Brest University Medical School Hospital

Brest, France

Brest University Medical School Hospital

Brest, France
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Agmon-Levin N.,The Zabludowicz Center for Autoimmune Diseases | Kivity S.,The Zabludowicz Center for Autoimmune Diseases | Kivity S.,Sheba Medical Center | Kivity S.,Rheumatic Disease Unit | And 10 more authors.
Journal of Autoimmunity | Year: 2012

Background/purpose: Primary Sjögren's syndrome (SS) is a chronic autoimmune disease primarily involving the exocrine glands. The clinical picture of SS ranges from exocrinopathy to systemic disease affecting the lung, kidney, liver, skin, musculockeletal and nervous systems. The morbidity of SS is mainly determined by extraglandular disease and increased prevalence of lymphoma. Environmental and hormonal factors, such as vitamin-D may play a role in the pathogenic process and disease expression. Thus, we aimed to evaluate levels of vitamin-D and their association with manifestations of SS. Methods: Vitamin-D levels were determined in 176 primary SS patients and 163 matched healthy volunteers utilizing the LIAISON chemiluminescent immunoassays (DiaSorin-Italy). A correlation between vitamin-D levels and clinical and serological manifestations of SS was performed. Results: Mean vitamin-D levels were comparable between SS patients and control 21.2 ± 9.4 ng/ml and 22.4 ± 10 ng/ml, respectively. Peripheral neuropathy was diagnosed in 23% of SS patients and associated with lower vitamin-D levels (18.6 ± 5.5 ng/ml vs. 22.6±8 ng/ml (p = 0.04)). Lymphoma was diagnosed in 4.3% of SS patients, who had lower levels of vitamin-D (13.2 ± 6.25 ng/ml), compared to SS patients without lymphoma (22 ± 8 ng/ml), (p = 0.03). Other clinical and serological manifestations did not correlate with vitamin-D status. Conclusions: In this study, low levels of vitamin-D correlated with the presence of peripheral neuropathy and lymphoma among SS patients. The link between vitamin-D and neuropathy or lymphoma was reported in other conditions, and may support a role for vitamin-D in the pathogenesis of these processes. Plausible beneficial effect for vitamin-D supplementation may thus be suggested. © 2012 Elsevier Ltd.

Nouel A.,Brest University Medical School Hospital | Segalen I.,Brest University Medical School Hospital | Jamin C.,Brest University Medical School Hospital | Jamin C.,Laboratory of Immunology | And 8 more authors.
Kidney International | Year: 2014

In kidney transplantation, the composition of the B-cell compartment is increasingly identified as an important determinant for graft outcome. Whereas naive and transitional B cells have been associated with long-term allograft survival and operational tolerance, memory B cells have been linked to graft rejection and graft loss. Chronic antibody-mediated rejection now represents a major complication in transplantation and is a challenge in current therapeutics. Here, we show that patients with chronic antibody-mediated rejection display a unique B-cell phenotype with a reduced ratio of activated to memory B cells associated with an impaired immunosuppressive activity. The regulatory functions of the B cells depended on their maturation status. Thus, phenotypic and functional analyses of the B-cell compartment may be indicated for appropriate follow-up after transplantation and drive therapy in the establishment of transplant tolerance processes. © 2013 International Society of Nephrology.

Canas F.,European University of Brittany | Canas F.,El Rosario University | Simonin L.,European University of Brittany | Simonin L.,Brest University Medical School Hospital | And 3 more authors.
Thrombosis Research | Year: 2015

Antiphospholipid syndrome (APS) is an autoimmune disease characterized by arterial, venous or small-vessel thrombotic events, and recurrent miscarriages or fetal loss. APS diagnosis is based on the repeated detection of anti-phospholipid (PL) antibodies (Ab), typically associatedwith anti-β2 glycoproteinI (β2GPI)-Ab. Recent studies suggest that anti-β2GPI Ab activity involves a protein complex including β2GPI and annexin A2 (ANXA2). Anti-ANXA2 Ab recognizes this complex, and these Ab can effectively promote thrombosis by inhibiting plasmin generation, and by activating endothelial cells. Therefore, anti-ANXA2 Ab represent a new biomarker, which can be detected in up to 25% of APS patients. Moreover, anti-ANXA2 Ab have been detected, in thrombotic associated diseases including pre-eclampsia, in other autoimmune diseases, and in cancer. © 2014 Elsevier Ltd. All rights reserved.

