With the award funds, Dr. Shlomchik will investigate the connection between the death of neutrophils, the body’s most abundant white blood cells, and lupus. There are many ways by which cells die, and it is possible that the way in which neutrophils die can affect whether their death stimulates an autoimmune response, like that which occurs in lupus. Many researchers believe lupus is the result of an abnormal immune response to dying cells. More than 70 billion neutrophil cells die per day, raising the question of how the body disposes of so many dead blood cells without having its immune system stimulated by them.
When neutrophils are activated by infection, they use a molecule called NADPH oxidase to fight the infection. It was thought that activation of this molecule, however, would cause these neutrophils to die in a way that promotes an autoimmune response.
However, to the surprise of most lupus researchers, Dr. Shlomchik discovered that lupus-prone mice that are missing NADPH oxidase have markedly worse disease—the opposite of the original theory. Strikingly, even mice lacking one copy of the gene also had more severe disease. Of great interest, boys who lack the X-chromosome linked gene for NADPH oxidase, and their mothers, who lack just one copy of the gene, also have a greatly increased incidence of lupus-like autoimmune diseases, suggesting a connection between mouse and man.
From these results, Dr. Shlomchik has developed a new theory about how neutrophil cell death might connect to lupus. He will use the Lupus Insight Prize funds to test this theory and delve into the mechanism of this surprising and fascinating finding. He will create new animal models that have neutrophils lacking NADPH oxidase and will then test them for incidence and severity of lupus. The outcomes of these studies could illuminate the well-known but mysterious connection between lupus onset and lupus flares with episodes of infection.
Dr. Shlomchik will be presented with the first annual Lupus Insight Prize on June 27 at the 13th Annual Meeting of the Federation of Clinical Immunology Societies (FOCIS 2013).