المؤلفون: Fiorella Vialard, Isabelle Allaeys, George Dong, Minh Phuong Phan, Urvashi Singh, Marie Josée Hébert, Mélanie Dieudé, David Langlais, Eric Boilard, David P. Labbé, Martin Olivier

المصدر: Frontiers in Immunology, Vol 14 (2023)

مصطلحات موضوعية: thermoneutrality, malaria, Leishmania, extracellular vesicles, Plasmodium berghei ANKA, Leishmania major, Immunologic diseases. Allergy, RC581-607

الوصف: IntroductionMost studies using murine disease models are conducted at housing temperatures (20 – 22°C) that are sub-optimal (ST) for mice, eliciting changes in metabolism and response to disease. Experiments performed at a thermoneutral temperature (TT; 28 – 31°C) have revealed an altered immune response to pathogens and experimental treatments in murine disease model that have implications for their translation to clinical research. How such conditions affect the inflammatory response to infection with Plasmodium berghei ANKA (PbA) and disease progression is unknown. We hypothesized that changes in environmental temperature modulate immune cells and modify host response to malaria disease. To test this hypothesis, we conducted experiments to determine: (1) the inflammatory response to malarial agents injection in a peritonitis model and (2) disease progression in PbA-infected mice at TT compared to ST.MethodsIn one study, acclimatized mice were injected intraperitoneally with native hemozoin (nHZ) or Leishmania at TT (28 – 31°C) or ST, and immune cells, cytokine, and extracellular vesicle (EV) profiles were determined from the peritoneal cavity (PEC) fluid. In another study, PbA-infected mice were monitored until end-point (i.e. experimental malaria score ≥4).ResultsWe found that Leishmania injection resulted in decreased cell recruitment and higher phagocytosis of nHZ in mice housed at TT. We found 398 upregulated and 293 downregulated proinflammatory genes in mice injected with nHZ, at both temperatures. We report the presence of host-derived EVs never reported before in a murine parasitic murine model at both temperatures. We observed metabolic changes in mice housed at TT, but these did not result to noticeable changes in disease progression compared to ST.DiscussionTo our knowledge, these experiments are the first to investigate the effect of thermoneutrality on a malaria murine model. We found important metabolic difference in mice housed at TT. Our results offer insights on how thermoneutrality might impact a severe malaria murine model and directions for more targeted investigations.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fimmu.2023.1128466/fullTest; https://doaj.org/toc/1664-3224Test

الوصول الحر: https://doaj.org/article/a6673d28ab5941949310f865f72713beTest

المؤلفون: Déborah Beillevaire, Francis Migneault, Julie Turgeon, Diane Gingras, Annie Karakeussian Rimbaud, Geneviève Marcoux, Crysta Spino, Nicolas Thibodeau, Eric Bonneil, Pierre Thibault, Éric Boilard, Mélanie Dieudé, Marie-Josée Hébert

المصدر: Cell Death and Disease, Vol 13, Iss 2, Pp 1-13 (2022)

مصطلحات موضوعية: Cytology, QH573-671

الوصف: Abstract Apoptotic exosome-like vesicles (ApoExos) are a novel type of extracellular vesicle that contribute to the propagation of inflammation at sites of vascular injury when released by dying cells. ApoExos are characterized by the presence of the C-terminal perlecan LG3 fragment and 20S proteasome, and they are produced downstream of caspase-3 activation. In the present study, we assessed the relative roles of autophagy and caspase-3-mediated pathways in controlling the biogenesis and secretion of immunogenic ApoExos. Using electron microscopy and confocal immunofluorescence microscopy in serum-starved endothelial cells, we identified large autolysosomes resulting from the fusion of lysosomes, multivesicular bodies, and autophagosomes as a site of ApoExo biogenesis. Inhibition of autophagy with ATG7 siRNA or biochemical inhibitors (wortmannin and bafilomycin) coupled with proteomics analysis showed that autophagy regulated the processing of perlecan into LG3 and its loading onto ApoExos but was dispensable for ApoExo biogenesis. Caspase-3 activation was identified using caspase-3-deficient endothelial cells or caspase inhibitors as a pivotal regulator of fusion events between autolysosomes and the cell membrane, therefore regulating the release of immunogenic ApoExos. Collectively, these findings identified autolysosomes as a site of ApoExo biogenesis and caspase-3 as a crucial regulator of autolysosome cell membrane interactions involved in the secretion of immunogenic ApoExos.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2041-4889Test

