The Experts below are selected from a list of 417 Experts worldwide ranked by ideXlab platform

H Leiss - One of the best experts on this subject based on the ideXlab platform.

  • SAT0164 Pristane-Induced Lupus in BALB/C mice: A model for Lupus arthritis
    Annals of the Rheumatic Diseases, 2020
    Co-Authors: H Leiss, Birgit Niederreiter, T Bandur, Stephan Bluml, G Steiner, Josef S Smolen, G H Stummvoll
    Abstract:

    Background Systemic Lupus erythematosus (SLE) is frequently featured by musculoskeletal issues as arthralgia and arthritis, which account for the most important burdens in patient-based questionnaires. In most cases, Lupus arthritis appears as non-erosive in projection radiography, but presented as (minimal) erosive disease in recent MRI-based observations. Despite its high prevalence, Lupus arthritis is not in the focus of intensive basic research, since it is rarely seen in murine Lupus models. The mineral oil pristane can induce a systemic Lupus-like disease in mice featured by typical auto-antibodies, the involvement of inner organs, and also by arthritis. Objectives To establish pristane induced Lupus (PIL) in BALB/c mice as suitable model for Lupus arthritis, provide in-depth analysis of both clinical and histological features by using an established work up procedure originating from RA basic research. Methods For disease induction BALB/c mice were injected i.p. with either 0.5ml of pristane (PIL group n=57) or PBS (healthy controls, HC, n=35) and sacrificed after 8 months. In addition, also Bl/6 mice were treated similarly (10 PIL, 10 HC). Animals were monitored for clinical signs of arthritis (paw swelling, loss of grip strength) and analyzed by histopathology techniques: H/E (overview), TRAP (osteoclasts), toluidine blue (cartilage). In order to analyze and compare disease severity, the histological features were quantified with an image analysis system (osteomeasure) and also combined to define an arthritis severity score (ASS). Specimens were also stained for granulocytes (G1), T- (anti-CD3) and B-Cells (anti-CD45) for immunohistochemistry. Blood samples were tested for anti-chromatin-abs, anti-histone-abs and rheumatoid factor. Results After 3 months, clinical signs of arthritis developed and constantly increased; finally 75% of mice experienced at least one episode of paw swelling, while HC were free of arthritis (p 0.7, p Histological analysis showed arthritis in 58% of PIL-group, but none in HC (p Conclusions In contrast to most murine models of SLE, PIL in BALB/c mice is featured by arthritis. Despite its erosive nature, PIL arthritis does not procede to joint destruction as seen in human RA or murine RA models. PIL may provide a good tool to study Lupus arthritis in knock-out or transgenic mouse models based on a BALB/c, but not on a Bl/6 background. Disclosure of Interest None Declared

  • MicroRNA 155-deficiency leads to decreased autoantibody levels and reduced severity of nephritis and pneumonitis in Pristane-Induced Lupus
    PLOS ONE, 2017
    Co-Authors: H Leiss, Stephan Bluml, Wilhelm Salzberger, Barbara Jacobs, Irina Gessl, Nicolas Kozakowski, Antonia Puchner, Attila Kiss, Bruno K. Podesser, Josef S Smolen
    Abstract:

    We herein examine the role of endogenous miR155 in the development of systemic manifestations in pristane induced Lupus. Systemic Lupus in miR155-deficient and wild type mice was induced upon injection of pristane and analyzed after 8 months, PBS-injected mice served as controls. Glomerulonephritis and pneumonitis were quantified using the kidney biopsy score and a newly adapted histomorphometric image analysis system; lung tissue was further analyzed by tissue cytometry. Serum levels of anti-dsDNA, anti-histone and anti-chromatin antibodies were measured by ELISA. Frequencies of B cells, activated and regulatory CD4+ T cells as well as Th1, Th2, Th17 cells were measured by flow cytometry. RT-qPCR was used to measure expression levels of interferon-signature and T-cell subset related as well as miR155-associated genes. After induction of Lupus, miR155-deficient mice had significant less pulmonary involvement (perivascular inflammatory area in mm2/mm2 lung area 0.00092±0.00015 vs. 0.0027±0.00075, p = 0.0347) and renal disease (glomerular activity score 1.95±0.19 vs 3±0.26, p = 0.0029) compared to wild types. MiR155-deficient mice had significantly lower serum levels of disease-associated auto-antibodies and decreased frequencies of activated CD4+CD25+ (Foxp3-) cells. Upon restimulation, CD4+ cells showed a less pronounced Th2 and Th17 and a slightly decreased Th1 response in mir155-deficient mice. Pristane-treated wild types showed significantly up-regulated expression of genes related to the INF-signature (MX1, IP10, IRF7, ISG15). MiR155-deficient mice had less severe organ involvement, lower serum auto-antibody levels, a less prominent T cell response and lower expressions of genes jointly responsible for disease development. Thus, antagonizing miR155 might be a future approach in treating SLE.

