scholarly journals POS0412 CD21-/LOW B-CELLS ARE INCREASED IN PATIENTS WITH ANKYLOSING SPONDYLITIS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 435.2-436
Author(s):  
R. Wilbrink ◽  
A. Spoorenberg ◽  
S. Arends ◽  
F. G. M. Kroese ◽  
G. M. Verstappen
Keyword(s):  
Ankylosing Spondylitis ◽  
B Cells ◽  
Autoimmune Disease ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Mononuclear Cells ◽  
Cell Subset ◽  
Memory B Cells ◽  
Clinical Parameters ◽  
Color Flow

Background:Ankylosing spondylitis (AS) is a chronic immune mediated inflammatory rheumatic disease, in which primarily the sacroiliac joints and the spine are affected. Extra-skeletal manifestations (ESM) include uveitis, psoriasis, inflammatory bowel disease and peripheral arthritis. In studies into the pathogenesis of AS, B-cells have received little attention most likely due to the lack of auto-antibodies1. A B-cell subset that has been particularly associated with autoreactivity is characterized by low expression of CD21. These CD21-/low B-cells are increased in systemic autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus and primary Sjögren syndrome (pSS)2. At least part of the CD21-/low B-cells are considered to represent anergic, autoreactive B-cells, that fail to become activated through conventional B-cell receptor and CD40 signaling2.Objectives:To phenotypically study the peripheral B-cell compartment in in the blood of AS patients compared to pSS patients, a typical B-cell-associated autoimmune disease, and healthy controls (HC). Special emphasis was given to the CD21-/low compartment.Methods:The proportions and phenotype of peripheral B-cells were assessed in cryopreserved peripheral blood mononuclear cells of 45 AS patients (62% male, mean age 49.2±13.2 years, mean ASDAS 2.5±1.0), 20 age-matched patients with pSS (20% male, mean age 50.6±12.0, median (IQR) ESSDAI 3±6.25) and 30 age- and sex-matched HCs, using 15-color flow-cytometry analysis. Differences between groups were tested using the Independent Samples t-test or Mann-Whitney U test depending on the distribution of variables. Associations between CD21-/low B-cells and clinical parameters were explored using the Pearson or Spearman correlation coefficient.Results:The percentage of total B-cells in AS patients did not differ from pSS patients and HCs. In AS patients, percentages of CD27+ memory B-cells and CD27-IgD+ naïve B-cells were also similar to HCs, whereas CD27+IgD- memory B-cells were significantly reduced in pSS patients, as expected. The proportions of CD27-CD38lowCD21-/low B-cells among total B-cells were significantly increased in both AS (median 6.4%, p<0.0001) and pSS patients (median 7.8%, p<0.0001) compared to HCs (median 4.9%). Interestingly, only in AS patients, expression of chemokine receptors CXCR3 and CXCR5 was significantly elevated on CD27-CD38lowCD21-/low B-cells compared to HCs (p<0.001 and p<0.01, respectively). In comparison to HCs the expression of the immune markers T-bet and CD11c by CD27-CD38lowCD21-/low B-cells was significantly lower in AS patients (p<0.01 and p<0.01, respectively). The distribution of IgM and IgD expression within the CD27-CD38lowCD21-/low B-cell population was similar between all three study groups. Regarding the association between CD27-CD38lowCD21-/low B-cells and clinical parameters in AS patients, we observed a positive correlation with age (r=0.347, p=0.02) and erythrocyte sedimentation rate (ρ=0.386, p=0.01). Furthermore, AS patients with ESM showed increased proportions of CD27-CD38lowCD21-/low B-cells compared to patients without ESM (p<0.05).Conclusion:In this cross-sectional study, we observed an increased proportion of circulating CD27-CD38lowCD21-/low B-cells in AS patients, similar as in patients with pSS, a typical B-cell-mediated autoimmune disease. The elevated expression of CXCR3 on CD27-CD38lowCD21-/low B-cells in AS patients is suggestive for active involvement in the inflammatory response. These findings are indicative of B-cell involvement in the pathogenesis of AS, against current dogma.References:[1]Ranganathan V et al. Nat Rev Rheumatol. 2017;13(6):359-367.[2]Thorarinsdottir K et al. Scand J Immunol. 2015;82(3):254-261.Disclosure of Interests:Rick Wilbrink: None declared, Anneke Spoorenberg: None declared, Suzanne Arends: None declared, Frans G.M. Kroese Speakers bureau: BMS, Roche, Janssen-Cilag, Consultant of: BMS, Grant/research support from: BMS, Gwenny M. Verstappen: None declared

