Publications by authors named "Yves Delneste"

83 Publications

Anti-Pentraxin Antibodies in Autoimmune Diseases: Bystanders or Pathophysiological Actors?

Front Immunol 2020 16;11:626343. Epub 2021 Feb 16.

Université d'Angers, INSERM, CRCINA, Angers, France.

Pentraxins are soluble innate immunity receptors involved in sensing danger molecules. They are classified as short (CRP, SAP) and long pentraxin subfamilies, including the prototypic long pentraxin PTX3. Pentraxins act mainly as bridging molecules favoring the clearance of microbes and dead cells. They are also involved in many other biological processes, such as regulation of complement activation, inflammation and tissue homeostasis. Autoantibodies directed against pentraxins have been reported in various autoimmune diseases, especially in systemic lupus erythematosus and ANCA-associated vasculitis. In this review, we review the main biological characteristics and functions of pentraxins and summarize data concerning autoantibodies directed against pentraxins in the context of autoimmune diseases and discuss their potential pathological role.
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http://dx.doi.org/10.3389/fimmu.2020.626343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921723PMC
February 2021

Fungal Polysaccharides Promote Protective Immunity.

Trends Microbiol 2021 Feb 17. Epub 2021 Feb 17.

Federative Structure of Research 'Cellular Interactions and Therapeutic Applications', SFR 4208 ICAT, Univ Angers, Angers, France; Host-Pathogen Interaction Study Group (GEIHP, EA 3142), UNIV Angers, UNIV Brest, Angers, France.

Fungal pathogens represent a rising threat against immunocompromised patients. By using Aspergillus fumigatus, Briard et al. showed that the cell wall galactosaminogalactan (GAG) triggers macrophage inflammasome activation, promoting protective immunity. This provides new insights into the role of GAG in host-pathogen interactions and also perspectives for developing GAG-based anti-inflammatory therapeutics.
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http://dx.doi.org/10.1016/j.tim.2021.02.004DOI Listing
February 2021

Macrophages: Checking Toxicity of Fungal Metabolites in the Colon.

Trends Endocrinol Metab 2021 02 17;32(2):63-65. Epub 2020 Dec 17.

Institute of Molecular Biology and Biotechnology - Foundation for Research and Technology HELLAS (IMBB-FORTH), University of Crete, Heraklion, Crete, Greece. Electronic address:

It is well known that the intestine absorbs nutrients, electrolytes, and water. Chikina et al. recently demonstrated that it is also able to sense, recognize, and block the absorption of toxins through a very sophisticated interactive cellular cooperation between novel subpopulations of macrophages and epithelial cells.
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http://dx.doi.org/10.1016/j.tem.2020.11.012DOI Listing
February 2021

Leukemic evolution of polycythemia vera and essential thrombocythemia: genomic profiles predict time to transformation.

Blood Adv 2020 Oct;4(19):4887-4897

Université d'Angers, Inserm, CRCINA, Angers, France.

Among myeloproliferative neoplasms, polycythemia vera (PV) and essential thrombocythemia (ET) are the 2 entities associated with the most chronic disease course. Leukemic evolution occurs rarely but has a grim prognosis. The interval between diagnosis and leukemic evolution is highly variable, from a few years to >20 years. We performed a molecular evaluation of 49 leukemic transformations of PV and ET by targeted next-generation sequencing. Using a hierarchical classification, we identified 3 molecular groups associated with a distinct time to leukemic transformation. Short-term transformations were mostly characterized by a complex molecular landscape and mutations in IDH1/2, RUNX1, and U2AF1 genes, whereas long-term transformations were associated with mutations in TP53, NRAS, and BCORL1 genes. Studying paired samples from chronic phase and transformation, we detected some mutations already present during the chronic phase, either with a significant allele burden (short-term transformation) or with a very low allele burden (especially TP53 mutations). However, other mutations were not detected even 1 year before leukemic transformation. Our results suggest that the leukemic transformation of PV and ET may be driven by distinct time-dependent molecular mechanisms.
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http://dx.doi.org/10.1182/bloodadvances.2020002271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556129PMC
October 2020

Dysfunctional T Cell Mitochondria Lead to Premature Aging.

Trends Mol Med 2020 09 22;26(9):799-800. Epub 2020 Jul 22.

Cellular Interactions and Therapeutic Applications (ICAT), Structure Féderative de Recherche (SFR) 4208, Université d'Angers, Angers, France; Host-Pathogen Interaction Study Group (GEIHP), Équipe d'Accueil (EA) 3142, Université d'Angers, Université de Bretagne Occidentale, Angers, France.

Desdín-Micó et al. have shown that Tfam specific knockout in mouse T cells disrupts mitochondrial genome integrity and induces a burst of inflammatory cytokines and tumor necrosis factor (TNF)-α production, resulting in increased senescence, neuromuscular and vascular dysfunction, and molecular features that recapitulate premature aging. Interestingly, treatment with nicotinamide riboside (NR) alleviates this phenotype by reducing senescence and systemic inflammation.
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http://dx.doi.org/10.1016/j.molmed.2020.07.001DOI Listing
September 2020

Fungal Melanin Rewires Macrophage Metabolism.

Trends Biochem Sci 2020 09 1;45(9):728-730. Epub 2020 Jul 1.

Interactions Cellulaires et Applications Thérapeutiques (ICAT), Structure Féderative de Recherche (SFR) 4208, Université d'Angers, Angers, France; Centre de Recherche en Cancérologie et Immunologie Nantes Angers (CRCINA), INSERM, Université de Nantes and Université d'Angers, Angers, France; CHU Angers, Département d'Immunologie Allergologie, Angers, France. Electronic address:

Aspergillus fumigatus is a deadly fungal pathogen in immunocompromised patients. A report by Gonçalves et al. reveals that melanin, a secondary metabolite present at the surface of infecting fungal spores, induces glycolysis in macrophages to promote inflammatory responses. This opens a window for the development of innovative host-directed antifungal therapies.
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http://dx.doi.org/10.1016/j.tibs.2020.06.006DOI Listing
September 2020

Involvement of the M-CSF/IL-34/CSF-1R pathway in malignant pleural mesothelioma.