  • fri0259 in vitro induced regulatory t cells can ameliorate severity of pristane induced Lupus pil
    Annals of the Rheumatic Diseases, 2017
    Co-Authors: Barbara Jacobs, H Leiss, Josef S Smolen, Irina Gessl, Antonia Puchner, G H Stummvoll
    Abstract:

    Background Pristane induced Lupus (PIL) is an established murine model of induced systemic Lupus erythematosus (SLE). Mice develop specific autoantibodies and show symptoms of SLE including arthritis, glomerulonephritis and haemorrhagic pulmonary capillaritis. Objectives To investigate the therapeutic effects of in vitro-induced regulatory T cells (iTreg) in the murine model of PIL. Methods BALB/c mice were injected i.p. with 0.5 ml of pristane (PIL) or PBS (control). Naive CD4+ thymocytes were sorted and cultured and cell suspensions with >80% CD4+FoxP3+ cells (iTreg) were injected i.v. (i) once when PIL was induced (5 × 106 iTreg (iTreg-single)) or (ii) every 4 weeks (1 × 106 iTreg, iTreg-rep). Mice were monitored for paw swelling and grip strength. After 8 months, histological analysis quantified cartilage degradation, number of osteoclasts, extent of inflammation and bone erosion. Glomerulonephritis and pneumonitis were quantified using the kidney biopsy score and a histomorphometric image analysis system; inflammatory tissue was analysed by tissue cytometry. Serum levels of auto-antibodies were measured by ELISA. Frequencies of B cells, activated and regulatory CD4+ T cells and Th1, Th2, Th17 cells were measured by flow cytometry. FlowCytomix Pro was used to measure serum cytokines. RT-qPCR was used to measure expression levels of interferon (IFN)-signature and T-cell subset related as well as inflammation-associated genes. Results Monthly injections of 1 × 106 iTreg reduced the clinical and histological severity of PIL-arthritis. This was seen by a higher mean grip strength, less mean paw swelling, retardation of symptom onset and a lower summative arthritis severity score (figure A). There was significant reduction of arthritis severity in all histological parameters and in the percentage of affected mice with erosive arthritis (33% of iTreg-rep mice vs 62% of PIL-mice). A single boost of 5 × 106 iTreg could not prevent joint manifestation, however a slight retardation in ‘loss of grip strength’ and significantly less erosive area was seen. In regards to cellular composition of the inflammatory tissue in paws, a significantly increased relative amount of CD4 +Foxp3+cells was seen in the iTreg-rep group compared to PIL group. Repeatedly injected mice (iTreg-rep) had significantly less renal disease (glomerular activity score) (figure B) and pulmonary involvement (perivascular inflammatory area) (figure C) compared to PIL. iTreg-rep mice had significantly lower serum levels of disease-associated auto-antibodies (figure D). Upon restimulation, splenic CD4+ cells in iTreg-rep showed a less pronounced Th1, Th2 and Th17 response as well as lower percentages in B- and activated T-cells, whereas the percentage of Treg was higher than in all other groups (figure E). FlowCytomix analysis showed reduced cytokine production after repeated iTreg administration. Correspondingly, iTreg-rep showed decreased expressions of IFN-signature-, T-cell subset- and inflammatory cytokine related genes (figure F). Conclusions Repeated injections of iTreg ameliorate the clinical, histological, serological as well as the genetic severity of PIL-manifestations. A single boost of iTreg at time of disease induction does not prevent manifestations, but retards the onset of symptoms. Thus iTreg have significant positive effects on PIL, which may have consequences for future approaches in treating SLE. Disclosure of Interest None declared

  • a3 10 characterisation of cd4 t cell response and effects of regulatory t cells in pristane induced Lupus pil
    Annals of the Rheumatic Diseases, 2014
    Co-Authors: H Leiss, Birgit Niederreiter, B Schwarzecker, Josef S Smolen, Irina Gessl, G H Stummvoll
    Abstract:

    Background CD4 + T cells and the Th1 and Th17 subsets in particular play a pivotal role in SLE. Regulatory T cells (Treg) are essential for maintaining peripheral tolerance, but their number and function in SLE is decreased. Objectives We herein characterize CD4+T cell and Treg homeostasis and severity of organ involvement in a murine model of SLE and analyze the effects of in vitro –induced iTreg. Methods Mice were injected i.p. with 0.5ml of pristane or PBS as control and killed after 8 months. Induction of Treg: Naive CD4 + thymocytes were cultured under specific conditions (including TGFβ, IL-2) and tested for CD4 + Foxp3 + expression by FACS (induced Treg, iTreg). Cell suspensions with >80% purity for CD4 + FoxP3 + iTreg were injected intravenously either once at start of experiments (5x10e6, iTreg-boost) or monthly (1x10e6, iTreg-repeated). Animals were monitored for clinical signs of arthritis and in order to analyze and compare disease severity, histological features of arthritis and pneumonitis were quantified by an image analysis system (Osteomeasure®). Lungs were scored for the severity of perivascular inflammation by analyzing the numbers of affected vessels and the area of the inflammatory infiltrate. Lymphocytes were isolated from granulomas (ectopic lymphoid tissue within the peritoneum), lymph nodes (LN) and spleens and were analyzed separately for each mouse by FACS. For analyzes of the Th1, 2, 17 subsets, respectively, cells were restimulated in vivo plate bound with anti-CD3 and anti-CD28abs. Results PIL mice presented with involvement of inner organs, most frequently affected were the lungs (100% pneumonitis); 52% of PIL developed arthritis, both clinically and histologically. Monthly iTreg-injection significantly decreased clinical signs of arthritis and histological lung and joint parameters. Out of 6 mice treated, 4 (66%) did not show any signs of arthritis at all. (Fig. 1A-F) The iTreg-boost did not prevent joint manifestations or pneumonitis, but appeared to have a retarding effect (Fig.1A-F) indicated by a delayed onset of clinical symptoms and by a significantly decreased erosive area at the end of observation (Fig.1B). Intraperitoneal granuloma typical for PIL appeared to be the hotspots of inflammation showing a significantly elevated Teff/Treg ratio of 1.3. Upon re-stimulation, CD4+ cells showed a pronounced Th1 response (27% IFNγ producers) compared to cells from LN and spleens from both PIL and HC (with Th1 percentages ranging from 9-16%). In addition, frequencies of Th2 and Th17 cells were elevated in PIL, again with the highest yield in granuloma. The repeated application of iTreg reduced the Teff/Treg ratio in PIL granuloma to 0.7. Conclusions Repeated injections of exogenously induced iTregs reduce severity of pneumonitis and arthritis as well as the T eff /T reg ratio. A single injection of iTregs (even when applied before the clinical onset) is not effective, but appears to retard onset of symptoms and progression of arthritis and pneumonitis. Thus, iTreg have significant effects on Lupus symptoms when applied repeatedly, which may have consequence for future therapeutic considerations. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.5386

