scholarly journals P2RY8 variants in lupus patients uncover a role for the receptor in immunological tolerance

2021 ◽  
Vol 219 (1) ◽  
Author(s):  
Yuke He ◽  
Antonia E. Gallman ◽  
Chengmei Xie ◽  
Qian Shen ◽  
Jianyang Ma ◽  
...  
Keyword(s):  
Cell Migration ◽  
B Cells ◽  
B Cell ◽  
Intracellular Signaling ◽  
Growth Regulation ◽  
Plasma Cells ◽  
De Novo ◽  
Immunological Tolerance ◽  
Cell Trafficking ◽  
B Cell Subsets

B cell self-tolerance is maintained through multiple checkpoints, including restraints on intracellular signaling and cell trafficking. P2RY8 is a receptor with established roles in germinal center (GC) B cell migration inhibition and growth regulation. Somatic P2RY8 variants are common in GC-derived B cell lymphomas. Here, we identify germline novel or rare P2RY8 missense variants in lupus kindreds or the related antiphospholipid syndrome, including a “de novo” variant in a child with severe nephritis. All variants decreased protein expression, F-actin abundance, and GPCR-RhoA signaling, and those with stronger effects increased AKT and ERK activity and cell migration. Remarkably, P2RY8 was reduced in B cell subsets from some SLE patients lacking P2RY8 gene variants. Low P2RY8 correlated with lupus nephritis and increased age-associated B cells and plasma cells. By contrast, P2RY8 overexpression in cells and mice restrained plasma cell development and reinforced negative selection of DNA-reactive developing B cells. These findings uncover a role of P2RY8 in immunological tolerance and lupus pathogenesis.

scholarly journals Dimethyl fumarate as a first- vs second-line therapy in MS

2018 ◽  
Vol 5 (6) ◽  
pp. e508 ◽  
Author(s):  
Elsebeth Staun-Ram ◽  
Eiman Najjar ◽  
Anat Volkowich ◽  
Ariel Miller
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Plasma Cells ◽  
Dimethyl Fumarate ◽  
Functional Markers ◽  
Immunomodulatory Effects ◽  
Immune Profile ◽  
Line Therapy ◽  
B Cell Subsets

ObjectiveTo elucidate the immunomodulatory effects of dimethyl fumarate (DMF) on B cells in patients with relapsing MS receiving DMF as a “1st-line” vs “2nd-line” therapy.MethodsB cells were isolated from 43 patients with MS at baseline and after 15-week DMF therapy. Phenotype and functional markers and cytokine profile were assessed by flow cytometry. Analysis included clinical and MRI parameters recorded during a 1-year follow-up.Results1st-line and 2nd-line patients presented several differences in their baseline immune profile, which corresponded with differences in their immunologic response to DMF treatment. DMF reduced the proportions of B cells and CD8 T cells whereas increased monocytes. DMF reduced memory B cells, including plasma cells in 2nd-line patients only, whereas strongly increased transitional B cells. Several IL10+ B-cell subsets and TGFβ+ B cells were increased. Proinflammatory LTα+ and TNFα+ B cells were reduced, while IL4+ B cells elevated, whereas IFNγ+ B cells showed opposite effects in 1st-line and 2nd-line patients. HLA and ICAM-1 expression was increased, but % CD86+ B cells reduced. The expression of B-cell activating factor receptor and the proportion of activated CD69 B cells were increased.ConclusionsDMF is associated with increased transitional and IL10+ and TGFβ+ regulatory B cells and a shift toward a more anti-inflammatory immune profile. Cell activation with reduced costimulatory capacity may induce immune hyporesponsiveness. Carryover effects of preceding therapies in 2nd-line patients and the stage of disease influence the immune profile of the patients and the immunomodulatory effects of DMF.

scholarly journals Multiple Myeloma Includes Phenotypically Defined Subsets of Clonotypic CD20+ B Cells that Persist during Treatment with Rituximab

