Enzyme Shortage May Lead to Lupus

Just as the garbage that collected in streets during the Middle Ages sustained rats and the bubonic plague they spread, DNA piling up in dead or dying cells creates an environment conducive to systemic lupus erythematosus, or lupus. Working with an enzyme that clears away such cellular debris, scientists in Germany have opened a new line of research into this autoimmune disease.

The body comes equipped with several proteins that chop up and clear away trash DNA. One of them, an enzyme called DNase I, appears less active in many lupus patients than in healthy people. When too much debris accumulates, immune cells identify it as an antigen—a foreign body to be destroyed—and make antibodies against it. This can engender a chain reaction of wanton cell death. The body offers no defense because its own soldiers, immune cells, orchestrate the killing.

To measure whether ample DNase I can clear the decks and prevent such an onslaught, the researchers created mice that lack the enzyme and compared them with healthy mice. “This is the first genetically defined DNase I-deficient animal,” says study coauthor Tarik Möröy, a molecular biologist at the Institute for Cell Biology at the University of Essen.

Möröy and his colleagues examined 69 mice missing the gene that encodes DNase I, as well as 78 others that had a partial enzyme deficiency and 37 that had a full complement of the enzyme. They observed the animals from birth. At 8 months, 43 of the 69 totally enzyme-deficient mice showed cell-destroying antibodies in their blood, as did 44 of the 78 partly deficient mice, the researchers report in the June Nature Genetics. Only 9 of the 37 normal mice had any such antibody present.

An antibody binding to material from a dead or dying cell isn’t likely to hurt the body, but the action unleashes other immune agents that can, says David S. Pisetsky, an immunologist at Duke University Medical Center in Durham, N.C. “Eventually, downstream, normal cells are affected,” he says.

While the precise cause of lupus remains unknown, the immune disruption typically starts in cells of the blood, skin, or intestines. Because these cells have rapid turnover, enzymes there can fall behind in clearing debris. Immune agents attracted by antibodies binding to trash DNA are often flushed into the bloodstream and deposited in the kidneys, causing inflammation there—often the most deadly symptom of lupus in people.

Indeed, Möröy and his colleagues found that 16 of the 69 fully DNase I-deficient mice and 13 of the 78 partially deficient mice had kidney inflammation. Only 2 of 37 normal mice did.

DNase I isn’t the only compound that clears cellular debris. Scientists have identified at least three others, which don’t necessarily work in concert with DNase I to remove trash DNA. “They may work on redundant or parallel pathways” to ensure that accumulation doesn’t reach critical levels, Pisetsky says.

Nevertheless, the study “adds strong support to the hypothesis that impairment of . . . disposal of cellular debris predisposes to needed development of systemic lupus erythematosus,” says Mark J. Walport of the Imperial College of Science, Technology, and Medicine in London, writing in the same journal.

It remains unclear whether simply giving DNase I to lupus patients will help. A genetically engineered form of DNase I considered safe for people is going through preliminary tests in lupus patients, Walport says. Although researchers haven’t yet established the enzyme’s effectiveness, “enhancing the ‘waste-disposal’ systems of people with [lupus] remains a viable approach to therapy,” he says.

Lupus researchers are trying to take advantage of any new technology available, says Evelyn V. Hess, a rheumatologist at the University of Cincinnati Medical Center and a vice president of the Lupus Foundation of America. By using genetically engineered mice to measure the effects of DNase I, Möröy and his colleagues have opened a new area of investigation, according to Hess. “It’s an interesting approach,” she says.

Lupus affects more than 1 million people in the United States.