Publications by authors named "Cécile Contin-Bordes"

34 Publications

Elevated Circulatory Levels of Microparticles Are Associated to Lung Fibrosis and Vasculopathy During Systemic Sclerosis.

Front Immunol 2020 23;11:532177. Epub 2020 Oct 23.

University of Bordeaux, CNRS, ImmunoConcEpT, UMR 5164, Bordeaux, France.

Background: Microparticles (MPs) are vesicular structures that derive from multiple cellular sources. MPs play important roles in intercellular communication, regulation of cell signaling or initiation of enzymatic processes. While MPs were characterized in Systemic Sclerosis (SSc) patients, their contribution to SSc pathogenesis remains unknown. Our aim was to investigate the potential role of MPs in SSc pathophysiology and their impact on tissue fibrosis.

Methods: Ninety-six SSc patients and 37 sex-matched healthy donors (HD) were enrolled in this study in order to quantify and phenotype their plasmatic MPs by flow cytometry. The ability of MPs purified from SSc patients and HD controls to modulate fibroblast's extra-cellular matrix genes expression was evaluated by reverse transcriptase quantitative polymerase chain reaction.

Results: SSc patients exhibited a higher concentration of circulatory MPs compared to HD. This difference was exacerbated when we only considered patients that were not treated with methotrexate or targeted disease-modifying antirheumatic drugs. Total circulatory MPs were associated to interstitial lung disease, lung fibrosis and diminished lung functional capacity, but also to vascular involvement such as active digital ulcers. Finally, contrary to HD MPs, MPs from SSc patients stimulated the production of extracellular matrix by fibroblast, demonstrating their profibrotic potential.

Conclusions: In this study, we provide evidence for a direct profibrotic role of MPs from SSc patients, underpinned by strong clinical associations in a large cohort of patients.
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http://dx.doi.org/10.3389/fimmu.2020.532177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645042PMC
April 2021

Feasibility and safety of tailored dosing schedule for eculizumab based on therapeutic drug monitoring: Lessons from a prospective multicentric study.

Br J Clin Pharmacol 2021 May 7;87(5):2236-2246. Epub 2020 Dec 7.

EA4245 Transplant Immunology and Inflammation, Université de Tours, Tours, France.

Aims: Eculizumab is an anti-C5 monoclonal antibody approved for rare diseases including atypical haemolytic-uraemic syndrome. The maintenance phase dosing regimen is identical for all adult patients: 1200 mg every 2 weeks. Recent studies reported an overexposure in many patients when considering a target trough concentration range of 50-100 mg/L. The aim of the present work was to validate the feasibility of therapeutic drug monitoring of eculizumab in atypical haemolytic-uraemic syndrome patients.

Methods: We performed a 2-step prospective multicentre study. In the first phase, we developed a pharmacokinetic population model using data from 40 patients and identified patients for whom a 1-week lengthening of interval between infusions would lead to a trough concentration above 100 mg/L. In the second phase, selected patients were allocated a 1-week extension and eculizumab trough concentrations were monitored.

Results: The model confirmed the previously reported influence of bodyweight on elimination clearance and predicted that 36 (90%) patients would be eligible for interval extension. In the second phase of the study, a 1-week lengthening of interval between infusions was performed in 15 patients whose trough concentration at the next visit was predicted with a Bayesian model to be above 100 mg/L. After interval extension, 10 patients (67%) presented measured trough concentrations over 100 mg/L. No biological or clinical recurrence of disease was observed, even in the 5 patients with concentrations below 100 mg/L in whom the initial dosing regimen was resumed.

Conclusion: Safe eculizumab interval adjustment is feasible with a PK monitoring.
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http://dx.doi.org/10.1111/bcp.14627DOI Listing
May 2021

Cocaïne et lésions destructrices centro-faciales : à propos d'un cas.

Rev Med Interne 2020 Sep 11;41(9):622-627. Epub 2020 Jul 11.

Service de médecine interne et immunologie clinique, hôpital Saint-André, CHU de Bordeaux, 1 Rue Jean Burguet, 33000 Bordeaux, France.

Introduction: Cocaine use is associated with multiple complications, some of which can mimic systemic diseases, especially Antineutrophil Cytoplasmic Antibody (ANCA) associated vasculitis. We report a case of Cocaine Induced Midline Destructive Lesions (CIMDL) for which a diagnosis of granulomatosis with polyangiitis (GPA) was discussed.

Case Report: A 42-year-old male, cocaine consumer, was admitted in our department for a centrofacial destructive process. He had no extra ear, nose and throat (ENT) involvement. ANCA were positive with a perinuclear fluorescence pattern and an anti-Proteinase 3 specificity. Regarding this unusual immunologic pattern and in the absence of histological argument for a GPA, a diagnosis of CIMDL was made.

Conclusion: CIMDL is a centrofacial destructive process due to intranasal cocaine use. It is frequently associated with the presence of p-ANCA with both anti-HNE and anti-PR3 specificity.
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http://dx.doi.org/10.1016/j.revmed.2020.04.010DOI Listing
September 2020

No Improvement of Hepatitis B Vaccination Response in Patients Dialysed with a Polymethylmethacrylate Membrane Compared to High-Flux Polysulfone: Results of the HEPADIAL Study.

Blood Purif 2020 13;49(3):265-271. Epub 2019 Nov 13.

Department of Immunology and Immunogenetics, Bordeaux University Hospital, Bordeaux, France.

Background: An altered immune response and decreased vaccine response are observed in patients with chronic renal failure. A preliminary study of 15 non-immunised patients, despite appropriate previous hepatitis B vaccination, showed a 60% seroconversion rate after 3 months of dialysis with a polymethylmethacrylate (PMMA) membrane. This response was associated with circulating soluble CD40 (CD40s) decrease, a natural inhibitor of the humoral immune response. The aim of the study is to confirm these results in a randomised study.

Methods: We conducted a multicentre randomised intention-to-treat superiority clinical trial comparing polysulfone and a PMMA membrane in 2 parallel patient groups. The primary end point was the vaccine response rate, as defined by an anti-HBs antibodies titre of >10 IU/L, 1 month after the last vaccination with a double dose of Engerix B20®, performed at weeks 12, 16, 20, and 36.

