Systemic lupus erythematosus and NETs

In other posts I have written about autoimmune diseases. These can be divided into those which are specific for one type of tissue and those which are systemic. The latter can affect many tissues. One of the commonest and best-known systemic autoimmune diseases is systemic lupus erythematosus (SLE). It is estimated by the Lupus Foundation of America that there about three and a half million people with this disease worldwide, with ninety per cent of them being women. Caucasians are underrepresented. Yesterday I heard a talk about some aspects of this disease by Virginia Pascual from Texas and this is what stimulated me to write this. Apparently there are few therapeutic possibilites at the moment. She said that no drug has been approved for use against SLE in the last fifty years but that she hopes that this will soon change. At one time the lifespan after diagnosis with this disease was five years. Nowadays, although there is no cure, the disease can be managed so well that with suitable medical care it does not lead to a significant decrease in life expectancy. The severity of the symptoms oscillates in time, with flares and remissions. An important mechanism of pathology in this disease is the accumulation of immune complexes and this leads to a danger of kidney failure. The antibodies forming these complexes are directed against parts of the cell nucleus, in particular DNA.

In the talk the speaker explained a network of mechanisms which are at work in SLE. Some of the key players are interferon , plasmacytoid dendritic cells (pDC’s), the toll-like receptors TLR7 and TLR9 and neutrophils. SLE patients typically have high levels of IFN in the blood and this is not changed by moderate doses of cortisone. It can be turned off by pulse therapy (e.g. 1 g prednisolone per day for 3 days) but it comes back. Under some circumstances it is found that in SLE patients less neutrophils die by apoptosis than in healthy controls. They are dying by another mechanism. This brings us to the NETs (neutrophil extracellular traps) of the title. This concept goes back to a paper of Brinkmann et. al. (Science 303, 1352). It was discovered that neutrophils can eject part of their contents including DNA to form a kind of net which traps bacteria. In fact, as mentioned in the talk yesterday this phenomenon was already observed in lupus patients by Rifkind and Godman in 1957 (J. Exp. Med. 106, 607) but at that time the possibilities of interpreting it were limited. A link between NETs and SLE was suggested in a paper by a group including Arturo Zychlinsky in PNAS in 2010. There it was proposed that in some SLE patients it may happen that NETs produced to combat an infection may be the cause of a flare.

Coming back to therapeutic prospects, it was noted that an inhibitor for TLR7 and TLR9 is under development as a drug against lupus by the company DYNAVAX.

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