B lymphocyte stimulator (BLyS) isoforms in systemic lupus erythematosus: disease activity correlates better with blood leukocyte BLyS mRNA levels than with plasma BLyS protein levels, Arthritis Research & Therapy, 2006, 8:R6, C. Collins, A.Gavin, T.S. Migone, et. al.

The immune protein BLyS, which is important to the survival and stimulation of the white blood cells called B-cells, has been tested as a marker for lupus in the past with variable outcomes. One of the proteins involved in regulating whether and how much BLyS protein is made by white blood cells might hold more promise.

As part of the immune response, B cells release inflammatory proteins and stimulate other B cells to change into special cells called plasma cells, which make antibodies. This process is regulated by a protein called BLyS that is made by another white blood cell type, the monocyte. BLyS stands for B lymphocyte stimulator, and it is released by monocytes when they confront foreign substances in the blood stream.

Overproduction of BLyS might play an important role in the development of lupus, but a number of studies that tried to link BLyS levels in the blood samples from lupus patients with how sick the patients were did not find a very good connection. A group of researchers headed by Dr. William Stohl at the University of Southern California have now identified a related protein that might make a better diagnostic test.

The researchers suspected that the levels of BLyS that are actually found in a blood sample might not be an accurate measure of whether or not the protein is overproduced in lupus, for a number of reasons. First, lupus patients might be making antibododies that bind to BLyS and hide its presence in a blood sample. Second, they might be eliminating it rapidly through the urine. Third, since BLyS causes more B cells to develop, it is possible that the expanded B cell population in lupus patients was binding up BLyS and removing it from the blood circulation.

Therefore, rather than testing the circulating levels of BLyS in lupus patients, Dr. Stohl and his colleagues looked at the levels of half-produced BLyS inside the monocytes that make BLyS. Whenever a protein is made, the blueprint is taken from the cell’s DNA, turned into a framework (called RNA), and the protein is made on this frame. It is possible to look at how much RNA for BlyS has been made inside a cell, and in that way dedtermine the amount of production that is going on before the protein leaves the cell.

The RNA is not targeted by antibodies, does not bind to B cells, and is still inside the cell so it has not been eliminated from the bloodstream in the urine. This makes the RNA a better diagnostic test to detect overproduction of BLyS than just measuring what can be found leftover in the blood after the protein is subjected to a lupus patient’s circulating environment.

Blood samples were donated by 60 lupus patients, 60 rheumatoid arthritis (RA), and 30 healthy people. Higher levels of BLyS RNA were found in patients with lupus than in the RA patients and the healthy people. Like the earlier studies that had been reported, the BLyS protein levels found in the circulation were also higher in lupus patients, but did not follow along well with the degree of lupus disease activity. However, the RNA for BLyS was increased in people with more clinical symptoms of lupus.

On the other hand there were some exceptions, including several patients who had high levels of RNA with low lupus activity and several who had high lupus activity but no increase of BLyS RNA. It is important to remember that lupus is a complicated disorder that does not always involve the B cell and that there are other ways to stimulate B cells without the involvement of BLyS. This suggests that the measurement of BLyS RNA might make a valuable diagnostic test but not a perfect one.

Larger studies might shed more light on the details of how this test could fit into the right mix of tests, so that some day physicians could rely confidently on blood samples to show what kind of lupus disease activity is going on and to select more strategic treatments for it.