scholarly journals Belimumab alters transitional B-cell subset proportions in patients with stable systemic lupus erythematosus

Lupus ◽  
2019 ◽  
Vol 28 (11) ◽  
pp. 1337-1343 ◽  
Author(s):  
A Benitez ◽  
K Torralba ◽  
M Ngo ◽  
L M Salto ◽  
K S Choi ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
B Cells ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Mononuclear Cells ◽  
Cell Subset ◽  
Systemic Lupus ◽  
Peripheral Blood Mononuclear ◽  
Healthy Donors ◽  
Immature B Cells

Objective We evaluated the effects of the B-cell activating factor (BAFF)-targeting antibody Belimumab on human nonmemory B-cell pools. Human B-cell pools were identified using surface markers adapted from mouse studies that specifically assessed reductions in immature B cells due to BAFF depletion. Patients with systemic lupus erythematosus (SLE) have high levels of both BAFF and immature B cells. Mechanistic mouse studies provide a framework for understanding human responses to therapies that target B cells. Methods Peripheral blood mononuclear cells were isolated from healthy donors and SLE patients on Belimumab or standard-of-care therapy (SCT). Cells were stained for flow cytometry to identify B-cell subsets based on CD21/CD24. Differences in subset proportions were determined by one-way ANOVA and Tukey’s post hoc test. Results Patients treated with Belimumab show alterations in the nonmemory B-cell pool characterized by a decrease in the Transitional 2 (T2) subset ( p = 0.002), and an increase in the proportion of Transitional 1 (T1) cells ( p = 0.005) as compared with healthy donors and SCT patients. The naïve B-cell compartment showed no significant differences between the groups ( p = 0.293). Conclusion Using a translational approach, we show that Belimumab-mediated BAFF depletion reduces the T2 subset in patients, similar to observations in mouse models with BAFF depletion.

scholarly journals Altered B cells homeostasis in child-onset immunoglobulin A vasculitis

2020 ◽  
Author(s):  
Deying Liu ◽  
Yanfang Jiang ◽  
Jinghua Wang ◽  
Jinxiang Liu ◽  
Meng Xu ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Mononuclear Cells ◽  
Immunoglobulin A ◽  
Cell Subset ◽  
Memory B Cells ◽  
Peripheral Blood Mononuclear ◽  
Cell Numbers ◽  
Cell Counts ◽  
Immunoglobulin A Vasculitis

AbstractBackgroundImmunoglobulin A vasculitis (IgAV), also called Henoch–Schönlein purpura, is a systemic small vessels vasculitis with immunoglobulin A1-dominant immune deposits. B-cells are a heterogeneous population with unique subsets distinguished by their phenotypes and cytokine production. Here, we explored the status of B cell subsets in patients with IgAV.MethodsThirty IgAV patients and fifteen age- and sex-matched healthy individuals were enrolled in this study. Fresh blood samples were collected from both healthy and IgAV patients. Upon the distinct expressions of CD3, CD19, CD20, CD38, CD27 and IgD, peripheral blood mononuclear cells (PBMCs) were initially categorized into plasmablasts and memory B cells. Subsequently, using surface markers including CD138 and IgM, and intracellular markers containing IgM and IgG, plasmablasts and memory B cells were further divided into distinct subgroups. A total of eleven populations were detected using multiple flow cytometry.ResultsCD3-CD19+IgD+CD27-, CD3-CD19+CD20-CD38+, CD3-CD19+CD20-CD38+IgM+, and CD3-CD19+CD20-CD38+CD138+ B cells were larger in patients with IgAV than in the HCs. Only CD3-CD19+IgD-CD27+IgM+ B cell counts were reduced in IgAV. The elevated B cell numbers returned to normal after treatment. Plasma and plasmablast B cell numbers correlated with plasma IgA levels. On the contrary, CD3-CD19+IgD-CD27+IgM+ B cell numbers were negatively proportional to the plasma IgA levels while naïve B cell numbers correlated with plasma and plasmablast B cell counts.ConclusionsWe hypothesized that immunoglobulin production was abnormally elevated in IgAV and could be explained by altered B-cell subset homeostasis.