الوصول الحر: https://doaj.org/article/27757613a90a474794ad11a2f3435e85Test

المؤلفون: Alexandre Brodeur, Francis Migneault, Maude Lanoie, Déborah Beillevaire, Julie Turgeon, Annie Karakeussian-Rimbaud, Nicolas Thibodeau, Éric Boilard, Mélanie Dieudé, Marie-Josée Hébert

المصدر: Cell Death and Disease, Vol 14, Iss 7, Pp 1-15 (2023)

مصطلحات موضوعية: Cytology, QH573-671

الوصف: Apoptosis of endothelial cells prompts the release of apoptotic exosome-like vesicles (ApoExos), subtype extracellular vesicles secreted by apoptotic cells after caspase-3 activation. ApoExos are different from both apoptotic bodies and classical exosomes in their protein and nucleic acid contents and functions. In contrast to classical apoptotic bodies, ApoExos induce immunogenic responses that can be maladaptive when not tightly regulated. In the present study, we elucidated the mechanisms by which ApoExos are internalized by endothelial cells, which leads to shared specific and functional mRNAs of importance to endothelial function. Using flow cytometry and confocal microscopy, we revealed that ApoExos were actively internalized by endothelial cells. SiRNA-induced inhibition of classical endocytosis pathways with pharmacological inhibitors showed that ApoExos were internalized via phosphatidylserine-dependent macropinocytosis independently of classical endocytosis pathways. An electron microscopy analysis revealed that ApoExos increased the macropinocytosis rate in endothelial cells, setting in motion a positive feedback loop that increased the amount of internalized ApoExos. Deep sequencing of total RNA revealed that ApoExos possessed a unique protein-coding RNA profile, with PCSK5 being the most abundant mRNA. Internalization of ApoExos by cells led to the transfer of this RNA content from the ApoExos to cells. Specifically, PCSK5 mRNA was transferred to cells that had taken up ApoExos, and these cells subsequently expressed PCSK5. Collectively, our findings suggest that macropinocytosis is an effective entry pathway for the delivery of RNAs carried by ApoExos and that these RNAs are functionally expressed by the endothelial cells that internalize them. As ApoExos express a specific mRNA signature, these results suggest new avenues to understand how ApoExos produced at sites of vascular injury impact vascular function.

العلاقة: https://doi.org/10.1038/s41419-023-05991-xTest; https://doaj.org/toc/2041-4889Test; https://doaj.org/article/d82037779e7540eb82097fb4963629adTest

الإتاحة: https://doi.org/10.1038/s41419-023-05991-xTest
https://doaj.org/article/d82037779e7540eb82097fb4963629adTest

المؤلفون: Robert Carroll, MD, (A)ACHI, Julie Turgeon, PhD, Sue Deayton, BSc (Hons), Tim Emery, BSc, Fiona Bilogrevic, Certificate, Sadia Jahan, MD, Annie Karakeussian Rimbaud, BSc, Barbara Georges, MD, Alexandre Tavares-Brum, BSc, Marie-Josée Hébert, MD, Héloïse Cardinal, MD, PhD

المصدر: Transplantation Direct, Vol 9, Iss 2, p e1437 (2023)

مصطلحات موضوعية: Surgery, RD1-811

الوصف: Background. Both angiotensin II receptor autoantibodies (ATRabs) and autoantibodies to LG3 have been linked to kidney graft rejection with alloimmune vascular injury (AVI). We aimed to examine whether positivity for both anti-LG3 and ATRabs is associated with rejection with AVI in kidney transplant recipients. Methods. We performed a retrospective cohort study including consecutive kidney transplant recipients between 2013 and 2017 at a single center. The primary outcome was acute rejection with AVI (Banff grade 2 or 3 T-cell-mediated rejection and/or antibody-mediated rejection) in the first 3 mo posttransplant. The secondary outcome was death-censored allograft loss. The independent variables, anti-LG3 and ATRab, were measured pretransplant. Results. Among the 328 study participants, 68 experienced acute rejection with AVI and 23 experienced graft loss over a median follow-up of 4.5 y. In a multivariable model, double pretransplant positivity for anti-LG3/ATRab was associated with acute rejection with AVI (odds ratio: 2.73, 95% confidence interval: 1.06-7.05). We did not observe an association between double positivity for anti-LG3/ATRab and death-censored graft loss. Conclusions. Double positivity for anti-LG3/ATRabs pretransplant is associated with a higher risk of acute rejection with AVI. Whether therapies that remove antibodies could decrease that risk remains to be studied. Supplemental Visual Abtract: http://links.lww.com/TXD/A494Test.