Results: Twenty-five patients were randomised and included in an intention-to-treat analysis. They were dialysed on polysulfone (n = 11) or PMMA (n = 14) for 40 weeks. Fifty percent of the PMMA patients versus 54.5% of the polysulfone patients achieved seroconversion (p = 1.00). The median anti-HBs antibody titre in responders at week 40 was 496 (92-750) versus 395 (43-572) UI/mL for PMMA and polysulfone, respectively (p = 0.46). The median CD40s titre at week 12 was 306 (193-448) versus 491 (281-515) pg/mL (p = 0.21). The CD40s median variation between week 0 and week 12 was 5 (-105 to 90) versus 64 (-63 to 123) pg/mL (p = 0.55). The CD40s level at week 12 in non-responders was slightly inferior to that of the responders: median 193 (168-331) versus 413 (281-512) pg/mL (p = 0.08).

Conclusion: We did not observe a better vaccine response with the PMMA membrane compared to high-flux polysulfone. The PMMA membrane did not decrease the CD40s more than the polysulfone membrane probably because the titre was previously low in the 2 groups.
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http://dx.doi.org/10.1159/000504035DOI Listing
April 2021

Outcome of children with Shiga toxin-associated haemolytic uraemic syndrome treated with eculizumab: a matched cohort study.

Nephrol Dial Transplant 2020 12;35(12):2147-2153

Service de Pédiatrie, Unité de Néphrologie, Centre de référence Maladies Rénales Rares du Sud-ouest, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.

Background: Treatment with eculizumab in Shiga toxin-associated haemolytic and uraemic syndrome (STEC-HUS) remains controversial despite its increasing utilization. The aim of our study was to evaluate the outcomes of children treated with eculizumab for STEC-HUS in a single-centre matched cohort study.

Methods: Data were retrospectively collected from medical records of children diagnosed with STEC-HUS. The outcomes of patients treated with eculizumab for STEC-HUS were compared with those of a control group of untreated patients matched for age, sex and severity of acute kidney injury with a 1:2 matching scheme.

Results: Eighteen children (median age 40.6 months) with STEC-HUS treated with eculizumab were compared with 36 matched control patients (median age 36.4 months) who did not receive eculizumab. All patients survived in the two groups. Within 1 month of HUS onset, the evolution of haematological and renal parameters did not differ between the two groups. At 12 months of follow-up, renal outcome was not significantly different between the two groups. At the last follow-up, the prevalence of decreased glomerular filtration rate in the eculizumab group (27%) was not statistically different from that in controls (38%), as was the prevalence of proteinuria and high blood pressure. Children who received eculizumab more often had extrarenal sequelae during follow-up. Eculizumab treatment appeared to be safe in children with STEC-HUS.

Conclusion: The benefit of eculizumab on renal and extrarenal outcomes in STEC-HUS could not be established based on our findings. However, efficacy and safety are not best assessed by the observational design and small sample size of our study. Randomized controlled trials are thus required to determine the efficacy of eculizumab in this indication.
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http://dx.doi.org/10.1093/ndt/gfz158DOI Listing
December 2020

Trypanosoma brucei gambiense excreted/secreted factors impair lipopolysaccharide-induced maturation and activation of human monocyte-derived dendritic cells.

Parasite Immunol 2019 08 27;41(8):e12632. Epub 2019 Jun 27.

Laboratoire de Parasitologie, UMR IRD CIRAD INTERTRYP 177, University of Bordeaux, Bordeaux, France.

Trypanosoma brucei gambiense, an extracellular eukaryotic flagellate parasite, is the main etiological agent of human African trypanosomiasis (HAT) or sleeping sickness. Dendritic cells (DCs) play a pivotal role at the interface between innate and adaptive immune response and are implicated during HAT. In this study, we investigated the effects of T gambiense and its excreted/secreted factors (ESF) on the phenotype of human monocyte-derived DCs (Mo-DCs). Mo-DCs were cultured with trypanosomes, lipopolysaccharide (LPS), ESF derived from T gambiense bloodstream strain Biyamina (MHOM/SD/82), or both ESF and LPS. Importantly, ESF reduced the expression of the maturation markers HLA-DR and CD83, as well as the secretion of IL-12, TNF-alpha and IL-10, in LPS-stimulated Mo-DCs. During mixed-leucocyte reactions, LPS- plus ESF-exposed DCs induced a non-significant decrease in the IFN-gamma/IL-10 ratio of CD4 + T-cell cytokines. Based on the results presented here, we raise the hypothesis that T gambiense has developed an immune escape strategy through the secretion of paracrine mediators in order to limit maturation and activation of human DCs. The identification of the factor(s) in the T gambiense ESF and of the DCs signalling pathway(s) involved may be important in the development of new therapeutic targets.
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http://dx.doi.org/10.1111/pim.12632DOI Listing
August 2019

OX40L/OX40 axis impairs follicular and natural Treg function in human SLE.

JCI Insight 2018 12 20;3(24). Epub 2018 Dec 20.

CNRS-UMR 5164 Immuno ConcEpT, Bordeaux University, Bordeaux, France.

Tregs are impaired in human systemic lupus erythematosus (SLE) and contribute to effector T cell activation. However, the mechanisms responsible for the Treg deficiency in SLE remain unclear. We hypothesized that the OX40L/OX40 axis is implicated in Treg and regulatory follicular helper T (Tfr) cell dysfunction in human SLE. OX40L/OX40 axis engagement on Tregs and Tfr cells not only specifically impaired their ability to regulate effector T cell proliferation, but also their ability to suppress T follicular helper (Tfh) cell-dependent B cell activation and immunoglobulin secretion. Antigen-presenting cells from patients with active SLE mediated Treg dysfunction in an OX40L-dependent manner, and OX40L-expressing cells colocalized with Foxp3+ cells in active SLE skin lesions. Engagement of the OX40L/OX40 axis resulted in Foxp3 downregulation in Tregs, and expression in SLE Tregs correlated with the proportion of circulating OX40L-expressing myeloid DCs. These data support that OX40L/OX40 signals are implicated in Treg dysfunction in human SLE. Thus, blocking the OX40L/OX40 axis appears to be a promising therapeutic strategy.
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http://dx.doi.org/10.1172/jci.insight.122167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338386PMC
December 2018

Innate Immunity in Systemic Sclerosis Fibrosis: Recent Advances.

Front Immunol 2018 23;9:1702. Epub 2018 Jul 23.

CNRS-UMR 5164, ImmunoConcEpT, Bordeaux University, Bordeaux, France.

