Expression Profile and Regulation of BAFF and APRIL Receptors in Chronic Lymphocytic Leukemia,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3880-3880
Author(s):  
Gerardo Ferrer ◽  
Kate E Hodgson ◽  
Victor Ciria ◽  
Tycho Baumann ◽  
Gael Roue ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Disease Progression ◽  
Cell Activation ◽  
Receptor Expression ◽  
Leukemic Cells ◽  
Healthy Controls ◽  
Cd40 Ligation ◽  
Mutational Status ◽  
Risk Of Disease

Abstract Abstract 3880 The two TNF family proteins, B-cell activating factor [BAFF] and a proliferation-inducing ligand [APRIL], and their three receptors, transmembrane activator and CAML interactor [TACI], B-cell maturation antigen [BCMA], and BAFF receptor [BAFF-R] are critical regulators of normal B-cell development and survival. In CLL, both proteins can rescue CLL cells from apoptosis as shown in in vitro studies. We and others have previously shown that patients with CLL and other B-cell chronic lymphoproliferative disorders show abnormal BAFF and APRIL serum levels. Additionally, a few reports indicate that CLL cells can express BAFF and APRIL receptors. Nevertheless, there is no a meaningful and comparative analysis of BAFF-R, TACI and BCMA levels in CLL. We therefore quantitatively assessed BAFF-R, TACI and BCMA on B-cells from patients with CLL and healthy controls. The expression of BAFF-R, TACI and BCMA was analyzed by flow cytometry in purified peripheral blood B cells from 42 patients with CLL and 13 healthy controls. BAFF receptor was the most highly expressed receptor in both CLL and normal B cells (MFI ratios, 161.5 and 179.1, respectively). TACI was heterogeneously expressed and almost undetectable in 15 CLL and 5 normal B cells. BCMA was expressed on all CLL and normal B cells. Furthermore, the expression of TACI and BCMA was significantly higher on CLL cells than on normal B cells (p=0.034 and p<0.001, respectively). A correlation was also observed between the expression of BAFF and APRIL receptors and prognostic factors (i.e, IGHV mutational status and cytogenetics). Higher BCMA expression on leukemic cells were detected in patients with unmutated IGHV gene and high-risk genetics (17p-, 11q-, trisomy 12 or 3 or more cytogenetics abnormalities) (p=0.045 and p=0.068). Additionally, patients with higher levels of BCMA on the CLL cells also had a significantly higher risk of disease progression, with a median progression-free interval of 57 vs. 206 months (p=0.021). We further examined whether activation signals can modulate BAFF-R, TACI and BCMA expression and thereby the sensitivity of CLL cells to respond to BAFF and APRIL. In 10 CLL patients (5 mutated, 5 unmutated) and six healthy controls, receptors expression was measured at 48 hours after stimulation with F(ab')2 antihuman IgM (10 μg/ml) and CD40L (500ng/ml) plus IL-4 (20ng/ml). Cell activation and viability, as assessed by labeling of CD69 and Annexin V/TO-PRO-3, were evaluated at 48 and 72 hours after co-stimulation with either soluble BAFF (100ng/ml) or APRIL (500ng/ml). After 48h culture, an increase of all three receptors was observed in normal B-cells in response to either BCR stimulation or CD40 ligation. In CLL cells, CD40 ligation induced a significant up-regulation of TACI expression (p=0.007) and a significant reduction of BCMA expression (p=0.007). In contrast, BCR stimulation induced almost no variation in CLL receptors expression. This was accompanied by a failure of cell activation and a significant decreased viability of CLL cells (from 36% to 24% p=0.013). Of note, no differences were observed in the regulation of BAFF and APRIL receptors nor in the activation or viability on CLL cells according to the IGHV mutational status. The addition of exogenous soluble BAFF or APRIL resulted in an increase in the viability of normal B-cells at 72 hours independently of cells stimulation through BCR or CD40 ligation. The viability of CLL cells was significantly increased upon CD40 stimulation whereas in non-stimulated or BCR-stimulated CLL cells the addition of BAFF and APRIL had a modest effect on their viability. Altogether, these results indicate that BAFF and APRIL receptors are differentially expressed on CLL and normal B-cells, with TACI and BCMA being highly expressed on leukemic cells. In addition, higher BCMA expression was significantly associated with poor prognostic variables (i.e, unmutated IGHV genes, poor cytogenetics) and higher risk of disease progression. Interestingly, activatory signals including BCR and CD40 ligation influenced BAFF and APRIL receptor expression and responsiveness to either BAFF or APRIL. CD40 ligation on CLL cells induced TACI up regulation by positively impacting on the survival promoting effect of BAFF and APRIL. Collectively, these findings link positive regulatory signals of BCR and CD40 ligation with the pro-survival effect of BAFF and APRIL and their receptors on leukemic CLL cells. Disclosures: No relevant conflicts of interest to declare.

