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- Wigerblad, G., et al.
(författare)
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Autoantibodies to citrullinated proteins induce joint pain independent of inflammation via a chemokine-dependent mechanism
- 2016
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 75:4, s. 730-738
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: An interesting and so far unexplained feature of chronic pain in autoimmune disease is the frequent disconnect between pain and inflammation. This is illustrated well in rheumatoid arthritis (RA) where pain in joints (arthralgia) may precede joint inflammation and persist even after successful anti-inflammatory treatment. In the present study, we have addressed the possibility that autoantibodies against citrullinated proteins (ACPA), present in RA, may be directly responsible for the induction of pain, independent of inflammation. METHODS: Antibodies purified from human patients with RA, healthy donors and murinised monoclonal ACPA were injected into mice. Pain-like behaviour was monitored for up to 28 days, and tissues were analysed for signs of pathology. Mouse osteoclasts were cultured and stimulated with antibodies, and supernatants analysed for release of factors. Mice were treated with CXCR1/2 (interleukin (IL) 8 receptor) antagonist reparixin. RESULTS: Mice injected with either human or murinised ACPA developed long-lasting pronounced pain-like behaviour in the absence of inflammation, while non-ACPA IgG from patients with RA or control monoclonal IgG were without pronociceptive effect. This effect was coupled to ACPA-mediated activation of osteoclasts and release of the nociceptive chemokine CXCL1 (analogue to human IL-8). ACPA-induced pain-like behaviour was reversed with reparixin. CONCLUSIONS: The data suggest that CXCL1/IL-8, released from osteoclasts in an autoantibody-dependent manner, produces pain by activating sensory neurons. The identification of this new pain pathway may open new avenues for pain treatment in RA and also in other painful diseases associated with autoantibody production and/or osteoclast activation.
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- Contarini, S., et al.
(författare)
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Euclid : cosmological forecasts from the void size function
- 2022
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 667
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Tidskriftsartikel (refereegranskat)abstract
- The Euclid mission - with its spectroscopic galaxy survey covering a sky area over 15 000 deg(2) in the redshift range 0.9 < z < 1.8 - will provide a sample of tens of thousands of cosmic voids. This paper thoroughly explores for the first time the constraining power of the void size function on the properties of dark energy (DE) from a survey mock catalogue, the official Euclid Flagship simulation. We identified voids in the Flagship light-cone, which closely matches the features of the upcoming Euclid spectroscopic data set. We modelled the void size function considering a state-of-the art methodology: we relied on the volume-conserving (Vdn) model, a modification of the popular Sheth & van de Weygaert model for void number counts, extended by means of a linear function of the large-scale galaxy bias. We found an excellent agreement between model predictions and measured mock void number counts. We computed updated forecasts for the Euclid mission on DE from the void size function and provided reliable void number estimates to serve as a basis for further forecasts of cosmological applications using voids. We analysed two different cosmological models for DE: the first described by a constant DE equation of state parameter, w, and the second by a dynamic equation of state with coefficients w(0) and w(a). We forecast 1 sigma errors on w lower than 10% and we estimated an expected figure of merit (FoM) for the dynamical DE scenario FoM(w0,wa) = 17 when considering only the neutrino mass as additional free parameter of the model. The analysis is based on conservative assumptions to ensure full robustness, and is a pathfinder for future enhancements of the technique. Our results showcase the impressive constraining power of the void size function from the Euclid spectroscopic sample, both as a stand-alone probe, and to be combined with other Euclid cosmological probes.
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- Pöntinen, M., et al.
(författare)
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Euclid: Identification of asteroid streaks in simulated images using deep learning
- 2023
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 679
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Tidskriftsartikel (refereegranskat)abstract
- The material composition of asteroids is an essential piece of knowledge in the quest to understand the formation and evolution of the Solar System. Visual to near-infrared spectra or multiband photometry is required to constrain the material composition of asteroids, but we currently have such data, especially in the near-infrared wavelengths, for only a limited number of asteroids. This is a significant limitation considering the complex orbital structures of the asteroid populations. Up to 150 000 asteroids will be visible in the images of the upcoming ESA Euclid space telescope, and the instruments of Euclid will offer multiband visual to near-infrared photometry and slitless near-infrared spectra of these objects. Most of the asteroids will appear as streaks in the images. Due to the large number of images and asteroids, automated detection methods are needed. A non-machine-learning approach based on the Streak Det software was previously tested, but the results were not optimal for short and/or faint streaks. We set out to improve the capability to detect asteroid streaks in Euclid images by using deep learning. We built, trained, and tested a three-step machine-learning pipeline with simulated Euclid images. First, a convolutional neural network (CNN) detected streaks and their coordinates in full images, aiming to maximize the completeness (recall) of detections. Then, a recurrent neural network (RNN) merged snippets of long streaks detected in several parts by the CNN. Lastly, gradient-boosted trees (XGBoost) linked detected streaks between different Euclid exposures to reduce the number of false positives and improve the purity (precision) of the sample. The deep-learning pipeline surpasses the completeness and reaches a similar level of purity of a non-machine-learning pipeline based on the StreakDet software. Additionally, the deep-learning pipeline can detect asteroids 0.25–0.5 magnitudes fainter than StreakDet. The deep-learning pipeline could result in a 50% increase in the number of detected asteroids compared to the StreakDet software. There is still scope for further refinement, particularly in improving the accuracy of streak coordinates and enhancing the completeness of the final stage of the pipeline, which involves linking detections across multiple exposures.
