Dynamic Regulation of Signaling Pathways in SLE
A certain type of B cell has recently been identified that makes many of the autoantibodies which cause damage in people with lupus. Building on the knowledge that patients with more of these cells can have worse disease, Dr. Pernis found some of the molecules that control the growth of these cells in mice. With her Lupus Mechanisms and Targets Award, she hopes to explore if these molecules, and this cell type, cause tissue damage in people with lupus.
What this means for people with lupus
This newly identified B cell subtype and the molecules that control these cells could serve as molecular markers to tell which patients are at risk of severe disease or may even serve as a target for new drugs.
Despite significant strides, many patients with Systemic Lupus Erythematosus (SLE) continue to live with poorly controlled disease. In addition to autoAb production and multi-organ involvement, it is now well-recognized that SLE patients often exhibit dysregulated interferon responses as evidenced by increased expression of interferon stimulated genes (ISGs). Although several factors contribute to the challenges that have been encountered in the development of new therapies for SLE, one potential roadblock is that the signaling pathways driving lupus pathogenesis are regulated in a dynamic and complex manner. While expansion of germinal center (GC) B cells and plasma cells (PC) has long been associated with SLE, murine studies have recently implicated new B cell subsets in lupus pathogenesis. Studies in aging mice indeed have identified a B cell subset, termed Autoimmune/Age-associated B cells (ABCs), which exhibit a unique phenotype, accumulate prematurely in murine lupus, and can produce pathogenic autoantibodies. Inappropriate expansion of ABCs has also been observed in human SLE. Notably, their expansion in SLE correlates with disease activity and clinical manifestations like kidney disease. Our laboratory previously isolated a protein termed Def6, which exhibits significant homology to only one other protein, SWAP-70. Importantly, mice lacking both Def6 and SWAP-70 (Double-knockout=DKO mice) develop SLE-like disease on a C57BL/6 background. Disease in DKO mice shares several key clinical features with human SLE including its sex-bias since disease primarily affects DKO female mice. Genetic studies, furthermore, have identified the Def6 locus as a genetic risk factor for human SLE. We have previously shown that ABC formation is enhanced in DKO mice. Interestingly, we have recently found that the accumulation of ABCs occurs to a greater extent in females than males DKO mice, and that, in contrast to ABCs from DKO males, ABCs from DKO females readily produce autoAbs upon stimulation and exhibit an “interferon signature”. Dysregulating TLR7 expression in DKO male mice reverses this sex-bias and promotes the dissemination of ABCs into the blood and target organs. One of the key targets controlled by the SWEF proteins is the ROCK2 kinase. We have recently found that, in B cells, ROCK2 promotes GC formation by controlling the activity of IRF8. Surprisingly, we have also found that TLR7 inhibits ROCK2 activation and that the lack of ROCK2 in B cells leads to the upregulation of ISGs and ABC markers. In this proposal we will test the hypothesis that while the TLR-ROCK-IRF interplay can promote “classical” GC B cell responses, it can inhibit the formation of ABCs and their acquisition of an ISG signature. We will also investigate whether this interplay can be controlled by TLR7 stimulation and whether the dissemination of ABCs into the blood and tissues will alter their function and response to treatment.