العلاقة: http://journals.lww.com/transplantationdirect/fulltext/10.1097/TXD.0000000000001437Test; https://doaj.org/toc/2373-8731Test; https://doaj.org/article/ffdf59fb0a6845a8877f4be26f1b92c8Test

الإتاحة: https://doi.org/10.1097/TXD.0000000000001437Test
https://doaj.org/article/ffdf59fb0a6845a8877f4be26f1b92c8Test

المؤلفون: Alexandra Tauzin, Guillaume Beaudoin-Bussières, Shang Yu Gong, Debashree Chatterjee, Gabrielle Gendron-Lepage, Catherine Bourassa, Guillaume Goyette, Normand Racine, Zineb Khrifi, Julie Turgeon, Cécile Tremblay, Valérie Martel-Laferrière, Daniel E. Kaufmann, Héloïse Cardinal, Marc Cloutier, Renée Bazin, Ralf Duerr, Mélanie Dieudé, Marie-Josée Hébert, Andrés Finzi

المصدر: iScience, Vol 25, Iss 9, Pp 104990- (2022)

مصطلحات موضوعية: Surgery, Immunology, Virology, Science

الوصف: Summary: Although SARS-CoV-2 mRNA vaccination has been shown to be safe and effective in the general population, immunocompromised solid organ transplant recipients (SOTRs) were reported to have impaired immune responses after one or two doses of vaccine. In this study, we examined humoral responses induced after the second and the third dose of mRNA vaccine in different SOTR (kidney, liver, lung, and heart). Compared to a cohort of SARS-CoV-2 naïve immunocompetent health care workers (HCWs), the second dose induced weak humoral responses in SOTRs, except for the liver recipients. The third dose boosted these responses but they did not reach the same level as in HCW. Interestingly, although the neutralizing activity against Delta and Omicron variants remained very low after the third dose, Fc-mediated effector functions in SOTR reached similar levels as in the HCW cohort. Whether these responses will suffice to protect SOTR from severe outcome remains to be determined.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2589004222012627Test; https://doaj.org/toc/2589-0042Test

الوصول الحر: https://doaj.org/article/c515ec76f27640b58bc73f10fe68503fTest

المؤلفون: Benoit Brilland, Patrick Laplante, Pamela Thebault, Karen Geoffroy, Marie-Joëlle Brissette, Mathieu Latour, Michaël Chassé, Shijie Qi, Marie-Josée Hébert, Héloïse Cardinal, Jean-François Cailhier

المصدر: International Journal of Molecular Sciences; Volume 23; Issue 8; Pages: 4094

مصطلحات موضوعية: MFG-E8, macrophage reprogramming, T-cell activation, aortic transplantation, transplant vasculopathy, murine model

جغرافية الموضوع: agris

الوصف: Transplant vasculopathy is characterized by endothelial apoptosis, which modulates the local microenvironment. Milk fat globule epidermal growth factor 8 (MFG-E8), which is released by apoptotic endothelial cells, limits tissue damage and inflammation by promoting anti-inflammatory macrophages. We aimed to study its role in transplant vasculopathy using the murine aortic allotransplantation model. BALB/c mice were transplanted with fully mismatched aortic transplants from MFG-E8 knockout (KO) or wild type (WT) C57BL/6J mice. Thereafter, mice received MFG-E8 (or vehicle) injections for 9 weeks prior to histopathological analysis of allografts for intimal proliferation (hematoxylin and eosin staining) and leukocyte infiltration assessment (immunofluorescence). Phenotypes of blood leukocytes and humoral responses were also evaluated (flow cytometry and ELISA). Mice receiving MFG-E8 KO aortas without MFG-E8 injections had the most severe intimal proliferation (p < 0.001). Administration of MFG-E8 decreased intimal proliferation, especially in mice receiving MFG-E8 KO aortas. Administration of MFG-E8 also increased the proportion of anti-inflammatory macrophages among graft-infiltrating macrophages (p = 0.003) and decreased systemic CD4+ and CD8+ T-cell activation (p < 0.001). An increase in regulatory T cells occurred in both groups of mice receiving WT aortas (p < 0.01). Thus, the analarmin MFG-E8 appears to be an important protein for reducing intimal proliferation in this murine model of transplant vasculopathy. MFG-E8 effects are associated with intra-allograft macrophage reprogramming and systemic T-cell activation dampening.

