Q&A with Stefan Feske, M.D.
by Rabiya Tuma

In a healthy person, immune cells become active when they detect an intruder like a foreign microbe. Scientists have known for decades that the process starts when a protein on the cell surface, called a receptor, finds the interloper and ends with a rush of calcium ions into the immune cell, which is necessary for activation. More recently, researchers have begun to decipher the molecules required for the steps in between the receptor and the calcium influx.

Dr. Feske, assistant professor of pathology, has devoted his career to understanding how immune cells are activated through calcium channels, research that may lead to novel ways to treat a number of autoimmune diseases. Three years ago, he and his coworkers cloned one of the key genes in the pathway, Orai1, and the previous year other investigators demonstrated that another gene, STIM1, was a second key component of the calcium signaling system in immune cells.

Initially a receptor on the cell’s surface passes the “we’ve got trouble” message through several signaling proteins until it reaches the surface of the endoplasmic reticulum (ER), a compartment in the cell that has many functions, including storing calcium and making proteins. When the signal hits the ER, calcium ions stored inside leak out. STIM1, a store-operated calcium entry protein, detects the reduction in calcium ions in the ER and responds by aggregating together with other STIM1 proteins. Scientists think that clusters of STIM1 proteins interact with Orai1, which is a calcium-release activated calcium (CRAC) channel, and cause it to open, allowing the large rush of calcium into the cell and activation of the immune cells.

In a study published in the May 7, 2009, issue of The New England Journal of Medicine, Dr. Feske and colleagues show that a mutation in the STIM1 gene found in three siblings caused their immune system to stop functioning.

Q: Your lab focuses on signaling in immune cells. When you look at the big picture why is that important?
A: The most striking answer comes from these patients with the STIM1 mutation and also from patients with a mutation in Orai1 that we had identified three years ago and published in Nature. In the absence of a functional calcium signaling pathway these patients suffer from life-threatening infections very early on in life. If we don’t treat them with bone marrow transplantation they are at great risk to die within their first year of life. So this calcium signaling pathway is obviously very important for activation of immune cells, mostly T cells, but probably other immune cells as well.

Q: Why did your study only involve three patients?
A: The severe inherited immunodeficiency disease in these patients is a very rare disorder which is closely related to Bubble Boy disease. Children born with this disorder usually lack almost all immune defenses and they often do not survive beyond infancy. They are vulnerable to life-threatening infections caused by bacteria and also by viruses and opportunistic germs, among other problems. While these types of inherited immunodeficiency diseases are rare, they offer very valuable insights into the function of the immune system.

Q: Will understanding what has gone wrong in these patients lead to better treatments for patients with immune deficiencies in the future?
A: Theoretically we could envision gene therapy for these patients, but really the disease is much too rare for this approach to be a practical option. One of the patients in this study had a bone marrow transplant that restored his immune system, and he is now 6 years old.

Q: Will the information you’ve learned about STIM1 and Orai1 help patients with other immune system disorders?
A: We may be able to use what we’ve learned to develop either a drug or antibody therapy that could be used to prevent aberrant T cell activation in autoimmune diseases, such as rheumatoid arthritis, which are more common than immunodeficiency diseases. Multiple sclerosis and rheumatoid arthritis are T cell-mediated autoimmune diseases, and potentially colitis and diabetes patients could benefit as well.

Q: When your group first cloned Orai1 were you looking specifically for molecules involved in the CRAC channels?
A: Absolutely. These CRAC channel currents had been measured by electrophysiology, but for 15 years their molecular nature was completely unclear.

Q: We often hear about calcium-mediated signaling in neurons but the signaling pathways you’ve described are completely different than those, right?
A: Yes, neurons have been studied for a long time, but calcium signaling in the immune system has only come to the forefront in the last five to 10 years. One reason that not many people paid attention to it is that we didn’t know which molecules mediated this calcium influx, but now we have STIM1 and Orai1. I think these patients demonstrate very well that these genes are really important for a functioning immune system.