SAT0170 B-cell phenotype and igd-cd27- memory b cells are affected by tnf-inhibitors and tocilizumab treatment in rheumatoid arthritis

Objective.Abatacept (ABA) is a chimeric molecule, able to block the CD28-mediated costimulatory pathway. To evaluate the hypothesis that, through this mechanism of action, ABA may down-modulate the immune responses of B lymphocytes in rheumatoid arthritis (RA), we investigated the serum levels of immunoglobulins (Ig), free light chains (FLC), anticitrullinated protein antibodies (ACPA), and rheumatoid factor (RF), as well as the number of B lymphocytes differentiated into post-switch memory cells in patients treated with ABA.Methods.The serum levels of Ig, FLC, different ACPA, RF isotypes, and the B cell phenotype were longitudinally evaluated in 30 patients with RA treated with ABA.Results.At baseline, the proportion of total and post-switch memory B cells was lower in RA than in healthy individuals. After 6 months of ABA treatment we observed significant reductions of serum levels of IgG, IgA, and IgM, as well as FLC, with a normalization in many patients who had initially abnormal values. A significant reduction of the titers of IgG- and IgA-ACPA, as well as of IgM-, IgA-, and IgG-RF was also observed. A decrease of autoantibodies below the upper limits of normal values was found in 2 of 26 patients (8%) initially seropositive for IgG-ACPA, 1 of 14 (7%) for IgA-ACPA, 5 of 22 (23%) for IgM-RF, 7 of 22 (30%) for IgA-RF, and 5 of 16 (31%) for IgG-RF. After treatment, the proportion of circulating post-switch memory B cells was also further significantly decreased.Conclusion.ABA treatment in patients with RA can reduce signs of polyclonal B cell activation, inducing a trend toward normalization of serum levels of different classes of Ig and of FLC, decreasing titers of ACPA and RF, and percentages of post-switch memory B cells.

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B-cell-activating factor receptor expression on naive and memory B cells: relationship with relapse in patients with rheumatoid arthritis following B-cell depletion therapy

Annals of the Rheumatic Diseases ◽

10.1136/ard.2010.131326 ◽

2010 ◽

Vol 69 (12) ◽

pp. 2181-2188 ◽

Cited By ~ 30

Author(s):

Inmaculada de la Torre ◽

Rita A Moura ◽

Maria J Leandro ◽

Jonathan Edwards ◽

Geraldine Cambridge

Keyword(s):

Rheumatoid Arthritis ◽

B Cells ◽

B Cell ◽

Memory B Cells ◽

Receptor Expression ◽

Cell Depletion ◽

B Cell Depletion ◽

B Cell Activating Factor ◽

Significant Difference ◽

Cell Repopulation

ObjectivesTo examine the expression of B-cell-activating factor receptor (BAFF-R) on naive CD27− and memory CD27+ B cells in normal individuals and patients with rheumatoid arthritis (RA) undergoing B-cell depletion therapy with rituximab.Patients and MethodsBAFF-R expression on B-cell subsets was determined in normal controls (NC; n=11), active patients with RA pre-rituximab (pre-RX; n=15), relapsing patients either concordant for B-cell repopulation (C-R, n=13) or discordant, with relapse more than 3 months after repopulation (D-R, n=11) and patients in remission over 3 months postrepopulation (discordant non-relapsing (D-NR), n=5). Serum BAFF was measured by ELISA and analysed using Mann–Whitney.ResultsThere was no significant difference between NC, pre-RX and D-NR patients in %BAFF-R-positive B cells or mean fluorescence intensity (MFI) in naive and memory B cells. Relapsing patients had significantly lower MFI and %BAFF-R-positive cells in both naive and memory compartments from NC and pre-RX (C-R and D-R; p<0.01). BAFF levels in pre-RX patients were within the normal range and did not correlate with BAFF-R expression in any patient group. D-NR patients had relatively lower proportions of pre and postswitch CD27+ B cells than pre-RX patients (D-NR vs pre-RX; p<0.05 for both) and also lower numbers of postswitch B cells than D-R patients (D-NR vs D-R, p<0.05).ConclusionBAFF-R expression was significantly reduced on both naive and memory B cells in patients at relapse, regardless of the relationship with B-cell repopulation or serum BAFF levels. Re-establishment of active disease was also associated with an increase in class-switch recombination. Factors responsible for lower levels of BAFF-R may relate to altered thresholds for autoreactive B-cell generation at relapse in patients with RA.