scholarly journals Characterization of a rare IL-10–competent B-cell subset in humans that parallels mouse regulatory B10 cells

Blood ◽  
2011 ◽  
Vol 117 (2) ◽  
pp. 530-541 ◽  
Author(s):  
Yohei Iwata ◽  
Takashi Matsushita ◽  
Mayuka Horikawa ◽  
David J. DiLillo ◽  
Koichi Yanaba ◽  
...  
Keyword(s):  
B Cells ◽  
Autoimmune Disease ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Ex Vivo ◽  
Cell Subset ◽  
Cell Subpopulation ◽  
B10 Cells

Abstract Regulatory B cells control inflammation and autoimmunity in mice, including the recently identified IL-10–competent B10 cell subset that represents 1% to 3% of spleen B cells. In this study, a comparable IL-10–competent B10 cell subset was characterized in human blood. B10 cells were functionally identified by their ability to express cytoplasmic IL-10 after 5 hours of ex vivo stimulation, whereas progenitor B10 (B10pro) cells required 48 hours of in vitro stimulation before they acquired the ability to express IL-10. B10 and B10pro cells represented 0.6% and approximately 5% of blood B cells, respectively. Ex vivo B10 and B10pro cells were predominantly found within the CD24hiCD27+ B-cell subpopulation that was able to negatively regulate monocyte cytokine production through IL-10–dependent pathways during in vitro functional assays. Blood B10 cells were present in 91 patients with rheumatoid arthritis, systemic lupus erythematosus, primary Sjögren syndrome, autoimmune vesiculobullous skin disease, or multiple sclerosis, and were expanded in some cases as occurs in mice with autoimmune disease. Mean B10 + B10pro-cell frequencies were also significantly higher in patients with autoimmune disease compared with healthy controls. The characterization of human B10 cells will facilitate their identification and the study of their regulatory activities during human disease.

scholarly journals Invariant NKT cells limit activation of autoreactive CD1d-positive B cells

2010 ◽  
Vol 207 (5) ◽  
pp. 943-952 ◽  
Author(s):  
Fredrik Wermeling ◽  
Sara M. Lind ◽  
Emilie Domange Jordö ◽  
Susanna L. Cardell ◽  
Mikael C.I. Karlsson
Keyword(s):  
B Cells ◽  
Autoimmune Disease ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Cell Activation ◽  
Cell Subset ◽  
Peripheral Tolerance ◽  
Inkt Cells ◽  
Autoantibody Production ◽  
Autoreactive B Cells

Faulty activation of autoreactive B cells is a hallmark of autoimmune diseases like systemic lupus erythematosus (SLE). An important feature restricting activation of autoreactive B cells is efficient removal of apoptotic material. Mounting evidence also connects a primary defect in invariant natural killer T (iNKT) cells to autoimmune disease development. However, exactly how this unconventional T cell subset is involved remains to be defined. Here, we identify a suppressive role for iNKT cells in a model where autoantibody production is triggered by an increased load of circulating apoptotic cells, resembling the situation in SLE patients. Absence or reduction of iNKT cells as well as absence of CD1d-expression on B cells, needed for direct iNKT–B cell interaction, leads to increased autoreactive B cell activation and symptoms of disease. The suppression mediated by the iNKT cells is observed before B cell entry into germinal centers and can be rescued by transferring iNKT cells to deficient mice. This links iNKT cells to handling of dying cells and identifies a novel peripheral tolerance checkpoint relevant for autoimmune disease. Thus, these observations connect two clinical observations in SLE patients previously considered to be unrelated and define a new target for immunotherapy.