J Immunother Cancer 2020 06;8(1)

Université de Nantes, CNRS, INSERM, CRCINA, F-44000 Nantes, France

Background: Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer related to asbestos exposure. The tumor microenvironment content, particularly the presence of macrophages, was described as crucial for the development of the disease. This work aimed at studying the involvement of the M-CSF (CSF-1)/IL-34/CSF-1R pathway in the formation of macrophages in MPM, using samples from patients.

Methods: Pleural effusions (PEs), frozen tumors, primary MPM cells and MPM cell lines used in this study belong to biocollections associated with clinical databases. Cytokine expressions were studied using real-time PCR and ELISA. The Cancer Genome Atlas database was used to confirm our results on an independent cohort. An original three-dimensional (3D) coculture model including MPM cells, monocytes from healthy donors and a tumor antigen-specific cytotoxic CD8 T cell clone was used.

Results: We observed that high interleukin (IL)-34 levels in PE were significantly associated with a shorter survival of patients. In tumors, expression of was correlated with 'M2-like macrophages' markers, whereas this was not the case with expression, suggesting two distinct modes of action of these cytokines. Expression of was higher in MPM cells compared with primary mesothelial cells. Particularly, high expression of was observed in MPM cells with an alteration of . Finally, using 3D coculture model, we demonstrated the direct involvement of MPM cells in the formation of immunosuppressive macrophages, through activation of the colony stimulating factor-1 receptor (CSF1-R) pathway, causing the inhibition of cytotoxicity of tumor antigen-specific CD8 T cells.

Conclusions: The M-CSF/IL-34/CSF-1R pathway seems strongly implicated in MPM and could constitute a therapeutic target to act on immunosuppression and to support immunotherapeutic strategies.
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http://dx.doi.org/10.1136/jitc-2019-000182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319783PMC
June 2020

Targeting Tumor Associated Macrophages to Overcome Conventional Treatment Resistance in Glioblastoma.

Front Pharmacol 2020 8;11:368. Epub 2020 Apr 8.

CRCINA, INSERM, Université de Nantes, Université d'Angers, Angers, France.

Glioblastoma (GB) is the most common and devastating form of brain cancer. Despite conventional treatments, progression or recurrences are systematic. In recent years, immunotherapies have emerged as an effective treatment in a number of cancers, leaving the question of their usefulness also faced with the particular case of brain tumors. The challenge here is major not only because the brain is the seat of our consciousness but also because of its isolation by the blood-brain barrier and the presence of a unique microenvironment that constitutes the central nervous system (CNS) with very specific constituent or patrolling cells. Much of the microenvironment is made up of immune cells or inflammation. Among these, tumor-associated macrophages (TAMs) are of significant interest as they are often involved in facilitating tumor progression as well as the development of resistance to standard therapies. In this review, the ubiquity of TAMs in GB will be discussed while the specific case of microglia resident in the brain will be also emphasized. In addition, the roles of TAMs as accomplices in the progression of GB and resistance to treatment will be presented. Finally, clinical trials targeting TAMs as a means of treating cancer will be discussed.
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http://dx.doi.org/10.3389/fphar.2020.00368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158850PMC
April 2020

Molecular and Cellular Interactions of Scavenger Receptor SR-F1 With Complement C1q Provide Insights Into Its Role in the Clearance of Apoptotic Cells.

Front Immunol 2020 31;11:544. Epub 2020 Mar 31.

Université Grenoble Alpes, CNRS, CEA, IBS, Grenoble, France.

The scavenger receptor SR-F1 binds to and mediates the internalization of a wide range of ligands, and is involved in several immunological processes. We produced recombinant SR-F1 ectodomain and fragments deleted from the last 2 or 5 C-terminal epidermal growth factor-like modules and investigated their role in the binding of acetylated low density lipoprotein (AcLDL), complement C1q, and calreticulin (CRT). C1q measured affinity was in the 100 nM range and C1q interaction occurs its collagen-like region. We identified two different binding regions on SR-F1: the N-terminal moiety interacts with C1q and CRT whereas the C-terminal moiety binds AcLDL. The role of SR-F1 N-linked glycans was also tested by mutating each of the three glycosylated asparagines. The three mutants retained binding activities for both AcLDL and C1q. A stable THP-1 cell line overexpressing SR-F1 was generated and C1q was shown to bind more strongly to the surface of SR-F1 overexpressing macrophages, with C1q/SR-F1 colocalization observed in some membrane areas. We also observed a higher level of CRT internalization for THP-1 SR-F1 cells. Increasing SR-F1 negatively modulated the uptake of apoptotic cells. Indeed, THP-1 cells overexpressing SR-F1 displayed a lower phagocytic capacity as compared with mock-transfected cells, which could be partially restored by addition of C1q in the extracellular milieu. Our data shed some light on the role of SR-F1 in efferocytosis, through its capacity to bind C1q and CRT, two proteins involved in this process.
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http://dx.doi.org/10.3389/fimmu.2020.00544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7137648PMC
March 2020

Transcriptomic features of tumour-infiltrating CD4CD8 double positive αβ T cells in melanoma.

Sci Rep 2020 04 3;10(1):5900. Epub 2020 Apr 3.

Université de Nantes, Inserm, CRCINA, F-44000, Nantes, France.