Activation and Proliferation of B Cell Chronic Lymphocytic Leukaemia (B-CLL) Cells through Anti-CD180, Anti-CD40 and IL-4.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4775-4775
Author(s):  
Nino Porakishvili ◽  
Maria Manoussaka ◽  
Nino Kulikova ◽  
James Walton ◽  
Amit Nathwani ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Normal Control ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Leukemic Cells ◽  
B Cell Activation ◽  
Cell Cycle Protein ◽  
Cd40 Ligation ◽  
Ki 67

Abstract Introduction: We have previously shown that Toll-like receptor RP105 (CD180) is heterogeneously expressed on B-CLL cells and that the ligation of CD180 by monoclonal antibodies (mAb) on CD180+ B-CLL cells resulted in delineation of responder and non-responder B-CLL clones [1]. In this study we have examined the role of IL-4 together with CD180 and CD40 as activation signals. Methods: Blood mononuclear cells were separated from 7 responder B-CLL patients with both mutated and unmutated Ig Vh genes and 11 controls and were cultured for 72 hours in optimum concentrations of anti-CD180 (G28-8) or anti-CD40 mAb or both in presence and absence of 15 ng/ml of IL-4. CD19+ B cells were stained with mAb to the activation marker CD86 or cell cycle protein Ki-67, measured by flow cytometry and expressed as Mean Fluorescence Intensity (MFI) or % of Ki-67+ cells. Results: B-CLL cells and normal control B cells responded to CD180-ligation by activation and proliferation (Table). Higher levels of CD86 and Ki67 were detected when both anti CD40 mAb and anti CD180 mAb were added (p&lt;0.05) compared with either alone. IL4 alone induced both activation and proliferation of control cells and this was even higher with the leukemic cells (p&lt;0.01) confirming that IL-4 also provides a strong survival/activatory stimulus for B-CLL cells. Addition of IL-4 had no significant enhancing effect on normal B-cells stimulated with both anti-CD180 and anti-CD40, although IL-4 synergised with anti-CD40 in B cell activation (p=0.026) and with CD180 in B cell proliferation (p=0.044). Conclusion: CD180 had an additive effect with CD40 ligation in activation and proliferation of both B-CLL cells and normal control B cells. IL-4 provides a strong additional stimulus for B-CLL cells. CD86 and Ki-67 expression by CD19+ cells CD86 Ki67 B-CLL Control B-CLL control Spontaneous −IL-4 7.2±4.1 4.0±1.0 8.1±2.7 17.4±2.3 +IL-4 22.4±11.8 11.2±4.2 17.0±12.8 23.6±14.8 CD180 −IL-4 14.7±5.8 26.9±13.0 17.1±10.9 28.1±12.0 +IL-4 35.4±14.5 30.0±14.6 26.9±25.6 48.3±9.7 CD40 −IL-4 19.4±8.8 14.8±5.2 14.9±9.7 34.0±5.1 +IL-4 286±145.5 44.0±19.4 52.7±22.8 41.0±19.8 CD180+CD40 −IL-4 32.5±12.6 97.0±26.2 28.0±10.4 65.5±26.6 +IL-4 299±163.2 63.5±27.4 49.3±14.6 55.5±26.4

B Cell Stimulation through BCR and CD40 Modulates the Response of Chronic Lymphocytic Leukemia Cells to BAFF and APRIL.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1361-1361
Author(s):  
Gerardo Ferrer ◽  
Kate E Hodgson ◽  
Victor Ciria ◽  
Gael Roue ◽  
Dolors Colomer ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Activation ◽  
Conflicts Of Interest ◽  
Critical Role ◽  
Lymphocytic Leukemia ◽  
Receptor Expression ◽  
Cd40 Ligation ◽  
Stimulation Of

