A. Benyamine

Igg4-related Systemic Disease: Features and Treatment Response in a French Cohort

AbstractIgG4-related systemic disease is now recognized as a systemic disease that may affect various organs. The diagnosis is usually made in patients who present with elevated IgG4 in serum and tissue infiltration of diseased organs by numerous IgG4+ plasma cells, in the absence of validated diagnosis criteria. We report the clinical, laboratory, and histologic characteristics of 25 patients from a French nationwide cohort. We also report the treatment outcome and show that despite the efficacy of corticosteroids, a second-line treatment is frequently necessary. The clinical findings in our patients are not different from the results of previous reports from Eastern countries. Our laboratory and histologic findings, however, suggest, at least in some patients, a more broad polyclonal B cell activation than the skewed IgG4 switch previously reported. These observations strongly suggest the implication of a T-cell dependent B-cell polyclonal activation in IgG4-related systemic disease, probably at least in part under the control of T helper follicular cells.

Correlation of clinicoserologic and pathologic classifications of inflammatory myopathies: study of 178 cases and guidelines for diagnosis.

AbstractThe idiopathic inflammatory myopathies (IIM) are acquired muscle diseases characterized by muscle weakness and inflammation on muscle biopsy. Clinicoserologic classifications do not take muscle histology into account to distinguish the subsets of IIM. Our objective was to determine the pathologic features of each serologic subset of IIM and to correlate muscle biopsy results with the clinicoserologic classification defined by Troyanov et al, and with the final diagnoses. We retrospectively studied a cohort of 178 patients with clinicopathologic features suggestive of IIM with the exclusion of inclusion body myositis. At the end of follow-up, 156 of 178 cases were still categorized as IIM: pure dermatomyositis, n = 44; pure polymyositis, n = 14; overlap myositis, n = 68; necrotizing autoimmune myopathy, n = 8; cancer-associated myositis, n = 18; and unclassified IIM, n = 4. The diagnosis of IIM was ruled out in the 22 remaining cases. Pathologic dermatomyositis was the most frequent histologic picture in all serologic subsets of IIM, with the exception of patients with anti-Ku or anti-SRP autoantibodies, suggesting that it supports the histologic diagnosis of pure dermatomyositis, but also myositis of connective tissue diseases and cancer-associated myositis. Unspecified myositis was the second most frequent histologic pattern. It frequently correlated with overlap myositis, especially with anti-Ku or anti-PM-Scl autoantibodies. Pathologic polymyositis was rare and more frequently correlated with myositis mimickers than true polymyositis. The current study shows that clinicoserologic and pathologic data are complementary and must be taken into account when classifying patients with IIM patients. We propose guidelines for diagnosis according to both clinicoserologic and pathologic classifications, to be used in clinical practice.

BTN3A molecules considerably improve Vγ9Vδ2T cells-based immunotherapy in acute myeloid leukemia

ABSTRACT Given their recognized ability to kill acute myeloid leukemia (AML) blasts both in vitro and in vivo, Vγ9Vδ2 T cells are of growing interest in the design of new strategies of immunotherapy. We show that the Butyrophilin3A (BTN3A, CD277) subfamily is a critical determinant of Vγ9Vδ2 TCR-mediated recognition of human primary AML blasts ex vivo. Moreover, anti-BTN3A 20.1 agonist monoclonal antibodies (mAbs) can trigger BTN3A on AML blasts leading to further enhanced Vγ9Vδ2 T cell-mediated killing, but this mAb had no enhancing effect upon NK cell-mediated killing. We show that monocytic differentiation of primary AML blasts accounts for their AminoBisphosphonate (N-BP)-mediated sensitization to Vγ9Vδ2 T cells. In addition, anti-BTN3A 20.1 mAbs could specifically sensitize resistant blasts to Vγ9Vδ2 T cells lysis and overcome the poor effect of N-BP treatment on those blasts. We confirmed the enhancement of Vγ9Vδ2 T cells activity by anti-BTN3A 20.1 mAb using a human AML xenotransplantation mouse model. We showed that anti-BTN3A 20.1 mAb combined with Vγ9Vδ2 T cells immunotherapy could increase animal survival and decrease the leukemic burden in blood and bone marrow. These findings could be of great interest in the design of new immunotherapeutic strategies for treating AML.