Peripheral CD4CD8 double positive (DP) T cells are a phenotypically and functionally heterogeneous population depending on their origin and pathologic context. We previously identified among tumour infiltrating lymphocytes in melanoma, a tumour-reactive MHC class-I restricted CD4CD8 DP αβ T-cell subpopulation with CD4-like function. In this study, we used an in-depth comparative transriptomic analysis of intra-melanoma DP T cells and CD4 and CD8 single positive (SP) T cells, to better comprehend the origin of this DP phenotype, and define the transcriptomic signature of activated DP T cells. We observed that intra-melanoma DP T cells were transcriptome-wise closer to their CD8 SP T-cell counterparts in terms of number of genes differentially expressed (97 in common with CD8 SP T cells and 15 with CD4 SP T cells) but presented hallmarks of a transition to a CD4-like functional profile (CD40LG) with a decreased cytotoxic signature (KLRC1) in favour of an increased cytokine-receptor interaction signature (IL4, IL24, IL17A…). This unleashed CD4-like program could be the results of the observed unbalanced expression of the THPOK/Runx3 transcription factors in DP T cells. Overall, this study allow us to speculate that intra-melanoma DP T cells arise from CD8 SP T cells being reprogrammed to a helper function.
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http://dx.doi.org/10.1038/s41598-020-62664-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125144PMC
April 2020

Skin-specific antibodies neutralizing mycolactone toxin during the spontaneous healing of infection.

Sci Adv 2020 02 26;6(9):eaax7781. Epub 2020 Feb 26.

Equipe ATOMycA, U1232 CRCINA, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Nantes, Université d'Angers, Angers, France.

Buruli ulcer, a neglected tropical infectious disease, is caused by . Without treatment, its lesions can progress to chronic skin ulcers, but spontaneous healing is observed in 5% of cases, suggesting the possible establishment of a host strategy counteracting the effects of . We reveal here a skin-specific local humoral signature of the spontaneous healing process, associated with a rise in antibody-producing cells and specific recognition of mycolactone by the mouse IgG2a immunoglobulin subclass. We demonstrate the production of skin-specific antibodies neutralizing the immunomodulatory activity of the mycolactone toxin, and confirm the role of human host machinery in triggering effective local immune responses by the detection of anti-mycolactone antibodies in patients with Buruli ulcer. Our findings pave the way for substantial advances in both the diagnosis and treatment of Buruli ulcer in accordance with the most recent challenges issued by the World Health Organization.
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http://dx.doi.org/10.1126/sciadv.aax7781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7043917PMC
February 2020

Lactic Acidosis Together with GM-CSF and M-CSF Induces Human Macrophages toward an Inflammatory Protumor Phenotype.

Cancer Immunol Res 2020 03 10;8(3):383-395. Epub 2020 Jan 10.

Université d'Angers, CHU d'Angers, Inserm U1232, CRCINA, Angers, France.

In established tumors, tumor-associated macrophages (TAM) orchestrate nonresolving cancer-related inflammation and produce mediators favoring tumor growth, metastasis, and angiogenesis. However, the factors conferring inflammatory and protumor properties on human macrophages remain largely unknown. Most solid tumors have high lactate content. We therefore analyzed the impact of lactate on human monocyte differentiation. We report that prolonged lactic acidosis induces the differentiation of monocytes into macrophages with a phenotype including protumor and inflammatory characteristics. These cells produce tumor growth factors, inflammatory cytokines, and chemokines as well as low amounts of IL10. These effects of lactate require its metabolism and are associated with hypoxia-inducible factor-1α stabilization. The expression of some lactate-induced genes is dependent on autocrine M-CSF consumption. Finally, TAMs with protumor and inflammatory characteristics (VEGF CXCL8 IL1β) are found in solid ovarian tumors. These results show that tumor-derived lactate links the protumor features of TAMs with their inflammatory properties. Treatments that reduce tumor glycolysis or tumor-associated acidosis may help combat cancer.
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http://dx.doi.org/10.1158/2326-6066.CIR-18-0749DOI Listing
March 2020

Quantitative chimerism in CD3-negative mononuclear cells predicts prognosis in acute myeloid leukemia patients after hematopoietic stem cell transplantation.

Leukemia 2020 05 25;34(5):1342-1353. Epub 2019 Nov 25.

CHU Angers, Laboratoire d'Hématologie, Angers, France.

Relapse is a major complication of acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (SCT). The objective of our study was to evaluate chimerism monitoring on the CD3-negative mononuclear cells by RQ-PCR to predict relapse of patients allografted for AML and to compare its performance with WT1 quantification. A cohort of 100 patients undergoing allogenic SCT for AML was retrospectively analyzed in a single institution. Patients without complete chimerism, defined as less than 0.01% of recipient's DNA in CD3-negative cells, had a significantly higher risk of relapse and a lower overall survival (p < 0.001). An increase in the percentage of recipient DNA in CD3-negative cells was associated with an increased risk of relapse (p < 0.001) but not with overall survival. Comparable performances between monitoring of CD3-negative cell chimerism and WT1 expression to predict relapse was observed up to more than 90 days before hematological relapse, with sensitivity of 82% and 78%, respectively, and specificity of 100% for both approaches. Quantitative specific chimerism of the CD3-negative mononuclear fraction, enriched in blastic cells, is a new and powerful tool for monitoring measurable residual disease and could be used for AML patients without available molecular markers.
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http://dx.doi.org/10.1038/s41375-019-0624-4DOI Listing
May 2020

Sequential mutational evaluation of CALR -mutated myeloproliferative neoplasms with thrombocytosis reveals an association between CALR allele burden evolution and disease progression.

Br J Haematol 2020 03 11;188(6):935-944. Epub 2019 Nov 11.

CRCINA, INSERM, Université de Nantes, Université d'Angers, Angers, France.