2008 ◽  
Vol 2 ◽  
pp. CMO.S615 ◽  
Author(s):  
Linda M. Pilarski ◽  
Eva Baigorri ◽  
Michael J. Mant ◽  
Patrick M. Pilarski ◽  
Penelope Adamson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
B Cells ◽  
B Cell ◽  
Plasma Cells ◽  
Cell Subset ◽  
Light Scatter ◽  
Cell Compartments ◽  
B Lineage ◽  
B Cell Subsets ◽  
Anti Cd20

Potential progenitor B cell compartments in multiple myeloma (MM) are clinically important. MM B cells and some circulating MM plasma cells express CD20, predicting their clearance by treatment with anti-CD20. Here we describe two types of clonotypic CD20+ B cell in peripheral blood of myeloma patients, identified by their expression of CD19 and CD20 epitopes, their expression of CD45RA and their light scatter properties. Thus, the circulating component of the MM clone includes at least two distinct CD19+ CD20+ B cell compartments, as well as CD138+CD20+ plasma cells. To determine whether either or both B cell subsets and the CD20+ plasma cell subset were depleted by anti-CD20 therapy, they were evaluated before, during and after treatment of patients with rituximab (anti-CD20), followed by quantifying B cell subsets over a 5 month period during and after treatment. Overall, all three types of circulating B lineage cells persist despite treatment with rituximab. The inability of rituximab to prolong survival in MM may result from this failure to deplete CD20+ B and plasma cells in MM.

Impact of Autologous Dendritic Cell Immunotherapy (Arcelis™) on B Cell Subsets in HIV-1-Infected Subjects Receiving Antiretroviral Therapy

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 80-80
Author(s):  
Mohamed-Rachid Boulassel ◽  
Bader Yassine-Diab ◽  
Don Healey ◽  
Charles Nicolette ◽  
Rafick-Pierre Sékaly ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Immune Responses ◽  
B Cell ◽  
Plasma Cells ◽  
Cell Subset ◽  
Cd8 T Cell ◽  
Memory B Cells ◽  
B Cell Subsets ◽  
Hiv 1

Abstract We demonstrated the enhancement of CD8-specific responses following the administration of an immune-based therapy consisting of dendritic cells (DC) electroporated with autologous amplified HIV-1 RNA and CD40 ligand (CD40 L) RNA manufactured by the Arcelis™ process in HIV patients receiving antiretroviral therapy (ART). We conducted a sub study on circulating B cell populations to further assess changes induced by this autologous DC therapy as CD40L is a major B cell co-stimulatory factor. To this end, we assessed B cell subset changes in relation to the proliferative capacity of CD4+ and CD8+ T cells response to DC targets containing the 4 HIV-1 antigens (Gag, Vpr, Rev, Nef). The co-expression of CD19, CD38, IgD, CD10, CD23, CD27, CD5, and CD138 were analyzed by multi-parametric flow cytometry to assess circulating B cell subsets such as naïve resting B-cells (Bm1), activated naïve B cells (Bm2), GC founder cells (Bm2’), centroblasts and centrocytes (Bm3 and Bm4), early memory B cells (eBm5), memory B cells (Bm5), IgD memory cells, plasma cells, and B-1 cells. Changes in B cells subsets were analyzed before and after the four intradermal injections of this immunotherapeutic product containing 1.2 × 107 DC. Ten ART treated subjects with undetectable viral load (< 50 copies/ml), median CD4+ count of 440 cells/μl (range: 316–1102), and with a CD4+ nadir > 200 cells/μl were studied. Throughout the study, no significant changes in CD4+ cell count, CD4/CD8 ratio, and no viral blips were noticed. The percentage of total B cells, Bm1, Bm2, Bm2′, eBm5, IgD memory, plasma cells, and B-1 cell subsets did not significantly change. However, a decrease in the percentage of Bm3 and Bm4 cells was found (0.36 [0.06–0.86] versus 0.11 [0.04–0.36]; P=0.05). Conversely, an important increase in the Bm5 cell subset was evidenced (10.4 [1.6–24.2] versus 18.1 [5.1–27.5]; P=0.005) suggesting a proliferation of B memory cells induced by DC immunization. In addition, the multifunctional and polyvalent CD8+ T cell proliferative responses to the 4 HIV genes used in this immunotherapy were noticed in 8 out of 9 subjects available for analysis and characterized by an effector memory phenotype. No CD4+ T cell immune responses were detected, consistent with the endogenous HLA class I loading of the antigens. Collectively, these results indicate that this immunotherapy induces an increase in the B memory cell population in the absence of inducing any clinically apparent autoimmunity along with strong HIV specific multifunctional CD8+ T cell specific immune responses.