Abstract Abstract 1361 The two TNF family proteins (B-cell activating factor [BAFF] and a proliferation-inducing ligand [APRIL]) and their three receptors (transmembrane activator and CAML interactor [TACI], B-cell maturation antigen [BCMA], and BAFF receptor [BAFF-R]) play a critical role in the process of differentiation, maturation and survival of normal B cells. Additionally, recent studies indicate that activation or inhibitory signals can modulate the sensitivity of normal B cells to BAFF and APRIL through the regulation of their receptors. In chronic lymphocytic leukemia (CLL), BAFF and APRIL have been shown to increase survival of neoplastic B cells in vitro. We investigated whether stimulation of CLL cells through the B cell receptor (BCR) or CD40 ligation could regulate the expression of BAFF-R, TACI and BCMA and enhance BAFF and APRIL sensitivity. Purified B cells were obtained from 23 CLL patients and nine healthy controls. Receptor expression was measured by flow cytometry at baseline and at 48 hours after stimulation with F(ab’)2 antihuman IgM (10 μg/ml) and CD40L (500ng/ml) plus IL-4 (20ng/ml). Cell activation and viability, as assessed by labeling CD69 and Annexin V/TO-PRO-3, were evaluated at 48, and at 72 hours after co-stimulation with either soluble BAFF (100ng/ml) or APRIL (500ng/ml). Baseline analyses showed that BAFF-R was the most highly expressed receptor in CLL cells and normal B cells (Mean fluorescence intensity (MFI) ratios, 213.5 and 185.8, respectively). TACI and BCMA were also expressed in all CLL cells and normal B cells (MFI ratios TACI: 2.5 and 1.9; BCMA: 14.8 and 6.6, respectively), but at a significantly lower level than BAFF-R (p<0.001). Furthermore, BCMA MFI ratio was significantly higher in CLL than in normal B cells (p=0.015). After 48h of culture, an increase of all three receptors was observed in normal B cells in response to either BCR stimulation or CD40 ligation. In contrast, in CLL cells BCR stimulation induced almost no variation in the receptors expression in all cases. This was accompanied by a failure of cell activation and a significant decreased viability of CLL cells (from 36% to 24% p=0.013). By contrast, CD40 ligation in CLL cells induced a significant upregulation of TACI expression (p=0.007) and a significant reduction of BCMA (p=0.007), which correlated with an increase of CLL cell activation and viability (p<0.001). BAFF-R levels did not change. The addition of exogenous soluble BAFF or APRIL showed increase in the viability of normal B cells at 72 hours independently of whether cells were unstimulated or stimulated through the BCR or by CD40 ligation. In CLL cells, however, the viability was significantly increased in CD40-stimulated cells whereas in either unstimulated or BCR-stimulated CLL cells, the addition of BAFF and APRIL had a modest effect on viability (Table). These findings indicate that stimulation of CLL cells through the BCR and CD40 modifies the sensitivity of CLL cells to respond to BAFF and APRIL which reflects the regulation of BCMA, TACI and BAFF-R. In contrast to normal B cells, CD40-ligation in CLL cells upregulated only TACI expression. The fact that the addition of CD40L plus IL-4 and BAFF increased viability in CLL cells while BAFF alone had almost no effect may be related to the ability of CD40 ligation to increase TACI expression. Although BCR stimulation failed to increase the expression of the receptors, co-stimulation by BAFF plus BCR increased viability in CLL cells. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Monovalent engagement of the BCR activates ovalbumin-specific transnuclear B cells

2014 ◽  
Vol 211 (2) ◽  
pp. 365-379 ◽  
Author(s):  
Ana M. Avalos ◽  
Angelina M. Bilate ◽  
Martin D. Witte ◽  
Albert K. Tai ◽  
Jiang He ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Synthetic Peptides ◽  
Cell Activation ◽  
Cell Receptor ◽  
Fine Tuning ◽  
B Cell Activation ◽  
Cd40 Ligation ◽  
Peptide Antigen ◽  
Peptide Epitope

