Systemic lupus erythematosus (SLE, lupus) is a chronic systemic autoimmune disease characterized by production and survival of autoreactive antibodies and deposition of immune complexes to various tissues, leading to organ damage. Lupus affects primarily women of reproductive age, with a female to male ratio of 9:1. Mortality in SLE is increased compared to the general population. Higher risk of death is associated with female sex, younger age, shorter SLE duration and African American race. Studies have shown that SLE is more severe among African American, Hispanic and women of other ethnic minorities. Over the last two decades, lupus mortality rates increased by 67.8% among African American women. Results of studies have suggested that this may be related to worse renal involvement and outcome in African American patients. Renal and other severe SLE manifestations respond poorly to current therapeutic modalities and often require replacement therapy. microRNAs (miRNAs) regulate a plethora of normal cellular and developmental processes and their function is linked to human disease. miRNAs are aberrantly expressed in human and mouse SLE, however their specific role in the immune response in lupus is not well understood. We study the function of miRNAs in SLE;our general hypothesis is that several miRNAs contribute to the disordered immunoregulation in lupus. Our long-term objective is to characterize and interfere with miRNA-regulated pathways common in mouse and human SLE and to investigate synthetic miRNA inhibitors as putative novel therapeutic direction in lupus. Our preliminary studies showed that LNA antimiRs efficiently antagonize endogenous miRNAs in peripheral lymphocytes in vivo and that LNA miR-21 inhibition ameliorates autoimmune manifestations in B6.Sle123. We will employ the same novel methodology for our in vivo and in vitro studies, to characterize the function of miR-21 and miR-155 in the immune system in lupus. In vivo studies in Aim I will inform us on role of miR-21 and miR-155 on autoantibody production, lymphocyte function and severe end-organ manifestations on genetic SLE models. In studies of inducible models we will examine the effect of selective miRNA inhibition targeting pathogenic, parental cells. We will investigate putative synergistic effect of miR-21 and miR- 155 and we will identify their targets in cells of the immune system. Experiments in Aim II will inform us on the role of miR-21 and miR-155 on T cell activation in lupus. In parallel, we will clone and sequence biologically relevant targets of all miRNAs in mouse SLE B and T lymphocytes, dendritic cells and macrophages, by employing two novel high throughput methods, HITS-CLIP and RNA seq. To our knowledge HITS-CLIP has not been previously performed in SLE and the combined results of HITS-CLIP and RNAseq will offer a panoramic view of all genes directly regulated by miRNAs in cells of the immune system in mouse lupus.
A recent multicenter study in a large cohort of 9,547 SLE patients confirmed a higher risk of death for younger female patients and a striking increase in mortality among African American SLE patients in the US. This higher risk has been linked to more severe lupus manifestations such as nephritis. Current therapeutic interventions for lupus nephritis are toxic and, despite their use, a large percentage of patients progress to kidney failure. In our proposed studies we will examine the effect of LNA antimiRs on SLE nephritis and lung disease, using mouse models of SLE. LNA antimiRs are novel compounds that have only recently been advanced to clinical trials in humans. Results from our studies in lupus-prone mice may pave the pathway for novel target-specific therapies in SLE.