scholarly journals Class-switched B cells display response to therapeutic B cell depletion in rheumatoid arthritis

2009 ◽  
Vol 11 (3) ◽  
pp. R62 ◽  
Author(s):  
Burkhard Moller ◽  
Daniel Aeberli ◽  
Stefan Eggli ◽  
Martin Fuhrer ◽  
Istvan Vajtai ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
B Cells ◽  
B Cell ◽  
Cell Depletion ◽  
B Cell Depletion

Steady-state generation of mucosal IgA+ plasmablasts is not abrogated by B-cell depletion therapy with rituximab

Blood ◽  
2010 ◽  
Vol 116 (24) ◽  
pp. 5181-5190 ◽  
Author(s):  
Henrik E. Mei ◽  
Daniela Frölich ◽  
Claudia Giesecke ◽  
Christoph Loddenkemper ◽  
Karin Reiter ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Steady State ◽  
B Cells ◽  
B Cell ◽  
Peripheral Blood ◽  
Plasma Cells ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Ki 67

AbstractThe anti-CD20 antibody rituximab depletes human B cells from peripheral blood, but it remains controversial to what extent tissue-resident B cells are affected. In representative patients with rheumatoid arthritis, we here demonstrate that recently activated presumably short-lived plasmablasts expressing HLA-DRhigh and Ki-67 continuously circulate in peripheral blood after B-cell depletion by rituximab at 26%-119% of their initial numbers. They circulate independent of splenectomy, express immunoglobulin A (IgA), β7 integrin, and C-C motif receptor 10 (CCR10) and migrate along CCL28 gradients in vitro, suggesting their mucosal origin. These plasmablasts express somatically hypermutated VH gene rearrangements and spontaneously secrete IgA, exhibiting binding to microbial antigens. Notably, IgA+ plasmablasts and plasma cells were identified in the lamina propria of patients treated with rituximab during peripheral B-cell depletion. Although a relation of these “steady state”–like plasmablasts with rheumatoid arthritis activity could not be found, their persistence during B-cell depletion indicates that their precursors, that is, B cells resident in the mucosa are not deleted by this treatment. These data suggest that a population of mucosal B cells is self-sufficient in adult humans and not replenished by CD20+ B cells immigrating from blood, lymphoid tissue, or bone marrow, that is, B cells depleted by rituximab.

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

2010 ◽  
Vol 69 (12) ◽  
pp. 2181-2188 ◽  
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.

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

PLoS ONE ◽  
2015 ◽  
Vol 10 (6) ◽  
pp. e0128269 ◽  
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

An extra dose of rituximab improves clinical response in rheumatoid arthritis patients with initial incomplete B cell depletion: a randomised controlled trial

2014 ◽  
Vol 74 (6) ◽  
pp. 1195-1201 ◽  
Author(s):  
Edward M Vital ◽  
Shouvik Dass ◽  
Maya H Buch ◽  
Andrew C Rawstron ◽  
Paul Emery
Keyword(s):  
Rheumatoid Arthritis ◽  
B Cells ◽  
B Cell ◽  
Clinical Response ◽  
Controlled Trial ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Double Blind ◽  
Acr20 Response ◽  
Randomised Controlled

ObjectivesSince clinical non-response to 2×1000 mg rituximab has previously been found to be associated with incomplete B cell depletion, we determined, in a randomised controlled proof of concept study, whether patients with initial incomplete B cell depletion would benefit from an additional infusion of rituximab at week 4.MethodsPatients with active rheumatoid arthritis despite methotrexate received a first infusion of rituximab 1000 mg and were tested for persistent B cells using highly sensitive flow cytometry on day 15. All received a second infusion of 1 g (according to license), but patients with persistent B cells were subsequently randomised double-blind to receive, 2 weeks later, either a third infusion of 1000 mg rituximab or placebo. Clinical response was determined by European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) criteria.ResultsBaseline characteristics were balanced between groups. Treatment with 3×1000 mg rituximab resulted in significantly greater depletion (lower B cell and plasmablast numbers between 8 and 28 weeks) paralleled by significantly better EULAR and ACR20 response rates at 40 weeks (p=0.035 and p=0.027, respectively) and 52 weeks (p=0.021 and p=0.043, respectively) compared with 2×1000 mg. Immunoglobulin titres remained stable in both arms, and adverse event rates were balanced.ConclusionsIn rituximab-treated patients with incomplete B cell depletion (predictive of poor response), an extra 1000 mg infusion of rituximab at 4 weeks produced both better depletion and clinical responses than placebo with no worsening of safety. Degree of depletion is an important, but modifiable, determinant of response.