  • pristane induced Lupus as a model of human Lupus arthritis evolvement of autoantibodies internal organ and joint inflammation
    Lupus, 2013
    Co-Authors: H Leiss, Birgit Niederreiter, T Bandur, B Schwarzecker, Stephan Bluml, G Steiner, W Ulrich, Josef S Smolen, G H Stummvoll
    Abstract:

    ObjectiveArthritis is frequently seen in human Lupus, but rarely in Lupus models. Pristane-Induced Lupus (PIL) can be induced in various mouse strains such as BALB/c and C57BL/6. We herein characterize clinical and histological features of arthritis in the context of systemic Lupus and provide a prudent comparison with models of rheumatoid arthritis (RA).MethodsA total of 57 BALB/c mice received pristane (PIL group) and were analyzed for serum autoantibodies (anti-chromatin-, -histone, -Sm, -dsDNA), as well as for clinical features and histopathology of joints, lungs and kidneys. Joint pathology was quantified by image analysis and tissue cytometry. Ten C57BL/6 mice (Bl/6-PIL) and historical groups of two different RA models were analyzed accordingly.ResultsIn BALB/c PIL, clinical arthritis started at three months, occurred finally in 79% of PIL (but not in controls, p   0...

Westley H Reeves - One of the best experts on this subject based on the ideXlab platform.

  • II-10 Role of macrophage-driven autoinflammation in SLE
    Lupus science & medicine, 2018
    Co-Authors: Haoyang Zhuang, Li-jun Yang, Westley H Reeves
    Abstract:

    Background Although SLE is a prototype of autoimmune (T cell/B cell-mediated) disease, there is increasing evidence implicating myeloid cells in its pathogenesis. We examined the role of macrophages (MΦ) in human SLE and the Pristane-Induced Lupus model. Methods Tissues of SLE patients and mice with Pristane-Induced Lupus were examined by double immunohistochemistry. MΦ were analyzed by flow cytometry, phagocytosis assay, real-time PCR, Seahorse assay, and RNA-Seq. Mice were injected daily with the liver X receptor (LXR) agonist T0901317. Results SLE patients’ bone marrow contained numerous activated caspase-3+ apoptotic cells located outside of MΦ. In contrast, in leukemia patients undergoing bone marrow ablation prior to transplantation, all caspase-3+ cells were inside of MΦ, suggesting that Lupus is associated with impaired clearance of apoptotic cells. MΦ in pristane-Lupus took up fluorescently-labeled apoptotic cells poorly compared with controls. Studies in pristane-treated knock-out mice indicated that the induction of diffuse alveolar hemorrhage (DAH), a serious pulmonary complication of Lupus, required opsonization of dead cells in the lung by ‘natural’ IgM (DAH absent in μMT mice, restored by infusion of IgM), C3, and C3b receptors (absent in C3-/- and CD18-/- mice, prevented by complement depletion with cobra venom factor). DAH also was prevented by MΦ depletion (clodronate liposomes) but not neutrophil depletion (anti-Ly6G). MΦ in Pristane-Induced Lupus exhibited features of classical activation (impaired phagocytosis of apoptotic cells, high glycolysis, low oxidative phosphorylation, increased HIF1α expression, M1 surface markers, and TNFα production), whereas control MΦ from mice treated with mineral oil (do not develop DAH) were M2-like, with high phagocytic activity, low glycolysis, high OxPhos, increased LXRα expression, M2 surface markers, and IL-10 production. In both Pristane-Induced Lupus MΦ and SLE patients’ monocytes, we found low levels of the LXRα-regulated reverse cholesterol transporter ABCA1. We hypothesized that it might be possible to treat DAH by ‘re-polarizing’ MΦ using a synthetic LXR agonist. Consistent with that idea, pristane-treated mice receiving T0901317 did not develop DAH and MΦ from mice receiving T0901317 exhibited an M2-like surface phenotype and decreased TNFα production compared with controls. Conclusions Our data suggest that Lupus-associated DAH is partly an autoinflammatory response caused by sluggish clearance of apoptotic cells by M1-like MΦ and that certain clinical manifestations (e.g. DAH) can be treated by repolarizing MΦ using an activator of the transcription factor LXRα. Low levels of LXR-driven ABCA1 expression also may have implications for the therapy of atherosclerosis in SLE.

