Pathways To Disease

The processes underlying lupus are known in a general way (flowchart). But many of the details remain murky, such as how hormones and environmental triggers precipitate immune attacks on the body's tissues.

For one, they tend to recruit immune system entities known as complement molecules, which can directly harm tissue. The complexes, either by themselves or with the help of the complement molecules, also elicit an inflammatory response. This response involves an invasion by white blood cells that attempt to wall off and destroy any disease-causing agents. Inflammation is a protective mechanism, but if it arises in


the absence of a true danger or goes on for too long, the inflammatory cells and their secretions can harm the tissues they are meant to protect. Inflammation can additionally involve the abnormal proliferation of cells native to an affected tissue, and this cellular excess can disrupt the normal functioning of the tissue. In the kidney, for instance, immune complexes can accumulate in glomeruli, the organ's blood-filtering i Lupus arises when the immune system mistakenly produces antibodies that attack the body's own tissues, including the kidneys, skin and brain. i The causes of this attack are complex, but a central component seems to be aberrant signaling within and between at least two types of immune cells: B lymphocytes (the antibody producers) and the T lymphocytes that help to activate the B cells.

i Several drugs under study aim to protect tissues by normalizing such signaling and quelling abnormal antibody production.

knots of capillary loops. Excessive deposition then initiates glomerulonephri-tis, a local inflammatory reaction that can lead to kidney damage.

Beyond inciting inflammation, certain lupus autoantibodies do harm directly. In laboratory experiments, they have been shown to bind to and then penetrate cells. There they become potent inhibitors of cellular function.

The real mystery about lupus is what precedes such events. Genetic predisposition seems to be part of the answer, at least in some people. About 10 percent of patients have close blood relatives with the disease, a pattern that usually implies a genetic contribution. Moreover, investigators have found greater lupus concor-dance—either shared lupus or a shared absence of it—in sets of identical twins (who are genetically indistinguishable) than in sets of fraternal twins (whose genes generally are no more alike than those of other pairs of siblings).

Genetic Hints spurred by such findings, geneticists are hunting for the genes at fault, including those that confer enhanced susceptibility to the vast majority of patients who have no obvious family history of the disease. Knowledge of the genes, the proteins they encode and the normal roles of these proteins should one day help clarify how lupus develops and could point to ways to better control it.

In mice prone to lupus, the work has identified more than 30 fairly broad chromosomal regions associated to some extent either with lupus or with resistance to it. Some are tied to specific elements of the disease. One region, for example, apparently harbors genes that participate in producing autoantibodies that recognize components of the cell nucleus (although the region itself does not encode antibodies); another influences the severity of the kidney inflammation triggered by lupus-related immune complexes.

In human lupus, the genetic story may be even more mind-boggling. An informative approach scans DNA from families with multiple lupus patients to identify genetic features shared by the patients but not by the other family members. Such work has revealed a connection between lupus and 48 chromosomal regions. Six of those regions (on five different chromosomes) appear to influence susceptibility most. Now investigators have to identify the lupus-related genes within those locales.

Already it seems fair to conclude that multiple human genes can confer lupus susceptibility, although each gene makes only a hard-to-detect contribution on its own. And different combinations of genes might lay the groundwork for lupus in different people. But clearly, single genes are rarely, if ever, the primary driver; if they were, many more children born to a parent with lupus would be stricken. Lupus arises in just about 5 percent of such children, and it seldom strikes in multiple generations of a family.

Many Triggers if genes alone rarely account for the disease, environmental contributors must play a role. Notorious among these is ultraviolet light. Some 40 to 60 percent of patients are photosensitive: exposure to sunlight, say for 10 minutes at midday in the summer, may suddenly cause a rash. Prolonged exposure may also cause flares, or increased symptoms. Precisely how it does so is still unclear. In one scenario, ultraviolet irradiation induces changes in the DNA of skin cells, rendering the DNA molecules alien (from the viewpoint of the body's immune defenses) and thus potentially an-tigenic. At the same time, the irradiation makes the cells prone to breakage, at which point they will release the antigens, which can then provoke an autoimmune response.

Environmental triggers of lupus also include certain medications, among them hydralazine (for controlling blood pressure) and procainamide (for irregular heartbeat). But symptoms usually fade when the drugs are discontinued. In other cases, an infection, mild or serious, may act as a lupus trigger or aggravator. One suspect is Epstein-Barr virus, perhaps best known for causing infectious mononucleosis, or "kissing disease." Even certain vaccines may provoke a lupus flare. Yet despite decades of research,

If genes alone rarely account for the disease, environmental contributors must play a role.

no firm proof of a bacterium, virus or parasite that transmits lupus has been put forth. Other possible factors include diets high in saturated fat, pollutants, cigarette smoking, and perhaps extreme physical or psychological stress.

Perils of Cell Suicide another line of research has revealed cellular and molecular abnormalities that could well elicit or sustain autoimmune activity. Whether these abnormalities are usually caused more by genetic inheritance or by environmental factors remains unknown. People may be affected by various combinations of influences.

One impressive abnormality involves a process known as apoptosis, or cell suicide. For the body to function properly, it has to continually eliminate cells that have reached the end of their useful life or turned dangerous. It achieves this pruning by inducing the cells to make proteins that essentially destroy the cell from within—such as by hacking to pieces cellular proteins and the chromosomes in the nucleus. But the rate of apoptosis in certain cells—notably, the B and T lymphocytes of the immune system—is excessive in those who have lupus.

When cells die by apoptosis, the body usually disposes of the remains efficiently. But in those with lupus, the disposal system seems to be defective. This double whammy of increased apoptosis and decreased clearance can promote auto-immunity in a fairly straightforward way: if the material inside the apoptotic cells is abnormal, its ejection from the cells in quantity could well elicit the production of antibodies that mistakenly perceive the aberrant material as a sign of invasion by a disease-causing agent. And such antibody production is especially likely if the ejected material, rather than being removed, accumulates enough to call attention to itself.

Unfortunately, the material that spills from apoptotic cells of those with lupus, especially the chromosomal fragments, is often abnormal. In healthy cells, certain short sequences of DNA carry methyl groups that serve as tags controlling gene activity. The DNA in circulating immune complexes from lupus patients is undermethylated. Scientists have several reasons to suspect that this methylation pattern might contribute to autoimmunity. In the test tube, abnormally methylated DNA can stimulate a number of cell types involved in immunity, including B lymphocytes, which, when mature, become antibody-spewing factories. (Perhaps the body misinterprets these improperly methylated stretches as a sign that a disease-causing agent is present and must be eliminated.) Also, certain drugs known to cause lupus symptoms lead to under-methylation of DNA in T cells, which leads to T cell autoreactivity in mice.

All in all, the findings suggest that apoptotic cells are a potential reservoir of autoantigens that are quite capable of provoking an autoantibody response. In further support of this idea, intravenous

ANTIBODIES directed against tissue at the junction of the epidermis and dermis glow yellow in this micrograph of guinea pig skin exposed to blood serum from a patient with lupus. Such antibodies can trigger a damaging, inflammatory reaction.

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