Systemic sclerosis (SSc) is a heterogeneous autoimmune disease characterized by three interconnected hallmarks (i) vasculopathy, (ii) aberrant immune activation, and (iii) fibroblast dysfunction leading to extracellular matrix deposition and fibrosis. Blocking or reversing the fibrotic process associated with this devastating disease is still an unmet clinical need. Although various components of innate immunity, including macrophages and type I interferon, have long been implicated in SSc, the precise mechanisms that regulate the global innate immune contribution to SSc pathogenesis remain poorly understood. Recent studies have identified new innate immune players, such as pathogen-recognition receptors, platelet-derived danger-associated molecular patterns, innate lymphoid cells, and plasmacytoid dendritic cells in the pathophysiology of SSc, including vasculopathy and fibrosis. In this review, we describe the evidence demonstrating the importance of innate immune processes during SSc development with particular emphasis on their role in the initiation of pathology. We also discuss potential therapeutic options to modulate innate immune cells or signaling in SSc that are emerging from these recent advances.
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http://dx.doi.org/10.3389/fimmu.2018.01702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6064727PMC
July 2018

T Follicular Helper Cells in Autoimmune Disorders.

Front Immunol 2018 17;9:1637. Epub 2018 Jul 17.

ImmunoConcept, UMR-CNRS 5164, Université de Bordeaux, Bordeaux, France.

T follicular helper (Tfh) cells are a distinct subset of CD4 T lymphocytes, specialized in B cell help and in regulation of antibody responses. They are required for the generation of germinal center reactions, where selection of high affinity antibody producing B cells and development of memory B cells occur. Owing to the fundamental role of Tfh cells in adaptive immunity, the stringent control of their production and function is critically important, both for the induction of an optimal humoral response against thymus-dependent antigens but also for the prevention of self-reactivity. Indeed, deregulation of Tfh activities can contribute to a pathogenic autoantibody production and can play an important role in the promotion of autoimmune diseases. In the present review, we briefly introduce the molecular factors involved in Tfh cell formation in the context of a normal immune response, as well as markers associated with their identification (transcription factor, surface marker expression, and cytokine production). We then consider in detail the role of Tfh cells in the pathogenesis of a broad range of autoimmune diseases, with a special focus on systemic lupus erythematosus and rheumatoid arthritis, as well as on the other autoimmune/inflammatory disorders. We summarize the observed alterations in Tfh numbers, activation state, and circulating subset distribution during autoimmune and some other inflammatory disorders. In addition, central role of interleukin-21, major cytokine produced by Tfh cells, is discussed, as well as the involvement of follicular regulatory T cells, which share characteristics with both Tfh and regulatory T cells.
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http://dx.doi.org/10.3389/fimmu.2018.01637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056609PMC
July 2018

Systemic lupus erythematosus and systemic sclerosis: All roads lead to platelets.

Autoimmun Rev 2018 Jun 7;17(6):625-635. Epub 2018 Apr 7.

Laboratoire d'Immunologie et Immunogénétique, FHU ACRONIM, Hôpital Pellegrin, Centre Hospitalier Universitaire, Place Amélie Raba Léon, 33076 Bordeaux, France; Université de Bordeaux, 146 rue Léo Saignat, 33076 Bordeaux, France; CNRS-UMR 5164, ImmunoConcept, Université de Bordeaux, 146 rue Léo Saignat, 33076 Bordeaux, France. Electronic address:

Systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) are two phenotypically distincts inflammatory systemic diseases. However, SLE and SSc share pathogenic features such as interferon signature, loss of tolerance against self-nuclear antigens and increased tissue damage such as fibrosis. Recently, platelets have emerged as a major actor in immunity including auto-immune diseases. Both SLE and SSc are characterized by strong platelet system activation, which is likely to be both the witness and culprit in their pathogenesis. Platelet activation pathways are multiple and sometimes redundant. They include immune complexes, Toll-like receptors activation, antiphospholipid antibodies and ischemia-reperfusion associated with Raynaud phenomenon. Once activated, platelet promote immune dysregulation by priming interferon production by immune cells, providing CD40L supporting B lymphocyte functions and providing a source of autoantigens. Platelets are actively implicated in SLE and SSc end-organ damage such as cardiovascular and renal disease and in the promotion of tissue fibrosis. Finally, after understanding the main pathogenic implications of platelet activation in both diseases, we discuss potential therapeutics targeting platelets.
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http://dx.doi.org/10.1016/j.autrev.2018.01.012DOI Listing
June 2018

Fibrocytes in Asthma and Chronic Obstructive Pulmonary Disease: Variations on the Same Theme.

Am J Respir Cell Mol Biol 2018 03;58(3):288-298

1 Université de Bordeaux, Centre de Recherche Cardio thoracique de Bordeaux, F 33000 Bordeaux, France.

Fibrocytes are circulating cells that have fibroblast properties. They are produced by the bone marrow stroma, and they move from the blood to injured organs using multiple chemokine pathways. They exhibit marked functional and phenotypic plasticity in response to the local tissue microenvironment to ensure a proinflammatory or a more resolving phenotype. They can adopt immune cell properties and modulate conventional immune cell functions. Although their exact function is not always clear, they have emerged as key effector cells in several fibrotic diseases such as keloid, scleroderma, and idiopathic pulmonary fibrosis. Recent evidence suggests that fibrocytes could contribute to bronchial obstructive diseases such as asthma and chronic obstructive pulmonary disease. This review summarizes the reported roles of fibrocytes and their pathways into the lung in the context of asthma and chronic obstructive pulmonary disease, provides an overview of the different roles played by fibrocytes, and discusses their possible contributions to these obstructive diseases.
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http://dx.doi.org/10.1165/rcmb.2017-0301PSDOI Listing
March 2018

Association of the Presence of Anti-Carbamylated Protein Antibodies in Early Arthritis With a Poorer Clinical and Radiologic Outcome: Data From the French ESPOIR Cohort.

Arthritis Rheumatol 2017 12;69(12):2292-2302

Bordeaux University Hospital, Bordeaux, France.

Objective: To assess the prevalence of anti-carbamylated protein (anti-CarP) antibodies in a French cohort of patients with early arthritis and to investigate their association with clinical features, final diagnosis, prognosis, and comorbidities.

Methods: The presence of anti-CarP antibodies among patients with early arthritis in the French Etude et Suivi des Polyarthrites Indifférenciées Récentes (ESPOIR) cohort (n = 720) was determined using enzyme-linked immunosorbent assay. We investigated the prevalence of anti-CarP antibodies in different patient subgroups stratified according to anti-citrullinated protein antibody (ACPA) and/or rheumatoid factor (RF) status. Diagnostic and prognostic values of the test were evaluated in this population.