Valency requirements for B cell activation upon antigen encounter are poorly understood. OB1 transnuclear B cells express an IgG1 B cell receptor (BCR) specific for ovalbumin (OVA), the epitope of which can be mimicked using short synthetic peptides to allow antigen-specific engagement of the BCR. By altering length and valency of epitope-bearing synthetic peptides, we examined the properties of ligands required for optimal OB1 B cell activation. Monovalent engagement of the BCR with an epitope-bearing 17-mer synthetic peptide readily activated OB1 B cells. Dimers of the minimal peptide epitope oriented in an N to N configuration were more stimulatory than their C to C counterparts. Although shorter length correlated with less activation, a monomeric 8-mer peptide epitope behaved as a weak agonist that blocked responses to cell-bound peptide antigen, a blockade which could not be reversed by CD40 ligation. The 8-mer not only delivered a suboptimal signal, which blocked subsequent responses to OVA, anti-IgG, and anti-kappa, but also competed for binding with OVA. Our results show that fine-tuning of BCR-ligand recognition can lead to B cell nonresponsiveness, activation, or inhibition.

scholarly journals Extrafollicular B cell activation by marginal zone dendritic cells drives T cell–dependent antibody responses

2012 ◽  
Vol 209 (10) ◽  
pp. 1825-1840 ◽  
Author(s):  
Craig P. Chappell ◽  
Kevin E. Draves ◽  
Natalia V. Giltiay ◽  
Edward A. Clark
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Marginal Zone ◽  
Receptor Expression ◽  
B Cell Activation ◽  
Cell Responses ◽  
B Cell Responses

Dendritic cells (DCs) are best known for their ability to activate naive T cells, and emerging evidence suggests that distinct DC subsets induce specialized T cell responses. However, little is known concerning the role of DC subsets in the initiation of B cell responses. We report that antigen (Ag) delivery to DC-inhibitory receptor 2 (DCIR2) found on marginal zone (MZ)–associated CD8α− DCs in mice leads to robust class-switched antibody (Ab) responses to a T cell–dependent (TD) Ag. DCIR2+ DCs induced rapid up-regulation of multiple B cell activation markers and changes in chemokine receptor expression, resulting in accumulation of Ag-specific B cells within extrafollicular splenic bridging channels as early as 24 h after immunization. Ag-specific B cells primed by DCIR2+ DCs were remarkably efficient at driving naive CD4 T cell proliferation, yet DCIR2-induced responses failed to form germinal centers or undergo affinity maturation of serum Ab unless toll-like receptor (TLR) 7 or TLR9 agonists were included at the time of immunization. These results demonstrate DCIR2+ DCs have a unique capacity to initiate extrafollicular B cell responses to TD Ag, and thus define a novel division of labor among splenic DC subsets for B cell activation during humoral immune responses.

Reduced Rates of B Cell Proliferation in Chronic Lymphocytic Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2821-2821
Author(s):  
Julien Defoiche ◽  
Christophe Debacq ◽  
Becca Asquith ◽  
Yan Zhang ◽  
Arsène Burny ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Healthy Controls ◽  
Kinetic Measurements ◽  
B And T Lymphocytes

Abstract Whether chronic lymphocytic leukemia (CLL) represents latent or proliferating disease has been intensively debated. Whilst the dogma that CLL results from accumulation of dormant lymphocytes is supported by the unresponsiveness of leukemic cells to antigens and polyclonal activators, recent in vivo kinetic measurements show that B-lymphocytes do divide at significant rates in CLL. However, B cell kinetics were not compared between CLL patients and healthy controls so it was not possible to ascertain to what extent lymphocyte kinetics were aberrant in CLL. We compared proliferation rates of B- and T-lymphocytes in CLL patients and healthy controls, using a pulse-chase approach based on incorporation of deuterium from 6,6-2H2-glucose into DNA. We found dramatically reduced in vivo rates of CD3−CD19+ cell proliferation in CLL compared with controls (mean 0.47 versus 1.66 %/day respectively, P=0.001), equivalent to an extended half-life of circulating B-cells (147 days versus 42 days). Labeled (dividing) CD3−CD19+ cells had death rates similar to the healthy controls (2.29 versus 3.55 %/day, P=0.495). Despite such aberrant B-cells kinetics, T-cell proliferation was unaffected by CLL (1.77 versus 1.40 %/day, P=0.488). We conclude that, B-cell proliferation rates are reduced in leukemic patients compared to healthy subjects and that most circulating CD3−CD19+ cells are quiescent, long-lived cells.

scholarly journals Detection and functional studies of p60-65 (Tac antigen) on activated human B cells.