  • II-03 Pathogenesis of diffuse alveolar haemorrhage (DAH) in Lupus
    Lupus science & medicine, 2016
    Co-Authors: Haoyang Zhuang, Li-jun Yang, Stepan Shumyak, Li Lu, Xin Qi, Westley H Reeves
    Abstract:

    Background Diffuse alveolar haemorrhage (DAH) in Lupus patients carries a mortality rate of over 50%. C57BL/6 mice with Pristane-Induced Lupus develop DAH closely resembling the human disease. The role of cell death, complement, immunoglobulin, Toll-like receptors, and myeloid cells was examined in pristane-treated mice with DAH. Materials and methods Clinical/pathological and immunological manifestations of Pristane-Induced Lupus in gene-targeted vs. wild type mice were compared with the manifestations in SLE patients. Tissue distribution of pristane was examined histologically and by mass spectrometry. The cell types responsible for disease were examined by in vivo depletion using clodronate liposomes (CloLip) and anti-neutrophil monoclonal antibodies (GR1). The effect of treatment with the C3b-analogue cobra venom factor (CVF) was examined. Results After peritoneal injection, pristane was detected in the lung by mass spectrometry and oil red staining, and was found to induce cell death, phagocytosis of the dead cells and erythrocytes by alveolar macrophages, consolidation of the alveolar spaces by erythrocytes and inflammatory cells, thickening of the alveolar wall, and extensive cellular proliferation (Ki-67 staining) within the alveolar septa. Small vessel vasculitis characterised by perivascular neutrophils and F4/80 + macrophages was present. Lung tissue from SLE patients with DAH had a similar appearance. B-cell-deficient (μMT) mice were resistant to the induction of DAH, but susceptibility was restored by infusing IgM. C3-deficient and CD18-deficient mice also were resistant, and DAH could be prevented in wild-type mice by depleting complement with CVF. Induction of DAH was independent of MyD88, TRIF, TNFα, and type I interferon, but mortality was increased in IL-10-deficient mice. In vivo neutrophil depletion had no effect on susceptibility, whereas treatment with CloLip depleted both resident alveolar macrophages and presumptive bone marrow-derived F4/80 + macrophages while preventing DAH, suggesting that macrophages are central to DAH pathogenesis. Conclusion Induction of DAH in pristane-Lupus is likely to involve opsonization of dead cells in the lung by natural IgM and complement followed by complement receptor 3 (CD11b/CD18) and/or CR4 (CD11c/CD18)-mediated phagocytosis, resulting in lung inflammation. Disease is macrophage-dependent and independent of type I interferon, TNFα, MyD88, and neutrophils. Complement inhibition and/or macrophage-targeted therapies may be attractive candidates for treating SLE-associated DAH.

  • "Lupoid hepatitis" in SLE patients and mice with experimental Lupus.
    Clinical Immunology, 2016
    Co-Authors: Stepan Shumyak, Li-jun Yang, Haoyang Zhuang, Westley H Reeves
    Abstract:

    Abstract The unusual subset of patients with severe hepatitis, hypergammaglobulinemia, arthritis, and LE cells in the blood reported by Henry Kunkel and others suggested to these investigators that “lupoid” hepatitis might share pathogenic mechanisms with SLE. More than half a century later, the etiology of autoimmune hepatitis remains unclear. The occurrence of autoimmune hepatitis in a small fraction (about 3%) of SLE patients in our Lupus cohort and in two mouse models of SLE supports their conclusion that lupoid hepatitis may be share pathogenic mechanisms with SLE. The development of autoimmune hepatitis in mice with Pristane-Induced Lupus provides an opportunity to further explore the potential link between these two autoimmune disorders.

  • Animal Models of Interferon Signature Positive Lupus
    Frontiers in Immunology, 2015
    Co-Authors: Haoyang Zhuang, Li-jun Yang, Christopher Szeto, Westley H Reeves
    Abstract:

    Human Lupus is strongly associated with a gene expression signature characterized by over-expression of type I interferon-regulated genes. A strong interferon signature is not seen in the standard mouse models of Lupus, despite considerable evidence for the involvement of toll-like receptor (TLR)-driven interferon production. In contrast, Pristane-Induced Lupus exhibits a prominent TLR7-dependent interferon signature. Importantly, genetic disorders with dysregulated interferon production in both humans and mice cause severe autoinflammatory diseases but not the typical manifestations of Lupus suggesting that interferon over-production by itself is insufficient to cause SLE. Murine single-gene models suggest that Lupus-like disease may result from abnormalities in B cell activation and the clearance of dead cells. Pristane may mimic human SLE by causing interferon production along with synergistic abnormalities affecting clearance of apoptotic cells and activation of B cell signaling.

  • serum autoantibodies in pristane induced Lupus are regulated by neutrophil gelatinase associated lipocalin
    Clinical Immunology, 2014
    Co-Authors: Rahul D Pawar, Westley H Reeves, Beatrice Goilav, Haoyang Zhuang, Leal C Herlitz, Chaim Putterman
    Abstract:

    The onset of autoantibodies in systemic autoimmunity can be the result of a breakdown in tolerance at multiple checkpoints. Genetic, hormonal, and immunological factors can combine with environmental influences to accelerate the onset of disease and aggravate disease outcome. Here, we describe a novel mechanism relating to the regulatory role of Neutrophil Gelatinase Associated Lipocalin (NGAL) in modulating the levels of autoantibodies in pristane induced Lupus. Following a single injection of pristane intraperitoneally, NGAL expression was induced in both the serum and spleen. Furthermore, NGAL deficient mice were more susceptible to the induction of pristane stimulated autoimmunity, and displayed higher numbers of autoantibody secreting cells and increased expression of activation induced cytidine deaminase (AID) and other inflammatory mediators in the spleen. In contrast, kidney damage was milder in NGAL deficient mice, indicating that NGAL was detrimental in autoantibody mediated kidney disease. These studies indicate that NGAL plays differential roles in different tissues in the context of Lupus, and suggest a previously unrecognized role for NGAL in adaptive immunity.

G H Stummvoll - One of the best experts on this subject based on the ideXlab platform.

