GILZ: Glucocorticoid Mediator, B Cell Regulator, and Lupus Target
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. Dr. Morand 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, Dr. Morand will improve our understanding of the role of GILZ in the immune system with the goal of using it as a new therapeutic target.
What this study means for people with lupus
Dr. Morand and his team have discovered a protein GILZ that may be a factor in causing lupus. If so, they will investigate if GILZ is a target for a safer therapy to replace the widely used steroids which can cause severe side effects that contribute to permanent organ damage and increased mortality.
Systemic lupus erythematosus (SLE) is a severe autoimmune disease. Glucocorticoids, used in over 70% 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.
In this project, we identified glucocorticoid-induced leucine zipper (GILZ) as a key glucocorticoid-induced anti-inflammatory protein. We have now shown that GILZ is reduced in human SLE blood mononuclear cells across multiple subtypes including B cells. Moreover, we have shown that GILZ is a powerful inhibitor of B cells, enforcing B cell quiescence, such that GILZ-deficient mice exhibit B cell hyperactivation and spontaneous lupus-like autoimmunity. A GULZ fusion protein which we engineered with LRA support was effective in reducing B cell hyperactivation, suggesting the potential benefit of a GILZ-based treatment. Moreover, we have shown that the loss of GILZ exacerbates the lyn-deficient model of SLE, resulting in more severe nephritis and increased production of cytokines including Type I interferons.
This latter result prompted a study of the GILZ-IFN interaction, in which we have now shown that GILZ is a powerful endogenous inhibitor of the IFN program, and in turn that IFN inhibits GILZ (manuscript in preparation). This result is confirmed in large public domain SLE patient gene expression datasets. This finding means that IFN may limit sensitivity of lupus to glucocorticoid treatment by inhibiting GILZ – and therefore that enhancing GILZ expression could improve treatment response and allow lower glucocorticoid doses in SLE.