1984 ◽  
Vol 160 (5) ◽  
pp. 1597-1602 ◽  
Author(s):  
L K Jung ◽  
T Hara ◽  
S M Fu
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Receptor Expression ◽  
Pokeweed Mitogen ◽  
Activated T Cells ◽  
Human B Cells ◽  
Activated B Cells

A monoclonal antibody, AT-1, is shown to precipitate a p60-65 molecule identical to the Tac antigen. With AT-1, the expression of IL-2 receptors by normal activated human B cells from peripheral blood and tonsils is documented by biosynthetic and immunofluorescence studies. AT-1 precipitated a p60-65 protein from [35S]methionine-labeled activated B cells, similar to that from activated T cells. The interleukin 2 (IL-2) receptor appeared shortly after activation with anti-IgM and B cell-stimulatory factor(s). Its expression reached its peak at 60-72 h with approximately 50% of the B blasts stained by AT-1. Other modes of activation of B cells, by T cell-independent, formalin-treated staphylococci and Epstein-Barr virus, and by T cell-dependent pokeweed mitogen, also induced IL-2 receptor expression. The functional significance of this finding was investigated using recombinant IL-2 (rIL-2). While rIL-2 did not induce resting B cells to proliferate in the presence of anti-IgM, it induced activated B cells to proliferate in the absence of other factors. On the other hand, rIL-2 did not induce the differentiation of these activated B lymphocytes. These data suggest that IL-2 may play a significant role in B cell activation.

scholarly journals Down-regulation of CD73 on B cells of patients with viremic HIV correlates with B cell activation and disease progression

2017 ◽  
Vol 101 (5) ◽  
pp. 1263-1271 ◽  
Author(s):  
Eun-Seong Kim ◽  
Christin Ackermann ◽  
Ilona Tóth ◽  
Patrick Dierks ◽  
Johanna M. Eberhard ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Disease Progression ◽  
Cell Activation ◽  
B Cell Activation ◽  
Down Regulation

T Cell Pathway Deficiencies in Chronic Lymphocityc Leukemia: Partial Restoration with OKT3/IL-2 Activation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4692-4692
Author(s):  
Mauro Di Ianni ◽  
Lorenzo Moretti ◽  
Beatrice Del Papa ◽  
Maria De Ioanni ◽  
Adelmo Terenzi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Activated T Cells ◽  
Mutational Status ◽  
The Impact

Abstract As Chronic Lymphocytic Leukemia (CLL) is associated with several defects in the T cell compartment, the impact of tumour burden on the autologous immune system was studied. Gene expression profiles (using Applied Biosystem Human Genome Microarray) identified 237 genes with significantly increased expression and 221 genes with significantly decreased expression (p<0.05) in CD3+ cells from CLL patients compared with healthy donors. Panther software analysis identified 34/237 upregulated genes and 26/221 downregulated genes that were involved in specific pathways, mainly cell differentiation and proliferation, survival, apoptosis, cytoskeleton formation, vesicle trafficking and T cell activation. The 26 dowregulated genes included Zap70, a member of the syk family protein tyrosine kinase, which is involved in T-cell activation. Zap-70 results were validated by mRNA quantification by RT-PCR (−1.77 fold in comparison with healthy controls) and by flow-cytometric analysis (Mean Intensity Fluorescence=33±12 vs 80±23.62 in controls, p<0.05). To test the hypothesis that activation with OKT3 /IL-2 could bypass these T cell deficiencies, activated T cells from 20 patients with CLL were tested in vitro for cytotoxicity (using the 51chromium release assay) against mutated and unmutated (according to IgVH mutational status) autologous B cells, DAUDI, K562 and P815 cell lines. After 10 days’ culture, the T cell count remained unchanged; CD8 cells expanded more than CD4; TCR spectratyping analysis indicated no differences in TCR repertoires. Activation restored the ZAP-70 mRNA (+1.67 fold). The 51chromium release cytotoxicity assay showed an index > 30% in 5/20 patients. The other 15 were partially cytotoxic against P815, K562 and Daudi. Cell line analysis in all 20 confirmed prevalently T cell-mediated cytotoxicity and poor NK/LAK activity. Cytotoxicity did not correlate with B cell mutational status. We tested the cytotoxic activity of autologous activated T cells in NOD/SCID mice co-transplanted with leukaemic B cells. Only activated T cells exerting cytotoxicity vs autologous B-cell CLL prevent CLL in human-mouse chimera, as confirmed by PCR and FACS analysis which visualised only CD3+ cells. In conclusion, in patients with CLL, activating autologous T cells with OKT3 /IL-2 bypasses, at least in part, the T cell immunological deficiencies. These in vitro and in vivo findings might serve to throw light on new mechanisms that could be exploited in immunotherapy designed to exert disease control.