The Chemokine Receptor Profile As Distinctive Criterion Between Normal B-Cell Subsets and As Potential Discriminative Marker to Identify the Cell of Origin in Patients with Chronic Lymphocytic Leukemia and Richter Syndrome

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3890-3890
Author(s):  
Katharina Troppan ◽  
Kerstin Wenzl ◽  
Peter Neumeister ◽  
Christine Beham-Schmid ◽  
Martina Przekopowitz ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Chemokine Receptor ◽  
Chemokine Receptors ◽  
De Novo ◽  
Memory B Cells ◽  
Cell Of Origin ◽  
Richter Syndrome ◽  
Receptor Profile ◽  
B Cell Subsets

Abstract Chemokine receptors are G-protein-coupled cell surface receptors, which dissociate upon activation by their ligands and cause downstream signaling. Several studies have revealed the crucial contribution of chemokine receptors and their ligands in normal B-cell differentiation and development of hematopoietic malignancies. The Richter syndrome (RS) represents the clinico-pathologic transformation of chronic lymphocytic leukaemia (CLL) to an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). Due to the lack of knowledge on the chemokine receptor, we aimed to investigate their expression profile in patients with CLL and Richter syndrome. Therefore, we investigated the mRNA expression levels of 18 known chemokine receptors (CCR1-CCR9, CXCR1-CXCR7, XCR1, CX3CR1) by using semi-quantitative real-time PCR on seven samples of paired (CLL and transformed DLBCL) RS samples, additionally four CLL samples -all of them subsequently transformed into DLBCL-, and eight transformed DLBCL samples originating from CLL. Additionally, 30 samples of de-novo DLBCL, including 10 germinal center B-cell (GCB) lymphomas, 12 non-germinal center B-cell lymphomas (non-GCB), and 8 unclassified DLBCL were included. Four samples of naïve B-cells (CD5 neg), CD5+ naïve B-cells and CD27+ memory B-cells (n=12) served as non-neoplastic controls. No differences in the chemokine receptor profile were detected between CD5+ and negative naïve B-cells. When comparing CD27+ memory B-cells to naïve B-cells a significant lower expression level was found for CCR7 (7-fold), CXCR4 (4-fold), and CXCR5 (1.5 fold). CCR7 (5-fold) and CXCR4 (5-fold) were also lower expressed in CD27+ memory B-cells compared to CD5+ naïve B-cells. Five out of 18 chemokine receptors were differentially expressed comparing the distinct normal B-cell subsets with RS samples. Comparing CLL samples and RS samples to CD5+ naïve B-cells, CXCR4 (12-fold for CLLs and 10-fold for RS samples) and CXCR5 (2-fold for CLLs and 2.4-fold for RS samples) were lower expressed, whereas CXCR3 (10-fold for CLLs and 8.5-fold for the transformed samples) was higher expressed and CCR5 de-novo expressed. Compared to naïve B-cells, the same chemokine receptors were deregulated: CXCR4 (10-fold for CLLs and 8.5-fold for the RS samples) and CXCR5 (2-fold for CLLs and 2.4-fold for the transformed samples) were lower expressed, CXCR3 (45-fold for CLLs and 30-fold for the transformed samples) was higher expressed and CCR5 was de-novo expressed. Comparing CLL samples and transformed RS samples to CD27+ memory B-cells, CCR5 (5.1-fold for CLLs and 4.3-fold for the RS samples) and CCR7 (8.7-fold for CLLs and 10-fold for the transformed samples) were higher expressed in both malignancies. Only one chemokine receptor was found to be differentially expressed in our seven paired RS samples: CCR6 showed a trend of a higher expression (1.4-fold) in CLL components. Considering RS and GCB DLBCL, CCR1, CCR5, and CXCR6 were found to be significantly down-regulated in RS (at least 4-fold), in contrast to CCR7 and CXCR4, which showed higher expression levels in RS (6-fold). CCR1 and CCR5 were lower expressed comparing RS and non-GCB DLBCL (25-fold and 8-fold), whereas CCR7 again, together with CXCR7, was higher expressed (3- fold and 6-fold respectively). Our data indicate a difference in the chemokine receptor profile within normal B-cell subsets. These differences are also reflected in the different expression profile of low and high aggressive component of CLL/RS compared to the distinct B cell subtypes. Hence, in future these multiple deregulated CC and CXC receptors might serve as a further hint in identifying the cell of origin of different B-cell malignancies. Disclosures No relevant conflicts of interest to declare.

