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lupus nephritis murine model

Man Chu, Lai Shan Tam, Jing Zhu, Delong Jiao, De Hua Liu, Zhe Cai, Jie Dong, Christopher Wei Kai Lam, Chun Kwok Wong
The newly named interleukin (IL)-36 subfamily member IL-38 has been shown to exert anti-inflammatory activity. However, the in vivo immunomodulatory activity of IL-38 was poorly investigated in systemic lupus erythematosus (SLE). We have investigated the expression of CD4(+)IL-17(+) Th17, CD4(+)IFN-γ(+) Th1 and CD3(+)CD4(-)CD8(-) double negative (DN) T cells and the related immunopathological mechanisms in female MRL/lpr mice model of spontaneous lupus-like disease, with or without IL-38 treatment. Intravenous administration of murine recombinant IL-38 into MRL/lpr mice can ameliorate the lupus-like clinical symptoms including proteinuria, leukocyteuria and skin lesions...
October 17, 2016: Immunobiology
Chelsea Corradetti, Neelakshi R Jog, Stefania Gallucci, Michael Madaio, Siddharth Balachandran, Roberto Caricchio
Immune mediated nephropathy is one of the most serious manifestations of lupus and is characterized by severe inflammation and necrosis that, if untreated, eventually leads to renal failure. Although lupus has a higher incidence in women, both sexes can develop lupus glomerulonephritis; nephritis in men develops earlier and is more severe than in women. It is therefore important to understand the cellular and molecular mechanisms mediating nephritis in each sex. Previous work by our lab found that the absence or pharmacological inhibition of Poly [ADP-ribose] polymerase 1 (PARP-1), an enzyme involved in DNA repair and necrotic cell death, affects only male mice and results in milder nephritis, with less in situ inflammation, and diminished incidence of necrotic lesions, allowing for higher survival rates...
2016: PloS One
Samantha A Chalmers, Jing Wen, Justine Shum, Jessica Doerner, Leal Herlitz, Chaim Putterman
Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease that can affect multiple end organs. Kidney and brain are two of the organs most commonly involved in SLE. Past studies have suggested the importance of macrophages in the pathogenesis of lupus nephritis (LN). Furthermore, as the immune effectors of the brain, microglia have been implicated in pathways leading to neuropsychiatric SLE (NPSLE). We depleted macrophages and microglia using GW2580, a small colony stimulating factor-1 receptor (CSF-1R) kinase inhibitor, in MRL-lpr/lpr (MRL/lpr) mice, a classic murine lupus model that displays features of both LN and NPSLE...
August 25, 2016: Clinical Immunology: the Official Journal of the Clinical Immunology Society
Fumi Miyagawa, Yutaka Tagaya, Keiko Ozato, Hideo Asada
Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease characterized by the production of autoantibodies against nuclear components. Recent genetic studies of SLE patients have revealed that IFN regulatory factor (IRF) 7 gene polymorphisms are associated with an increased risk of SLE, but the precise role of IRF7 in SLE development is not fully understood. We investigated the role of IRF7 in the pathogenesis of SLE using a mouse model and saw a curious dissociation of autoantibody production and development of glomerulonephritis...
September 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Hui Wang, Jason S Knight, Jeffrey B Hodgin, Jintao Wang, Chiao Guo, Kyle Kleiman, Daniel T Eitzman
Systemic lupus erythematosus (SLE) is associated with an elevated risk of vascular complications, including premature stroke. Therapies targeting leukocyte recruitment may be beneficial in reducing vascular complications associated with SLE. Lupus was induced in female wild-type (WT) and P-selectin glycoprotein ligand-1 deficient (Psgl-1(-/-)) mice with pristane. Stroke was induced following photochemical injury to the middle cerebral artery (MCA). Stroke size was increased in pristane-treated WT mice compared to non-pristane-treated WT controls...
