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 aberrant expression and function is linked to human disease. miRNAs are aberrantly expressed in human and mouse SLE lymphocytes, however their specific function in lupus is poorly understood. We study the expression and function of miRNAs in SLE mouse models and our general hypothesis is that several miRNAs regulate pathways that contribute to the disordered immunoregulation in lupus. Our long-term objective is to characterize and interfere with miRNA-regulated pathways that are common in mouse and human SLE and to investigate the potential of miRNA inhibition as a novel therapeutic direction in lupus. Our preliminary studies showed that LNA antimiRs can be used to efficiently antagonize endogenous miRNAs in peripheral lymphocytes in vivo and that inhibition of a miR-21 using such compounds ameliorates the autoimmune disease phenotype of the B6.Sle123 model. Using the same novel methodology, we propose to study the effect of LNA antimiR inhibition in two of the most severe SLE manifestations: renal and lung disease. With experiments described in Aim I we will study the effect of in vivo miR-21 and miR-155 inhibition on renal disease manifestations in two mouse models of SLE, which recapitulate two different histological classes of human SLE nephritis. With experiments described in Aim II we will examine the effect of in vivo and in vitro miR-21 inhibition on interstitial lung disease in SLE using a mouse model and primary lung fibroblasts from SLE patients.
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 lupus and primary cells from patients with SLE. LNA antimiRs are novel compounds that have only recently been advanced to clinical trials in humans. Results from our studies in mouse models of lupus may pave the pathway for novel target-specific therapies for lupus nephritis and pneumonitis.