Identification of Phlogacantholide C as a Novel ADAM10 Enhancer from Traditional Chinese Medicinal Plants

Background: Alzheimer’s disease is one of the most prevalent dementias in the elderly population with increasing numbers of patients. One pivotal hallmark of this disorder is the deposition of protein aggregates stemming from neurotoxic amyloid-beta peptides. Synthesis of those peptides has been efficiently prevented in AD model mice by activation of an enzyme called alpha-secretase. Therefore, drugs with the capability to increase the expression of this enzyme, named ADAM10, have been suggested as a valuable therapeutic medication. Methods: We investigated 69 substances from a drug library derived from traditional Chinese medicine by luciferase reporter assay in human neuronal cells for th…

IL-34–Dependent Intrarenal and Systemic Mechanisms Promote Lupus Nephritis in MRL-Faslpr Mice

Background In people with SLE and in the MRL- Fas lpr lupus mouse model, macrophages and autoantibodies are central to lupus nephritis. IL-34 mediates macrophage survival and proliferation, is expressed by tubular epithelial cells (TECs), and binds to the cFMS receptor on macrophages and to a newly identified second receptor, PTPRZ. Methods To investigate whether IL-34–dependent intrarenal and systemic mechanisms promote lupus nephritis, we compared lupus nephritis and systemic illness in MRL- Fas lpr mice expressing IL-34 and IL-34 knockout (KO) MRL- Fas lpr mice. We also assessed expression of IL-34 and the cFMS and PTPRZ receptors in patients with lupus nephritis. Results Intrarenal IL-3…

Fatigue in SLE: diagnostic and pathogenic impact of anti-N-methyl-D-aspartate receptor (NMDAR) autoantibodies.

ObjectivesWe explored the impact of circulating anti-N-methyl-D-aspartate receptor (NMDAR) antibodies on the severity of fatigue in patients with systemic lupus erythematosus (SLE).MethodsSerum samples of 426 patients with SLE were analysed for the presence of antibodies to the NR2 subunit of the NMDAR. In parallel, the severity of fatigue was determined according to the Fatigue Scale for Motor and Cognitive functions questionnaire. In a subgroup of patients with SLE, the hippocampal volume was correlated with the levels of anti-NR2 antibodies. Isolated immunoglobulin G from patients with anti-NR2 antibodies were used for murine immunohistochemical experiments and functional assays on neuro…

Knockout of the KH-Type Splicing Regulatory Protein Drives Glomerulonephritis in MRL-Faslpr Mice

KH-type splicing regulatory protein (KSRP) is an RNA-binding protein that promotes mRNA decay and thereby negatively regulates cytokine expression at the post-transcriptional level. Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by dysregulated cytokine expression causing multiple organ manifestations

Renal tubular epithelial cell-derived BAFF expression mediates kidney damage and correlates with activity of proliferative lupus nephritis in mouse and men.

B-cell activating factor of the tumour necrosis factor family (BAFF) is a cytokine, mainly produced by hematopoietic cells (e.g. monocytes/macrophages, dendritic cells), indispensable for B-cell maturation. The BLISS studies have demonstrated that blocking BAFF by the human monoclonal antibody belimumab is a valuable therapeutic approach in patients with clinically and serologically active systemic lupus erythematosus (SLE). However, the defined sources of BAFF, which contributes to SLE, are still unclear. Recent findings show that BAFF expression is not restricted to myeloid cells. Since lupus nephritis is the main cause of morbidity and mortality for SLE patients, the aim of this study wa…

PS7:145 Il-34, not csf-1, similarly mediates rheumatoid and lupus arthritis in patients

While Myeloid cells are abundant in lupus arthritis (LA) and rheumatoid arthritis (RA), based on clinical presentation LA and RA are considered distinct diseases. Although inflammatory arthritis is common in patients with lupus, the pivotal mechanisms leading to joint damage have not been investigated. We tested the hypothesis that IL-34, but not CSF-1, is a predictive biomarker that is integral in perpetuating synovial destructive inflammation in both LA and RA. We report the novel findings that: using longitudinally tracked patients, IL–34, not CSF–1, is a clinical predictive biomarker for both LA and RA; and IL–34 is more robustly expressed in the synovial tissue, cells and fluid compare…

Lipid presentation by the protein C receptor links coagulation with autoimmunity.

A lipid-protein autoimmunity target Several autoimmune diseases, including systemic lupus erythematosus and primary antiphospholipid syndrome, are characterized by the presence of antiphospholipid antibodies (aPLs). These molecules can activate the complement and coagulation cascades, which contributes to pathologies such as thrombosis, stroke, and pregnancy complications. Müller-Calleja et al. found that endothelial protein C receptor (EPCR) in complex with lysobisphosphatidic acid (LBPA) is the cell-surface target for aPL and mediates its internalization (see the Perspective by Kaplan). aPL binding to EPCR-LBPA resulted in the activation of tissue factor–mediated coagulation and interfero…

The relationship between BAFF serum levels, anti-NMDAR autoantibodies and fatigue in patients with systemic lupus erythematosus and multiple sclerosis.

The combination of chemotherapy and radiotherapy towards more efficient drug delivery.

Research on anticancer therapies has advanced significantly in recent years. New therapeutic platforms that can further improve the health of patients are still highly demanded. We propose the idea of combining regular chemotherapy with radiation therapy to minimize side effects as well as increase drug-delivery efficiency. In this Focus Review, we seek to provide an overview of recent advances that can combine chemotherapy and radiotherapy. We begin by reviewing the current state of systems that can combine chemotherapy and gamma radiation. Among them, diselenide-containing polymers are highlighted as sensitive drug-delivery vehicles that can disassemble under gamma radiation. Then X-ray r…

P68 A diet rich in wheat alpha-amylase/trypsin inhibitors (ATIs) enhances disease progression in the MRL-Fas(lpr) mouse model of systemic lupus erythematosus

Background Wheat alpha-amylase/trypsin inhibitors (ATIs) are the second most prevalent proteins in wheat (3–4% vs 80–90% for gluten) and potent activators of the innate immune system via the toll like receptor 4 (TLR4)-MD2-CD14 complex in cells of the mononuclear phagocyte system (Junker Y et al, J Exp Med 2012), triggering several autoimmune/inflammatory diseases. In contrast, pure gluten that is de-enriched of ATIs shows no stimulatory activity. MRL-Fas(lpr) mice develop progressive and spontaneous glomerular, tubulointerstitial and perivascular kidney disease, arthritis, lymphadenopathy, splenomegaly and circulating autoantibodies in a syndrome that resembles systemic lupus erythematosus…

PS5:100 Patophysiological role of type i and iii interferons in systemic lupus erythematosus (sle)

Systemic Lupus erythematosus (SLE) is an autoimmune disease characterised by activated autoreactive lymphocytes and autoantibodies, resulting in tissue damage in multiple organs. An important factor for the disease´s mortality is the development of Lupus nephritis (LN). Type I and III interferons, which are both part of the antiviral defense, have both been associated with the disease´s activity. In sera and urine of SLE patients an enhanced level of IL28/29 was described, but their distinct functional role in the course of disease need to be further investigated. To determine the role of type I and III interferons during onset and progression of autoimmunity – with focus on the development…