2016: Scientific Reports
Rubina Novelli, Elena Gagliardini, Barbara Ruggiero, Ariela Benigni, Giuseppe Remuzzi
BACKGROUND/AIMS: Lupus nephritis (LN) is a frequent complication and a major predictor of poor prognosis of systemic lupus erythematosus. Immune complex deposition and T cell infiltration are crucial events in LN pathogenesis. B7-1 (CD80), normally expressed by antigen-presenting cells, is one of the major co-stimulators of T-cell activation through the binding with its counter-receptors CD28 and cytotoxic T-lymphocyte antigen-4. Unexpectedly, B7-1 induction was described at the podocyte level in patients affected by different renal diseases, including LN...
2016: Nephron
Yuko Matsuki-Muramoto, Kazuhisa Nozawa, Kaori Uomori, Iwao Sekigawa, Yoshinari Takasaki
OBJECTIVE: To clarify the mechanisms underlying lupus nephritis (LN) amelioration following bortezomib treatment. METHODS: Bortezomib was administered subcutaneously every 3 days to NZB/W F1 mice, and the serum anti-double stranded (ds) deoxyribonucleic acid (DNA) antibody titers and proteinuria levels were measured. The renal samples and the splenocytes were examined histologically or used for real-time quantitative reverse transcription-polymerase chain reaction analysis after 18 weeks of treatment...
May 11, 2016: Modern Rheumatology
Kichul Ko, Jianing Wang, Stuart Perper, Yulei Jiang, Denisse Yanez, Natalya Kaverina, Junting Ai, Vladimir M Liarski, Anthony Chang, Yahui Peng, Li Lan, Susan Westmoreland, Lisa Olson, Maryellen L Giger, Li Chun Wang, Marcus R Clark
OBJECTIVE: In lupus nephritis (LuN), tubulointerstitial inflammation (TII) is associated with in situ adaptive immune cell networks that amplify local tissue damage. As patients with severe TII often fail conventional therapy and develop renal failure, understanding these in situ mechanisms might reveal new therapeutic targets. We hypothesized that in TII, dysregulated apoptotic regulators maintain local adaptive immunity and drive inflammation. METHODS: We developed novel computational approaches that, when applied to multicolor confocal images, quantified apoptotic regulator protein expression in selected lymphocyte subsets...
May 9, 2016: Arthritis & Rheumatology
Xiao Han, Yan Wang, Xiaoyan Zhang, Yuting Qin, Bo Qu, Lingling Wu, Jianyang Ma, Zhenyuan Zhou, Jie Qian, Min Dai, Yuanjia Tang, Edward K L Chan, John B Harley, Shiyu Zhou, Nan Shen
OBJECTIVE: Type I interferon (IFN) is a critical pathogenic factor during the progression of lupus nephritis (LN). Although microRNAs (miRNAs) have been shown to control the IFN response in immune cells in LN, the role of miRNAs in resident renal cells remains unclear. We undertook this study to investigate the role of microRNA-130b (miR-130b) in the IFN pathway in renal cells as well as its therapeutic effect in LN. METHODS: Kidney tissues from patients and (NZB × NZW)F1 lupus-prone mice were collected for detecting miR-130b levels...
September 2016: Arthritis & Rheumatology
A Wiener, A Schippers, N Wagner, F Tacke, T Ostendorf, N Honke, K Tenbrock, K Ohl
The recruitment of immune cells to sites of tissue inflammation is orchestrated by chemokine/chemokine receptor networks. Among these, the CXCL13/CXCR5 axis is thought to be involved critically in systemic lupus erythematosus (SLE) and lupus nephritis pathogenesis. Beyond B cell abnormalities, another hallmark of SLE disease is the occurrence of aberrant T cell responses. In particular, double-negative (DN) T cells are expanded in the peripheral blood of patients with SLE and in lupus-prone mice. DN T cells induce immunoglobulin production, secrete proinflammatory cytokines and infiltrate inflamed tissue, including kidneys...
