural Diversity Converges on CD36

A team from New York University has shown how molecules with very different structures manage to activate the inflammasome in autoinflammatory disease. Inflammation in the absence of an infection contributes to major diseases including neurodegenerative disorders, diabetes, and atherosclerosis. In their experiments, the authors showed that different peptides and proteins that accumulate in such diseases are converted into amyloid fibrils that are sensed by the pattern recognition receptor CD36, and that this recognition activates the inflammasome, a protein complex that activates inflammation. Inhibiting CD36 in mice with atherosclerosis reduced the production of proinflammatory cytokines. The authors concluded that the pathways activated by CD36 "may hold promise for diminishing inflammasome activation in human disease." Their findings appeared in the June 30, 2013, advance online edition of Nature Immunology.

– Anette Breindl, Science Editor