ZAP-70+ B Cell Subset Influences Response to B Cell Depletion Therapy and Early Repopulation in Rheumatoid Arthritis

2012 ◽  
Vol 39 (12) ◽  
pp. 2276-2285 ◽  
Author(s):  
ELISA GREMESE ◽  
BARBARA TOLUSSO ◽  
ANNA LAURA FEDELE ◽  
SILVIA CANESTRI ◽  
STEFANO ALIVERNINI ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
B Cells ◽  
Clinical Outcome ◽  
B Cell ◽  
Peripheral Blood ◽  
Cell Subset ◽  
Cell Depletion ◽  
Poor Responders ◽  
B Cell Depletion ◽  
Switch Memory

Objective.To define the role of ZAP-70+ B cells (CD19+/ZAP-70+) as a biomarker of response to B cell depletion therapy (BCDT), their relationship with clinical outcome, and their behavior during repopulation of peripheral blood in patients with rheumatoid arthritis (RA).Methods.Thirty-one patients with RA underwent BCDT and were followed for 12 months. Disease activity was assessed with the European League Against Rheumatism (EULAR) criteria. Cytofluorimetric analysis of peripheral blood B cell subsets at baseline and at 6- and 12-month intervals after BCDT was performed using surface markers (CD45, CD3, CD56, CD19, IgD, CD38, CD27) and intracellular ZAP-70.Results.A moderate/good EULAR response was achieved in 66.6% of the RA cohort. The baseline percentage of CD19+/ZAP-70+ cells was lower in good responder patients (1.8% ± 1.7%) compared to poor responders (5.6% ± 4.9%; p = 0.02). A decrease of plasmablasts (IgD-CD27+CD38+) and pre-switch memory (IgD+CD27+) B cells occurred after BCDT. Recovery of B cells in peripheral blood after the first course of BCDT was characterized by the reappearance of B cell subtypes that showed a naive, activated phenotype, coupled with a decrease in memory cells. B cells carrying intracytoplasmic ZAP-70 increased significantly from the baseline value of 4.4% ± 4.5% to 12.4% ± 9.2% (p = 0.001) at the 6-month and to 9.4% ± 6.4% (p = 0.002) at the 12-month followup.Conclusion.Baseline percentage of CD19+/ZAP-70+ cells is associated with the clinical outcome after BCDT in patients with RA. Depletion of plasmablasts and pre-switch memory B cells and increase of CD19+/ZAP-70+ cells are features of the recovery of the B cell pool after BCDT.

The level of serum visfatin (PBEF) is associated with total number of B cells in patients with rheumatoid arthritis and decreases following B cell depletion therapy

Cytokine ◽  
2011 ◽  
Vol 55 (1) ◽  
pp. 116-121 ◽  
Author(s):  
Ladislav Šenolt ◽  
Olga Kryštůfková ◽  
Hana Hulejová ◽  
Markéta Kuklová ◽  
Mária Filková ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
B Cells ◽  
B Cell ◽  
Cell Depletion ◽  
B Cell Depletion

scholarly journals B cell depletion with anti-CD20 mAb exacerbates anti-donor CD4+ T cell responses in highly sensitized transplant recipients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Asuka Tanaka ◽  
Kentaro Ide ◽  
Yuka Tanaka ◽  
Masahiro Ohira ◽  
Hiroyuki Tahara ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
T Cell Responses ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Transplant Recipients ◽  
Cell Responses ◽  
Anti Cd20

AbstractPretransplant desensitization with rituximab has been applied to preformed donor-specific anti-human leukocyte antigen antibody (DSA)-positive recipients for elimination of preformed DSA. We investigated the impact of pretransplant desensitization with rituximab on anti-donor T cell responses in DSA-positive transplant recipients. To monitor the patients’ immune status, mixed lymphocyte reaction (MLR) assays were performed before and after desensitization with rituximab. Two weeks after rituximab administration, the stimulation index (SI) of anti-donor CD4+ T cells was significantly higher in the DSA-positive recipients than in the DSA-negative recipients. To investigate the mechanisms of anti-donor hyper responses of CD4+ T cells after B cell depletion, highly sensitized mice models were injected with anti-CD20 mAb to eliminate B cells. Consistent with clinical observations, the SI values of anti-donor CD4+ T cells were significantly increased after anti-CD20 mAb injection in the sensitized mice models. Adding B cells isolated from untreated sensitized mice to MLR significantly inhibited the enhancement of anti-donor CD4+ T cell response. The depletion of the CD5+ B cell subset, which exclusively included IL-10-positive cells, from the additive B cells abrogated such inhibitory effects. These findings demonstrate that IL-10+ CD5+ B cells suppress the excessive response of anti-donor CD4+ T cells responses in sensitized recipients.

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