In myeloproliferative neoplasms (MPN), JAK2V617F allele burden measurement has an impact on prognosis that helps in patient monitoring. Less is known about its usefulness in CALR-mutated cases. Additional mutations found by next-generation sequencing have also shown an impact on prognosis that may drive therapeutic choices, especially in myelofibrosis, but few studies focused on CALR-mutated patients. We performed a molecular evaluation combining next-generation sequencing with a myeloid panel and CALR allele burden measurement at diagnosis and during follow-up in a cohort of 45 patients with CALR-mutated essential thrombocythaemia. The bone marrow histology was also blindly reviewed in order to apply the WHO2016 classification. The most frequently mutated gene was TET2 (11/21 mutations). CALR type 1-like patients appear to have a more complex molecular landscape. We found an association between disease progression and CALR allele burden increase during follow-up, independently of additional mutations and WHO2016-reviewed diagnosis. Patients with disease progression at the time of follow-up showed a significant increase in CALR allele burden (+16·7%, P = 0·005) whereas patients without disease progression had a stable allele burden (+3·7%, P = 0·194). This result argues for clinical interest in CALR allele burden monitoring.
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http://dx.doi.org/10.1111/bjh.16276DOI Listing
March 2020

Pre-transplant CD45RC expression on blood T cells differentiates patients with cancer and rejection after kidney transplantation.

PLoS One 2019 29;14(3):e0214321. Epub 2019 Mar 29.

LUNAM Université, Angers, France.

Background: Biological biomarkers to stratify cancer risk before kidney transplantation are lacking. Several data support that tumor development and growth is associated with a tolerant immune profile. T cells expressing low levels of CD45RC preferentially secrete regulatory cytokines and contain regulatory T cell subset. In contrast, T cells expressing high levels of CD45RC have been shown to secrete proinflammatory cytokines, to drive alloreactivity and to predict acute rejection (AR) in kidney transplant patients. In the present work, we evaluated whether pre-transplant CD45RClow T cell subset was predictive of post-transplant cancer occurrence.

Methods: We performed an observational cohort study of 89 consecutive first time kidney transplant patients whose CD45RC T cell expression was determined by flow cytometry before transplantation. Post-transplant events including cancer, AR, and death were assessed retrospectively.

Results: After a mean follow-up of 11.1±4.1 years, cancer occurred in 25 patients (28.1%) and was associated with a decreased pre-transplant proportion of CD4+CD45RChigh T cells, with a frequency below 51.9% conferring a 3.7-fold increased risk of post-transplant malignancy (HR 3.71 [1.24-11.1], p = 0.019). The sensibility, specificity, negative predictive and positive predictive values of CD4+CD45RChigh<51.9% were 84.0, 54.7, 89.8 and 42.0% respectively. Confirming our previous results, frequency of CD8+CD45RChigh T cells above 52.1% was associated with AR, conferring a 20-fold increased risk (HR 21.7 [2.67-176.2], p = 0.0004). The sensibility, specificity, negative predictive and positive predictive values of CD8+CD45RChigh>52.1% were 94.5, 68.0, 34.7 and 98.6% respectively. Frequency of CD4+CD45RChigh T cells was positively correlated with those of CD8+CD45RChigh (p<0.0001), suggesting that recipients with high AR risk display a low cancer risk.

Conclusion: High frequency of CD45RChigh T cells was associated with AR, while low frequency was associated with cancer. Thus, CD45RC expression on T cells appears as a double-edged sword biomarker of promising interest to assess both cancer and AR risk before kidney transplantation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0214321PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440623PMC
December 2019

IL-26, a Cytokine With Roles in Extracellular DNA-Induced Inflammation and Microbial Defense.

Front Immunol 2019 12;10:204. Epub 2019 Feb 12.

CRCINA, INSERM, Université de Nantes, Université d'Angers, Angers, France.

Interleukin 26 (IL-26) is the most recently identified member of the IL-20 cytokine subfamily, and is a novel mediator of inflammation overexpressed in activated or transformed T cells. Novel properties have recently been assigned to IL-26, owing to its non-conventional cationic, and amphipathic features. IL-26 binds to DNA released from damaged cells and, as a carrier molecule for extracellular DNA, links DNA to inflammation. This observation suggests that IL-26 may act both as a driver and an effector of inflammation, leading to the establishment of a deleterious amplification loop and, ultimately, sustained inflammation. Thus, IL-26 emerges as an important mediator in local immunity/inflammation. The dysregulated expression and extracellular DNA carrier capacity of IL-26 may have profound consequences for the chronicity of inflammation. IL-26 also exhibits direct antimicrobial properties. This review summarizes recent advances on the biology of IL-26 and discusses its roles as a novel kinocidin.
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http://dx.doi.org/10.3389/fimmu.2019.00204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6379347PMC
January 2020

Transcriptional profiling of Scedosporium apiospermum enzymatic antioxidant gene battery unravels the involvement of thioredoxin reductases against chemical and phagocytic cells oxidative stress.

Med Mycol 2019 Apr;57(3):363-373

Groupe d'Etude des Interactions Hôte-Pathogène (EA 3142), UNIV Angers, UNIV Brest, Université Bretagne-Loire, Angers, France.

Scedosporium species rank the second, after Aspergillus fumigatus, among the filamentous fungi colonizing the airways of patients with cystic fibrosis (CF). Development of microorganisms in the respiratory tract depends on their capacity to evade killing by the host immune system, particularly through the oxidative response of macrophages and neutrophils, with the release of reactive oxygen species (ROS) and reactive nitrogen species (RNS). This is particularly true in the airways of CF patients which display an exacerbated inflammatory reaction. To protect themselves, pathogens have developed various enzymatic antioxidant systems implicated in ROS degradation, including superoxide dismutases, catalases, cytochrome C peroxidases, chloroperoxidases and enzymes of the glutathione and thioredoxin systems, or in RNS degradation, that is, flavohemoglobins, nitrate reductases, and nitrite reductases. Here we investigated the transcriptional regulation of the enzymatic antioxidant gene battery in 24-h-old hyphae of Scedosporium apiospermum in response to oxidative stress induced chemically or by exposure to activated phagocytic cells. We showed that 21 out of the 33 genes potentially implicated in the oxidative or nitrosative stress response were overexpressed upon exposure of the fungus to various chemical oxidants, while they were only 13 in co-cultures with macrophages or neutrophils. Among them, genes encoding two thioredoxin reductases and to a lesser extent, a peroxiredoxin and one catalase were found to be overexpressed after chemical oxidative stress as well as in co-cultures. These results suggest that thioredoxin reductases, which are known to be virulence factors in other pathogenic fungi, play a key role in pathogenesis of scedosporiosis, and may be new drug targets.
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http://dx.doi.org/10.1093/mmy/myy033DOI Listing
April 2019

Concomitant CALR and LNK mutations leading to essential thrombocythemia with erythrocytosis.