Results: Anti-CarP antibodies were present in approximately one-third of the patients (32.6%) and in 23.6% of the patients who were seronegative for both RF and ACPA. Anti-CarP positivity was associated with a more active disease status at baseline and over time. Anti-CarP-positive patients had a significantly higher Disease Activity Score in 28 joints using the erythrocyte sedimentation rate at month 36 than anti-CarP-negative patients (3.1 ± 0.11 versus 2.8 ± 0.06; P = 0.03). Anti-CarP-positive early arthritis was associated with a higher risk of developing erosions after 96 months of follow-up (55.6% of anti-CarP-positive patients versus 37.3% of anti-CarP-negative patients) (odds ratio 2.1 [95% CI 1.2-3.6]; P = 0.009). This association was particularly true when anti-CarP was associated with ACPA positivity. Moreover, ACPA positivity alone in early arthritis was not associated with a higher risk of erosive evolution.

Conclusion: Our findings indicate that anti-CarP antibodies are present in one-third of patients with early arthritis and in one-fourth of the RF-negative and ACPA-negative patients. They are particularly associated with a more severe radiographic outcome. Anti-CarP antibody positivity may help to accurately identify those at risk of erosive evolution in an early arthritis population.
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http://dx.doi.org/10.1002/art.40237DOI Listing
December 2017

Immune-Mediated Repair: A Matter of Plasticity.

Front Immunol 2017 24;8:454. Epub 2017 Apr 24.

ImmunoConcept, UMR5164, Immunology, CNRS, University of Bordeaux, Bordeaux, France.

Though the immune system is generally defined as a system of defense, it is increasingly recognized that the immune system also plays a crucial role in tissue repair and its potential dysregulations. In this review, we explore how distinct immune cell types are involved in tissue repair and how they interact in a process that is tightly regulated both spatially and temporally. We insist on the concept of immune cell plasticity which, in recent years, has proved fundamental for the success/understanding of the repair process. Overall, the perspective presented here suggests that the immune system plays a central role in the physiological robustness of the organism, and that cell plasticity contributes to the realization of this robustness.
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http://dx.doi.org/10.3389/fimmu.2017.00454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5403426PMC
April 2017

Neutrophil-derived mitochondrial DNA promotes receptor activator of nuclear factor κB and its ligand signalling in rheumatoid arthritis.

Rheumatology (Oxford) 2017 07;56(7):1200-1205

ImmunoConcept, UMR CNRS 5164, Université de Bordeaux.

Objectives: Mitochondrial DNA (mtDNA) contains sequestered damage-associated molecular patterns that might be involved in osteoimmunological pathogenesis of RA. Here, we aimed to investigate the cellular source of mtDNA and its role in RANK ligand (RANKL) expression by RA SF neutrophils.

Methods: The gene expression signature of SF neutrophils was examined by proteomic quantitative analysis. Levels of mtDNA in circulating and SF neutrophils from RA patients and OA control subjects were assessed by real-time PCR. Purified neutrophils were challenged in vitro with Toll-like receptor agonists as well as mtDNA. RANKL expression by neutrophils was studied by flow cytometry.

Results: SF neutrophils from RA patients displayed a gene expression signature of oxidative stress. This stress signature was associated with the release of mtDNA in SF as observed by a significant increase of mtDNA in the SF of RA patients compared with OA patients. mtDNA in RA SF was correlated with systemic inflammation as assessed by CRP concentrations. We also showed that mtDNA drives neutrophil RANKL expression to the same extent as Toll-like receptor agonists.

Conclusion: Our data identify SF neutrophils as a cellular source of mtDNA that leads to a subsequent expression of RANKL. This highlights the important role of neutrophils in RA osteoimmunology.
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http://dx.doi.org/10.1093/rheumatology/kex041DOI Listing
July 2017

Platelets Induce Thymic Stromal Lymphopoietin Production by Endothelial Cells: Contribution to Fibrosis in Human Systemic Sclerosis.

Arthritis Rheumatol 2016 11 9;68(11):2784-2794. Epub 2016 Oct 9.

CNRS-UMR 5164 Immuno ConcEpT, Bordeaux University and Bordeaux Hospital, Bordeaux, France.

Objective: To investigate the relationship between vascular damage and fibrosis in systemic sclerosis (SSc) by testing the hypothesis that platelets contribute to skin fibrosis via the activation of human dermal microvascular endothelial cells (HDMECs) and subsequent production of profibrotic mediators.

Methods: A total of 203 SSc patients and 30 healthy donors were prospectively enrolled between 2012 and 2015 at the University Hospital of Bordeaux. Immunohistochemistry and immunofluorescence analyses were performed on skin biopsy sections from 18 SSc patients and 5 healthy donors. Serum thymic stromal lymphopoietin (TSLP) levels were measured by enzyme-linked immunosorbent assay in the entire cohort. HDMECs and fibroblasts were purified from biopsy sections. Extracellular matrix production by cultured fibroblasts was assessed by real-time quantitative polymerase chain reaction.

Results: Serum TSLP levels were significantly increased in SSc patients compared to healthy donors (P < 0.0001) and were associated with a higher frequency of vasculopathy (P = 0.02). The proportion of TSLP-positive dermal cells was increased in the skin of SSc patients compared with healthy donors (P < 0.0001) and was correlated with fibrosis (modified Rodnan skin thickness score) (r = 0.6146, P = 0.0001). In SSc dermis, TSLP was mainly expressed by CD31-positive endothelial cells. In vitro, activated platelets induced TSLP production by HDMECs in an interleukin-1β-dependent manner. SSc fibroblasts responded differently according to their original TSLP environment.

Conclusion: Taken together, these results identify HDMECs as contributors to TSLP production in SSc and suggest a potential mechanism by which platelets may profoundly affect the fibrotic process in SSc.
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http://dx.doi.org/10.1002/art.39817DOI Listing
November 2016

Atypical haemolytic uraemic syndrome and pregnancy: outcome with ongoing eculizumab.

Nephrol Dial Transplant 2016 12 1;31(12):2122-2130. Epub 2016 Sep 1.

Department of Nephrology Transplantation-Dialysis, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.

Background: A therapeutic strategy based on complement blockade by eculizumab is widely used to treat atypical haemolytic uraemic syndrome (aHUS). Recent data are available on the administration of eculizumab during pregnancy in patients treated for paroxysmal nocturnal haemoglobinuria but there are very few data for aHUS patients.