Cornec D.,Brest University Medical School Hospital | Jousse-Joulin S.,Brest University Medical School Hospital | Pers J.-O.,Brest University Medical School Hospital | Marhadour T.,Brest University Medical School Hospital | And 6 more authors.
Arthritis and Rheumatism | Year: 2013

Objective To determine the accuracy of salivary gland ultrasonography (SGUS) for diagnosing primary Sjögren's syndrome (SS) and to suggest modifications of the American-European Consensus Group (AECG) classification criteria. Methods We conducted a cross-sectional study in a prospective cohort of patients with suspected primary SS that was established between 2006 and 2011. The echostructure of the bilateral parotid and submandibular glands was graded from 0 to 4, and the gland size was measured; blood flow to the parotid gland was assessed using Doppler waveform analysis. The reference standard was a clinical diagnosis of primary SS as determined by a group of experts blinded to the results of SGUS. Receiver operating characteristic (ROC) curve analysis was performed to compare the diagnostic value of the 0-4-point echostructure grade for each of the 4 major salivary glands, the sum of the grades for the 4 glands, and the highest grade among the 4 glands. Results Of the 158 patients in the study, 78 had a diagnosis of primary SS according to the experts, including 61 patients (78.2%) who met the AECG criteria. Doppler waveform analysis and gland size measurement showed poor diagnostic performance. The results of ROC curve analysis showed that the highest grade among the 4 glands provided the best diagnostic value. The optimal grade cutoff was 2 (62.8% sensitivity and 95.0% specificity). A weighted score was constructed using scores for the 5 variables selected by logistic regression analysis, as follows: (salivary flow × 1.5) + (Schirmer's test × 1.5) + (salivary gland biopsy × 3) + (SSA/SSB × 4.5) + (SGUS × 2). According to ROC curve analysis, a score of ≥5 of 12.5 had 85.7% sensitivity and 94.9% specificity, compared with 77.9% sensitivity and 98.7% specificity for the AECG criteria. The addition of SGUS to the AECG criteria increased sensitivity to 87.0% but did not change specificity. Conclusion Modifications of the AECG criteria, including the addition of a SGUS score, notably improved diagnostic performance. Copyright © 2013 by the American College of Rheumatology.

Cosimo E.,University of Glasgow | McCaig A.M.,University of Glasgow | McCaig A.M.,Royal Alexandra Hospital | Carter-Brzezinski L.J.M.,University of Glasgow | And 10 more authors.
Clinical Cancer Research | Year: 2013

Purpose: Chronic lymphocytic leukemia (CLL) is currently incurable with standard chemotherapeutic agents, highlighting the need for novel therapies. Overcoming proliferative and cytoprotective signals generated within the microenvironment of lymphoid organs is essential for limiting CLL progression and ultimately developing a cure. Experimental Design: We assessed the potency of cyclin-dependent kinase (CDK) inhibitor CR8, a roscovitine analog, to induce apoptosis in primary CLL from distinct prognostic subsets using flow cytometry-based assays. CLL cells were cultured in in vitro prosurvival and proproliferative conditions to mimic microenvironmental signals in the lymphoid organs, to elucidate the mechanism of action of CR8 in quiescent and proliferating CLL cells using flowcytometry, Western blotting, and quantitative real-time PCR. Results: CR8 was 100-fold more potent at inducing apoptosis in primary CLL cells than roscovitine, both in isolated culture and stromal-coculture conditions. Importantly, CR8 induced apoptosis in CD40-ligated CLL cells and preferentially targeted actively proliferating cells within these cultures. CR8 treatment induced downregulation of the antiapoptotic proteins Mcl-1 and XIAP, through inhibition of RNA polymerase II, and inhibition of NF-κB signaling at the transcriptional level and through inhibition of the inhibitor of IκB kinase (IKK) complex, resulting in stabilization of Ik Ba expression. Conclusions: CR8 is a potent CDK inhibitor that subverts pivotal prosurvival and proproliferative signals present in the tumor microenvironment of CLL patient lymphoid organs. Our data support the clinical development of selective CDK inhibitors as novel therapies for CLL. ©2013 AACR.