  • SAT0164 Pristane-Induced Lupus in BALB/C mice: A model for Lupus arthritis
    Annals of the Rheumatic Diseases, 2020
    Co-Authors: H Leiss, Birgit Niederreiter, T Bandur, Stephan Bluml, G Steiner, Josef S Smolen, G H Stummvoll
    Abstract:

    Background Systemic Lupus erythematosus (SLE) is frequently featured by musculoskeletal issues as arthralgia and arthritis, which account for the most important burdens in patient-based questionnaires. In most cases, Lupus arthritis appears as non-erosive in projection radiography, but presented as (minimal) erosive disease in recent MRI-based observations. Despite its high prevalence, Lupus arthritis is not in the focus of intensive basic research, since it is rarely seen in murine Lupus models. The mineral oil pristane can induce a systemic Lupus-like disease in mice featured by typical auto-antibodies, the involvement of inner organs, and also by arthritis. Objectives To establish pristane induced Lupus (PIL) in BALB/c mice as suitable model for Lupus arthritis, provide in-depth analysis of both clinical and histological features by using an established work up procedure originating from RA basic research. Methods For disease induction BALB/c mice were injected i.p. with either 0.5ml of pristane (PIL group n=57) or PBS (healthy controls, HC, n=35) and sacrificed after 8 months. In addition, also Bl/6 mice were treated similarly (10 PIL, 10 HC). Animals were monitored for clinical signs of arthritis (paw swelling, loss of grip strength) and analyzed by histopathology techniques: H/E (overview), TRAP (osteoclasts), toluidine blue (cartilage). In order to analyze and compare disease severity, the histological features were quantified with an image analysis system (osteomeasure) and also combined to define an arthritis severity score (ASS). Specimens were also stained for granulocytes (G1), T- (anti-CD3) and B-Cells (anti-CD45) for immunohistochemistry. Blood samples were tested for anti-chromatin-abs, anti-histone-abs and rheumatoid factor. Results After 3 months, clinical signs of arthritis developed and constantly increased; finally 75% of mice experienced at least one episode of paw swelling, while HC were free of arthritis (p 0.7, p Histological analysis showed arthritis in 58% of PIL-group, but none in HC (p Conclusions In contrast to most murine models of SLE, PIL in BALB/c mice is featured by arthritis. Despite its erosive nature, PIL arthritis does not procede to joint destruction as seen in human RA or murine RA models. PIL may provide a good tool to study Lupus arthritis in knock-out or transgenic mouse models based on a BALB/c, but not on a Bl/6 background. Disclosure of Interest None Declared

  • pristane induced Lupus as a model of human Lupus arthritis evolvement of autoantibodies internal organ and joint inflammation
    Lupus, 2013
    Co-Authors: H Leiss, Birgit Niederreiter, T Bandur, B Schwarzecker, Stephan Bluml, G Steiner, W Ulrich, Josef S Smolen, G H Stummvoll
    Abstract:

    ObjectiveArthritis is frequently seen in human Lupus, but rarely in Lupus models. Pristane-Induced Lupus (PIL) can be induced in various mouse strains such as BALB/c and C57BL/6. We herein characterize clinical and histological features of arthritis in the context of systemic Lupus and provide a prudent comparison with models of rheumatoid arthritis (RA).MethodsA total of 57 BALB/c mice received pristane (PIL group) and were analyzed for serum autoantibodies (anti-chromatin-, -histone, -Sm, -dsDNA), as well as for clinical features and histopathology of joints, lungs and kidneys. Joint pathology was quantified by image analysis and tissue cytometry. Ten C57BL/6 mice (Bl/6-PIL) and historical groups of two different RA models were analyzed accordingly.ResultsIn BALB/c PIL, clinical arthritis started at three months, occurred finally in 79% of PIL (but not in controls, p   0...

  • ab0127 arthritis in a model for systemic Lupus involvement of joints inner organs and course of autoantibodies in pristane induced Lupus
    Annals of the Rheumatic Diseases, 2013
    Co-Authors: H Leiss, Birgit Niederreiter, T Bandur, B Schwarzecker, Stephan Bluml, G Steiner, W Ulrich, Josef S Smolen, G H Stummvoll
    Abstract:

    Objectives Arthritis is frequently seen in human Lupus, but rarely in Lupus models. Pristane-Induced Lupus (PIL) can be induced in various mouse strains such as BALB/c and C57Bl/6. We herein characterize clinical and histological features of arthritis in the context of systemic Lupus and provide a prudent comparison with models of rheumatoid arthritis (RA). Methods Arthritis is frequently seen in human Lupus, but rarely in Lupus models. Pristane-Induced Lupus (PIL) can be induced in various mouse strains such as BALB/c and C57Bl/6. We herein characterize clinical and histological features of arthritis in the context of systemic Lupus and provide a prudent comparison with models of rheumatoid arthritis (RA). Results In BALB/c, clinical arthritis started at 3 months, occurred finally in 79% of PIL (but not in controls, p 0.7, p Conclusions PIL in BALB/c mice is characterized by severe organ involvement, typical auto-abs and by a mild-erosive arthritis with similarities, but also with distinct differences to RA. PIL may help to study arthritis along with other key features of SLE after therapeutic interventions or in knockout models based on a BALB/c, but not on a Bl/6 background. Disclosure of Interest None Declared

  • sat0164 pristane induced Lupus in balb c mice a model for Lupus arthritis
    Annals of the Rheumatic Diseases, 2013
    Co-Authors: H Leiss, Birgit Niederreiter, T Bandur, Stephan Bluml, G Steiner, Josef S Smolen, G H Stummvoll
    Abstract:

    Background Systemic Lupus erythematosus (SLE) is frequently featured by musculoskeletal issues as arthralgia and arthritis, which account for the most important burdens in patient-based questionnaires. In most cases, Lupus arthritis appears as non-erosive in projection radiography, but presented as (minimal) erosive disease in recent MRI-based observations. Despite its high prevalence, Lupus arthritis is not in the focus of intensive basic research, since it is rarely seen in murine Lupus models. The mineral oil pristane can induce a systemic Lupus-like disease in mice featured by typical auto-antibodies, the involvement of inner organs, and also by arthritis. Objectives To establish pristane induced Lupus (PIL) in BALB/c mice as suitable model for Lupus arthritis, provide in-depth analysis of both clinical and histological features by using an established work up procedure originating from RA basic research. Methods For disease induction BALB/c mice were injected i.p. with either 0.5ml of pristane (PIL group n=57) or PBS (healthy controls, HC, n=35) and sacrificed after 8 months. In addition, also Bl/6 mice were treated similarly (10 PIL, 10 HC). Animals were monitored for clinical signs of arthritis (paw swelling, loss of grip strength) and analyzed by histopathology techniques: H/E (overview), TRAP (osteoclasts), toluidine blue (cartilage). In order to analyze and compare disease severity, the histological features were quantified with an image analysis system (osteomeasure) and also combined to define an arthritis severity score (ASS). Specimens were also stained for granulocytes (G1), T- (anti-CD3) and B-Cells (anti-CD45) for immunohistochemistry. Blood samples were tested for anti-chromatin-abs, anti-histone-abs and rheumatoid factor. Results After 3 months, clinical signs of arthritis developed and constantly increased; finally 75% of mice experienced at least one episode of paw swelling, while HC were free of arthritis (p 0.7, p Histological analysis showed arthritis in 58% of PIL-group, but none in HC (p Conclusions In contrast to most murine models of SLE, PIL in BALB/c mice is featured by arthritis. Despite its erosive nature, PIL arthritis does not procede to joint destruction as seen in human RA or murine RA models. PIL may provide a good tool to study Lupus arthritis in knock-out or transgenic mouse models based on a BALB/c, but not on a Bl/6 background. Disclosure of Interest None Declared

Dongya Zhang - One of the best experts on this subject based on the ideXlab platform.

  • baicalein ameliorates pristane induced Lupus nephritis via activating nrf2 ho 1 in myeloid derived suppressor cells
    Arthritis Research & Therapy, 2019
    Co-Authors: Dan Li, Jiali Wang, Dongya Zhang
    Abstract:

    Lupus nephritis (LN) is a representative manifestation in systemic Lupus erythematosus (SLE). Some studies have shown that myeloid-derived suppressor cells (MDSCs) play a vital role in the regulation of the SLE process. MDSC infiltration in the kidney as well as inflammation and oxidative stress provokes the acceleration and deterioration of LN. Nuclear factor E2-related factor 2 (Nrf2) is thought to be a major regulator of the antioxidant response. Baicalein is a flavonoid with known anti-inflammatory effects and antioxidant response. However, the effects of baicalein on MDSCs, inflammation, and oxidative stress are not evaluated in the development of Pristane-Induced LN in mice. The renoprotective effect of baicalein was detected in a Pristane-Induced Lupus mice model. NLRP3 inflammasome activation and NF-κB phosphorylation as well as reactive oxygen species (ROS) production and Nrf2 activation were examined. The percentages and function changes of MDSCs were measured. The possible mechanisms of the underlying effects of baicalein on ROS production and signaling pathways of Nrf2/heme-oxygenase (HO)-1, NLRP3 inflammasome, and NF-κB phosphorylation in lipopolysaccharide (LPS)-primed MDSCs were analyzed. Baicalein reduced proteinuria and attenuated renal function impairment and renal histopathology including intrinsic cell proliferation, cellular crescents, and podocyte injury as well as glomerulonephritis activity in Lupus mice. Moreover, baicalein downregulated the activation of NLRP3 inflammasome and levels of ROS or NF-κB phosphorylation, and it enhanced Nrf2 activation. Of note, baicalein inhibited the expansion of MDSCs and improved the function of MDSCs in Lupus mice. Through analyzing LPS-primed MDSCs in vitro, baicalein was found to exhibit cytoprotective effects coincident with the induction of Nrf2/HO-1 signaling and the suppression of the NLRP3 inflammasome. The data show that baicalein alleviates the symptoms of Pristane-Induced LN and suggest that the alleviation may be attributed to inhibition of MDSC expansion and regulation of the balance of the Nrf2/HO-1 signal and NLRP3 expression in MDSCs.

  • Baicalein ameliorates Pristane-Induced Lupus nephritis via activating Nrf2/HO-1 in myeloid-derived suppressor cells
    Arthritis Research & Therapy, 2019
    Co-Authors: Dan Li, Jiali Wang, Dongya Zhang
    Abstract:

    Lupus nephritis (LN) is a representative manifestation in systemic Lupus erythematosus (SLE). Some studies have shown that myeloid-derived suppressor cells (MDSCs) play a vital role in the regulation of the SLE process. MDSC infiltration in the kidney as well as inflammation and oxidative stress provokes the acceleration and deterioration of LN. Nuclear factor E2-related factor 2 (Nrf2) is thought to be a major regulator of the antioxidant response. Baicalein is a flavonoid with known anti-inflammatory effects and antioxidant response. However, the effects of baicalein on MDSCs, inflammation, and oxidative stress are not evaluated in the development of Pristane-Induced LN in mice. The renoprotective effect of baicalein was detected in a Pristane-Induced Lupus mice model. NLRP3 inflammasome activation and NF-κB phosphorylation as well as reactive oxygen species (ROS) production and Nrf2 activation were examined. The percentages and function changes of MDSCs were measured. The possible mechanisms of the underlying effects of baicalein on ROS production and signaling pathways of Nrf2/heme-oxygenase (HO)-1, NLRP3 inflammasome, and NF-κB phosphorylation in lipopolysaccharide (LPS)-primed MDSCs were analyzed. Baicalein reduced proteinuria and attenuated renal function impairment and renal histopathology including intrinsic cell proliferation, cellular crescents, and podocyte injury as well as glomerulonephritis activity in Lupus mice. Moreover, baicalein downregulated the activation of NLRP3 inflammasome and levels of ROS or NF-κB phosphorylation, and it enhanced Nrf2 activation. Of note, baicalein inhibited the expansion of MDSCs and improved the function of MDSCs in Lupus mice. Through analyzing LPS-primed MDSCs in vitro, baicalein was found to exhibit cytoprotective effects coincident with the induction of Nrf2/HO-1 signaling and the suppression of the NLRP3 inflammasome. The data show that baicalein alleviates the symptoms of Pristane-Induced LN and suggest that the alleviation may be attributed to inhibition of MDSC expansion and regulation of the balance of the Nrf2/HO-1 signal and NLRP3 expression in MDSCs.