July 2016: Clinical and Experimental Immunology
Wei Li, Hu Li, Mu Zhang, Mengqi Wang, Youxiu Zhong, Hezhen Wu, Yanfang Yang, Laurence Morel, Qun Wei
Systemic lupus erythematosus (SLE) is a serious disorder of immune regulation characterized by overproduction of autoantibodies, lupus nephritis, CD4+ T cell aberrant activation, and immune complex-mediated inflammation. The chronic graft vs. host disease (cGVHD) mouse model is a well-established model of SLE. Quercitrin is a natural compound found in Tartary buckwheat with a potential anti-inflammatory effect that is used to treat heart and vascular conditions. In our previous study, we determined that quercitrin is an immunosuppressant with beneficial effects in mouse models of immune diseases...
July 1, 2016: American Journal of Physiology. Renal Physiology
Andrew T Bender, Albertina Pereira, Kai Fu, Eileen Samy, Yin Wu, Lesley Liu-Bujalski, Richard Caldwell, Yi-Ying Chen, Hui Tian, Federica Morandi, Jared Head, Ursula Koehler, Melinda Genest, Shinji L Okitsu, Daigen Xu, Roland Grenningloh
Bruton's tyrosine kinase (Btk) is expressed in a variety of immune cells and previous work has demonstrated that blocking Btk is a promising strategy for treating autoimmune diseases. Herein, we utilized a tool Btk inhibitor, M7583, to determine the therapeutic efficacy of Btk inhibition in two mouse lupus models driven by TLR7 activation and type I interferon. In BXSB-Yaa lupus mice, Btk inhibition reduced autoantibodies, nephritis, and mortality. In the pristane-induced DBA/1 lupus model, Btk inhibition suppressed arthritis, but autoantibodies and the IFN gene signature were not significantly affected; suggesting efficacy was mediated through inhibition of Fc receptors...
March 2016: Clinical Immunology: the Official Journal of the Clinical Immunology Society
Hege Lynum Pedersen, Kjersti Daae Horvei, Dhivya Thiyagarajan, Natalya Seredkina, Ole Petter Rekvig
Lupus nephritis is one of the most serious manifestations of systemic lupus erythematosus, and represents one of the criteria implemented to classify systemic lupus erythematosus. Although studied for decades, no consensus has been reached related to the basic cellular, molecular, and immunologic mechanism(s) responsible for lupus nephritis. No causal treatments have been developed; therapy is approached mainly with nonspecific immunosuppressive medications. More detailed insight into disease mechanisms therefore is indispensable to develop new therapeutic strategies...
September 2015: Seminars in Nephrology
Teja Celhar, Richard Hopkins, Susannah I Thornhill, Raquel De Magalhaes, Sun-Hee Hwang, Hui-Yin Lee, Hiroko Yasuga, Leigh A Jones, Jose Casco, Bernett Lee, Thomas P Thamboo, Xin J Zhou, Michael Poidinger, John E Connolly, Edward K Wakeland, Anna-Marie Fairhurst
Glomerulonephritis is a common and debilitating feature of systemic lupus erythematosus (SLE). The precise immune mechanisms that drive the progression from benign autoimmunity to glomerulonephritis are largely unknown. Previous investigations have shown that a moderate increase of the innate Toll-like receptor 7 (TLR7) is sufficient for the development of nephritis. In these systems normalization of B-cell TLR7 expression or temporal depletion of plasmacytoid dendritic cells (pDCs) slow progression; however, the critical cell that is responsible for driving full immunopathology remains unidentified...
November 10, 2015: Proceedings of the National Academy of Sciences of the United States of America
M D Morse, K L Clark, M Cascalho, J M Kahlenberg
OBJECTIVE: Caspase-1 is required for nephritis and robust autoantibody development in the pristane model of murine lupus. The objective of this study was to evaluate the immune response and to study the splenic B and T cell populations in wild-type (WT) and caspase-1-/- mice following pristane injection in order to develop an understanding of why absence of caspase-1 is protective in pristane-induced lupus. METHODS: Immunization responses to NP-Ficoll and NP-ovalbumin were assessed in WT and caspase-1-/- mice...