Blood Cells Mol Dis 2018 07 23;71:75-76. Epub 2018 Apr 23.

CHU Angers, Laboratoire d'Hématologie, Institut de Biologie en Santé, Angers, France; Université d'Angers, UFR Santé, Angers, France; CRCINA, INSERM, Université de Nantes, Université d'Angers, Angers, France; Fédération Hospitalo-Universitaire (FHU) GOAL, 'Grand Ouest Against Leukemia', France. Electronic address:

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http://dx.doi.org/10.1016/j.bcmd.2018.04.002DOI Listing
July 2018

Loss of vascular expression of nucleoside triphosphate diphosphohydrolase-1/CD39 in hypertension.

Purinergic Signal 2018 03 13;14(1):73-82. Epub 2017 Dec 13.

MITOVASC Institute - UMR CNRS 6015 INSERM U1083 University of Angers, Angers, France.

Ectonucleoside triphosphate diphosphohydrolase-1, the major vascular/immune ectonucleotidase, exerts anti-thrombotic and immunomodulatory actions by hydrolyzing extracellular nucleotides (danger signals). Hypertension is characterized by vascular wall remodeling, endothelial dysfunction, and immune infiltration. Here our aim was to investigate the impact of arterial hypertension on CD39 expression and activity in mice. Arterial expression of CD39 was determined by reverse transcription quantitative real-time PCR in experimental models of hypertension, including angiotensin II (AngII)-treated mice (1 mg/kg/day, 21 days), deoxycorticosterone acetate-salt mice (1% salt and uninephrectomy, 21 days), and spontaneously hypertensive rats. A decrease in CD39 expression occurred in the resistance and conductance arteries of hypertensive animals with no effect on lymphoid organs. In AngII-treated mice, a decrease in CD39 protein levels (Western blot) was corroborated by reduced arterial nucleotidase activity, as evaluated by fluorescent (etheno)-ADP hydrolysis. Moreover, serum-soluble ADPase activity, supported by CD39, was significantly decreased in AngII-treated mice. Experiments were conducted in vitro on vascular cells to determine the elements underlying this downregulation. We found that CD39 transcription was reduced by proinflammatory cytokines interleukin (IL)-1β and tumor necrosis factor alpha on vascular smooth muscle cells and by IL-6 and anti-inflammatory and profibrotic cytokine transforming growth factor beta 1 on endothelial cells. In addition, CD39 expression was downregulated by mechanical stretch on vascular cells. Arterial expression and activity of CD39 were decreased in hypertension as a result of both a proinflammatory environment and mechanical strain exerted on vascular cells. Reduced ectonucleotidase activity may alter the vascular condition, thus enhancing arterial damage, remodeling, or thrombotic events.
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http://dx.doi.org/10.1007/s11302-017-9597-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5842157PMC
March 2018

The roles of CSFs on the functional polarization of tumor-associated macrophages.

FEBS J 2018 02 16;285(4):680-699. Epub 2017 Dec 16.

CRCINA, INSERM, Université de Nantes, Université d'Angers, France.

Macrophages have a central role in numerous physiological processes, such as immune defense, maintenance of tissue homeostasis, wound healing, and inflammation. Moreover, in numerous severe disorders, such as cancer or chronic inflammation, their functions can be profoundly affected. Macrophages continuously sense their environment and adapt their phenotypes and functions to the local requirements; this process is called plasticity. In addition to stress signals, metabolites, and direct cell-contact interactions with surrounding cells, numerous cytokines play a central role in controlling macrophage polarization. In this review, we will focus on three human macrophage differentiation factors: macrophage colony-stimulating factor (M-CSF), IL-34, and granulocyte M-CSF. These CSFs allow human monocyte survival, promote their differentiation into macrophages, and control macrophage polarization as they give rise to cells with different phenotype and functions. Based on recent observations, the role of granulocyte CSF on macrophage polarization is also addressed. Finally, our current knowledge on the expression of these growth factors in tumor microenvironment and their impact on the generation and polarization of tumor-associated macrophages are summarized.
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http://dx.doi.org/10.1111/febs.14343DOI Listing
February 2018

Anti-pentraxin antibodies in autoimmune systemic diseases: Focus on anti-pentraxin-3 autoantibodies.

Int Rev Immunol 2017 05 4;36(3):145-153. Epub 2017 May 4.

b Angers University Hospital , University of Angers , Angers , France.

Pentraxins are soluble pattern recognition molecules implicated not only in the opsonization and removal of microorganisms but also in the clearance of modified self (i.e., dying cells). Pentraxins can be classified into short pentraxins (C-reactive protein and serum amyloid-P component) and long pentraxins with pentraxin-3 (PTX3), the prototypic one of the latter. Pentraxins are involved in various physiological or pathophysiological processes such as inflammation and autoimmunity. A breakdown in immune tolerance to pentraxins has been reported in various autoimmune diseases. In the present review, we analyzed the current knowledge concerning anti-pentraxin antibodies, with a special focus on anti-PTX3 autoantibodies.
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http://dx.doi.org/10.1080/08830185.2017.1284210DOI Listing
May 2017

IL-26 Confers Proinflammatory Properties to Extracellular DNA.