Lemoine S.,European University of Brittany | Lemoine S.,Brest University Medical School Hospital | Morva A.,European University of Brittany | Youinou P.,European University of Brittany | And 3 more authors.
Journal of Autoimmunity | Year: 2011

Regulatory functions for B lymphocytes have been reported in murine models of autoimmune diseases in which B-cell deficient mice were shown to exhibit exacerbated disease. The B cells responsible for the immune regulations were identified as a subpopulation of interleukin 10-secreting cells. However, the mechanism of induction and the characteristics of regulatory B cells in humans have been hardly studied. This study reports that regulation of T cell responses can be induced by B cells following CD40-dependent cognate interaction. T cell proliferation and cytokine production were differentially regulated. Thus, CD40-induced regulatory B cells partially inhibited T cell proliferation following CD40 interaction without requirement of soluble factor. In contrast, modulation of Th1 differentiation resulted from CD80- and CD86-dependent interactions and from IL-10 production. The suppressive effects were mediated by CD19highIgD+CD38highCD24highCD5high B cells and appeared to be indirect, through the induction of regulatory T cells as indicated by the appearance of Foxp3+CD4+CD25+T cells. These data suggest that activation signals from T cells initiate regulatory properties in B cells that modulate T cell responses involving regulatory T cells. Finally, studies in autoimmune patients revealed that regulation of T cell proliferation was defective in systemic lupus erythematosus but efficient in other diseases. Restoration of efficient B-cell regulatory activity could provide innovative B-cell based treatment of autoimmune diseases. © 2011 Elsevier Ltd.

Youinou P.,European University of Brittany | Youinou P.,Brest University Medical School Hospital | Saraux A.,European University of Brittany | Saraux A.,Brest University Medical School Hospital | And 2 more authors.
Current Pharmaceutical Biotechnology | Year: 2012

T cells have originally occupied central stage of the debate on the type of lymphocytes governing the pathogenesis of Sjögren's syndrome (SS). However, B cells has since been substituted for T cells, and insights into their functions have revealed that they accomplish various tasks. Beyond the paradigm that T lymphocytes maintain strict control over B lymphocytes, these latter cells solicit their own help from the former, release a flurry of cytokines, and act as antigen- presenting cells. In SS, excessive of the B cell-activating factor (BAFF) may cause B-cell quantitative anomalies, such as inflation of mature B (Bm)2/Bm2' cells in the circulation, or accumulation of transitional type 2, marginal zone (MZ) and memory B cells within the exocrine gland infiltrates. These excesses are also associated with B-cell qualitative anomalies, such as the internal synthesis of BAFF, and a default mechanism that promotes the autoantibody production in ectopic germinal centers or MZ equivalents. Thus, SS should rather be conceived as a quintessential model for B cellinduced autoimmunity. Such a view opens novel prospects for treatment, and indeed B cell-ablative therapy has already been shown to be beneficial to these patients. © 2012 Bentham Science Publishers.