January 2016: Lupus
B T Stocks, A J Wilhelm, C S Wilson, A F Marshall, N E Putnam, A S Major, D J Moore
The strongly immunogenic environment in autoimmune diseases such as lupus may pose a stringent barrier to transplantation. Despite available murine models of lupus, transplant tolerance in this setting has yet to be fully investigated in highly penetrant genetic models of disease. Such studies are of clear clinical importance because lupus is a transplant indication in which transplanted kidneys have a substantially increased risk of rejection including a role for recurrent nephritis. In the fully penetrant B6...
January 2016: American Journal of Transplantation
Samantha A Chalmers, Violeta Chitu, Meera Ramanujam, Chaim Putterman
Systemic lupus erythematosus (SLE) is an autoimmune disease which results in multiple different end organ pathologies, including the kidney. Lupus nephritis (LN) is one of the most serious complications of SLE, and a leading cause of morbidity and mortality. Current treatment options are suboptimal, involving non-specific immunosuppression which exposes patients to potentially serious side effects with no guarantee of remission. More targeted therapeutic approaches may improve treatment results. Many studies have implicated macrophages as actively contributing to LN pathogenesis in both human and murine disease...
July 2015: Discovery Medicine
Kaitlyn L Clark, Tamra J Reed, Sonya J Wolf, Lori Lowe, Jeffrey B Hodgin, J Michelle Kahlenberg
Systemic lupus erythematosus is clinically characterized by episodes of flare and remission. In patients, cutaneous exposure to ultraviolet light has been proposed as a flare trigger. However, induction of flare secondary to cutaneous exposure has been difficult to emulate in many murine lupus models. Here, we describe a system in which epidermal injury is able to trigger the development of a lupus nephritis flare in New Zealand Mixed (NZM) 2328 mice. 20-week old NZM2328 female mice underwent removal of the stratum corneum via duct tape, which resulted in rapid onset of proteinuria and death when compared to sham-stripped littermate control NZM2328 mice...
December 2015: Journal of Autoimmunity
Yan Li, Amanda R Eskelund, Hua Zhou, David P Budac, Connie Sánchez, Maria Gulinello
Neuropsychiatric symptoms of systemic lupus erythematosus (NP-SLE) have been understudied compared to end-organ failure and peripheral pathology. Neuropsychiatric symptoms, particularly affective and cognitive indications, may be among the earliest manifestations of SLE. Among the potential pathophysiological mechanisms responsible for NP-SLE are increased peripheral pro-inflammatory cytokines, subsequent induction of indoleamine-2,3-dioxygenase (IDO) and activation of the kynurenine pathway. In the MRL/MpJ-Faslpr (MRL/lpr) murine model of lupus, depression-like behavior and cognitive dysfunction is evident before significant levels of autoantibody titers and nephritis are present...
2015: International Journal of Molecular Sciences
Emad E Ghobrial, Azza A El Hamshary, Ashraf G Mohamed, Yomna A Abd El Raheim, Ahmed A Talaat
Systemic lupus erythematosus (SLE) is a life-long, life-limiting and multi-systemic autoimmune disease. Glomerulonephritis is one of the most serious manifestations of SLE. Younger children have an increased incidence, severity and morbidity of lupus nephritis (LN) compared with adult-onset disease. Monocyte chemoattractant protein-1 (MCP-1) enhances leukocyte adhesiveness and endothelial permeability in the kidneys of murine and human LN models. Our study aimed to assess the role of urinary MCP-1 in the early diagnosis of LN activity...
May 2015: Saudi Journal of Kidney Diseases and Transplantation
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