scholarly journals OP0186 CHANGES IN CIRCULATING B CELL LEVELS AND IMMUNOPHENOTYPE ARE ASSOCIATED WITH DEVELOPMENT OF ARTHRITIS FOLLOWING TREATMENT WITH CHECKPOINT INHIBITORS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 112.2-113
Author(s):  
M. Gatto ◽  
S. Bjursten ◽  
C. Jonell ◽  
C. Jonsson ◽  
S. Mcgrath ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
B Cells ◽  
Adverse Events ◽  
B Cell ◽  
Mononuclear Cells ◽  
Checkpoint Inhibitors ◽  
Therapy Monitoring ◽  
Cell Subset ◽  
Peripheral Blood Mononuclear ◽  
Transitional B Cells

Background:Inflammatory arthritis (IA) is frequent among rheumatic side effects induced by checkpoint inhibitor (CPI) therapy for metastatic malignancies1. While T cells are likely to sustain the inflammatory process2, fewer data are available concerning the role of B cells3.Objectives:To investigate the phenotype of circulating B cells in patients who develop CPI-induced IA (CPI-IA) and to compare it with features of B cells in patients not developing immune-related adverse events (irAE) upon CPI treatment.Methods:B cell subsets at baseline (before CPI initiation) and during CPI treatment were analyzed in CPI-IA patients and in patients receiving CPI but who did not develop irAE (non-irAE). Peripheral blood mononuclear cells (PBMC) were analyzed by flow cytometry and B cells were identified as CD19+ and divided into naïve (CD27-IgD+), memory (CD27+IgD+/-), double negative (CD27-IgD-) and transitional (CD10+CD24+CD38+/hi) B cells. Levels of CD21, an activation marker on transitional B cells, were also analyzed. Non-parametric tests were used for analysis of differences between groups.Results:Six CPI-IA and 7 non-irAE patients matched for age, gender and CPI treatment were included, who had received CPI treatment due to metastatic melanoma. Flow cytometry revealed a significant increase of circulating B cells (p=0.002) (Figure 1A) and especially of transitional B cells in CPI-IA patients vs. non-irAE (median %, range: 7.8 (4.5-11.4) vs. 3.2 (1.6-4.3),p=0.007) (Figure 1B), while no remarkable changes were seen across other subsets. Transitional B cell levels significantly decreased from active to quiescent CPI-IA in all patients (p=0.008). In two CPI-IA patients for whom baseline sampling was available, the increase of transitional levels occurred early after CPI treatment and before CPI-IA onset. Levels of expression of CD21 on transitional B cells were increased in CPI-IA vs. non-irAE (p=0.01).Conclusion:Transitional B cells are expanded in CPI-IA patients and seem to increase early after start of CPI therapy. Monitoring this B cell subset might lead to closer follow-up and earlier diagnosis of CPI-IA.References:[1]Ramos-Casals M, Brahmer JR, Callahan MK, et al. Immune-related adverse events of checkpoint inhibitors. Nat Rev Dis Primers 2020;6:38[2]Murray-Brown W, Wilsdon TD, Weedon H, et al. Nivolumab-induced synovitis is characterized by florid T cell infiltration and rapid resolution with synovial biopsy-guided therapy. J Immunother Cancer 2020;8:e000281[3]Das R, Bar N, Ferreira M, et al. Early B cell changes predict autoimmunity following combination immune checkpoint blockade. J Clin Invest. 2018;128:715-2Disclosure of Interests:None declared

scholarly journals Proportions of B-cell subsets are altered in incomplete systemic lupus erythematosus and correlate with interferon score and IgG levels

Rheumatology ◽  
2020 ◽  
Vol 59 (9) ◽  
pp. 2616-2624
Author(s):  
Svenja Henning ◽  
Wietske M Lambers ◽  
Berber Doornbos-van der Meer ◽  
Wayel H Abdulahad ◽  
Frans G M Kroese ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Cell Subset ◽  
Cross Sectional Study ◽  
Type I ◽  
Healthy Controls ◽  
Sectional Study ◽  
Cross Sectional ◽  
B Cell Subsets