Morva A.,European University of Brittany | Morva A.,University of Western Brittany | Morva A.,Brest University Medical School Hospital | Lemoine S.,European University of Brittany | And 14 more authors.
Blood | Year: 2012

Mature dendritic cells (DCs) are stimulators of T-cell immune response, whereas immature DCs support T-cell tolerance. Murine B cells can inhibit the production of IL-12 by DCs and thereby hinder the inflammatory response. Notwithstanding the importance of this modulation, only a few studies are available in humans. Here, we have developed an in vitro model of cocultures to assess its significance. We establish that human activated B cells restrained the development of monocytes into immature DCs and their differentiation into mature DCs. In addition, they decreased the density of HLA-DR from mature DCs, the expression of CD80 and CD86 coactivation molecules, the production of IL-12p70 required for antigen presentation and Th1 differentiation, and inhibited the DC-induced T-cell proliferation. These modulations were mediated by CD19 +IgD lowCD38 +CD24 lowCD27 -B cells and needed direct cell-to-cell contacts that involved CD62L for the control of CD80 and CD86 expression and a soluble factor for the control of IL-12 production. Moreover, mature DCs from patients with systemic lupus erythematosus displayed insensitivity to the regulation of IL-12. Overall, it appears that human B cells can regulate DC maturation and function and that inefficient B-cell regulation may influence an improper balance between an effector inflammatory response and tolerance induction. © 2012 by The American Society of Hematology.

Tobon G.J.,University of Western Brittany | Renaudineau Y.,University of Western Brittany | Hillion S.,University of Western Brittany | Cornec D.,Brest University Medical School Hospital | And 3 more authors.
Arthritis and Rheumatism | Year: 2010

Objective To determine if the Fms-like tyrosine kinase 3 ligand (Flt-3L), a cytokine implicated in B cell ontogenesis and proliferation in hematologic malignancies, might be responsible for the increased numbers of circulating Bm2 and Bm2- B cell subsets in patients with primary Sjögren's syndrome (SS). Methods Serum levels of Flt-3L were measured in 64 patients with primary SS and in 20 healthy controls matched for age and sex. Flt-3L and its receptor Flt-3 were quantified in circulating B cells and in salivary gland (SG) biopsy tissues by immunofluorescence analysis. The effect of Flt-3L on circulating B lymphocytes was then determined by coculture with cells of a human SG (HSG) epithelial cell line. Results Serum levels of Flt-3L were increased in patients with primary SS as compared with controls (mean ± SD 135.8 ± 5.5 versus 64.4 ± 4.5 pg/ml; P < 0.001). Serum levels of Flt-3L in primary SS patients correlated with the numbers of Bm2 and Bm2- cells (r = 0.46, P < 0.0006), and Flt-3 was selectively expressed in Bm2 and Bm2- cells. B cell culture experiments showed that Flt-3L potentiated the proliferative effect of anti-IgM stimulation. In SGs, we found that infiltrating B cells expressed Flt-3 and epithelial cells produced Flt-3L. Finally, Flt-3L levels were associated with high disease activity scores and increased risk of developing lymphoma. Conclusion Serum levels of Flt-3L are elevated in patients with primary SS and correlate with abnormal B cell distribution. Flt-3 is mainly expressed by Bm2 and Bm2- cells. Serum levels of Flt-3L might explain the clinical evolution of primary SS to B cell lymphoma that is observed in some patients, thus opening the possibility of new avenues for therapy. © 2010 by the American College of Rheumatology.

Seite J.-F.,University of Western Brittany | Cornec D.,University of Western Brittany | Cornec D.,Brest University Medical School Hospital | Renaudineau Y.,University of Western Brittany | And 5 more authors.
Blood | Year: 2010

Among various mechanisms for interactions with B cells, intravenous immunoglobulin (IVIg) may operate through the insertion of its Fc part into the Fc-γ receptor, or the binding of its sialic acid (SA) - bearing glycans to the negatively regulating CD22 lectin. It appeared that IVIg reduces B lymphocyte viability in a doseand time-dependent manner. Furthermore, we show by confocal microscopy that SA-positive IgG, but not SA-negative IgG bind to CD22. This interaction reduces the strength of B-cell receptor-mediated signaling trough down-regulating tyrosine phosphorylation of Lyn and the B-cell linker proteins, and up-regulating phospholipase Cγ2 activation. This cascade resulted in a sustained activation of Erk 1/2 and arrest of the cell cycle at the G1 phase. These changes may be accounted for the efficacy of IVIg in autoimmune diseases. © 2010 by The American Society of Hematology.

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