Methods: We analysed the use of eculizumab for the treatment of aHUS during five pregnancies in three patients and studied an additional pregnancy without eculizumab. Obstetrical data and maternal and foetal complications during pregnancy, at delivery, and during the post-partum period were recorded.

Results: The mean age at pregnancy was 28.5 (range 25-33) years. The mean serum creatinine before pregnancy was 189 (range 130-300) µmol/L and the mean eGFR was 32 (range 18-45) mL/min/1.73 m. One patient who stopped eculizumab 3 weeks after conception had a termination due to a relapse of HUS at 12 weeks of gestation (WG) during a first pregnancy and an intrauterine death at 24 WG despite continuous eculizumab treatment during a second pregnancy. In the other four pregnancies, treatment stabilized clinical and laboratory markers until 29-34 WG, but did not prevent hemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome in one patient or pre-eclampsia in two other patients. All babies were born preterm and two presented with growth retardation. The mean body weight was 1632.5 (range 1070-2500) g. The dose of eculizumab had to be increased during all pregnancies due to incomplete complement blockade.

Conclusions: Eculizumab therapy during pregnancy displayed no overt safety issues but did not appear to prevent HELLP syndrome or pre-eclampsia in these high-risk chronic kidney disease patients.
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http://dx.doi.org/10.1093/ndt/gfw314DOI Listing
December 2016

CD95-Mediated Calcium Signaling Promotes T Helper 17 Trafficking to Inflamed Organs in Lupus-Prone Mice.

Immunity 2016 07;45(1):209-23

Centre Eugène Marquis, Rue Bataille Flandres Dunkerque, 35042 Rennes, France; INSERM ERL440-OSS, Equipe Labellisée, Ligue Contre Le Cancer, 35042 Rennes, France; Université de Rennes 1, 2 Ave. du Prof. Léon Bernard, 35043 Rennes, France; Biosit, Plateforme H2P2, Biogenouest, 2 Ave. du Prof. Léon Bernard, 35043 Rennes, France. Electronic address:

CD95 ligand (CD95L) is expressed by immune cells and triggers apoptotic death. Metalloprotease-cleaved CD95L (cl-CD95L) is released into the bloodstream but does not trigger apoptotic signaling. Hence, the pathophysiological role of cl-CD95L remains unclear. We observed that skin-derived endothelial cells from systemic lupus erythematosus (SLE) patients expressed CD95L and that after cleavage, cl-CD95L promoted T helper 17 (Th17) lymphocyte transmigration across the endothelial barrier at the expense of T regulatory cells. T cell migration relied on a direct interaction between the CD95 domain called calcium-inducing domain (CID) and the Src homology 3 domain of phospholipase Cγ1. Th17 cells stimulated with cl-CD95L produced sphingosine-1-phosphate (S1P), which promoted endothelial transmigration by activating the S1P receptor 3. We generated a cell-penetrating CID peptide that prevented Th17 cell transmigration and alleviated clinical symptoms in lupus mice. Therefore, neutralizing the CD95 non-apoptotic signaling pathway could be an attractive therapeutic approach for SLE treatment.
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http://dx.doi.org/10.1016/j.immuni.2016.06.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4961226PMC
July 2016

IgE Inhibits Toll-like Receptor 7- and Toll-like Receptor 9-Mediated Expression of Interferon-α by Plasmacytoid Dendritic Cells in Patients With Systemic Lupus Erythematosus.

Arthritis Rheumatol 2016 09;68(9):2221-31

Université de Bordeaux, Immuno ConcEpT, CNRS-UMR 5164, and Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.

Objective: Plasmacytoid dendritic cells (PDCs) play a central role in pathogenesis of systemic lupus erythematosus (SLE) through their unique ability to produce large amounts of type I interferon (IFN) upon Toll-like receptor 7 (TLR-7) and TLR-9 triggering. PDCs express specific surface regulatory receptors involved in negative regulation of IFNα secretion. These receptors use the γ-chain of high-affinity Fc receptor (FcR) for IgE, FcɛRI. We undertook this study to test our hypothesis that IgE engagement of FcɛRI on PDCs may impact IFNα production in SLE patients.

Methods: Serum levels of total IgE were measured in healthy volunteers, SLE patients, and patients with IgE-dependent allergic disorders. FcɛRI expression on PDCs from SLE patients was evaluated by flow cytometry. Purified PDCs were incubated with monoclonal IgE for 24 hours, then stimulated for 18 hours with TLR agonists or immune complexes (ICs). IFNα production by PDCs was detected by quantitative real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay. Expression of TLR-7, TLR-9, and IFN regulatory factor 7 (IRF-7) in PDCs was quantified by quantitative real-time PCR.

Results: We observed significantly higher IgE levels in SLE patients with quiescent disease than in those with active disease. In SLE patients, IgE levels correlated inversely with disease activity. IgE levels were not associated with the presence of antinuclear IgE. Purified PDCs treated for 24 hours with monoclonal IgE up-regulated FcɛRI expression in an IgE dose-dependent manner. IgE-treated PDCs significantly decreased IFNα secretion and down-regulated CCR7 expression upon stimulation with TLR-7 and TLR-9 ligands and ICs from lupus patients. IgE treatment down-regulated expression of TLR-9 and IRF-7.

Conclusion: Our results support the notion that IgE plays a protective role in SLE pathogenesis through the modulation of inflammatory response by PDCs.
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http://dx.doi.org/10.1002/art.39679DOI Listing
September 2016

Prevalence of IgA Antibodies to β2-Glycoprotein I: A Population-Dependent Feature?

Transplantation 2016 Mar;100(3):e13-4

1 Laboratoire d'Immunologie et Immunogénétique, Hôpital Pellegrin, CHU de Bordeaux, Bordeaux, France. 2 UMR CNRS 5164, Université de Bordeaux, Bordeaux, France. 3 Laboratoire d'Hématologie, Hôpital Pellegrin, CHU de Bordeaux, Bordeaux, France. 4 Service de Néphrologie, Transplantation, Dialyse, Hôpital Pellegrin, CHU de Bordeaux, Bordeaux, France.

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http://dx.doi.org/10.1097/TP.0000000000001062DOI Listing
March 2016

Role of extracellular vesicles in autoimmune diseases.

Autoimmun Rev 2016 Feb 7;15(2):174-83. Epub 2015 Nov 7.