وصف الملف: application/pdf

العلاقة: Molecular Immunology; https://dx.doi.org/10.3390/ijms23084094Test

الإتاحة: https://doi.org/10.3390/ijms23084094Test

المؤلفون: Eric Boilard, Marie-Hélene Normand, Shanshan Lan, Sandrine Juillard, Julie Turgeon, Annie Karakeussian-Rimbaud, Francis Migneault, Guillaume Bollée, Marie-Josée Hébert, Mélanie Dieudé

المصدر: Lupus Science and Medicine, Vol 8, Iss Suppl 2 (2021)

مصطلحات موضوعية: Immunologic diseases. Allergy, RC581-607

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2053-8790Test

الوصول الحر: https://doaj.org/article/ceae5ee51aab47449e12a25883abf381Test

المؤلفون: Laura I. Mazilescu, MD, Peter Urbanellis, MD, MSc, Moritz J. Kaths, MD, MSc, Sujani Ganesh, MSc, Toru Goto, MD, Yuki Noguchi, MD, PhD, Rohan John, MD, Ana Konvalinka, MD, PhD, Istvan Mucsi, MD, PhD, Anand Ghanekar, MD, PhD, Darius J. Bagli, MD, MSc, Julie Turgeon, PhD, Annie Karakeusian Rimbaud, BSc, Marie-Josée Hébert, MD, Mélanie Dieudé, PhD, Isabelle Alleys, PhD, Etienne Dore, MSc, Eric Boilard, PhD, Herman S. Overkleeft, PhD, Lianne I. Willems, PhD, Lisa A. Robinson, MD, Markus Selzner, MD

المصدر: Transplantation Direct, Vol 7, Iss 10, p e751 (2021)

مصطلحات موضوعية: Surgery, RD1-811

الوصف: Background. The increased usage of marginal grafts has triggered interest in perfused kidney preservation to minimize graft injury. We used a donation after circulatory death (DCD) porcine kidney autotransplantation model to compare 3 of the most frequently used ex vivo kidney perfusion techniques: nonoxygenated hypothermic machine perfusion (non-oxHMP), oxygenated hypothermic machine perfusion (oxHMP), and normothermic ex vivo kidney perfusion (NEVKP). Methods. Following 30 min of warm ischemia, grafts were retrieved and preserved with either 16 h of non-oxHMP, oxHMP, or NEVKP (n = 5 per group). After contralateral nephrectomy, grafts were autotransplanted and animals were followed for 8 d. Kidney function and injury markers were compared between groups. Results. NEVKP demonstrated a significant reduction in preservation injury compared with either cold preservation method. Grafts preserved by NEVKP showed superior function with lower peak serum creatinine (NEVKP versus non-oxHMP versus oxHMP: 3.66 ± 1.33 mg/dL, 8.82 ± 3.17 mg/dL, and 9.02 ± 5.5 mg/dL) and more rapid recovery. The NEVKP group demonstrated significantly increased creatinine clearance on postoperative day 3 compared with the cold perfused groups. Tubular injury scores on postoperative day 8 were similar in all groups. Conclusions. Addition of oxygen during HMP did not reduce preservation injury of DCD kidney grafts. Grafts preserved with prolonged NEVKP demonstrated superior initial graft function compared with grafts preserved with non-oxHMP or oxHMP in a model of pig DCD kidney transplantation.