J Immunol 2017 05 29;198(9):3650-3661. Epub 2017 Mar 29.

CRCINA, INSERM, Université de Nantes, Université d'Angers, LabEx IGO, 49000 Angers, France;

In physiological conditions, self-DNA released by dying cells is not detected by intracellular DNA sensors. In chronic inflammatory disorders, unabated inflammation has been associated with a break in innate immune tolerance to self-DNA. However, extracellular DNA has to complex with DNA-binding molecules to gain access to intracellular DNA sensors. IL-26 is a member of the IL-10 cytokine family, overexpressed in numerous chronic inflammatory diseases, in which biological activity remains unclear. We demonstrate in this study that IL-26 binds to genomic DNA, mitochondrial DNA, and neutrophil extracellular traps, and shuttles them in the cytosol of human myeloid cells. As a consequence, IL-26 allows extracellular DNA to trigger proinflammatory cytokine secretion by monocytes, in a STING- and inflammasome-dependent manner. Supporting these biological properties, IL-10-based modeling predicts two DNA-binding domains, two amphipathic helices, and an in-plane membrane anchor in IL-26, which are structural features of cationic amphipathic cell-penetrating peptides. In line with these properties, patients with active autoantibody-associated vasculitis, a chronic relapsing autoimmune inflammatory disease associated with extensive cell death, exhibit high levels of both circulating IL-26 and IL-26-DNA complexes. Moreover, in patients with crescentic glomerulonephritis, IL-26 is expressed by renal arterial smooth muscle cells and deposits in necrotizing lesions. Accordingly, human primary smooth cells secrete IL-26 in response to proinflammatory cytokines. In conclusion, IL-26 is a unique cationic protein more similar to a soluble pattern recognition receptor than to conventional cytokines. IL-26 expressed in inflammatory lesions confers proinflammatory properties to DNA released by dying cells, setting up a positive amplification loop between extensive cell death and unabated inflammation.
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http://dx.doi.org/10.4049/jimmunol.1600594DOI Listing
May 2017

CD40L confers helper functions to human intra-melanoma class-I-restricted CD4CD8 double positive T cells.

Oncoimmunology 2016;5(12):e1250991. Epub 2016 Oct 28.

CRCNA, INSERM, CNRS, Université d'Angers, Université de Nantes, Nantes, France; LabEx IGO "Immunotherapy, Graft, Oncology", Nantes, France.

Although CD4CD8 double positive (DP) T cells represent a small fraction of peripheral T lymphocytes in healthy human donors, their frequency is often increased under pathological conditions (in blood and targeted tissues). In solid cancers such as melanoma, we previously demonstrated an enrichment of tumor reactive CD4CD8αβ DP T cells among tumor-infiltrating lymphocytes of unknown function. Similarly to their single positive (SP) CD8 counterparts, intra-melanoma DP T cells recognized melanoma cell lines in an HLA-class-I restricted context. However, they presented a poor cytotoxic activity but a strong production of diverse Th1 and Th2 cytokines. The aim of this study was to clearly define the role of intra-melanoma CD4CD8αβ DP T cells in the antitumor immune response. Based on a comparative transcriptome analysis between intra-melanoma SP CD4, SP CD8 and DP autologous melanoma-infiltrating T-cell compartments, we evidenced an overexpression of the CD40L co-stimulatory molecule on activated DP T cells. We showed that, like SP CD4 T cells, and through CD40L involvement, DP T cells are able to induce both proliferation and differentiation of B lymphocytes and maturation of functional DCs able to efficiently prime cytotoxic melanoma-specific CD8 T-cell responses. Taken together, these results highlight the helper potential of atypical DP T cells and their role in potentiating antitumor response.
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http://dx.doi.org/10.1080/2162402X.2016.1250991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5214764PMC
October 2016

The ecto-ATPDase CD39 is involved in the acquisition of the immunoregulatory phenotype by M-CSF-macrophages and ovarian cancer tumor-associated macrophages: Regulatory role of IL-27.

Oncoimmunology 2016 Jul 28;5(7):e1178025. Epub 2016 Apr 28.

CRCNA, INSERM, CNRS, Université de Nantes, Université d'Angers, Angers, France; LabEx ImmunoGraftOnco, Angers, France; Equipe labellisée Ligue contre le Cancer, Angers, France.

Tumor-associated macrophages (TAM) are immunosuppressive cells that can massively accumulate in the tumor microenvironment. In patients with ovarian cancer, their density is correlated with poor prognosis. Targeting mediators that control the generation or the differentiation of immunoregulatory macrophages represents a therapeutic challenge to overcome tumor-associated immunosuppression. The ectonucleotidase CD39 hydrolyzes ATP into extracellular adenosine that exhibits potent immunosuppressive properties when signaling through the A2A adenosine receptor. We report here that CD14(+) CD163(+) TAM isolated from ovarian cancer patients and macrophages generated in vitro with M-CSF, express high levels of the membrane ectonucleotidase CD39 compared to classically activated macrophages. The CD39 inhibitor POM-1 and adenosine deaminase (ADA) diminished some of the immunosuppressive functions of CD14(high) CD163(high) CD39(high) macrophages, such as IL-10 secretion. We identified the cytokine IL-27, secreted by tumor-infiltrating neutrophils, located close to infiltrating CD163(+) macrophages, as a major rheostat of CD39 expression and consequently, on the acquisition of immunoregulatory properties by macrophages. Accordingly, the depletion of IL-27 downregulated CD39 and PD-L1 expression as well as IL-10 secretion by M-CSF-macrophages. Collectively, these data suggest that CD39, drived by IL-27 and CD115 ligands in ovarian cancer, maintains the immunosuppressive phenotype of TAM. This work brings new information on the acquisition of immunosuppressive properties by tumor-infiltrating macrophages.
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http://dx.doi.org/10.1080/2162402X.2016.1178025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5006905PMC
July 2016

Pleural Effusions from Patients with Mesothelioma Induce Recruitment of Monocytes and Their Differentiation into M2 Macrophages.

