University scientists have identified a protein that can reduce chances that immune B cells will erroneously attack the body’s tissues, causing autoimmune disorders such as lupus, allergies, arthritis and diabetes.
The protein is the first of its kind to be identified in B cells and could provide scientists with a new target for treatments of those conditions.
Scientists assumed for many decades that misguidance was the crux of the problem when immune attack cells went awry and assaulted the body’s tissues, causing autoimmune conditions.
But a theory gaining widespread favor suggests a more complicated picture with new possibilities for treatments that ease or prevent autoimmune disorders.
“We used to think of mature immune cells like T cells and B cells as metabolically inactive when waiting for infections or other signals that trigger an attack,” said Stanford L. Peng, M.D., Ph.D., assistant professor of internal medicine and of pathology and immunology. “We’re now thinking these resting cells actually are very active but are kept in a quiescent state by genes actively working to shut down activating proteins.”
Peng and his colleagues, who earlier this year discovered the first of these immune system “leashes” in T cells, now have given the theory another key boost by identifying the first leash in a B cell: a protein called microphthalmia-associated transcription factor (MITF).
Peng and his colleagues found MITF through study of a lupus mouse model produced by scientists selectively breeding mice for other research goals in the 1960s and ’70s.
Peng’s group compared levels of messenger RNA for various genes in cells of normal mice to mice with lupus-like conditions. Messenger RNA acts like an order slip for production of a copy of a gene’s protein, so scientists believe levels of messenger RNA for a particular gene are likely representative of that gene’s level of activity in a cell.
They found that MITF was much less active in the B cells of mice with lupus-like conditions than in normal mice. When they suppressed MITF activity in normal mice, B cells turned themselves on and began making antibodies, clumps of proteins normally designed to attack invaders. However, the new antibodies in the mice were autoantibodies, antibodies targeted to the body’s tissues that are a characteristic symptom of lupus.
“This is the first transcription factor we’ve found that has to be active in the resting B cell to keep it that way,” Peng said.
MITF appears to restrain interferon regulatory factor 4 (IRF4), a transcription factor previously linked to the activation of B cells. But it appears to have that effect through its influence on several other genes that in turn act to keep IRF4 in check.
Peng and his colleagues are working to further understand the effects of MITF, and they have also begun looking for signs of abnormal MITF activity in human patients.
“We’ve been focusing our efforts to develop new treatments for autoimmune disease on pathological targets — genes that are overused or used inappropriately, leading to immune system attacks on self,” Peng said.
“Another concept we should keep in mind is that the loss of one of these regulatory genes that keep the immune cells in check also may contribute to autoimmune problems.”