وصف الملف: electronic resource

العلاقة: http://journals.lww.com/transplantationdirect/fulltext/10.1097/TXD.0000000000001218Test; https://doaj.org/toc/2373-8731Test

الوصول الحر: https://doaj.org/article/af252ed324fa4c4ba755708e4549c1cbTest

المؤلفون: Sergi Clotet-Freixas, PhD, Max Kotlyar, PhD, Caitriona M. McEvoy, MD, PhD, Chiara Pastrello, PhD, Sonia Rodríguez-Ramírez, MD, Sofia Farkona, PhD, Heloise Cardinal, MD, PhD, Mélanie Dieudé, PhD, Marie-Josée Hébert, MD, PhD, Yanhong Li, BSc, Olusegun Famure, MPH, MEd,, Peixuen Chen, HBSc, BScN, S. Joseph Kim, MD, PhD, Emilie Chan, MD, Igor Jurisica, PhD, Rohan John, MD, Andrzej Chruscinski, MD, PhD, Ana Konvalinka, MD, PhD

المصدر: Transplantation Direct, Vol 7, Iss 10, p e768 (2021)

مصطلحات موضوعية: Surgery, RD1-811

الوصف: Background. Antibody-mediated rejection (AMR) causes more than 50% of late kidney graft losses. In addition to anti-human leukocyte antigen (HLA) donor-specific antibodies, antibodies against non-HLA antigens are also linked to AMR. Identifying key non-HLA antibodies will improve our understanding of AMR. Methods. We analyzed non-HLA antibodies in sera from 80 kidney transplant patients with AMR, mixed rejection, acute cellular rejection (ACR), or acute tubular necrosis. IgM and IgG antibodies against 134 non-HLA antigens were measured in serum samples collected pretransplant or at the time of diagnosis. Results. Fifteen non-HLA antibodies were significantly increased (P < 0.05) in AMR and mixed rejection compared with ACR or acute tubular necrosis pretransplant, and 7 at diagnosis. AMR and mixed cases showed significantly increased pretransplant levels of IgG anti-Ro/Sjögren syndrome-antigen A (SS-A) and anti-major centromere autoantigen (CENP)-B, compared with ACR. Together with IgM anti-CENP-B and anti-La/SS-B, these antibodies were significantly increased in AMR/mixed rejection at diagnosis. Increased IgG anti-Ro/SS-A, IgG anti-CENP-B, and IgM anti-La/SS-B were associated with the presence of microvascular lesions and class-II donor-specific antibodies (P < 0.05). Significant increases in IgG anti-Ro/SS-A and IgM anti-CENP-B antibodies in AMR/mixed rejection compared with ACR were reproduced in an external cohort of 60 kidney transplant patients. Conclusions. This is the first study implicating autoantibodies anti-Ro/SS-A and anti-CENP-B in AMR. These antibodies may participate in the crosstalk between autoimmunity and alloimmunity in kidney AMR.

وصف الملف: electronic resource

العلاقة: http://journals.lww.com/transplantationdirect/fulltext/10.1097/TXD.0000000000001215Test; https://doaj.org/toc/2373-8731Test

الوصول الحر: https://doaj.org/article/ad1e0b13d49a4debb40ec96a023a64d7Test

المؤلفون: Mélanie Dieudé, Imane Kaci, Marie-Josée Hébert

المصدر: Frontiers in Immunology, Vol 12 (2021)

مصطلحات موضوعية: tertiary lymphoid structure, antibodies, inflammation, apoptosis, injury, Immunologic diseases. Allergy, RC581-607

الوصف: Tertiary lymphoid structures are clusters of lymphoid tissue that develop post-natally at sites of chronic inflammation. They have been described in association with infection, autoimmune disorders, cancer, and allograft rejection. In their mature stage, TLS function as ectopic germinal centers, favoring the local production of autoantibodies and cytokines. TLS formation tends to parallel the severity of tissue injury and they are usually indicative of locally active immune responses. The presence of TLS in patients with solid tumors is usually associated with a better prognosis whereas their presence predicts increased maladaptive immunologic activity in patients with autoimmune disorders or allograft transplantation. Recent data highlight a correlation between active cell death and TLS formation and maturation. Our group recently identified apoptotic exosome-like vesicles, released by apoptotic cells, as novel inducers of TLS formation. Here, we review mechanisms of TLS formation and maturation with a specific focus on the emerging importance of tissue injury, programmed cell death and extracellular vesicles in TLS biogenesis.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fimmu.2021.696311/fullTest; https://doaj.org/toc/1664-3224Test

الوصول الحر: https://doaj.org/article/46375f54e95e4a7c9ea3fef61d206bdaTest