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Cytoplasmic FOXO1 identifies a novel disease-activity associated B cell phenotype in SLE

Lupus Science & Medicine ◽

10.1136/lupus-2018-000296 ◽

2018 ◽

Vol 5 (1) ◽

pp. e000296 ◽

Cited By ~ 4

Author(s):

Molly K Hritzo Ahye ◽

Amit Golding

Keyword(s):

B Cells ◽

Disease Activity ◽

B Cell ◽

Lupus Erythematosus ◽

Cell Activation ◽

Activity Index ◽

Human Lymphocytes ◽

Disease Activity Index ◽

Memory B Cells ◽

Cell Phenotype

Systemic lupus erythematosus (SLE) is a manifestation of hyperactivated lymphocytes and results, in part, from the loss of normal tolerance checkpoints. FOXO1 is a transcription factor involved at critical early and late B cell development checkpoints; however, its role in regulating peripheral B cell tolerance is not fully understood. We have applied our published approach for using imaging flow cytometry to study native FOXO1 localisation in human lymphocytes to peripheral blood samples from healthy individuals versus patients with SLE. We report, here, on dramatic cytoplasmic localisation of FOXO1 in two peripheral B cell SLE subsets: IgD-CD27+ (class-switched memory) B cells and IgD-CD27- (atypical memory) B cells. The latter, so-called ‘Double Negative’ (DN) B cells have previously been shown to be increased in SLE and enriched in autoreactive clones. Cytoplasmic-predominant FOXO1 (CytoFOX) B cells are significantly increased in patients with SLE as compared to healthy controls, and the levels of CytoFoOX DN B cells correlate directly with SLE disease activity. The highest abundance of CytoFox DN B cells was observed in African American females with SLE Disease Activity Index (SLEDAI)≥6. The phenotype of CytoFOX DN B cells in SLE includes uniquely low CD20 expression and high granularity/side scatter. As FOXO1 phosphorylation downstream of B cell receptor-dependent signalling is required for nuclear exclusion, CytoFOX B cells likely represent a high state of B cell activation with excess signalling and/or loss of phosphatase activity. We hypothesise that CytoFOX B cells in lupus represent a novel biomarker for the expansion of pathological, autoreactive B cells which may provide new insights into the pathophysiology of SLE.

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A pathogenic and clonally expanded B cell transcriptome in active multiple sclerosis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2008523117 ◽

2020 ◽

Vol 117 (37) ◽

pp. 22932-22943 ◽

Cited By ~ 5

Author(s):

Akshaya Ramesh ◽

Ryan D. Schubert ◽

Ariele L. Greenfield ◽

Ravi Dandekar ◽

Rita Loudermilk ◽

...

Keyword(s):

Multiple Sclerosis ◽

B Cells ◽

B Cell ◽

Single Cell ◽

Rna Sequencing ◽

Chemokine Receptors ◽

Plasma Cells ◽

Cholesterol Biosynthesis ◽

Memory B Cells ◽

Cell Phenotype

Central nervous system B cells have several potential roles in multiple sclerosis (MS): secretors of proinflammatory cytokines and chemokines, presenters of autoantigens to T cells, producers of pathogenic antibodies, and reservoirs for viruses that trigger demyelination. To interrogate these roles, single-cell RNA sequencing (scRNA-Seq) was performed on paired cerebrospinal fluid (CSF) and blood from subjects with relapsing-remitting MS (RRMS; n = 12), other neurologic diseases (ONDs; n = 1), and healthy controls (HCs; n = 3). Single-cell immunoglobulin sequencing (scIg-Seq) was performed on a subset of these subjects and additional RRMS (n = 4), clinically isolated syndrome (n = 2), and OND (n = 2) subjects. Further, paired CSF and blood B cell subsets (RRMS; n = 7) were isolated using fluorescence activated cell sorting for bulk RNA sequencing (RNA-Seq). Independent analyses across technologies demonstrated that nuclear factor kappa B (NF-κB) and cholesterol biosynthesis pathways were activated, and specific cytokine and chemokine receptors were up-regulated in CSF memory B cells. Further, SMAD/TGF-β1 signaling was down-regulated in CSF plasmablasts/plasma cells. Clonally expanded, somatically hypermutated IgM+ and IgG1+ CSF B cells were associated with inflammation, blood–brain barrier breakdown, and intrathecal Ig synthesis. While we identified memory B cells and plasmablast/plasma cells with highly similar Ig heavy-chain sequences across MS subjects, similarities were also identified with ONDs and HCs. No viral transcripts, including from Epstein–Barr virus, were detected. Our findings support the hypothesis that in MS, CSF B cells are driven to an inflammatory and clonally expanded memory and plasmablast/plasma cell phenotype.

