“In a previous study,” he says, “we found that because they transition from bone marrow to the periphery, these cells undergo four stages of maturation and regulation. We determined that between stages one and two, the majority of potentially dangerous B lymphocytes are removed. In SSc patients, however, there is a defect in the checkpoint between stages one and two.
“So our conclusion is that patients with SSc have a wiring system of B lymphocytes that is problematic—the signaling inside these cells has gone awry,” Dr. Mageed says. “They do indeed receive the death signal, but they do not respond.
“These B lymphocytes in SSc patients also produce excess amounts of interleukin (IL) 6 and IL-8,” he says. This is important because IL-6 promotes, while IL-8 augments, inflammation. Combine this with the production of self-reactive antibodies by B lymphocytes and it leads to the pathology we associate with SSc.
‘Patients with SSc have a wiring system of B lymphocytes that is problematic—the signaling inside these cells has gone awry.’ —Dr. Mageed
Tailor-Made Drugs
“Our next step,” says Dr. Mageed, “is to determine what distinguishes bad B cells in SSc patients from normal B cells, which is complicated [because] there are many unknowns. It may be in the nature of the proteins they express. A cell expresses thousands of proteins, each of which functions to keep the cell alive and ensure it functions properly. We must examine all proteins expressed and compare them with the good B cells. Is there a particular protein expressed on the surface of, or even inside, the cell that makes the bad B lymphocytes different from the healthy ones? Once we know that, it’s a fairly straightforward procedure and we can formulate new types of medications—biological therapies.
“Biologics are directed at one specific target, unlike aspirin, paracetamol, steroids, etc., which act systemically,” Dr. Mageed says. “At this point, there are thousands of biologics being successfully used for specific diseases, so this is a promising realm for SSc patients as well. One particular drug, an anti-B lymphocyte, binds to B lymphocytes and kills them—but it also kills the good cells. Our goal is to design a specific biological therapy that will target [only] the bad B cells. In roughly two to three years, we may have identified the proteins that are differentially expressed in bad B lymphocytes; then we can begin making the biologics to target them. This is the foundation of designer therapy.”