scholarly journals Abnormalities of Bone Marrow B Cells and Plasma Cells in Primary Immune Thrombocytopenia

2021 ◽  
Author(s):  
Tianshu Yu ◽  
Haoyi Wang ◽  
Yajing Zhao ◽  
Yafei Yu ◽  
Yu Hou ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Immune Thrombocytopenia ◽  
Plasma Cells ◽  
Plasma Concentrations ◽  
Mrna Levels ◽  
Primary Immune Thrombocytopenia ◽  
B Cell Subsets

Primary immune thrombocytopenia (ITP) is an autoantibody-mediated hemorrhagic disorder where B cells play an essential role. Previous studies have focused on peripheral blood (PB), but B cells in bone marrow (BM) have not been well characterized. We aimed to explore the profile of B cell subsets and their cytokine environments in BM of ITP patients to further clarify the pathogenesis of the disease. B cell subpopulations and their cytokine/chemokine receptors were detected by flow cytometry. Plasma concentrations of cytokines/chemokines were measured by ELISA. mRNA levels of B cell-related transcription factors were determined by qPCR. Regulatory B cell (Breg) function was assessed by quantifying their inhibitory effects on monocytes and T cells in vitro. Decreased proportions of total B cells, naïve B cells and defective Bregs were observed in ITP patients compared with healthy controls (HCs), whereas elevated frequency of long-lived plasma cells was found in BM of autoantibody-positive patients. No statistical difference was observed in plasmablasts or in short-lived plasma cells between ITP patients and HCs. The immunosuppressive capacity of BM Bregs from ITP patients was considerably weaker than that from HCs. In vivo study using an active ITP murine model revealed that Breg transfusion could significantly alleviate thrombocytopenia. Moreover, over-activation of CXCL13-CXCR5 and BAFF/APRIL systems were found in ITP patient BM. Taken together, B cell subsets in BM were skewed toward a proinflammatory profile in ITP patients, suggesting the involvement of dysregulated BM B cells in the development of the disease.

scholarly journals The Role of CXCL13 in Antibody Responses to HIV-1 Infection and Vaccination

2021 ◽  
Vol 12 ◽  
Author(s):  
Yonas Bekele Feyissa ◽  
Francesca Chiodi ◽  
Yongjun Sui ◽  
Jay A. Berzofsky
Keyword(s):  
B Cells ◽  
B Cell ◽  
Neutralizing Antibodies ◽  
Plasma Cells ◽  
B Cell Lymphoma ◽  
Cell Trafficking ◽  
Broadly Neutralizing Antibodies ◽  
G Protein Coupled ◽  
Hiv 1