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PERIPHERAL BLOOD B-CELL PHENOTYPE IS AFFECTED BY TNF-INHIBITORS AND TOCILIZUMAB TREATMENT IN RHEUMATOID ARTHRITIS

10.26226/morressier.56e174d9d462b8028d88acc8 ◽

2016 ◽

Author(s):

Rita A. Moura

Keyword(s):

Rheumatoid Arthritis ◽

B Cell ◽

Peripheral Blood ◽

Tnf Inhibitors ◽

Cell Phenotype

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IgM+ memory B cells induced in response to Plasmodium berghei adopt a germinal centre B cell phenotype during secondary infection

Parasitology ◽

10.1017/s003118202000061x ◽

2020 ◽

Vol 147 (9) ◽

pp. 994-998 ◽

Cited By ~ 1

Author(s):

Halina M. Pietrzak ◽

Lisa J. Ioannidis ◽

Diana S. Hansen

Keyword(s):

B Cells ◽

B Cell ◽

Plasma Cells ◽

Secondary Infection ◽

Memory B Cells ◽

Germinal Centre ◽

Cell Phenotype ◽

Memory B Cell ◽

Humoral Immune ◽

Transfer Strategies

AbstractEmerging evidence started to delineate multiple layers of memory B cells, with distinct effector functions during recall responses. Whereas most studies examining long-lived memory B cell responses have focussed on the IgG+ memory B cell compartment, IgM+ memory B cells have only recently started to receive attention. It has been proposed that unlike IgG+ memory B cells, which differentiate into antibody-secreting plasma cells upon antigen re-encounter, IgM+ memory B cells might have the additional capacity to establish secondary germinal centre (GC) responses. The precise function of IgM+ memory B cells in the humoral immune response to malaria has not been fully defined. Using a murine model of severe malaria infection and adoptive transfer strategies we found that IgM+ memory B cells induced in responses to P. berghei ANKA readily proliferate upon re-infection and adopt a GC B cell-like phenotype. The results suggest that that IgM+ memory B cells might play an important role in populating secondary GCs after re-infection with Plasmodium, thereby initiating the induction of B cell clones with enhanced affinity for antigen, at faster rates than naive B cells.

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Expansion of Activated Peripheral Blood Memory B Cells in Rheumatoid Arthritis, Impact of B Cell Depletion Therapy, and Biomarkers of Response

PLoS ONE ◽

10.1371/journal.pone.0128269 ◽

2015 ◽

Vol 10 (6) ◽

pp. e0128269 ◽

Cited By ~ 68

Author(s):

Diana G. Adlowitz ◽

Jennifer Barnard ◽

Jamie N. Biear ◽

Christopher Cistrone ◽

Teresa Owen ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

B Cells ◽

B Cell ◽

Peripheral Blood ◽

Memory B Cells ◽

Cell Depletion ◽

B Cell Depletion

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Remission Induced by TNF Inhibitors Plus Methotrexate is Associated With Changes in Peripheral Naïve B Cells in Patients With Rheumatoid Arthritis

Frontiers in Medicine ◽

10.3389/fmed.2021.683990 ◽

2021 ◽

Vol 8 ◽

Author(s):

Borja Hernández-Breijo ◽

Chamaida Plasencia-Rodríguez ◽

Victoria Navarro-Compán ◽

Carlota García-Hoz ◽

Israel Nieto-Gañán ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

B Cells ◽

B Cell ◽

Mononuclear Cells ◽

Tnf Inhibitors ◽

Concomitant Therapy ◽

Peripheral Blood Mononuclear ◽

Logistic Regression Models ◽

Cell Percentage ◽

B Cell Subsets

Biological therapies, such as TNF inhibitors (TNFi), are increasing remission (REM) rates in rheumatoid arthritis (RA) patients, although these are still limited. The aim of our study was to analyze changes in the profile of peripheral blood mononuclear cells (PBMC) in patients with RA treated with TNFi in relation to the clinical response. This is a prospective and observational study including 78 RA patients starting the first TNFi. PBMC were analyzed by flow cytometry both at baseline and at 6 months. Disease activity at the same time points was assessed by DAS28, establishing DAS28 ≤ 2.6 as the criteria for REM. Logistic regression models were employed to analyze the association between the changes in PBMC and REM. After 6 months of TNFi treatment, 37% patients achieved REM by DAS28. Patients who achieved REM showed a reduction in the percentage of naive B cells, but only when patients had received concomitant methotrexate (MTX) (OR: 0.59; 95% CI: 0.39–0.91). However, no association was found for patients who did not receive concomitant MTX (OR: 0.85; 95% CI: 0.63–1.16). In conclusion, PBMC, mainly the B-cell subsets, are modified in RA patients with TNFi who achieve clinical REM. A significant decrease in naive B-cell percentage is associated with achieving REM after 6 months of TNFi treatment in patients who received concomitant therapy with MTX.

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