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- Harre, U, et al.
(författare)
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Glycosylation of immunoglobulin G determines osteoclast differentiation and bone loss
- 2015
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6, s. 6651-
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Tidskriftsartikel (refereegranskat)abstract
- Immunglobulin G (IgG) sialylation represents a key checkpoint that determines the engagement of pro- or anti-inflammatory Fcγ receptors (FcγR) and the direction of the immune response. Whether IgG sialylation influences osteoclast differentiation and subsequently bone architecture has not been determined yet, but may represent an important link between immune activation and bone loss. Here we demonstrate that desialylated, but not sialylated, immune complexes enhance osteoclastogenesis in vitro and in vivo. Furthermore, we find that the Fc sialylation state of random IgG and specific IgG autoantibodies determines bone architecture in patients with rheumatoid arthritis. In accordance with these findings, mice treated with the sialic acid precursor N-acetylmannosamine (ManNAc), which results in increased IgG sialylation, are less susceptible to inflammatory bone loss. Taken together, our findings provide a novel mechanism by which immune responses influence the human skeleton and an innovative treatment approach to inhibit immune-mediated bone loss.
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- Sakuraba, K, et al.
(författare)
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METABOLIC CHANGES INDUCED BY ANTI-MALONDIALDEHYDE/MALINDIALDEHYDE-ACETALDEHYDE ANTIBODIES PROMOTE OSTEOCLAST DEVELOPMENT
- 2020
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 79, s. 934-935
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Malondialdehyde (MDA) is a highly reactive compound produced by lipid-peroxidation in situations associated with oxidative stress. MDA can irreversibly modify proteins residues such as lysine, arginine and histidine. In addition, MDA adducts can further react with acetaldehyde to generate malondialdehyde-acetaldehyde (MAA) modifications. Such modifications can give rise to immunogenic neo-epitopes that are recognized by autoantibodies. In fact, anti-MDA/MAA IgG antibodies are significantly increased in the serum of patients with autoimmune diseases, such as rheumatoid arthritis (RA) (1) and systemic lupus erythematosus (2). Recently, we have shown that anti-MDA/MAA IgG antibodies are able to promote osteoclast (OC) differentiationin vitro(1).Objectives:To investigate the molecular mechanisms triggered by anti-MDA/MAA autoantibodies during osteoclastogenesis.Methods:OCs were generated from monocyte-derived macrophages in the presence of the cytokines RANK-L and M-CSF. The development of OCs was monitored by light microscopy following tartrate-resistant acid phosphatase (TRAP) staining and erosion area on synthetic calcium phosphate-coated plates. Three different recombinant human monoclonal anti-MDA/MAA antibodies, cloned from single synovial B cells of RA patients, control antibodies and Fab fragments of the antibodies were added to OC cultures. Glycolysis was inhibited by 2-deoxyglucose, and Fc-gamma receptor I or II by anti-CD64 or anti-CD16 neutralizing antibodies. IL-8 levels were measured by enzyme linked immunosorbent assay. Cellular metabolism was monitored using Seahorse XF Analyzer (extracellular acidification rate and oxygen consumption) and a colorimetric L-Lactate assay.Results:Lactic acid production correlated with the osteoclastogenetic effect of some but not all anti-MDA/MAA antibodies on OCs (R=0.4758, p=0.0252) suggesting an antibody-mediated regulation of glycolysis. Further, extracellular acidification (ECAR) and oxygen consumption (OCR) rate of the developing OCs were increased by the osteoclastogenic anti-MDA/MAA clones (maximum increase of 54% for the ECAR and 78% for the OCR by clone 146+:01G07, and maximum increase of 28% for the ECAR and 39% for the OCR by clone 1103:01H05), but not by the non-osteoclastogenetic anti-MDA/MAA clones or control antibodies. The glycolysis inhibitor 2-deoxyglucose completely abolished the osteoclastogenetic effect of the anti-MDA/MAA clones at drug concentrations that did not influenced baseline OC development. Fab2 fragments of the osteocalstogenetic anti-MDA/MAA clones had no effect on OC development and metabolism. In accordance with this, Fc-gamma receptor I neutralizing antibodies completely abolished the osteocalstogenetic effect of the anti-MDA/MAA clones. The osteoclastogenetic effect of the anti-MDA/MAA antibodies was independent of IL-8 production. In contrast to anti MDA/MAA antibodies, ACPA-mediated osteoclastogenesis was independent of glycolysis and Fc-gamma receptors but dependent on IL-8.Conclusion:Our results describe a novel glycolysis-dependent mechanism by which anti-MDA/MAA antibodies promote osteoclast development that is different from the one previously described for ACPA.References:[1] C. Grönwall et al. Journal of Autoimmunity 84 (2017) 29-45.[2] C. Wang et al. Arthritis and Rheumatism 62 (2010) 2064-2072Disclosure of Interests:Koji Sakuraba: None declared, Akilan Krishnamurthy: None declared, Alexandra Circiumaru: None declared, Meng Sun: None declared, Vijay Joshua: None declared, Marianne Engström: None declared, Xiaowei Zheng: None declared, Cheng Xu: None declared, Khaled Amara: None declared, Vivianne Malmström Grant/research support from: VM has had research grants from Janssen Pharmaceutica, Sergiu-Bogdan Catrina: None declared, Caroline Grönwall: None declared, Bence Réthi: None declared, Anca Catrina: None declared
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| 25. |
- Sakuraba, K, et al.