UMR-5164 CNRS, CIRID, University of Bordeaux, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France; Internal Medicine and Clinical Immunology Department, Bordeaux Hospital, 1 rue Jean Burguet, 33075 Bordeaux Cedex, France. Electronic address:

Extracellular vesicles (EVs) consist of exosomes released upon fusion of multivesicular bodies with the cell plasma membrane and microparticles shed directly from the cell membrane of many cell types. EVs can mediate cell-cell communication and are involved in many processes including inflammation, immune signaling, angiogenesis, stress response, senescence, proliferation, and cell differentiation. Accumulating evidence reveals that EVs act in the establishment, maintenance and modulation of autoimmune processes among several others involved in cancer and cardiovascular complications. EVs could also present biomedical applications, as disease biomarkers and therapeutic targets or agents for drug delivery.
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http://dx.doi.org/10.1016/j.autrev.2015.11.004DOI Listing
February 2016

OX40 Ligand Contributes to Human Lupus Pathogenesis by Promoting T Follicular Helper Response.

Immunity 2015 Jun 9;42(6):1159-70. Epub 2015 Jun 9.

University Bordeaux, CIRID, UMR/CNRS 5164, F-33000 Bordeaux, France; CNRS, CIRID, UMR 5164, F-33000 Bordeaux, France; Baylor Institute for Immunology Research, Dallas, TX 75204, USA; CHU de Bordeaux, F-33076 Bordeaux, France. Electronic address:

Increased activity of T follicular helper (Tfh) cells plays a major pathogenic role in systemic lupus erythematosus (SLE). However, the mechanisms that cause aberrant Tfh cell responses in SLE remain elusive. Here we showed the OX40 ligand (OX40L)-OX40 axis contributes to the aberrant Tfh response in SLE. OX40L was expressed by myeloid antigen-presenting cells (APCs), but not B cells, in blood and in inflamed tissues in adult and pediatric SLE patients. The frequency of circulating OX40L-expressing myeloid APCs positively correlated with disease activity and the frequency of ICOS(+) blood Tfh cells in SLE. OX40 signals promoted naive and memory CD4(+) T cells to express multiple Tfh cell molecules and were sufficient to induce them to become functional B cell helpers. Immune complexes containing RNA induced OX40L expression on myeloid APCs via TLR7 activation. Our study provides a rationale to target the OX40L-OX40 axis as a therapeutic modality for SLE.
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http://dx.doi.org/10.1016/j.immuni.2015.05.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4570857PMC
June 2015

Distal Angiopathy and Atypical Hemolytic Uremic Syndrome: Clinical and Functional Properties of an Anti-Factor H IgAλ Antibody.

Am J Kidney Dis 2015 Aug 23;66(2):331-6. Epub 2015 May 23.

Service de Néphrologie Transplantation Dialyse, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France; INSERM U1026, Université de Bordeaux, Bordeaux, France.

Abnormal regulation of the alternative pathway of the complement system is a well-described trigger of microangiopathy leading to atypical hemolytic uremic syndrome (aHUS). However, the involvement of complement dysregulation in distal angiopathy has not been reported in adults. We describe the clinical course of a patient with severe distal angiopathy (amputation of all fingers and toes) followed 3 years later by aHUS with end-stage renal disease. This course was attributed to a circulating monoclonal immunoglobulin A λ light chain (IgAλ) with unusual properties: it bound complement factor H (CFH) and impaired CFH-glycosaminoglycan interaction and cell-surface protection. Local complement activation with distal angiopathy and microvascular injury was suggested by deposition of IgA, C4d, and C5b-9 in limb and preglomerular arteries. We therefore postulated that the monoclonal IgAλ inhibited activity of endothelial cell-bound CFH, which led to local activation of complement, vasoconstriction (distal angiopathy), and aHUS. While the patient was dependent on dialysis and plasma exchange, treatment with the anti-C5 antibody eculizumab induced remission of distal angiopathy and aHUS. During eculizumab treatment, kidney transplantation was performed. The patient had normal kidney function at the 3-year follow-up. We suggest that the association of distal angiopathy and aHUS in this patient is clearly linked to anti-CFH properties of the monoclonal IgAλ.
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http://dx.doi.org/10.1053/j.ajkd.2015.03.039DOI Listing
August 2015

Septic shock sera containing circulating histones induce dendritic cell-regulated necrosis in fatal septic shock patients.

Crit Care Med 2015 Apr;43(4):e107-16

1Medical Intensive Care Unit, Saint Andre Hospital, University Hospital of Bordeaux, Bordeaux, France. 2CNRS UMR 5164 CIRID, University of Bordeaux, Bordeaux, France. 3INSERM U892-CRCNA, University of Angers, Angers, France. 4Laboratory of Immunology and Immunogenetics, University Hospital of Bordeaux, Bordeaux, France. 5GECMIA (Groupe Epidemiologie Clinique des Maladies Inflammatoires d'Aquitaine) Study Group, University Hospital of Bordeaux, Bordeaux, France. 6Department of Rheumatology, University Hospital of Bordeaux, Bordeaux, France. 7Department of Internal Medicine, University Hospital of Bordeaux, Bordeaux, France. 8Department of Infectious and Tropical Diseases, University Hospital of Bordeaux, Bordeaux, France. 9Department of Interventional Cardiology, University Hospital of Bordeaux, Bordeaux, France. 10Medical Intensive Care Unit, Pellegrin Hospital, University Hospital of Bordeaux, Bordeaux, France.

Objectives: Innate immune system alterations, including dendritic cell loss, have been reproducibly observed in patients with septic shock and correlated to adverse outcomes or nosocomial infections. The goal of this study is to better understand the mechanisms behind this observation in order to better assess septic shock pathogenesis.

Design: Prospective, controlled experimental study.

Setting: Research laboratory at an academic medical center.

Subjects: The study enrolled 71 patients, 49 with septic shock and 22 with cardiogenic shock. Seventeen healthy controls served as reference. In vitro monocyte-derived dendritic cells were generated from healthy volunteers.

Interventions: Sera were assessed for their ability to promote in vitro dendritic cell death through flow cytometry detection in each group of patients. The percentage of apoptotic or necrotic dendritic cells was evaluated by annexin-V and propidium iodide staining.