J Thorac Oncol 2016 10 12;11(10):1765-73. Epub 2016 Jul 12.

Cancer Research Center Nantes-Angers, Inserm, U892, Nantes, France; Cancer Research Center Nantes-Angers, CNRS, UMR6299, Nantes, France; Nantes University, Nantes, France. Electronic address:

Introduction: Mesothelioma is a rare and aggressive cancer related to asbestos exposure. We recently showed that pleural effusions (PEs) from patients with mesothelioma contain high levels of the C-C motif chemokine ligand 2 (CCL2) inflammatory chemokine. In the present work, we studied the effect of CCL2 contained in mesothelioma samples, particularly on monocyte recruitment. Then, we studied the fate of these monocytes in malignant pleural mesothelioma (MPM) PEs and their impact on tumor cells' properties.

Methods: The implication of CCL2 in monocyte recruitment was evaluated using transmigration assays and a CCL2 blocking antibody. The phenotype of macrophages was determined by flow cytometry and enzyme-linked immunosorbent assay. Immunohistochemical analysis was used to support the results. Cocultures of macrophages with mesothelioma cells were performed to study cancer cell proliferation and resistance to treatment.

Results: We showed that CCL2 is a major factor of monocyte recruitment induced by MPM samples. Macrophages obtained in MPM samples were M2 macrophages (high CD14, high CD163, and interleukin-10 secretion after activation). The colony-stimulating factor 1 receptor/macrophage colony-stimulating factor (M-CSF) pathway is implicated in M2 polarization, and high levels of M-CSF were measured in MPM samples compared with benign PE (4.17 ± 2.75 ng/mL and 1.94 ± 1.47 ng/mL, respectively). Immunohistochemical analysis confirmed the presence of M2 macrophages in pleural and peritoneal mesothelioma. Finally, we showed that M2 macrophages increased mesothelioma cell proliferation and resistance to treatment.

Conclusions: These results demonstrate the implication of CCL2 in MPM pathogenesis and designate M-CSF as a new potential biomarker of MPM. This study also identifies CCL2 and colony-stimulating factor 1 receptor/M-CSF as interesting new targets to modulate pro-tumorigenic properties of the tumor microenvironment.
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http://dx.doi.org/10.1016/j.jtho.2016.06.022DOI Listing
October 2016

The angiotensin II type 2 receptor activates flow-mediated outward remodelling through T cells-dependent interleukin-17 production.

Cardiovasc Res 2016 10 21;112(1):515-25. Epub 2016 Jun 21.

MITOVASC Institute, UMR CNRS 6214, INSERM U1083, Angers University, F-49045 Angers, France Cardiovascular Functions In Vitro (CARFI) Facility, Angers University, F-49045 Angers, France Department of Vascular Medicine, University Hospital, F-49045 Angers, France

Aims: The angiotensin II type 1 receptor (AT1R) through the activation of immune cells plays a key role in arterial inward remodelling and reduced blood flow in cardiovascular disorders. On the other side, flow (shear stress)-mediated outward remodelling (FMR), involved in collateral arteries growth in ischaemic diseases, allows revascularization. We hypothesized that the type 2 receptor (AT2R), described as opposing the effects of AT1R, could be involved in FMR.

Methods And Results: We studied FMR using a model of ligation of feed arteries supplying collateral pathways in the mouse mesenteric arterial bed in vivo. Seven days after ligation, diameter increased by 30% in high flow (HF) arteries compared with normal flow vessels. FMR was absent in mice lacking AT2R. At Day 2, T lymphocytes expressing AT2R were present preferentially around HF arteries. FMR did not occur in athymic (nude) mice lacking T cells and in mice treated with anti-CD3ε antibodies. AT2R activation induced interleukin-17 production by memory T cells. Treatment of nude mice or AT2R-deficient mice with interleukin-17 restored diameter enlargement in HF arteries. Interleukin-17 increased NO-dependent relaxation and matrix metalloproteinases activity, both important in FMR. Remodelling of feeding arteries in the skin flap model of ischaemia was also absent in AT2R-deficient mice and in anti-interleukin-17-treated mice. Finally, remodelling, absent in 12-month-old mice, was restored by a treatment with the AT2R non-peptidic agonist C21.

Conclusion: AT2R-dependent interleukin-17 production by T lymphocyte is necessary for collateral artery growth and could represent a new therapeutic target in ischaemic disorders.
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http://dx.doi.org/10.1093/cvr/cvw172DOI Listing
October 2016

IL-9 promotes the survival and function of human melanoma-infiltrating CD4(+) CD8(+) double-positive T cells.

Eur J Immunol 2016 07 6;46(7):1770-82. Epub 2016 May 6.

INSERM, U892, Nantes, France.

We previously demonstrated an accumulation of tumor-reactive CD4(+) CD8(+) double positive (DP) T cells within melanoma-infiltrating lymphocytes, supporting their role in the regulation of anti-tumor immune responses. Similarly to their CD8(+) counterparts, intra-tumor DP T cells are MHC class-I restricted but differed by a limited lytic activity against autologous melanoma cells. Based on these observations and to further characterize DP T cells, both populations were compared at the transcriptional level. Our results revealed the overexpression of the IL-9 receptor (IL-9R) by DP T cells and prompted us to investigate the impact of IL-9 on their biology. We show that IL-9 favors DP T-cell survival by protecting them from apoptosis and by promoting their proliferation. In addition, IL-9 enhances their ability to produce cytokines and increased their levels of granzyme B/perforin as well as degranulation capacity, leading to a strengthened cytotoxic activity against melanoma cells. Taken together, the IL-9R(high) DP T-cell population could be a new preferential target for IL-9, which could take part in their retention within the melanoma infiltrate while also favoring their anti-tumor activity. More generally, our results extend the pleiotropic effects of IL-9 to IL-9R-expressing intra-tumor T cells, which could further potentiate anti-tumor immune responses.
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http://dx.doi.org/10.1002/eji.201546061DOI Listing
July 2016

Clinical Features of Spontaneous Partial Healing During Mycobacterium ulcerans Infection.