Abstract Objectives Incomplete SLE (iSLE) patients display symptoms typical for SLE but have insufficient criteria to fulfil the diagnosis. Biomarkers are needed to identify iSLE patients that will progress to SLE. IFN type I activation, B-cell-activating factor (BAFF) and B-cell subset distortions play an important role in the pathogenesis of SLE. The aim of this cross-sectional study was to investigate whether B-cell subsets are altered in iSLE patients, and whether these alterations correlate with IFN scores and BAFF levels. Methods iSLE patients (n = 34), SLE patients (n = 41) with quiescent disease (SLEDAI ≤4) and healthy controls (n = 22) were included. Proportions of B-cell subsets were measured with flow cytometry, IFN scores with RT-PCR and BAFF levels with ELISA. Results Proportions of age-associated B-cells were elevated in iSLE patients compared with healthy controls and correlated with IgG levels. In iSLE patients, IFN scores and BAFF levels were significantly increased compared with healthy controls. Also, IFN scores correlated with proportions of switched memory B-cells, plasma cells and IgG levels, and correlated negatively with complement levels in iSLE patients. Conclusion In this cross-sectional study, distortions in B-cell subsets were observed in iSLE patients and were correlated with IFN scores and IgG levels. Since these factors play an important role in the pathogenesis of SLE, iSLE patients with these distortions, high IFN scores, and high levels of IgG and BAFF may be at risk for progression to SLE.

scholarly journals Selective dysregulation of the FcγIIB receptor on memory B cells in SLE

2006 ◽  
Vol 203 (9) ◽  
pp. 2157-2164 ◽  
Author(s):  
Meggan Mackay ◽  
Anfisa Stanevsky ◽  
Tao Wang ◽  
Cynthia Aranow ◽  
Margaret Li ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Cell Activation ◽  
Cell Receptor ◽  
Memory B Cells ◽  
Therapeutic Interventions ◽  
B Cell Activation ◽  
Loss Of Self ◽  
Novel Target

The inappropriate expansion and activation of autoreactive memory B cells and plasmablasts contributes to loss of self-tolerance in systemic lupus erythematosus (SLE). Defects in the inhibitory Fc receptor, FcγRIIB, have been shown to contribute to B cell activation and autoimmunity in several mouse models of SLE. In this paper, we demonstrate that expression of FcγRIIB is routinely up-regulated on memory B cells in the peripheral blood of healthy controls, whereas up-regulation of FcγRIIB is considerably decreased in memory B cells of SLE patients. This directly correlates with decreased FcγRIIB-mediated suppression of B cell receptor–induced calcium (Ca2+) response in those B cells. We also found substantial overrepresentation of African-American patients among those who failed to up-regulate FcγRIIB. These results suggest that the inhibitory receptor, FcγRIIB, may be impaired at a critical checkpoint in SLE in the regulation of memory B cells; thus, FcγRIIB represents a novel target for therapeutic interventions in this disease.

Peripheral B cell abnormalities in patients with systemic lupus erythematosus in quiescent phase: Decreased memory B cells and membrane CD19 expression

2010 ◽  
Vol 34 (4) ◽  
pp. 426-434 ◽  
Author(s):  
Anne-Sophie Korganow ◽  
Anne-Marie Knapp ◽  
Hélène Nehme-Schuster ◽  
Pauline Soulas-Sprauel ◽  
Vincent Poindron ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
B Cells ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Memory B Cells ◽  
Systemic Lupus ◽  
Quiescent Phase ◽  
Cd19 Expression

scholarly journals Optimisation of ex vivo memory B cell expansion/differentiation for interrogation of rare peripheral memory B cell subset responses

2018 ◽  
Vol 2 ◽  
pp. 97 ◽  
Author(s):  
Luke Muir ◽  
Paul F. McKay ◽  
Velislava N. Petrova ◽  
Oleksiy V. Klymenko ◽  
Sven Kratochvil ◽  
...  
Keyword(s):  
Cell Culture ◽  
B Cells ◽  
B Cell ◽  
Cell Expansion ◽  
Ex Vivo ◽  
Cell Subset ◽  
Human Memory ◽  
Memory B Cells ◽  
Memory B Cell ◽  
B Cell Subsets

