SLE is caused by cell debrisBMJ 2000; 320 doi: https://doi.org/10.1136/bmj.320.7248.1495/a (Published 03 June 2000) Cite this as: BMJ 2000;320:1495
Good direct evidence that the body's inability to clear up cell debris leads to systemic lupus erythematosus (SLE) has been confirmed by German scientists.
Cell biologists have confirmed that a lack of DNase1, an enzyme that degrades DNA, leads to the development of SLE. Their finding is not only important in understanding the pathogenesis of SLE, but also suggests that detection of high risk cases may be possible. Early diagnosis may also allow treatment with compounds containing DNase1 as a useful adjunct to conventional treatment with immunosuppressive drugs (Nature Genetics 2000;25:177-81).
This enzyme is secreted in bodily fluids and tends to be active at sites of cell destruction. It is responsible for clearing up cellular debris and does so by chopping up long strands of DNA into short pieces to facilitate their disposal.
While trying to elucidate some of the processes involved in apoptosis (programmed cell death), Professor Tarik Mïrïy at the University of Essen and his colleague Professor Hans-Georg Mannherz at the Ruhr-University of Bochum produced a “knock out” mouse genetically engineered to make no DNase1. “Rather surprisingly,” said Professor Mïrïy, “we found an SLE phenotype in the knock out mouse.” The team discovered they had produced mice that became ill at about 6 months, developed glomerulonephritis, and produced antinuclear antibodies (ANA) characteristic of SLE.
This, together with earlier work that had established a connection between DNase1 and SLE in humans, suggested that the knock out mice were developing full blown SLE. This work confirms the role of poor clearance of cellular debris in SLE and fits in with research that showed that people with SLE tended to have low serum levels of DNase1.
“If glomerulonephritis and ANA are already present,” said Professor Mïrïy, “it is probably too late for the administration of DNase1 to make much difference.” But he does think that if people who are at high risk of developing the disease can be identified by serum DNase1 levels, then administering the enzyme might be beneficial in reducing the worse effects of SLE: “I see it as preventive more than therapeutic.” Professor Mark Walport at Hammersmith Hospital agrees that the link between cellular waste disposal and the development of SLE is strong. His team studied both C1q (a protein in the complement system) and serum amyloid P component. Both are implicated in cellular waste disposal, and a lack of these molecules also seems to trigger the autoimmune response in SLE.