Timing lupus

A 24-year-old woman undergoes medical evaluation for kidney failure and epilepsylike convulsions that fail to respond to antiepileptic drugs. Her most visible sign of illness, though, is a red rash extending over the bridge of her nose and onto her cheeks, in a shape resembling a butterfly.

A 63-year-old woman insists on hospitalization to determine why she is fatigued, her joints hurt, and breathing sometimes causes sharp pain. Ever since her teen years she has avoided the sun, which raises painful blistering rashes wherever her skin is unprotected.

A 20-year-old woman is surprised to learn from a routine health exam that her urine has an abnormally high protein level—a sign of disturbed kidney function. A renal biopsy reveals inflammation.

Although the symptoms vary, the underlying disease in all three patients is the same—systemic lupus erythe-matosus, which afflicts an estimated 1.4 million Americans, including one out of every 250 African-American women aged 18 to 65. It may disrupt almost any part of the body: skin, joints, kidneys, heart, lungs, blood vessels or brain. At times, it becomes life-threatening.

Scientists have long known that, fundamentally, lupus arises from an immunological malfunction involving antibody molecules. The healthy body produces antibodies in response to invaders, such as bacteria. These antibodies latch onto specific molecules that are sensed as foreign (antigens) on an invader and then damage the interloper directly or mark it for destruction by other parts of the immune system. In patients with lupus, however, the body produces antibodies that perceive its own molecules as foreign and then launch an

LUPUS, technically lupus erythematosus, means "the red wolf." It was so named because a face rash particular to the disorder often makes people look wolflike.

attack targeted to those "self-antigens" on the body's own tissues.

Self-attack—otherwise known as autoimmunity—is thought to underpin many diseases, including type 1 diabetes, rheumatoid arthritis, multiple sclerosis and, possibly, psoriasis. Lupus, however, is at an extreme. The immune system reacts powerfully to a surprising variety of the patient's molecules, ranging from targets exposed at the surface of cells to some inside of cells to even some within a further sequestering chamber, the cell nucleus. In fact, lupus is notorious for the presence of antibodies that take aim at the patient's DNA. In the test tube, these anti-DNA "autoantibodies" can directly digest genetic material.

Until recently, researchers had little understanding of the causes of this multipronged assault. But clues from varied lines of research are beginning to clarify the underlying molecular events. The work is also probing the most basic, yet still enigmatic, facets of immune system function: the distinction of self from nonself; the maintenance of self-tolerance (nonaggression against native tissues); and the control over the intensity of every immune response. The discoveries suggest tantalizing new means of treating or even preventing not only lupus but also other autoimmune illnesses.

Some Givens one thing about lupus has long been clear: the autoantibodies that are its hallmark contribute to tissue damage in more than one way. In the blood, an autoantibody that recognizes a particular self-antigen can bind to that antigen, forming a so-called immune complex, which can then deposit itself in any of various tissues. Autoan-tibodies can also recognize self-antigens already in tissues and generate immune complexes on-site. Regardless of how the complexes accumulate, they spell trouble.

Teasing out the causes of this autoimmune disorder is a daunting challenge. But the payoff should be better, more specific treatments

By Moncef Zouali

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