Re-thinking drug strategies for lupus

By Susan Gammon, Ph.D.
November 14, 2013

Sanford-Burnham researchers have completed a study that shows how treating lupus and other autoimmune diseases may require a broader approach than previously thought. The study, recently published in the journal Cell Reports, implicates a signaling pathway called “PI3K,” that is essential for B cell survival. The discovery changes our understanding of what B cells need to prosper, and suggests that therapeutic strategies targeting B cells may be more potent if they incorporate PI3K as a drug target.

Autoimmune diseases are among the leading causes of death among young and middle-aged women in the United States. Lupus, one of the many autoimmune diseases for which there is no cure, occurs when a patient’s antibodies, produced by B cells, mistakenly attack the body’s own cells. Lupus patients suffer from inflammation, swelling, and damage to organs including kidneys, heart, and lungs. Traditional therapy for lupus—as well as other autoimmune diseases—is the administration of anti-inflammatory drugs to suppress the immune system.

Newer drugs that eliminate B cells by depleting B-cell activating factor (BAFF) have recently received FDA approval for treatment of lupus. BAFF signals through the BAFF receptor (BAFF-R), promoting the survival of mature B cells. By targeting BAFF to deplete mature B cells, scientists believe they can efficiently reduce the progression of lupus. Until now, BAFF-R signaling was thought to be primarily dependent upon an enzyme termed IKK1.

Using mice that are genetically designed to decipher the complex communication system of the immune system, Robert Rickert, Ph.D., associate dean of the Graduate Program and professor of the Infectious and Inflammatory Disease Center at Sanford-Burnham, led a team of scientists to show that in the absence of IKK1, B cells were able to grow and survive—meaning that IKK1 is not essential for B cell survival. The team went on attribute B cell survival to the PI3K pathway.

The PI3K pathway is a complex signaling cascade that in concert with other signaling networks, regulates cell growth and survival. The pathway is known to impact cancer-cell growth, survival, motility, and metabolism. Consequently, therapeutics targeting the PI3K pathway are being developed at a rapid pace, and preclinical and early clinical studies are beginning to suggest specific strategies to effectively use them.

“Our study suggests that activation of the PI3K-signaling pathway is the primary process supporting B cell survival. These findings represent a paradigm shift, providing new insight into the biochemical processes of B cell survival, and also suggest new therapeutic avenues to pursue. In particular, PI3K inhibitors—currently under development for treatment of cancer—may be useful in the treatment of lupus,” said Rickert.

About B cells
The basic function of B cells is to produce antibodies to protect the body against foreign invaders such as viruses, bacteria, and tumor cells. B cell development begins in the fetal liver and continues in the bone marrow throughout our lives. Once a B cell expresses the proteins that make up an antibody, it’s officially a B cell. However, it is still immature and can be easily killed by contact with self-antigens—a process that fails in lupus and leads to antibodies that react against “self.”

About lupus
According to the Lupus Foundation of America (LFA), 1.5 to 2 million Americans have some form of lupus. The prevalence is about 40 cases per 100,000 persons among Northern Europeans and 200 per 100,000 persons among African-Americans. Although the disease affects both males and females, women are diagnosed nine times more often than men, usually between the ages of 15 and 45. African-American women suffer from more severe symptoms and a higher mortality rate.

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About Author

Susan Gammon, Ph.D.

Susan is editor of Communications at SBP.


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