Long-term follow-up after autologous adipose-derived stromal vascular fraction injection into fingers in systemic sclerosis patients

INTRODUCTION Hand involvement confers a substantial handicap in work and daily activities in patients with Systemic sclerosis (SSc). Autologous adipose-derived stromal vascular fraction is as an easily accessible source of cells with regenerative effects. We previously performed a phase I open-label clinical trial (NTC01813279) assessing the safety of subcutaneous injection of autologous adipose-derived stromal vascular fraction. Six and 12-month data have been reported. As patients were followed in our medical centre, we report their longer-term outcome beyond the end of the trial. PATIENTS AND METHOD Twelve females, mean age 54.5±10.3 years, initially enrolled in the clinical trial were assessed during a scheduled medical care, which took place between 22 and 30months after treatment. RESULTS Multiple patient-reported outcomes showed sustained improvement, in comparison with the assessment performed just before surgery: 62.5% in the Cochin Hand Function Scale, 51.1% in the Scleroderma Health Assessment Questionnaire, 33.1% in hand pain, and 88.3% in the Raynaud Condition Score. A decrease in the number of digital ulcers number was noted. Mobility, strength and fibrosis of the hand also showed improvement. None of the 8 patients who had previously received iloprost infusion required new infusion. CONCLUSION Despite the limits of an open label study, the data are in favour of the long-term safety of the adipose-derived stromal vascular fraction injection. Two randomized double blind, placebo-controlled trials of this therapeutic agent are ongoing in the USA (NCT02396238) and in France (NCT02558543) and will help determine the place of this innovative therapy for SSc patients.

Vena Cava Filter Migration: An Unappreciated Complication. About Four Cases and Review of the Literature

Inferior vena cava filter placement is performed to prevent pulmonary risk secondary to deep venous thrombosis. Indications for this treatment are limited to patients experiencing recurrences under well-managed anticoagulant treatment or presenting with contraindication to anticoagulant treatment. Nowadays, as these clinical situations are rare, this device is less and less used, all the more since, for several years now, thrombosis, fracture, or infectious complications as well as filter migration have been reported. Filter migrations are responsible for atypical and varied clinical presentations likely to defer diagnosis. To treat them, the filter is extracted, which is very risky in patients with a thromboembolic history. In our center, during a period of 14 years, we retrospectively collected and studied partial or complete vena cava filter migration cases that had been treated by extraction. We are reporting four very different clinical cases and, more specifically, the second published case of migration to a renal vein, which mimicked a systemic disease. Because of its very atypical clinical presentations, cava filter migration is an unappreciated and certainly underdiagnosed complication. However, this complication must not question cava filter placement when it is justified. In contrast, it prompts early filter extraction or long-term radiological surveillance.

BTN3A is a prognosis marker and a promising target for Vγ9Vδ2 T cells based-immunotherapy in pancreatic ductal adenocarcinoma (PDAC)

ABSTRACT Vγ9Vδ2 T cells are anti-tumor immune effectors of growing interest in cancer including Pancreatic Ductal Adenocarcinoma (PDAC), an especially aggressive cancer characterized by a hypoxic and nutrient-starved immunosuppressive microenvironment. Since Butyrophilin 3 A (BTN3A) isoforms are critical activating molecules of Vγ9Vδ2 T cells, we set out to study BTN3A expression under both basal and stress conditions in PDAC primary tumors, and in novel patient-derived xenograft and PDAC-derived cell lines. BTN3A2 was shown to be the most abundant isoform in PDAC and was stress-regulated. Vγ9Vδ2 T cells cytolytic functions against PDAC required BTN3A and this activity was strongly enhanced by the agonist anti-BTN3A 20.1 mAb even under conditions of hypoxia. In PDAC primary tumors, we established that BTN3A expression and high plasma levels of soluble BTN3A were strongly associated with a decreased survival. These findings may have important implications in the design of new immunotherapeutic strategies that target BTN3A for treating PDAC.

