By David N. Leff
Most autoimmune diseases have the decency to attack one specific organ system in the human body. Thus, Grave's disease goes after the thyroid gland; diabetes mellitus, the insulin-producing cells of the pancreas; rheumatoid arthritis, the bones and joints; multiple sclerosis, the central nervous system; myasthenia gravis, the musculature; psoriasis, the skin; ulcerative colitis, the colon.
This one-organ-per-malady rule enables researchers and clinicians to specialize in scoping and coping with the individual autoantigens targeted by the self-destructive cells of an immune system gone haywire.
But there's one autoimmune ailment that doesn't play by these rules. Systemic lupus erythematosus (SLE) attacks virtually every organ system - hence the name systemic - in the human body. And thence the checklist of symptoms that assail an SLE patient during flare-ups of the disease - notably fever, weakness, joint pain, erythematous skin lesions, pleurisy, and above all, kidney dysfunction.
As a jack-of-all-antigens, lupus autoantibodies find their targets everywhere in the body because that ailing body is lacking an enzyme called DNase1, which is dedicated to clearing out the debris constantly generated by the normal and pathological processes of apoptosis and necrosis. (See BioWorld Today, April 27, 2000, p. 1.)
As molecular biologist Tarik Mvrvy, at the University of Essen, Germany, explained: "This antigen-clearance enzyme removes nuclear debris. Cells that are destroyed, nuclei that are left over containing chromosomes and DNA, are chopped up by DNase1 and cleared from the body."
Mvrvy is senior author of a paper in the June issue of Nature Genetics, titled: "Features of systemic lupus erythematosus in DNase1-deficient mice."
"When we created a knockout mouse that didn't make this DNase1 enzyme," Mvrvy told BioWorld Today, "all of a sudden there was no DNase at all in this mouse, and it developed over several months an immune response against its own cell-nucleus debris. This response," he pointed out, "is fatal in the sense that its immune system turned against its own body. The result was life-threatening kidney inflammation - glomerular nephritis - and a lot of other symptoms that very closely resemble the human condition of lupus."
How About Supplying DNase1 To SLE Patients?
"What makes these KO mice novel," Mvrvy pointed out, "is that they confirm to the lupus community that antigen clearance is a key factor for the disease. In addition, our paper in Nature Genetics brings up the issue of whether or not DNase1, the enzyme we knocked out, could be used for therapy.
"The question is more complicated than that," he continued, "because once people get lupus and are very sick, kidney destruction cannot be restored just by giving DNase. But in the earlier phase of the disease, one could envision that DNase might be helpful to remove antigen and slow down disease progression."
Clinical rheumatologist and immunologist Mark Walport, at the Imperial College of Science, Technology and Medicine in London, is the author of a commentary titled, "Lupus, DNase and defective disposal of cellular debris," which accompanies Mvrvy's paper. "The concept connecting DNase and lupus," Walport told BioWorld Today, "goes back to the mid-1960s when Peter Lachmann was working at the Rockefeller Institute. About that time it had been discovered that DNA was one of the major autoantigens to lupus, and Lachmann realized that the enzyme, DNase1 could digest DNA.
"Therefore, to see if there was any abnormality in DNase1 expression in lupus, he did some very preliminary human experiments, using bovine DNase. But of course that's not feasible therapy to use long term, because it's a foreign protein. So it wasn't really until DNase1 was made from humans, and used therapeutically for the treatment of cystic fibrosis - where it digests the thick secretions in the lungs - that it became possible to think about using that same enzyme as a therapy in lupus."
Walport added, "There has been an early study using DNaseI in lupus patients, published about a year ago by John Klippel, then at the National Institute of Arthritis & Musculoskeletal & Skin Diseases." He reported in the journal Lupus (1999:8) a Phase Ib, randomized, double-masked, placebo-controlled trial of recombinant human DNase in 17 patients with lupus nephritis. The abstract's bottom line: "Serum markers of disease were unchanged during the study period."
Mvrvy and his co-authors "are now trying to determine more of the genetic background that leads to the disease. "What we're going to do is cross our mice with other mice that have other deficiencies around lupus, and see if we could accelerate the disease, or maybe slow its progression. Because we are not clinicians but research scientists, we will not be so involved in therapies.
DNase1-Patented KO Mice Offered To Industry
"There's a patent pending on the mouse, by the way," Mvrvy observed, adding that he and his collaborators "are in touch with biotech and pharma companies that are interested in mouse models."
Britain's Walport finds the German KO mouse "an interesting model. It's another example," he observed, "of targeted mutants in mice, which led to the development of the concept that SLE patients have defects in their cells' waste-disposal mechanism. So this wasn't the first animal model that supported this hypothesis. Actually, it was the third."
He explained: "A very small proportion of patients with SLE are deficient in a protein in the complement system called C1q. Also, a protein called amyloid P binds to chromatin outside cells. So these DNase1-deficient mice are the third example of a mutation that is compatible with the idea that if you are not able to clear cellular and extracellular debris properly, that may increase your predisposition to develop SLE. (See BioWorld International, April 29, 1998, p. 1)
"But I think it's important," Walport went on, "to recognize that for most patients with lupus, there are probably abnormalities in several different mechanisms. I think it's very unlikely that a single defect can be responsible for the disease. So the second approach that's going on is to do genetic studies in both mice and human families with lupus, to see if one can identify other genes that may contribute to the SLE process. And there's a great deal of activity on that front."