  • Myeloid-Derived Suppressor Cells Induce Podocyte Injury Through Increasing Reactive Oxygen Species in Lupus Nephritis
    Frontiers in Immunology, 2018
    Co-Authors: Dongya Zhang, Jingjing Xu, Liang Ding, Dan Li
    Abstract:

    The expansion of myeloid-derived suppressor cells (MDSCs) has been documented in murine models and patients with Lupus nephritis (LN), but the exact role of MDSCs in this process remains largely unknown. In this study, we investigated whether MDSCs are involved in the process of podocyte injury in the development of LN. In toll-like receptor-7 (TLR-7) agonist imiquimod-induced Lupus mice, we found the severe podocyte injury in glomeruli of Lupus mice and significant expansion of MDSCs in spleens and kidneys of Lupus mice. The function of TLR-7 activated-MDSCs was enhanced including the increased generation of reactive oxygen species (ROS) in vivo and vitro. Moreover, the ROS production of MDSCs induced podocyte injury through activating the p-38MAPK and NF-kB signaling. Furthermore, we verified that podocyte injury was indeed correlated with expansion of MDSCs and their ROS secretion in LN of Pristane-Induced Lupus mice. These findings first indicate that the podocyte injury in LN was associated with the increased MDSCs in kidney and MDSCs may be a promising therapeutic target of LN in the future.

Hanno B Richards - One of the best experts on this subject based on the ideXlab platform.

  • induction of apoptosis by the hydrocarbon oil pristane implications for pristane induced Lupus
    Journal of Immunology, 2005
    Co-Authors: Nicola Calvani, Eric S. Sobel, Roberto Caricchio, Marco Tucci, Franco Silvestris, Paola Tartaglia, Hanno B Richards
    Abstract:

    Intraperitoneal injection of the hydrocarbon oil pristane into normal mice leads to a Lupus-like autoimmune syndrome. Although advances in defining the roles of cellular and humoral mediators involved in this syndrome have been made, the mechanisms that initiate a break in tolerance leading to autoimmunity remain unknown. We describe in this study that pristane induces apoptosis both in vivo and in vitro. Pristane arrests cell growth and induces cell death by apoptosis via the mitochondrial pathway of caspase activation in a dose-dependent manner. Nuclear autoantigens created by Pristane-Induced apoptosis of lymphoid cells within the peritoneal cavity in the setting of a profoundly altered cytokine milieu may be the initiating event in the development of autoimmunity in this syndrome. These findings suggest that apoptosis may be a critical initial event in the pathogenesis of Pristane-Induced Lupus and are of potential relevance for human systemic Lupus erythematosus.

  • modulation of the immune response in pristane induced Lupus by expression of activation and inhibitory fc receptors
    Clinical and Experimental Immunology, 2005
    Co-Authors: Raphael Clynes, Byron P. Croker, Nicola Calvani, Hanno B Richards
    Abstract:

    Altered homeostasis in Fcγ receptor (FcγR) expression has been implicated in the induction of both immune complex-mediated glomerulonephritis and autoantibody production in systemic Lupus erythematosus. FcyRI and III are required for immune complexes to activate inflammatory cells, thereby inciting tissue injury. In contrast, FcγRIIB functions as a negative regulator of immune complex-mediated inflammation and autoantibody production. We investigated the role of FcγRI/III versus FcγRIIB on Pristane-Induced Lupus in mice. FcγRI/III and FcγRIIB-deficient ( -/- ) and control ( +/+ ) BALB/c mice were injected with either pristane or PBS. Proteinuria and glomerular immune deposits were evaluated 9 months after treatment and serial sera were analysed for total IgG levels and Lupus-specific autoantibodies. The incidence of nephritis was higher in pristane-treated FcγRIIIB -/- mice than pristane-treated FcγRI/III -/- and +/+ mice. Hypergammaglobulinaemia and spontaneous anti-DNA/chromatin autoantibody production were associated with interleukin (IL)-6 over-expression in FcγRIIB -/- mice and were augmented further by pristane treatment when compared to both FcγRI/III -/- and +/+ mice. Lack of either FcγRIIB or FcγRI/III had little effect on both anti-nRNP/Sm and anti-Su production induced by pristane. Our results confirm that spontaneous autoimmunity occurs in the absence of FcγRIIB. Moreover, the Lupus-like syndrome induced by pristane in BALB/c mice was regulated by opposing activating and inhibitory FcyRs. Activating FcyRs were required for significant proteinuria and unbridled activation in the absence of FcγRIIB dramatically exacerbated glomerular inflammatory responses. FcγRIIB may be a key modulator that suppresses cell activation in the inflammatory immune response in systemic Lupus erythematosus in humans.

