2015 Distinguished Innovator Awardee
GILZ: Glucocorticoid mediator, B cell regulator, and lupus target
The Study and What It Means to Patients
“Glucocorticoids, a type of steroids, have proven to be an effective treatment for lupus, but their severe side effects that can cause organ damage and increased mortality make finding an alternative imperative. Our research will explore whether a protein we recently discovered, GILZ, is a factor in causing lupus and if it can be used to develop a safer treatment with less side effects.”
Glucocorticoids are a type of steroid used to treat over 70 percent of lupus patients to reduce the immune response and the resulting inflammation. Unfortunately, glucocorticoids have very severe side effects including possible permanent organ damage and an increased risk of death, and safer treatments are urgently needed. We recently discovered a protein called GILZ that is produced by glucocorticoids and when activated reduces inflammation. With GILZ there appears to be none of the side effects usually associated with steroids, and the protein appears to play a very specific role in lupus, acting only on B cells (a type of white blood cell). In this research, we will improve our understanding of the role of GILZ in the immune system with the goal of using it as a new therapeutic target.
Systemic lupus erythematosus (SLE) is a severe autoimmune disease. Glucocorticoids, used in over 70 percent of SLE patients, lessen the harmful effects of autoantibodies and dampen systemic inflammation. However, serious metabolic adverse effects measurably contribute to permanent organ damage, morbidity, and mortality in SLE. An alternative to glucocorticoids in SLE is critically needed. SLE is caused by a failure of B cell tolerance towards self-antigens, disruption of B cell quiescence, and resulting innate immune activation. Thus, discovery of a metabolically-inert glucocorticoid mimetic, with specific actions on B cells, could represent a major breakthrough in SLE. Recently, we identified glucocorticoid-induced leucine zipper (GILZ) as a key glucocorticoid-induced anti-inflammatory protein. However, whether GILZ is important in B cells, and hence in SLE, is unexplored. Strong preliminary data indicate that B cell GILZ is reduced in human SLE; GILZ is a powerful inhibitor of B cells, enforcing B cell quiescence; GILZ-deficient mice exhibit B cell hyperactivation and spontaneous lupus-like autoimmunity; GILZ mediates a transcriptional profile in B cells that encompasses multiple lupus susceptibility loci. We propose a research program which will determine the role of GILZ in B cell activation, and thus as a therapeutic target in SLE.