March 20, 2008
Uncovering the Mysteries of Immunity, and of Lupus
By ANDREA PEIRCE

Lupus is in many ways the most fundamental of betrayals. The body’s immune system, schooled to identify and purge outside invaders like bacteria and viruses, mistakenly turns its force instead on healthy organs. The result is inflammation and often lasting damage to the heart, lungs, joints, brain, kidneys, blood and skin.

Despite an urgent need to find effective ways to understand and manage lupus, the tool set for doing so has been sparse and simplistic. Nearly a half century has passed since the Food and Drug Administration approved a new lupus treatment. Powerful yet imprecise medicines to control symptoms and complications, like the immune-suppressing steroid prednisone, are all that doctors have had to offer. Medicines to treat lupus are often as damaging as the disease itself.

But in the last five years, the field of lupus investigation has started to percolate. Many experts now say there is realistic hope that techniques and medicines to better monitor and manage the illness will soon emerge.

“This is probably the most promising and exciting time in lupus research, as we tease out the controlling influences of this complex disease and identify the disease drivers that actually lead to abnormalities in the immune system,” said Dr. Lee S. Simon, a former F.D.A. division director and associate clinical professor of medicine at Harvard Medical School.

Much of the new optimism stems from enhanced understanding of how the immune system functions, in health and illness. “We are becoming so much more sophisticated about immunology in general,” said Dr. Betty A. Diamond, head of the Feinstein Institute’s Center for Autoimmune Diseases at the North Shore-Long Island Jewish Health System in New York. “We have identified so many more molecules and pathways leading to lupus, which means so many more pathways and targets for lupus treatments.”

A new array of molecular tools to explore the immune system are now in the hands of medical researchers. And unlike a decade ago, investigators have brought into focus specific immune system components they suspect are involved in the disease. These include the various T cells and antibody-producing B cells that fight invaders. Additional targets include specialized cells and proteins, like the toll-like receptors, interferons and dendritic cells that act as sentinels and goad the immune system into action.

The sequencing of the human genome and techniques that knock out single genes in laboratory animals have shifted interest to the role of genetics as well. Confidence is growing that researchers will identify inherited genes that confer susceptibility to lupus, though most agree that DNA alone is not enough to explain who gets the disease.

External factors almost certainly come into play. A trigger in the environment to jump-start or accelerate the disease process is likely, concluded an August 2007 National Institutes of Health report called “The Future Directions of Lupus Research.” Under suspicion are elements like exposure to ultraviolet light, crystalline silica used in industry and the Epstein-Barr virus that causes mononucleosis. Since 9 out of 10 lupus patients are women, sex hormones almost certainly play a role.

Identification of early signals of disease flare-ups holds the promise of vastly clarifying what is going on inside the body of the individual with lupus. Researchers are on the hunt for useful markers in the blood or urine. Such biomarkers would be useful for monitoring the effectiveness of new or existing treatments.

Rendering all these discoveries relevant to the person with lupus, however, hinges on bridging the gap between basic science findings and a practical application in humans. “We still have to determine the relative benefit to risk of these potentially exciting new therapies,” Dr. Simon said.

The F.D.A. has issued guidelines that spell out just what needs to be done to have a lupus medicine approved, a move that has spurred drug makers to step up pursuits of new products. The surge in clinical trials for lupus, from a handful a few years ago to dozens today, suggests that the attempt to translate findings into the tangible care of people with the illness may be close at hand.

Publish date: 3/21/2008