(författare)
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METABOLIC CHANGES INDUCED BY ANTI-MALONDIALDEHYDE/MALINDIALDEHYDE- ACETALDEHYDE ANTIBODIES PROMOTE OSTEOCLAST DEVELOPMENT
- 2021
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 80, s. 429-429
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Malondialdehyde (MDA) is a highly reactive compound generated during lipid-peroxidation in conditions associated with oxidative stress. MDA can irreversibly modify proteins (e.g. lysine, arginine and histidine residues). In addition, acetaldehyde can further react with MDA adducts to form malondialdehyde-acetaldehyde (MAA) modification. Such protein modifications can lead to immunogenic neo-epitopes that are recognized by autoantibodies. In fact, anti-MDA/MAA IgG antibodies are significantly increased in the serum of patients with autoimmune diseases, such as rheumatoid arthritis (RA) (1). Interestingly, anti-MDA/MAA antibodies have been shown to promote osteoclast (OC) differentiation in vitro suggesting a potential role for these autoantibodies in bone damage associated with RA (1).Objectives:Little is known about the molecular mechanisms activated by autoantibodies in RA. Here, we elucidate the pathways specifically triggered by anti-MDA/MAA autoantibodies in developing osteoclasts.Methods:Recombinant human monoclonal anti-MDA/MAA antibodies, which were previously cloned from single synovial B cells of RA patients, were added to different OC assays. OCs were generated from monocyte-derived macrophages in the presence of the cytokines RANK-L and M-CSF. OC development was monitored by light microscopy following tartrate-resistant acid phosphatase staining and by erosion assays using calcium phosphate-coated plates. Bone morphometrics were studied in anti-MDA/MAA-injected mice using X-ray microscopy. Cellular metabolism was analyzed by mass spectrometry, Seahorse XF Analyzer and a colorimetric L-Lactate assay.Results:Anti-MDA/MAA antibodies induced a robust OC differentiation in vitro and bone loss in vivo. The anti-MDA/MAA antibodies acted on developing OCs by increasing glycolysis via an Fcγ receptor I-mediated pathway and the upregulation of the transcription factors HIF-1α, Myc and CHREBP. Such regulation of cellular metabolism was exclusively observed in the presence of the osteoclastogenic anti-MDA/MAA clones, whereas other RA-associated autoantibodies (anti-MDA/MAA or anti-citrullinated protein antibodies) had no effect on metabolism. The anti-MDA/MAA treatment induced a shift in the tricarboxylic acid (TCA) cycle activity in developing OCs, leading to the accumulation of citrate and aconitate.Conclusion:We described a novel type of autoantibody-induced pathway in RA, which might contribute to increased OC activation and a consequent bone loss. Anti-MDA/MAA antibodies promoted osteoclast development by increasing glycolysis and by modulating the TCA cycle through a signaling pathway that included Fcγ receptor I and a network of transcription factors acting on glycolysis. A TCA cycle bias towards citrate production suggests that the anti-MDA/MAA antibodies might stimulate OCs via increasing lipid biosynthesis in the cells.References:[1]Grönwall C. et al. J. Autoimmunity 84 (2017): 29-45.Acknowledgements:This Project has received funding from FOREUM, Foundation for Research in Rheumatology, from the European Research Council (ERC) grant agreement CoG 2017 - 7722209_PREVENT RA, the EU/EFPIA Innovative Medicine Initiative grant agreement 777357_RTCure, the Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse and Knut and Alice Wallenberg Foundation.Disclosure of Interests:Koji Sakuraba: None declared, Akilan Krishnamurthy: None declared, Alexandra Circiumaru: None declared, Vijay Joshua: None declared, Heidi Wähämaa: None declared, Marianne Engström: None declared, Meng Sun: None declared, Xiaowei Zheng: None declared, Cheng Xu: None declared, Khaled Amara: None declared, Vivianne Malmström Grant/research support from: collaboration with Pfizer, unrelated to the abstract, Sergiu-Bogdan Catrina: None declared, Caroline Grönwall: None declared, Bence Réthi: None declared, Anca Catrina Grant/research support from: collaboration with BMS and Pfizer, unrelated to the present abstract
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