scholarly journals Identification and characterization of circulating human transitional B cells

Blood ◽  
2005 ◽  
Vol 105 (11) ◽  
pp. 4390-4398 ◽  
Author(s):  
Gary P. Sims ◽  
Rachel Ettinger ◽  
Yuko Shirota ◽  
Cheryl H. Yarboro ◽  
Gabor G. Illei ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Cell Activation ◽  
Cell Receptor ◽  
Interleukin 4 ◽  
Type I ◽  
Cd40 Ligation ◽  
Transitional B Cells

Abstract Murine B-cell development begins in bone marrow and results in the generation of immature transitional B cells that transit to the spleen to complete their maturation. It remains unclear whether the same developmental pathway takes place in humans. Using markers characteristic of human bone marrow immature B cells, we have identified a population of circulating human B cells with a phenotype most similar to mouse transitional type I (T1) B cells, although these human counterparts express CD5. These cells die rapidly in culture, and B-cell activation factor member of the tumor necrosis factor (TNF) family (BAFF) does not effect their survival regardless of B-cell receptor (BCR) stimulation. In contrast, bone marrow stromal cells or interleukin-4 (IL-4) significantly enhanced their survival. In the presence of T-cell signals provided by IL-4 or CD40 ligation, BCR stimulation can induce progression into cell cycle. Interestingly, circulating B cells that phenotypically and functionally resemble murine T2 B cells are found in cord blood and adult peripheral blood, suggesting that B-cell maturation may not be restricted to the spleen. Notably, increased proportions of T1 B cells were found in blood of patients with systemic lupus erythematosus (SLE), although bone marrow production and selection appeared to be normal.

scholarly journals Single cell analysis of RA synovial B cells reveals a dynamic spectrum of ectopic lymphoid B cell activation and hypermutation characterized by NR4A nuclear receptor expression

2021 ◽  
Author(s):  
Nida Meednu ◽  
Javier Rangel-Moreno ◽  
Fan Zhang ◽  
Katherine Escalera-Rivera ◽  
Elisa Corsiero ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Single Cell ◽  
Protein Level ◽  
Cell Activation ◽  
Receptor Expression ◽  
Intermediate Phenotype ◽  
B Cell Activation ◽  
Orphan Nuclear Receptors

Ectopic lymphoid structures (ELS) are present in rheumatoid arthritis (RA) synovial tissue, but the precise pathways of B cell activation and the role of in situ synovial B cell differentiation and selection in disease are not well understood. Here, we identified a B cell population in the synovium characterized by expression of NR4A1-3, a family of orphan nuclear receptors, that is highly enriched at both early and late stages of RA. NR4A B cells are rare in healthy peripheral blood, RA blood, and SLE kidney, but share markers with blood transcriptomic signatures that peak during RA disease flare. Using combined single cell transcriptomics and B cell receptor (BCR) sequencing, we demonstrate that NR4A synovial B cells have an activated transcriptomic profile that significantly overlaps with germinal center (GC) light zone (LZ) B cells and an accrual of somatic hypermutation that correlates with loss of naive B cell status. NR4A B cells uniquely co-express lymphotoxin β and IL6, supporting important functions in ELS promotion and pro-inflammatory cytokine production. The presence of shared clones in this activated B cell state, NR4A expressing synovial plasma cells (PC), and CCR6+ memory B cell (MBC) precursors further points to in situ differentiation. NR4A1 was expressed at the protein level in RA synovial B cells and PC, was high in tonsil GC B cells with a LZ-DZ intermediate phenotype, and was rapidly induced at both the RNA and protein level upon activation through the BCR. Taken together, we identified a dynamic progression of B cell activation in RA synovial ELS, with NR4A as a read-out of likely antigen activation and local adaptive immune responses.

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