Background:Human memory B cells play a vital role in the long-term protection of the host from pathogenic re-challenge. In recent years the importance of a number of different memory B cell subsets that can be formed in response to vaccination or infection has started to become clear. To study memory B cell responses, cells can be culturedex vivo,allowing for an increase in cell number and activation of these quiescent cells, providing sufficient quantities of each memory subset to enable full investigation of functionality. However, despite numerous papers being published demonstrating bulk memory B cell culture, we could find no literature on optimised conditions for the study of memory B cell subsets, such as IgM+memory B cells.Methods:Following a literature review, we carried out a large screen of memory B cell expansion conditions to identify the combination that induced the highest levels of memory B cell expansion. We subsequently used a novel Design of Experiments approach to finely tune the optimal memory B cell expansion and differentiation conditions for human memory B cell subsets. Finally, we characterised the resultant memory B cell subpopulations by IgH sequencing and flow cytometry.Results:The application of specific optimised conditions induce multiple rounds of memory B cell proliferation equally across Ig isotypes, differentiation of memory B cells to antibody secreting cells, and importantly do not alter the Ig genotype of the stimulated cells. Conclusions:Overall, our data identify a memory B cell culture system that offers a robust platform for investigating the functionality of rare memory B cell subsets to infection and/or vaccination.

scholarly journals Favorable efficacy of rituximab in ANCA-associated vasculitis patients with excessive B cell differentiation

2020 ◽  
Author(s):  
Yusuke Miyazaki ◽  
Shingo Nakayamada ◽  
Satoshi Kubo ◽  
Yuichi Ishikawa ◽  
Maiko Yoshikawa ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Selection Criteria ◽  
Memory B Cells ◽  
Phenotypic Characterization ◽  
B Cell Differentiation ◽  
Color Flow ◽  
Anca Associated Vasculitis ◽  
Cell Phenotypes

Abstract Objectives: B-cell depletion by rituximab (RTX) is an effective treatment for anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV). However, peripheral B cell phenotypes and the selection criteria for RTX therapy in AAV remain unclear.Methods: Phenotypic characterization of circulating B cells was performed by 8-color flow cytometric analysis in 54 newly diagnosed AAV patients (20 granulomatosis with polyangiitis and 34 microscopic polyangiitis). Patients were considered eligible to receive intravenous cyclophosphamide pulse (IV-CY) or RTX. All patients also received high-dose glucocorticoids (GC). We assessed circulating B cell phenotypes and evaluated the efficacy after 6 months of treatment. Results: There were no significant differences in the rate of clinical improvement, relapses, or serious adverse events between patients receiving RTX and IV-CY. The rate of Birmingham Vasculitis Activity Score (BVAS)-improvement at 6 months tended to be higher in the RTX group than in the IV-CY group. The proportion of effector or class-switched memory B cells increased in 24 out of 54 patients (44%). The proportions of peripheral T and B cell phenotypes did not correlate with BVAS at baseline. However, among peripheral B cells, the proportion of class-switched memory B cells negatively correlated with the rate of improvement in BVAS at 6 months after treatment initiation (r = -0.28, p = 0.04). Patients with excessive B cell differentiation were defined as those in whom the proportion of class-switched memory B cells or IgD-CD27- B cells among all B cells was >2 SDs higher than the mean in the HCs. The rate of BVAS-remission in patients with excessive B cell differentiation was significantly lower than that in patients without. In patients with excessive B cell differentiation, the survival rate, the rate of BVAS-remission, and dose reduction of GC were significantly improved in the RTX group compared to those in the IV-CY group after 6 months of treatment. Conclusions: The presence of excessive B cell differentiation was associated with treatment resistance. However, in patients with circulating B cell abnormality, RTX was effective and increased survival compared to IV-CY. The results suggest that multi-color flow cytometry may be useful to determine the selection criteria for RTX therapy in AAV patients. (349/350 words)

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