CXCL13 signals through the G protein-coupled chemokine receptor CXCR5 to drive development of secondary lymphoid tissue as well as B cell and Tfh cell trafficking to germinal centers (GC), which leads to the differentiation of B cells to plasma cells and memory B cells. CXCL13 has been proposed as a general plasma biomarker for GC activities. In HIV-1 infected individuals, plasma CXCL13 levels have been associated with the rate of disease progression to AIDS. Moreover, CXCL13 production has been reported to be increased in HIV-1-infected lymph nodes, which may drive increased downregulation of CXCR5. In this review, we address the role of CXCL13 in HIV-1 infected individuals with regard to GC formation, generation of broadly neutralizing antibodies after infection and vaccination, and AIDS-related B cell lymphoma.

scholarly journals B cell-intrinsic requirement for WNK1 kinase in T cell-dependent antibody responses

2021 ◽  
Author(s):  
Darryl Hayward ◽  
Lesley Vanes ◽  
Stefanie Wissmann ◽  
Sujana Sivapatham ◽  
Harald Hartweger ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Migration ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Plasma Cells ◽  
Antibody Responses ◽  
B Cell Activation

AbstractMigration and adhesion play critical roles in B cells, regulating recirculation between lymphoid organs, migration within lymphoid tissue and interaction with CD4+ T cells. However, there is limited knowledge of how B cells integrate chemokine receptor and integrin signaling with B cell activation to generate efficient humoral responses. Here we show that the WNK1 kinase, a regulator of migration and adhesion, is essential in B cells for T-dependent antibody responses. We demonstrate that WNK1 transduces signals from the BCR, CXCR5 and CD40, and using intravital imaging we show that WNK1 regulates migration of naive and activated B cells, and their interactions with T cells. Unexpectedly, we show that WNK1 is required for BCR- and CD40-induced proliferation, acting through the OXSR1 and STK39 kinases, and for efficient B cell-T cell collaboration in vivo. Thus, WNK1 is critical for humoral immune responses, by regulating B cell migration, adhesion and T cell-dependent activation.SummaryThe WNK1 kinase is essential in B cells for T-dependent antibody responses because it is activated by signaling from BCR, CXCR5 and CD40 and regulates B cell migration, adhesion, T-dependent activation, and differentiation into germinal center B cells and plasma cells.

scholarly journals The B cell-specific transcription factor BSAP regulates B cell proliferation.

1994 ◽  
Vol 179 (4) ◽  
pp. 1099-1108 ◽  
Author(s):  
Y Wakatsuki ◽  
M F Neurath ◽  
E E Max ◽  
W Strober
Keyword(s):  
Cell Proliferation ◽  
Transcription Factor ◽  
B Cells ◽  
B Cell ◽  
Plasma Cells ◽  
Cell Function ◽  
De Novo ◽  
Interleukin 4 ◽  
Cross Linking ◽  
Nuclear Extracts

The B cell-specific activator protein (BSAP) is a DNA-binding transcription factor expressed in pro-B, pre-B, and mature B cells, but not in plasma cells. In this study, we explored the role of BSAP in B cell function by assessing how the content of this protein varies in cells driven by proliferative stimuli and, conversely, how artificial manipulation of BSAP activity affects cell proliferation. We found that BSAP activity of nuclear extracts increased when B cells were activated by mitogen (lipopolysaccharide [LPS]), antigen receptor-mediated signaling (surface immunoglobulin D [IgD] cross-linking) or T cell-dependent stimulation (CD40 cross-linking). We could suppress BSAP activity by exposure of B cells to phosphorothioate oligonucleotides antisense to the BSAP translation initiation start site, whereas control oligonucleotides were virtually inactive. Antisense-induced BSAP suppression was associated with a striking reduction in LPS-induced proliferation of splenic B cells and in the spontaneous proliferation of B lymphoma cells (CH12.LX), but the antisense oligonucleotide had virtually no effect on proliferation of two cell lines lacking BSAP: the T lymphoma line EL-4 and the plasma cell line MOPC-315. Overexpression of BSAP in splenic B cells or de novo expression in MOPC-315 plasma cells induced by transfection of a BSAP expression plasmid stimulated cell proliferation. Taken together, these results suggest that BSAP activity is a rate-limiting regulator of B cell proliferation. We also found that treatment with the antisense BSAP oligonucleotide downregulated Ig class switching induced by interleukin 4 plus LPS. This effect may be secondary to reduced proliferation or could be mediated through BSAP binding sites in the IgH locus.