Immunomodulatory Drugs Exert Anti-Leukemia Effects in Acute Myeloid Leukemia by Direct and Immunostimulatory Activities

Immunomodulatory drugs (IMiDs) are anticancer drugs with immunomodulatory, anti-angiogenesis, anti-proliferative, and pro-apoptotic properties. IMiDs are currently used for the treatment of multiple myeloma, myelodysplastic syndrome, and B-cell lymphoma; however, little is known about efficacy in acute myeloid leukemia (AML). We proposed in this study to investigate the relevance of IMiDs therapy for AML treatment. We evaluated the effect of IMiDs on primary AML blasts (n = 24), and the impact in natural killer (NK) cell-mediated immunosurveillance of AML. Using primary AML cells and an immunodeficient mouse leukemia xenograft model, we showed that IMiDs induce AML cell death in vitro and impair leukemia progression in vivo. In addition, treatment of AML blasts with IMiDs resulted in enhanced allogeneic NK cell anti-leukemia reactivity. Treatment by pomalidomide of AML blasts enhanced lysis, degranulation, and cytokine production by primary allogeneic NK cells. Furthermore, the treatment with lenalidomide of patients with myeloid malignancies resulted in NK cell phenotypic changes similar to those observed in vitro. IMiDs increased CD56 and decreased NKp30, NKp46, and KIR2D expression on NK cells. Finally, AML blasts treatment with IMiDs induced phenotypic alterations including downregulation of HLA-class I. The effect of pomalidomide was not correlated with cereblon expression and A/G polymorphism in AML cells. Our data revealed, a yet unobserved, dual effects on AML affecting both AML survival and their sensitivity to NK immunotherapy using IMiDs. Our study encourages continuing investigation for the use of IMiDs in AML, especially in combination with conventional therapy or immunotherapy strategies.

Increased serum levels of fractalkine and mobilisation of CD34+CD45− endothelial progenitor cells in systemic sclerosis

BackgroundThe disruption of endothelial homeostasis is a major determinant in the pathogenesis of systemic sclerosis (SSc) and is reflected by soluble and cellular markers of activation, injury and repair. We aimed to provide a combined assessment of endothelial markers to delineate specific profiles associated with SSc disease and its severity.MethodsWe conducted an observational, single-centre study comprising 45 patients with SSc and 41 healthy control subjects. Flow cytometry was used to quantify circulating endothelial microparticles (EMPs) and CD34+ progenitor cell subsets. Colony-forming unit-endothelial cells (CFU-ECs) were counted by culture assay. Circulating endothelial cells were enumerated using anti-CD146-based immunomagnetic separation. Blood levels of endothelin-1, vascular endothelial growth factor (VEGF) and soluble fractalkine (s-Fractalkine) were evaluated by enzyme-linked immunosorbent assay. Disease-associated markers were identified using univariate, correlation and multivariate analyses.ResultsEnhanced numbers of EMPs, CFU-ECs and non-haematopoietic CD34+CD45− endothelial progenitor cells (EPCs) were observed in patients with SSc. Patients with SSc also displayed higher serum levels of VEGF, endothelin-1 and s-Fractalkine. s-Fractalkine levels positively correlated with CD34+CD45− EPC numbers. EMPs, s-Fractalkine and endothelin-1 were independent factors associated with SSc. Patients with high CD34+CD45− EPC numbers had lower forced vital capacity values. Elevated s-Fractalkine levels were associated with disease severity, a higher frequency of pulmonary fibrosis and altered carbon monoxide diffusion.ConclusionsThis study identifies the mobilisation of CD34+CD45− EPCs and high levels of s-Fractalkine as specific features of SSc-associated vascular activation and disease severity. This signature may provide novel insights linking endothelial inflammation and defective repair processes in the pathogenesis of SSc.

Identification of CD146 as a novel molecular actor involved in systemic sclerosis

We highlight for the first time that CD146/sCD146 is involved in fibrotic process during SSc. sCD146 could thus constitute a new biomarker to assess disease activity, and potentially a new target for therapeutic applications.

Should we look for anti-RNA polymerase III antibodies in systemic sclerosis patients with anti-centromere or anti-topoisomerase I antibodies?

HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L’archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d’enseignement et de recherche français ou étrangers, des laboratoires publics ou privés. Should we look for anti-RNA polymerase III antibodies in systemic sclerosis patients with anti-centromere or anti-topoisomerase I antibodies? Audrey Benyamine, Daniel Bertin, Xavier Heim, Brigitte Granel, Nathalie Bardin