GILZ: glucocorticoid mediator, B cell regulator, and lupus target

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 metabotically-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 (i) B cell GILZ is reduced in human SLE; (ii) GIL Z is a powerful inhibitor of B cells, enforcing B cell quiescence; (iii) GILZ ^m deficient mice exhibit B cell hyperactivation and spontaneous lupus-like autoimmunity; (iv) GIL Z mediates a transcriptional profile in B cells that encompasses multiple lupus susceptibility loci. We propose a research program which will determine the role of GIL Z in B cell activation, and thus as a therapeutic target in SLE.