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Objective Delayed detection of LN associates with worse outcomes. There are conflicting recommendations regarding a threshold level of proteinuria at which biopsy will likely yield actionable management. This study addressed the association of urine protein:creatinine ratios (UPCR) with clinical characteristics and investigated the incidence of proliferative and membranous histology in patients with a UPCR between 0.5 and 1. Methods A total of 275 SLE patients (113 first biopsy, 162 repeat) were enrolled in the multicentre multi-ethnic/racial Accelerating Medicines Partnership across 15 US sites at the time of a clinically indicated renal biopsy. Patients were followed for 1 year. Results At biopsy, 54 patients had UPCR Conclusion In this prospective study, three-quarters of patients with UPCR

Bone marrow mesenchymal stem cells are multipotent adult stem cells that can differentiate into osteoblasts, adipocytes, and chondrocytes. Our recently published data demonstrate that systemic lupus erythematous bone marrow mesenchymal stem cells produce increased quantities of interferon β based on a positive feedback loop involving the innate signaling molecule mitochondrial antiviral signaling protein. Moreover, this pathway contributes to human systemic lupus erythematous bone marrow mesenchymal stem cell senescence-like features. Here we investigate the differentiation defects of systemic lupus erythematous bone marrow mesenchymal stem cells and the potential for therapeutic interventions.The six systemic lupus erythematous patients recruited in this study satisfy the American College of Rheumatology 1997 classification criteria for systemic lupus erythematous. Systemic Lupus Erythematous Disease Activity Index-2K was used to determine disease activity. Systemic lupus erythematous bone marrow mesenchymal stem cells were isolated with Ficoll centrifugation and phenotyped using flow cytometry. In vitro studies included real-time polymerase chain reaction and western blotting.We compared six age-paired bone marrow aspirates from healthy controls and systemic lupus erythematous patients. Systemic lupus erythematous bone marrow mesenchymal stem cells display significantly reduced alkaline phosphatase staining, as well as reduced expression of osteogenic markers alkaline phosphatase, Runt-related transcription factor 2, and bone sialoprotein. When healthy bone marrow mesenchymal stem cells were treated with interferon β for 6 hours, expression of these same osteogenic markers was markedly reduced. Conversely the application of interferon β neutralizing antibody enhanced the expression of osteoblastogenesis markers. When the underlying mechanisms for interferon β inhibition of osteoblastogenesis were investigated, we found that IFNβ pre-treatment activates the inhibitory Smad6 and Smad7 expression through JAK1/STAT1, leading to reduced Smad1 phosphorylation and nuclear translocation.Our present work suggests that interferon β affects osteogenesis. By revealing the essential role of interferon β on systemic lupus erythematous bone marrow mesenchymal stem cell differentiation, our study sheds light on systemic lupus erythematous pathogenesis and provides a new potential therapeutic target for the bone complications found in systemic lupus erythematous.

Bone marrow-derived mesenchymal stem cells (BM-MSCs) create a special microenvironment for hematopoiesis and immunity and display robust immunomodulatory properties that are impaired in systemic lupus erythematosus (SLE). This study was undertaken to identify the mechanisms of defects in human SLE BM-MSCs.Patients fulfilling SLE classification criteria and healthy controls (n = 6 per group) were recruited according to an institutional review board-approved protocol. BM-MSCs were isolated with low-density Ficoll-Hypaque, verified by flow cytometry, and studied using immunocytochemistry, real-time polymerase chain reaction, Western blotting, comet assay, β-galactosidase assay, and RNA interference.SLE BM-MSCs had a senescent phenotype characterized by a reduced proliferation rate, increased production of reactive oxygen species, increased DNA damage and repair, increased expression of p53 and p16, which block the cell cycle, and altered cytokine production (increased proinflammatory cytokine production and decreased immunomodulatory cytokine production). Moreover, SLE BM-MSCs had a 5-fold increase in interferon-β (IFNβ) levels (P 0.05 versus healthy controls) and increased IFNβ-induced messenger RNAs (mRNAs), including mRNA for the intracellular nucleic acid-sensing adaptor protein mitochondrial antiviral signaling protein (MAVS), whose expression was highly correlated with IFNβ levels (r 0.9, P 0.01). Since MAVS is known to induce IFNβ production, we hypothesized that there is a positive feedback loop between MAVS and IFNβ. Notably, silencing of MAVS markedly decreased IFNβ, p53, and p16 protein levels and expression of mRNAs for proinflammatory cytokines.This study demonstrates a novel pathway for elevated IFNβ signaling in SLE that is not dependent on stimulation by immune complexes but rather is cell intrinsic and critically mediated by IFNβ and MAVS, implicating new pathways as potential therapeutic targets.

