By David N. Leff
Editor's note: Science Scan is a roundup of recently published, biotechnology-relevant research.
During the 1980s, the Swedish navy suspected that foreign submarines were surfacing around the country's islands. So it distributed a map depicting submarine silhouettes, foreign and domestic, for residents to report which ones they saw. Of course, most of the U-boats the citizenry spotted turned out to be Swedish. Thereupon, the navy wised up and produced a new map showing only the profiles of Sweden's own three submarine types. It asked residents to call in only if the shapes they sighted were not like those on the map.
Swedish immunologists tell this story to explain the function of natural killer cells (NK). These patrols scan other cells in the body, looking for a security badge called MHC (major histocompatibility locus) class I. That marker, perched on cell surfaces, identifies them as friend, not foe - this is, "self," not "other." The NK cells promptly terminate cells that can't flash that MHC class I emblem. The immune system's macrophages engulf and eat their dead bodies.
Immunologist Per-Arne Oldenborg invokes the submarine and NK analogies to explain a novel self identifier called CD47 - a ubiquitously expressed, integrin-associated, cell-surface glycoprotein. Oldenborg, a postdoctoral fellow at Washington University in St. Louis, is lead author of a paper in Science dated June 16, 2000. Its title: "Role of CD47 as a marker of self on red blood cells."
Red blood cells (RBCs) normally don't wear MHC class 1 markers, but do sport CD47. The paper's co-authors showed in experiments that RBCs lacking the CD47 identity badges were rapidly cleared from the bloodstream by local macrophages.
Knockout mice devoid of CD47, they reported, nevertheless "are viable and have normal RBC parameters." To see whether these RBCs, denuded of CD47, can survive in wild-type mice, they transfused CD47-minus KO animals with RBCs both with and without CD47 identification. Result: "Transfused CD47-/- RBCs were rapidly eliminated from the circulation of wild-type recipients, but were not affected in CD47-/- recipients."
Thus, their paper points out, "macrophages may use a number of nonspecific activating receptors, and rely on the presence or absence of CD47, to distinguish self from foreign." It added that this mechanism "may represent a potential pathway for the control of hemolytic anemia." Hemolytic - i.e., blood-lysing - anemia is an autoimmune disorder that occurs when macrophages destroy RBCs that lack CD47 personal identification numbers.
Moreover, "Ovarian cancer cells express high levels of CD47, and CD47 analogs are encoded by smallpox and vaccinia viruses. In both these instances," the paper concludes, "it is possible that the pathogen is taking advantage of [CD47 receptor] signaling to disable normal defenses."
Anti-Inflammatory Monoclonal Antibody Curbs Atherosclerotic Lesions In Mice
Atherosclerosis has traditionally been regarded as blockage of the coronary arteries feeding the heart by fatty buildup of clot-forming plaques. Much of the blame for this presumed process lay on excess cholesterol intake. But a commentary in the June 20, 2000, Proceedings of the National Academy of Sciences (PNAS) proposes a different indictment: "Atherosclerosis can now be viewed as a problem of wound healing and of chronic inflammation."
That comment, by microbiologist Richard Phipps at the University of Rochester, New York, bears the title "Atherosclerosis: The emerging role of inflammation and the CD40-CD40 ligand system." The PNAS paper in the same issue - the object of Phipps' commentary - is titled "Inhibition of CD40 signaling limits evolution of established atherosclerosis in mice." Its authors are in the cardiovascular division of Harvard-affiliated Brigham and Women's Hospital in Boston.
For 13 weeks, the co-authors fed 30 young mice a high-cholesterol diet, calculated to promote atherosclerosis. Then, they treated one group of those animals with a monoclonal antibody against the CD40 molecule paired with its ligand, CD40L. This proinflammatory dyad galvanizes the immune system's B and T cells to release cytokines, which make for the blood vessel walls where atheromas grow.
When the paper's co-authors autopsied the blood vessels of their treated mice after 26 weeks, they found that "interfering with CD40 signaling did not regress, but did inhibit the progression of already established atherosclerotic lesions."
"Disrupting the CD40-CD40L system," Phipps observed, "has generated much excitement." But he concluded his commentary with a caveat: "Obviously, there is a need for caution, because interference with the CD40-CD40L system is immune suppressive."
Simulating Normal But Limited Brain-Cell Repair, Apoptosis Treatment Regenerated Neuronal Cells
Once a fetus has finished furnishing its future person's brain with all the neurons it will need after childbirth, that neurogenesis presumably shuts down for good. Except for a few defined neuronal regions, the mature brain can expect no regeneration of neurons lost to injury or neurodegenerative disease. Those major exceptions are limited areas of the adult mammalian brain - the hippocampus, olfactory bulb and epithelium.
In two smaller cerebral regions of neurogenesis, point out Swedish neuroscientists at the University of Lund, "there is seemingly a continuous turnover of interneurons and granule cells, implying that the newborn neurons replace dying cells." They made this observation in a "News & Views" editorial titled "Self-repair in the brain," in Nature dated June 22, 2000. It was commenting on a paper in the same issue headed, "Induction of neurogenesis in the neocortex of adult mice."
That article's senior author is neurobiologist Jeffrey Macklis, at Harvard-affiliated Children's Hospital in Boston. He and his co-authors point out that "neuronal death can trigger increased neuron addition." They report inducing stem cells deep in the cortex of adult mice to replace damaged neurons. These grew from immature precursor cells into fully formed, connected and mature replacements.
To jump-start this neoneurogenesis, the co-authors used biophysical targeting to coax certain neurons to undergo apoptosis - cell suicide. In a press statement, Macklis asserted: "Not for a moment would any of us suggest that to repair the brain we want to go around inducing cell death. It's that we want to use this as an experimental tool to dissect out what the controls are. Our approach of targeted apoptosis has given us a crude, external lever over a whole program of genes that we're investigating now."