Editor's Note: Science Scan is a roundup of recently published biotechnology-relevant research.

A fortuitous encounter between research laboratories at Washington University School of Medicine in St. Louis and the University of California at Berkeley has resurrected a moribund theory. It revitalizes one of the body's most important immune defense systems, namely T lymphocytes.

Sciencexpress, dated Sept. 25, 2003, reports the unexpected finding under the title "The immunological synapse balances T-cell receptor signaling and degradation." The new findings are a key step toward understanding the intricate molecular processes that allow the body's immune system to recognize and destroy a cell infected by an invading pathogen.

Ironically, the theory revived by the new results involves two immune cells bumping together. The paper's co-senior author, chemical engineering professor Arup Chakraborty at UC-Berkeley, phoned his counterpart Andrey Shaw, professor of pathology and immunology at Washington University, and asked him to look over their joint report.

It featured a computational model of the immune synapse theory, a hypothesis formulated eight years earlier by Shaw and others at Washington.

Their theory speculated that when T lymphocytes encountered another type of immune system cell, the antigen presenting on both cellular surfaces enhanced transmission of the message to the T cell: "Invaders are here, start the counterattack!" Nerve cells exchange such alarms across synapses to and from each other.

"The nail in the coffin," Shaw recalled, "came when we tested cells that were deficient in CD2AP, a protein that helps to form the synapse. When we looked at those cells' ability to form synapses, we found that, in fact, the cells did not form any recognizable synapse. Despite this synaptic deficiency," he continued, "T cells came away from the collisions activated - as though they'd received the attack' message. This led us to speculate," Shaw went on, "that the synapse might form to deactivate the T cell. This was a disappointment to us," he observed, "because the idea that the synapse was uniquely involved in whether a cell would be turned on was a beautiful idea that we really liked."

Chakraborty's computational model rescued Shaw's "beautiful idea" by suggesting that the immune synapse was linked in two ways: turning T cells on and shutting them down. That is, the greater the synapse's ability to amplify the "attack" message upon initial contact, the harder the synapse had to work to shut the same message down in later stages of contact.

Shaw's group quickly proved that interpretation correct.

"We adopted the engineering term adaptive controller' to describe the synapse. It helps to amplify weak signals by concentrating ligands and receptors in the same area of the cells. But simultaneously it prevents strong signals from overpowering the cells, which in most cases would lead to cell death by rapidly turning off the very strongest signals," Shaw concluded.

In Vivo Neurotoxic Pathway Cleaves Chemokine By Induced MMP, Leading To Neurodegeneration

Individuals unfortunate enough to be infected with HIV-1 - the human immunodeficiency virus type 1 - might develop AIDS dementia, owing to the death of neurons in the brain. But paradoxically, HIV-1 does not infect neurons. That suggests that an indirect process must be at work. The answer might be a potent neurotoxin produced by interacting signals from non-neuronal brain cells.

So reports an article in the October 2003 issue of Nature Neuroscience. Its title: "HIV-induced metalloproteinase processing of the chemokine stromal cell-derived factor-1 causes neurodegeneration." Its co-authors are at the University of Calgary in Alberta.

The report suggests that therapeutic drugs already in clinical trials for another disease may be effective for treating HIV-associated dementia. The authors found that certain immune-system macrophage cells infected with HIV-1 released a substance toxic to neurons. The inactive form of the enzyme metalloprotease (MMP2) was itself not the killer. Rather, neurons converted it into another enzyme that cleaved another protein, called stromal-derived factor (SDF-1).

SDF has a number of normal functions in the brain. However, its shortened form, SDF-1, was highly toxic to neurons. Rats that received the inactive MMP2 suffered loss of neurons and exhibited severe behavioral problems. These were abrogated by neutralizing antibodies to SDF-1 and an MMP inhibitor drug. By using drugs to block the activation of MMP2 (and thus the cleavage of SDF-1), the researchers could diminish the toxic effects. Such MMP2 inhibitors are already in clinical trials for cancer.

Oral Anticlotting Therapy Reduces Frequency, Severity, Mortality, Risk Of Ischemic Stroke

Heart patients with atrial fibrillation (palpitations) who receive an appropriate level of anticoagulation therapy reduce their risk of suffering an ischemic stroke. Therapy also cuts the risk that any stroke they do suffer will result in death or serious disability. A study appearing in the New England Journal of Medicine, dated Sept. 11, 2003, bears the title "Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation."

Its authors, at the Harvard-affiliated Massachusetts General Hospital (MGH), are the first to report the risk factor. The study's lead author, Elaine Hylek, who heads the MGH General Medicine Division, observed, "It is very unusual to have a stroke when on anticoagulation (anti-atherosclerosis) therapy, but this study shows that it is possible to reduce the severity and complications for patients who do experience that uncommon event. By leading to the formation of blood clots that travel to the brain," she continued, "the condition is believed to account for about 80,000 strokes a year, and can increase a patient's overall stroke risk fivefold."

The study reached 13,559 patients with atrial fibrillation.