  • nephritogenic autoantibodies but absence of nephritis in il 12p35 deficient mice with pristane induced Lupus
    Kidney International, 2003
    Co-Authors: Nicola Calvani, Byron P. Croker, Westley H Reeves, Minoru Satoh, Hanno B Richards
    Abstract:

    Nephritogenic autoantibodies but absence of nephritis in Il-12p35–deficient mice with Pristane-Induced Lupus. Background There is strong evidence that Th1 cytokines are essential for disease in murine models of Lupus. Interleukin-12 (IL-12) is essential for Th1 cell differentiation and induces interferon-γ (IFN-γ) production. Paradoxically, it has been suggested that an IL-12 defect drives the pathogenesis of Lupus, although its precise role remains unclear. We investigated the role of IL-12 for Lupus-like disease induced by pristane. IL-12p35–deficient (-/-) and control (+/+) BALB/c mice were treated with pristane or phosphate-buffered saline (PBS). Methods Proteinuria was measured and renal pathology evaluated 10 months after treatment. Sera were analyzed for autoantibodies and total immunoglobulin levels. Cytokine expression and production was analyzed. Results Pristane induced nephritogenic autoantibodies and renal immunoglobulin and complement deposition in both IL-12 -/- and +/+ mice. However, proliferative pathology and proteinuria were absent in IL-12-/- mice, whereas pristane induced severe nephritis in one third of the +/+ mice. As expected, cytokine balance was skewed toward a Th2 response in pristane-treated IL-12 -/- mice. Conclusion These data indicate that renal immune complex deposition can occur in the absence of IL-12p35, but that structural renal damage requires the presence of IL-12p35 or mediators induced by this molecule, such as IFN-γ. In contrast to the abrogation of nephritogenic autoantibodies by the lack of IFN-γ, such antibodies are induced by pristane in IL-12p35–deficient mice. Absence of structural renal disease, despite the presence of nephritogenic autoantibodies in pristane-treated IL-12-/- mice, indicates that antibody deposition alone is not sufficient for the development of Lupus nephritis in this model.

  • widespread susceptibility among inbred mouse strains to the induction of Lupus autoantibodies by pristane
    Clinical and Experimental Immunology, 2000
    Co-Authors: Minoru Satoh, Victoria M Shaheen, Hanno B Richards, J O Naim, Paul H. Wooley, Hideo Yoshida, M. Shaw, Westley H Reeves
    Abstract:

    Unlike other agents associated with drug-induced Lupus, the isoprenoid alkane pristane induces autoantibodies pathognomonic of Lupus, including anti-Sm, anti-dsDNA, and anti-ribosomal P in BALB/c and SJL/J mice. The susceptibility of other strains of mice to Pristane-Induced Lupus is unknown and is the focus of the present study. Anti-nRNP/Sm, anti-Su, and anti-ribosomal P autoantibodies were produced by most strains of mice surveyed within several months of pristane treatment, although there was marked interstrain variability in their frequencies, levels, and times of onset. In sharp contrast, the production of autoantibodies against the double-stranded RNA binding proteins NF45/NF90/p110 was restricted to B6 and B10.S mice. We conclude that pristane selectively induces Lupus-specific autoantibodies in virtually any strain of mouse regardless of its genetic background. However, H-2-linked as well as non-H2 genes influenced the expression of individual autoantibody markers. The widespread susceptibility of pristane-treated mice to Lupus autoantibody production and the relatively small effect of MHC are unique features of this chemically induced Lupus syndrome, with potential implications for understanding the pathogenesis of autoantibodies in idiopathic human systemic Lupus erythematosus.

  • fas and fas ligand mutations inhibit autoantibody production in pristane induced Lupus
    Journal of Immunology, 2000
    Co-Authors: Minoru Satoh, Victoria M Shaheen, Hanno B Richards, Jory P Weintraub, Melody Shaw, Hideo Yoshida, Westley H Reeves
    Abstract:

    Mutations of Fas ( lpr ) or Fas ligand ( gld ) cause a limited Lupus-like syndrome in B6 mice by interfering with the deletion of autoreactive B and/or T cells. A more generalized Lupus syndrome reminiscent of that of MRL mice can be induced in nonautoimmune strains by pristane, which causes a nonspecific inflammatory response in the peritoneal cavity. We hypothesized that, as in MRL mice, the lpr and gld mutations might accelerate Lupus in pristane-treated mice. Pristane-treated B6 mice developed anti-nRNP/Sm, Su, and ribosomal P Abs, but little anti-ssDNA or chromatin. In contrast, B6/ lpr and B6/ gld mice spontaneously developed anti-ssDNA/chromatin Abs, but not anti-nRNP/Sm/Su/ribosomal P. Unexpectedly, B6/ lpr and B6/ gld mice were highly resistant to the induction by pristane of IgM anti-ssDNA (2 wk) and IgG anti-nRNP/Sm/Su/ribosomal P autoantibodies (6 mo), suggesting that intact Fas signaling is necessary. Interestingly, pristane did not enhance IgG chromatin Ab production in B6/ lpr or B6/ gld mice, suggesting that it did not influence the production of autoantibodies that develop spontaneously in the setting of Fas deficiency. Pristane treatment also decreased lymphoproliferation in B6/ lpr mice. Increased production of IL-12 was associated consistently with the production of anti-nRNP/Sm/Su/ribosomal P as well as anti-DNA/chromatin. In contrast, production of anti-DNA/chromatin Abs was associated with IL-6 overproduction in pristane-treated mice, but not in lpr mice. The data strongly support the idea that different subsets of autoantibodies are regulated differentially by cytokine stimulation and/or Fas signaling.