The central feature of systemic lupus erythematosus (SLE) pathogenesis is loss of immunologic self-tolerance. Here, we address a current controversy regarding whether neutrophils influence the development of B cell auto-reactivity SLE. While both human and murine lupus neutrophils produce factors known to fuel adaptive immune dysregulation, including type I interferon, B cell survival factors, and extracellular traps (a putative source of self-antigen), some studies have contended that neutrophils in peripheral lymphoid organs (PLO) suppress B cell activation and differentiation. In order to ask whether neutrophils exert regulatory or deleterious effects on loss of B cell self-tolerance and immune activation, we compare changes in SLE progression following neutrophil depletion in the NZB/W lupus model, either during or after establishment of disease. Following depletion early in disease, we observe pronounced acceleration of proteinuria, anti-dsDNA titers, and germinal center formation. However, neutrophil depletion after onset of overt disease pathology (including proteinuria) does not strongly alter SLE progression, implicating neutrophils as playing a protective role only apparent during disease onset. To elucidate the specific mechanisms underlying neutrophil effects on B cell auto-reactivity, we examine the cytokine profile of neutrophils in direct proximity to B cells in PLO during several stages of disease. With progression of disease, we observe an influx of interferon-alpha-producing neutrophils in direct proximity to B cells in PLO. These data delineate a shifting balance of both regulatory and activating roles for neutrophils in auto-reactive B cell activation/proliferation during SLE progression.

Systemic lupus erythematosus (SLE) is an autoimmune disease involving dysregulation of both innate and adaptive immune compartments. The hallmark of SLE is loss of B cell tolerance and production of auto-antibodies, which results in tissue damage and inflammation. Factors driving loss of B cell tolerance are incompletely characterized, but include failure of central tolerance mechanisms, inadequate clearance of cell debris, and alterations in the cytokine milieu, including elevated interferon alpha (IFNα). Our lab and others have shown that SLE neutrophils are a significant source of IFNα as well as self-antigen in the form of apoptotic debris and neutrophil extracellular traps (NETs). However, it is unknown whether neutrophils contribute to B cell activation and tolerance loss in lupus. To address this, we examined both splenic and bone marrow (BM) tissues from lupus prone mice to determine whether neutrophils secrete cytokines that alter the inflammatory milieu. Our data shows that neutrophil numbers and apoptosis are increased in lupus BM. BM neutrophils from lupus prone mice have elevated production of the B cell survival cytokines BAFF and APRIL, as well as IFNα. There was an enrichment of IFNα-producing neutrophils in the spleen in close proximity to both B and T cells. These data suggests that neutrophils likely participate in the creation of an inflammatory microenvironment that sustains auto-reactive B cells and exacerbates SLE pathogenesis in the spleen and the BM.

Systemic lupus erythemaotsus (SLE) is an autoimmune disease involving multiple organ systems and characterized by anti-nuclear antibodies. While T cells and dendritic cells may play major roles in SLE, several lines of evidence strongly suggest a central role for B cells. This article will review the role of B cells in human SLE as well as the currently available data on the treatment of SLE by depleting B cells with anti-CD20 (rituximab).