Measurements And Main Results: We observed that only patients with septic shock and not patients with pure cardiogenic shock were characterized by a rapid and profound loss of circulating dendritic cells. In vitro analysis revealed that sera from patients with septic shock induced higher dendritic cell death compared to normal sera or cardiogenic shock (p<0.005). Sera from surviving patients induced dendritic cell death through a caspase-dependent apoptotic pathway, whereas sera from nonsurviving patients induced dendritic cell-regulated necrosis. Dendritic cell necrosis was not due to necroptosis but was dependent of the presence of circulating histone. The toxicity of histones toward dendritic cell could be prevented by recombinant human activated protein C. Finally, we observed a direct correlation between the levels of circulating histones in patients and the ability of the sera to promote dendritic cell-regulated necrosis.

Conclusions: The study demonstrates a differential mechanism of dendritic cell death in patients with septic shock that is dependent on the severity of the disease.
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http://dx.doi.org/10.1097/CCM.0000000000000879DOI Listing
April 2015

Deciphering complement interference in anti-human leukocyte antigen antibody detection with flow beads assays.

Transplantation 2014 Sep;98(6):625-31

1 Laboratoire d'Immunologie et Immunogénétique, Hôpital Pellegrin, CHU de Bordeaux, Bordeaux, France. 2 UMR CNRS 5164, Université de Bordeaux, Talence, France. 3 Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Laboratoire d'immunologie biologique, Paris, France. 4 Service des Maladies Respiratoires, Hôpital Haut-Lévêque, CHU de Bordeaux, Pessac, France. 5 Service de Chirurgie Cardiaque, Hôpital Haut-Lévêque, CHU de Bordeaux, Pessac, France. 6 Service de Transplantation Hépatique, Hôpital Pellegrin, CHU de Bordeaux, Bordeaux, France. 7 Address correspondence to: Jean-Luc Taupin, Pharm. D., Ph.D., Laboratoire d'Immunologie et Immunogénétique, Hôpital Pellegrin, CHU de Bordeaux, Place Amélie Raba Léon, 33076 Bordeaux Cedex, France.

Background: Anti-human leukocyte antigen (HLA) antibody detection in solid-phase flow beads assays can be quenched by complement activation, but the precise mechanism of this interference is not fully elucidated yet.

Methods: Using the Luminex flow beads screening assay for detection of anti-HLA antibodies, we analyzed the binding of high concentrations of the pan class I anti-HLA monoclonal antibody W6/32 in neat normal, ethylenediaminetetraacetic acid-treated normal and complement factors C1q, C4/C3, C2, C3, factor B or C5-depleted human sera, using anti-mouse immunoglobulin G as the detection antibody. Complement activation and binding to beads were revealed using anti-human C1q, C4d, and C3d antibodies. To translate our findings to the human setting, we used the class I and class II HLA single-antigen flow beads assays and sera from four patients with high titers of antibodies.

Results: Detection of W6/32 did not suffer any interference with C1q and C4/C3-depleted sera. A partial quenching was observed with C2, C3, and factor B-depleted sera, but was more pronounced with the factor B-depleted serum. W6/32 was undetectable in presence of C5-depleted serum. The binding of activation products derived from C3 principally, and also from C4, impaired immunoglobulin G and C1q detection. Accordingly, C4d detection was hindered by deposition of activated C3. Similar findings were obtained with patients' sera.

Conclusion: Binding of C4 and C3 activation products is the main responsible for complement interference in flow beads assays. A complete quenching requires complement activation through C3 cleavage and its amplification by the alternative pathway.
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http://dx.doi.org/10.1097/TP.0000000000000315DOI Listing
September 2014

A proof-of-concept, randomized, controlled trial of omalizumab in patients with severe, difficult-to-control, nonatopic asthma.

Chest 2013 Aug;144(2):411-419

Université Paris-Sud, Faculté de Médecine, Le Kremlin Bicêtre; Assistance Publique Hôpitaux de Paris, Hôpital Bicêtre, Service de Pneumologie, DHU Thorax Innovation, Le Kremlin-Bicêtre; Institut National de la Santé et de la Recherche médicale (INSERM) U999, LabEx LERMIT, Le Plessis Robinson. Electronic address:

Background: While up to 50% of patients with severe asthma have no evidence of allergy, IgE has been linked to asthma, irrespective of atopic status. Omalizumab, an anti-IgE monoclonal antibody, is reported to significantly benefit a subset of patients with severe, persistent, allergic asthma. Therefore, we investigated whether omalizumab has biologic and clinical effects in patients with refractory nonatopic asthma.

Methods: Forty-one adult patients who, despite daily treatment with or without maintenance oral corticosteroids, had severe, nonatopic, refractory asthma according to GINA (Global Initiative for Asthma) step 4, were randomized to receive omalizumab or placebo in a 1:1 ratio. The primary end point was the change in expression of high-affinity IgE receptor (FcεRI) on blood basophils and plasmacytoid dendritic cells (pDC2) after 16 weeks. The impact of omalizumab on lung function and clinical variables was also examined.

Results: Compared with placebo, omalizumab resulted in a statistically significant reduction in FcεRI expression on basophils and pDC2 (P < .001). The omalizumab group also showed an overall increase in FEV1 compared with baseline (+250 mL, P = .032; +9.9%, P = .029). A trend toward improvement in global evaluation of treatment effectiveness and asthma exacerbation rate was also observed.

Conclusions: Omalizumab negatively regulates FcεRI expression in patients with severe nonatopic asthma, as it does in severe atopic asthma. Omalizumab may have a therapeutic role in severe nonatopic asthma. Nonetheless, our preliminary findings support further investigation to better assess the clinical efficacy of omalizumab.

Trial Registry: ClinicalTrials.gov; No.: NCT01007149; URL: www.clinicaltrials.gov and European Clinical Trials Database, EudraCT; No.: 2009-010937-38; URL: https://www.clinicaltrialsregister.eu.
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http://dx.doi.org/10.1378/chest.12-1961DOI Listing
August 2013

Tocilizumab treatment decreases circulating myeloid dendritic cells and monocytes, 2 components of the myeloid lineage.

J Rheumatol 2012 Jun 1;39(6):1192-7. Epub 2012 Apr 1.

Département de Rhumatologie, CHU Bordeaux, Hôpital Pellegrin, Place Amélie Raba Léon, 33076 Bordeaux, France.

Objective: Interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) are proinflammatory cytokines involved in inflammatory response. Effective TNF-α blocker treatment is associated with an increase in circulating myeloid dendritic cells (mDC), suggesting their release from inflamed synovium. Currently, in vivo effects of IL-6 inhibition on DC are unknown. We monitored the changes in circulating mDC and plasmacytoid DC (pDC) during tocilizumab (TCZ) therapy in patients with rheumatoid arthritis (RA).