scholarly journals Recovery of Memory B-cell Subsets and Persistence of Antibodies in Convalescent COVID-19 Patients

2021 ◽  
Author(s):  
Anuradha Rajamanickam ◽  
Nathella Pavan Kumar ◽  
Arul Nancy P ◽  
Nandhini Selvaraj ◽  
Saravanan Munisankar ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Neutralizing Antibodies ◽  
Plasma Cells ◽  
Ex Vivo ◽  
Cell Subset ◽  
Memory B Cells ◽  
Memory B Cell ◽  
Immature B Cells ◽  
B Cell Subsets

It is essential to examine the longevity of the defensive immune response engendered by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. We examined the SARS-CoV-2-specific antibody responses and ex vivo memory B-cell subsets in seven groups of individuals with COVID-19 classified based on days since reverse-transcription polymerase chain reaction confirmation of SARS-CoV-2 infection. Our data showed that the levels of IgG and neutralizing antibodies started increasing from days 15 to 30 to days 61 to 90, and plateaued thereafter. The frequencies of naive B cells and atypical memory B cells decreased from days 15 to 30 to days 61 to 90, and plateaued thereafter. In contrast, the frequencies of immature B cells, classical memory B cells, activated memory B cells, and plasma cells increased from days 15 to 30 to days 61 to 90, and plateaued thereafter. Patients with severe COVID-19 exhibited increased frequencies of naive cells, atypical memory B cells, and activated memory B cells, and lower frequencies of immature B cells, central memory B cells, and plasma cells when compared with patients with mild COVID-19. Therefore, our data suggest modifications in memory B-cell subset frequencies and persistence of humoral immunity in convalescent individuals with COVID-19.

scholarly journals Single-cell repertoire tracing identifies rituximab refractory B cells during myasthenia gravis relapses

2019 ◽  
Author(s):  
Ruoyi Jiang ◽  
Miriam L. Fichtner ◽  
Kenneth B. Hoehn ◽  
Panos Stathopoulos ◽  
Richard J. Nowak ◽  
...  
Keyword(s):  
B Cells ◽  
Myasthenia Gravis ◽  
B Cell ◽  
Single Cell ◽  
De Novo ◽  
Cell Receptor ◽  
Memory B Cells ◽  
Cell Repertoire ◽  
B Cell Subsets ◽  
Antibody Secreting Cells

AbstractRituximab, a B cell-depleting therapy, is indicated for treating a growing number of autoantibody-mediated autoimmune disorders. However, relapses can occur after treatment and autoantibody-producing B cell subsets may be found during relapses. It is not understood if these autoantibody-producing B cell subsets emerge from the failed depletion of pre-existing B cells or are re-generated de novo. To further define the mechanisms that cause post-rituximab relapse, we studied patients with autoantibody-mediated muscle-specific kinase (MuSK) myasthenia gravis (MG) who relapsed after treatment. We carried out single-cell transcriptional and B cell receptor (BCR) profiling on longitudinal B cell samples. We identified clones present prior to therapy that continued to persist during relapse. Persistent B cell clones included both antibody-secreting cells and memory B cells characterized by gene expression signatures associated with B cell survival. A subset of persistent antibody-secreting cells and memory B cells were specific for the MuSK autoantigen. These results demonstrate that rituximab is not fully effective at eliminating autoantibody-producing B cells and provide a mechanistic understanding of post-rituximab relapse in MuSK MG.

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