Open Forum Infect Dis 2016 Jan 25;3(1):ofw013. Epub 2016 Feb 25.

Atip/Avenir Team, Centre de Recherche en Cancérologie Nantes-Angers (CRCNA) , Université et Centre Hospitalier Universitaire (CHU) d'Angers .

Background.  Buruli ulcer, caused by Mycobacterium ulcerans, is a necrotizing skin disease leading to extensive cutaneous and subcutaneous destruction and functional limitations. Spontaneous healing in the absence of medical treatment occurs in rare cases, but this has not been well described in the literature. Methods.  In a retrospective case study in an area of Benin where this disease is highly endemic, we selected 26 Buruli ulcer patients presenting features of spontaneous healing from a cohort of 545 Buruli ulcer patients treated between 2010 and 2013. Results.  The 26 patients studied had a median age of 13.5 years and were predominantly male (1.4:1). Three groups of patients were defined on the basis of their spontaneous healing characteristics. The first group (12 patients) consisted of patients with an ulcer of more than 1 year's duration showing signs of healing. The second (13 patients) group contained patients with an active Buruli ulcer lesion some distance away from a first lesion that had healed spontaneously. Finally, the third group contained a single patient displaying complete healing of lesions from a nodule, without treatment and with no relapse. Conclusions.  We defined several features of spontaneous healing in Buruli ulcer patients and highlighted the difficulties associated with diagnosis and medical management. Delays in consultation contributed to the high proportion of patients with permanent sequelae and a risk of squamous cell carcinoma. Early detection and antibiotic treatment are the best ways to reduce impairments.
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http://dx.doi.org/10.1093/ofid/ofw013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767261PMC
January 2016

FVB/N Mice Spontaneously Heal Ulcerative Lesions Induced by Mycobacterium ulcerans and Switch M. ulcerans into a Low Mycolactone Producer.

J Immunol 2016 Mar 12;196(6):2690-8. Epub 2016 Feb 12.

Equipe Atip-Avenir, Centre Régional de Recherche en Cancérologie Nantes/Angers, INSERM U892, CNRS U6299, Centre Hospitalier Universitaire d'Angers and Université d'Angers, 49100 Angers, France;

Buruli ulcer, a debilitating disease, is caused by Mycobacterium ulcerans. The incidence of this neglected tropical disease is steadily increasing. As a rule, without treatment, skin ulcers occur and a lengthy healing process may be observed associated with severe functional disabilities. Mouse models are already available to study establishment of lesions or evaluation of therapy but a lack of a suitable animal model, mimicking all clinical stages, in particular the healing process, remains an obstacle to understand the pathophysiology of M. ulcerans infection. M. ulcerans was s.c. inoculated in three consanguine mouse strains, that is, BALB/c and C57BL/6, classically used to study mycobacterial infection, and FVB/N. Strikingly, FVB/N mice, although as sensitive as all other mouse strains with respect to M. ulcerans infection, presented a spontaneous healing after the ulcerative phase despite stable bacterial load, and mycolactone toxin was not detected in the healed tissues. The spontaneous healing process was accompanied by an activation of the innate immune system. The adaptive response initiated by FVB/N mice was not involved in the healing process and did not confer protection against M. ulcerans. Our work highlights the importance of innate immune responses to control M. ulcerans infection. This in vivo model of M. ulcerans infection now paves the way for new avenues of research toward the elucidation of critical stages of this disease, such as the characterization of the regulation of mycolactone production, a better understanding of the pathophysiology of M. ulcerans infection, and the development of new therapeutic strategies.
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http://dx.doi.org/10.4049/jimmunol.1502194DOI Listing
March 2016

Detection of Anti-Pentraxin-3 Autoantibodies in ANCA-Associated Vasculitis.

PLoS One 2016 21;11(1):e0147091. Epub 2016 Jan 21.

Nephrology Department, University Hospital of Angers, Angers, France.

Objectives: Pentraxin 3 (PTX3), in common with myeloperoxidase and proteinase 3, is stored in human neutrophil granules and is expressed on apoptotic neutrophil surface. We therefore investigated the presence of anti-PTX3 autoantibodies (aAbs) in the sera of antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) patients.

Methods: Presence of anti-PTX3 autoantibodies was analysed by a specific enzyme-linked immunosorbent assay in sera from 150 patients with microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA), and in sera of 227 healthy subjects (HS), 40 systemic sclerosis (SSc) patients, and 25 giant cell arteritis patients (GCA). Using indirect immunofluorescence on fixed human neutrophils, we also analyzed the staining pattern associated with the presence of anti-PTX3 aAbs.

Results: Anti-PTX3 aAbs were detected in 56 of 150 (37.3%) of the AAV patients (versus 12 of 227 (5.3%) of HS, p<0.001) and, interestingly, in 7 of 14 MPO and PR3 ANCA negative AAV patients. Moreover, by indirect immunofluorescence on fixed neutrophils, anti-PTX3 aAbs gave rise to a specific cytoplasmic fluorescence pattern distinct from the classical cytoplasmic (c-ANCA), perinuclear (p-ANCA), and atypical (a-ANCA) pattern. Anti-PTX3 aAbs levels were higher in patients with active AAV as compared to patients with inactive disease.

Conclusion: Our work suggests that PTX3 is as a novel ANCA antigen. Anti-PTX3 aAbs appear thus as a promising novel biomarker in the diagnosis of AAV, including in patients without detectable MPO and PR3 ANCA.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0147091PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4721655PMC
August 2016