Methods: DC subset levels were evaluated by flow cytometry in patients with RA (n = 43) and in healthy volunteers (n = 20). In patients with RA, these levels were measured before and during TCZ therapy (8 mg/kg every 4 weeks). Response to TCZ therapy was evaluated at 12 weeks. Statistical analysis was based on Mann-Whitney U tests or Wilcoxon signed-rank tests.

Results: At baseline, patients with active RA were characterized by a significantly lower level of circulating mDC and pDC compared to healthy donors. However, this difference did not correlate with any disease activity score. TCZ-treated patients who met the European League Against Rheumatism (EULAR) improvement criteria at Week 12 had significant reductions in mDC and monocyte levels as compared with EULAR nonresponders. Levels of pDC, CD4+ T cells, and CD8+ T cells remained stable during the TCZ courses, regardless of treatment response.

Conclusion: Our study reveals an unexpected reduction of circulating mDC and monocytes in patients with RA in response to TCZ therapy. In accord with reports on neutrophils and platelets decreasing during TCZ therapy, our data suggest an effect of IL-6 inhibition on cells from myeloid lineage.
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http://dx.doi.org/10.3899/jrheum.111439DOI Listing
June 2012

Potential role of Mycoplasma hominis in interleukin (IL)-17-producing CD4+ T-cell generation via induction of IL-23 secretion by human dendritic cells.

J Infect Dis 2011 Dec 4;204(11):1796-805. Epub 2011 Oct 4.

Univ. de Bordeaux, Unité sous Contrat Mycoplasmal and chlamydial infections in humans.

Background: Mycoplasma hominis, a human urogenital pathogen, is involved in genital and extragenital infections and arthritis, particularly in immunocompromised patients. The interleukin (IL) 23/T helper (Th) 17 axis is associated with inflammatory and autoimmune diseases. The aim of this study was to assess the IL-23 response to M. hominis in human dendritic cells (DCs) and the CD4(+) T-cell differentiation in response to M. hominis-infected DCs.

Methods: Human monocyte-derived DCs were cultured with phosphate-buffered saline, lipopolysaccharide, or M. hominis PG21. Cocultures with heterologous T cells were performed. Extracts from M. hominis were separated and incubated with DCs. Isolates from different clinical syndromes were tested.

Results: M. hominis induced the maturation of human DCs with predominant IL-23 secretion in a Toll-like receptor 2-dependent manner. The in vitro immunomodulatory capacity of M. hominis was contained in a lipoprotein-enriched fraction from the mycoplasma. M. hominis-activated DCs induced IL-17-producing CD4(+) T cells. Interestingly, clinical isolates differed in their ability to promote IL-23 secretion by DCs.

Conclusions: Taken together, our findings demonstrate a major role for the IL-23/Th17 axis in the defense against M. hominis and indicate a potential role for these bacteria in inflammatory and autoimmune diseases.
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http://dx.doi.org/10.1093/infdis/jir630DOI Listing
December 2011

The naturally processed CD95L elicits a c-yes/calcium/PI3K-driven cell migration pathway.

PLoS Biol 2011 Jun 21;9(6):e1001090. Epub 2011 Jun 21.

Université de Rennes-1, Rennes, France.

Patients affected by chronic inflammatory disorders display high amounts of soluble CD95L. This homotrimeric ligand arises from the cleavage by metalloproteases of its membrane-bound counterpart, a strong apoptotic inducer. In contrast, the naturally processed CD95L is viewed as an apoptotic antagonist competing with its membrane counterpart for binding to CD95. Recent reports pinpointed that activation of CD95 may attract myeloid and tumoral cells, which display resistance to the CD95-mediated apoptotic signal. However, all these studies were performed using chimeric CD95Ls (oligomerized forms), which behave as the membrane-bound ligand and not as the naturally processed CD95L. Herein, we examine the biological effects of the metalloprotease-cleaved CD95L on CD95-sensitive activated T-lymphocytes. We demonstrate that cleaved CD95L (cl-CD95L), found increased in sera of systemic lupus erythematosus (SLE) patients as compared to that of healthy individuals, promotes the formation of migrating pseudopods at the leading edge of which the death receptor CD95 is capped (confocal microscopy). Using different migration assays (wound healing/Boyden Chamber/endothelial transmigration), we uncover that cl-CD95L promotes cell migration through a c-yes/Ca²⁺/PI3K-driven signaling pathway, which relies on the formation of a CD95-containing complex designated the MISC for Motility-Inducing Signaling Complex. These findings revisit the role of the metalloprotease-cleaved CD95L and emphasize that the increase in cl-CD95L observed in patients affected by chronic inflammatory disorders may fuel the local or systemic tissue damage by promoting tissue-filtration of immune cells.
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http://dx.doi.org/10.1371/journal.pbio.1001090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3119658PMC
June 2011

Expansion of myelin autoreactive CD8+ T lymphocytes in patients with neuropsychiatric systemic lupus erythematosus.

Ann Rheum Dis 2011 May 27;70(5):868-71. Epub 2010 Dec 27.

Laboratoire d’Immunologie, Hôpital Pellegrin, CHU de Bordeaux, Bordeaux, France.

Objectives: Delineation of mechanisms underlying neuropsychiatric systemic lupus erythematosus (NPSLE) and determination of biological markers could guide treatment choice. A study was undertaken to analyse the potential role of activated CD8+ T cells in NPSLE as previously reported in SLE nephritis.

Methods: Flow cytometric immunophenotyping of blood lymphocytes was performed in 30 patients with NPSLE and 36 healthy individuals. The antigenic specificity of CD8+ T cells was studied using HLA-A0201 tetramers loaded with several myelin-derived peptides. The intracellular level of interferon γ (IFNγ) produced by activated CD8+ T cells was determined by flow cytometry.

Results: A large increase in circulating activated CD8+ T lymphocytes expressing surface HLA-DR was found in patients with NPSLE without antiphospholipid syndrome (APS) (n=18) compared with patients with APS (n=12) or healthy controls (n=36). IFNγ-secreting myelin-specific CD8+ T cells were detected exclusively in the blood of patients with NPSLE without APS but with white matter lesions.

Conclusions: These data strongly support the existence of a new immune effector mechanism responsible for CNS involvement in patients with NPSLE and suggest that analysing HLA-DR expression combined with myelin-specific tetramer staining on CD8+ T lymphocytes may be a valuable additional tool for the monitoring of these patients.
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http://dx.doi.org/10.1136/ard.2010.140012DOI Listing
May 2011