The Diagnostic Challenge

Physicians who suspect that a patient, whether female or male, has lupus continue to be hampered by the lack of a conclusive test. Because immunological self-attack may underlie many illnesses, even a classic sign of lupus—the presence of antinuclear autoantibodies—does not unmistakably diagnose this disorder.

In the absence of a sure test, doctors might gather information from a variety of sources, including not only laboratory tests but also the patient's description of current symptoms and medical history. To assist, the American College of Rheumatology has issued a list of 11 criteria that could indicate lupus. Seven concern symptoms, such as arthritis, sensitivity to sunlight or a butterfly facial rash. (The butterfly pattern is still unexplained.) The other four describe laboratory findings that include the presence of antinuclear autoantibodies or depressed concentrations of lymphocytes.

Researchers will consider a subject to have lupus if the person meets four of the criteria, but physicians might base a diagnosis on fewer cues, especially if a patient has strong indicators of the disorder, such as clinical evidence of abnormalities in several different organ systems combined with the presence of antinuclear autoantibodies. For more on common manifestations of lupus, visit the Lupus Foundation of America: or the Lupus site: — M.Z.

Current Criteria

Malar rash (a rash, often butterfly-shaped, over the cheeks) Discoid rash (a type involving red raised patches)

Photosensitivity (reaction to sunlight in which a skin rash arises or worsens)

Nose or mouth ulcers, typically painless

Nonerosive arthritis (which does not involve damage to the bones around the joints) in two or more joints

Inflammation of the lining in the lung or heart (also known as pleuritis or pericarditis)

Kidney disorder marked by high levels in the urine of protein or of abnormal substances derived from red or white blood cells or kidney tubule cells

Neurological disorder marked by seizures or psychosis not explained by drugs or metabolic disturbances (such as an electrolyte imbalance)

Blood disorder characterized by abnormally low concentrations of red or white blood cells or platelets (specifically, hemolytic anemia, leukopenia, lymphopenia or thrombocytopenia) and not caused by medications

Positive test for antinuclear antibodies (ANA) not explained by drugs known to trigger their appearance

Positive test for antibodies against double-stranded DNA or certain phospholipids or a false positive result on a syphilis test

the self-antigens they release. Abundantly available to the body's unbalanced immune surveillance, the antigens then misdirect the immune system, inducing it to attack the self.

Drugs do exist for lupus, but so far they focus on dampening the overall immune system. In other words, they are nonspecific: instead of targeting immu-nological events underlying lupus in particular, they dull the body's broad defenses against infectious diseases. Corticosteroids, for instance, reduce inflammation at the cost of heightening susceptibility to infections.

The challenge is to design new drugs that prevent autoimmune self-attacks without seriously hobbling the body's ability to defend itself against infection. To grasp the logic of the approaches being attempted, it helps to know a bit more about how helper T cells usually abet the transformation of B cells into vigorous antibody makers [see box on pages 74 and 75].

First, the helper cells themselves must be activated, which occurs through interactions with so-called professional antigen-presenting cells (such as macrophages and dendritic cells). These antigen presenters ingest bacteria, dead cells and cellular debris, chop them up, join the fragments to larger molecules (called MHC class II molecules) and display the resulting MHC-antigen complexes on the cell surface. If the receptor on a helper T cell recognizes a complex and binds to it, the binding conveys an antigen-specific signal into the T cell. If, at the same time, a certain T cell projection near the receptor links to a particular partner (known as a B7 molecule) on the antigen-presenting cell, this binding will convey an antigen-independent, or co-stimulatory, signal into the T cell. Having received both messages, the T cell will switch on; that is, it will produce or display molecules needed to activate B cells and will seek out those cells.

Like the professional antigen-presenting cells, B cells display fragments of ingested material—notably fragments of an antigen they have snared—on MHC class II molecules. If an activated helper T cell binds through its receptor

The challenge is to prevent immune self-attacks without hobbling the body's ability to defend itself.

to such a complex on a B cell, and if the T and B cells additionally signal each other through co-stimulatory surface molecules, the B cell will display receptors for small proteins called cytokines. These cytokines, which are secreted by activated helper T cells, induce the B cell to proliferate and mature into a plasma cell, which dispatches antibodies that specifically target the same antigen recognized by the coupled B and T cells.

Of course, any well-bred immune response shuts itself off when the danger has passed. Hence, after an antigen-presenting cell activates a helper T cell, the T cell also begins to display a "shutoff" switch known as CTLA-4. This molecule binds to B7 molecules on antigen-presenting cells so avidly that it links to most or even all of them, thereby putting a break on any evolving helper T and, consequently, B cell responses.

One experimental approach to treating lupus essentially mimics this shutoff step, dispatching CTLA-4 to cap over B7 molecules. In mice prone to lupus, this method prevents kidney disease from progressing and prolongs life. This substance is beginning to be tested in lupus patients; in those with psoriasis, initial clinical trials have shown that the treatment is safe.

A second approach would directly impede the signaling between helper T cells and B cells. The T cell molecule that has to "clasp hands" with a B cell molecule to send the needed co-stimulatory signal into B cells is called CD154. The helper cells of lupus patients show increased production of CD154, and in mice prone to the disease, antibodies engineered to bind to CD154 can block B cell activation, preserve kidney function and prolong life. So far early human tests of different versions of anti-CD154 antibodies have produced a mixture of good news and bad. One version significantly reduced autoantibodies in the blood, protein in the urine and certain symptoms, but it also elicited an unacceptable degree of blood-clot formation. A different version did not increase thrombosis but worked poorly. Hence, no one yet knows whether this approach to therapy will pan out.

A third strategy would interfere with B cell activity in a different way. Certain factors secreted by immune system cells, such as the cytokine BAFF, promote cell survival after they bind to B cells. These molecules have been implicated in various autoimmune diseases, including lupus and its flares: mice genetically engineered to overproduce BAFF or one of its three receptors on B cells develop signs of autoimmune disease, and BAFF appears to be overabundant both in lupus-prone mice and in human patients. In theory, then, preventing BAFF from binding to its receptors should minimize antibody synthesis. Studies of animals and humans support this notion. In mice, a circulating decoy receptor, designed to mop up BAFF before it can find its true receptors, alleviates lupus and lengthens survival. Findings for a second decoy receptor are also encouraging. Human trials are in progress.

Targeting other cytokines might help as well. Elevated levels of interleu-kin-10 and depressed amounts of transforming growth factor beta are among the most prominent cytokine abnormalities reported in lupus, and lupus-prone mice appear to benefit from treatments that block the former or boost the latter. Taking a different tack, investigators studying various autoimmune conditions are working on therapies aimed specifically at reducing B cell numbers. An agent called rituximab, which removes B cells from circulation before they are able to secrete antibodies, has

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