scholarly journals Serum from patients with SLE instructs monocytes to promote IgG and IgA plasmablast differentiation

2012 ◽  
Vol 209 (7) ◽  
pp. 1335-1348 ◽  
Author(s):  
HyeMee Joo ◽  
Christine Coquery ◽  
Yaming Xue ◽  
Ingrid Gayet ◽  
Stacey R. Dillon ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Type I ◽  
Dependent Manner ◽  
Blood Monocytes ◽  
Independent Manner ◽  
Monocyte Differentiation ◽  
Cell Responses

The development of autoantibodies is a hallmark of systemic lupus erythematosus (SLE). SLE serum can induce monocyte differentiation into dendritic cells (DCs) in a type I IFN–dependent manner. Such SLE-DCs activate T cells, but whether they promote B cell responses is not known. In this study, we demonstrate that SLE-DCs can efficiently stimulate naive and memory B cells to differentiate into IgG- and IgA-plasmablasts (PBs) resembling those found in the blood of SLE patients. SLE-DC–mediated IgG-PB differentiation is dependent on B cell–activating factor (BAFF) and IL-10, whereas IgA-PB differentiation is dependent on a proliferation-inducing ligand (APRIL). Importantly, SLE-DCs express CD138 and trans-present CD138-bound APRIL to B cells, leading to the induction of IgA switching and PB differentiation in an IFN-α–independent manner. We further found that this mechanism of providing B cell help is relevant in vivo, as CD138-bound APRIL is expressed on blood monocytes from active SLE patients. Collectively, our study suggests that a direct myeloid DC–B cell interplay might contribute to the pathogenesis of SLE.

scholarly journals OP0005 ELEVATED STAT1 EXPRESSION BUT NOT PHOSPHORYLATION IN LUPUS B CELLS CORRELATES WITH DISEASE ACTIVITY AND INCREASED PLASMABLAST SUSCEPTIBILITY

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 4-5
Author(s):  
A. Aue ◽  
F. Szelinski ◽  
S. Weißenberg ◽  
A. Wiedemann ◽  
T. Rose ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
B Cells ◽  
Autoimmune Diseases ◽  
Disease Activity ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Type I ◽  
Type I Ifn ◽  
Systemic Lupus ◽  
B Cell Subsets

Background:Systemic lupus erythematosus (SLE) is characterized by two pathogenic key signatures, type I interferon (IFN) (1.) and B-cell abnormalities (2.). How these signatures are interrelated is not known. Type I-II IFN trigger activation of Janus kinase (JAK) – signal transducer and activator of transcription (STAT).Objectives:JAK-STAT inhibition is an attractive therapeutic possibility for SLE (3.). We assess STAT1 and STAT3 expression and phosphorylation at baseline and after IFN type I and II stimulation in B-cell subpopulations of SLE patients compared to other autoimmune diseases and healthy controls (HD) and related it to disease activity.Methods:Expression of STAT1, pSTAT1, STAT3 and pSTAT3 in B and T-cells of 21 HD, 10 rheumatoid arthritis (RA), 7 primary Sjögren’s (pSS) and 22 SLE patients was analyzed by flow cytometry. STAT1 and STAT3 expression and phosphorylation in PBMCs of SLE patients and HD after IFNα and IFNγ incubation were further investigated.Results:SLE patients showed substantially higher STAT1 but not pSTAT1 in B and T-cell subsets. Increased STAT1 expression in B cell subsets correlated significantly with SLEDAI and Siglec-1 on monocytes, a type I IFN marker (4.). STAT1 activation in plasmablasts was IFNα dependent while monocytes exhibited dependence on IFNγ.Figure 1.Significantly increased expression of STAT1 by SLE B cells(A) Representative histograms of baseline expression of STAT1, pSTAT1, STAT3 and pSTAT3 in CD19+ B cells of SLE patients (orange), HD (black) and isotype controls (grey). (B) Baseline expression of STAT1 and pSTAT1 or (C) STAT3 and pSTAT3 in CD20+CD27-, CD20+CD27+ and CD20lowCD27high B-lineage cells from SLE (orange) patients compared to those from HD (black). Mann Whitney test; ****p≤0.0001.Figure 2.Correlation of STAT1 expression by SLE B cells correlates with type I IFN signature (Siglec-1, CD169) and clinical activity (SLEDAI).Correlation of STAT1 expression in CD20+CD27- näive (p<0.0001, r=0.8766), CD20+CD27+ memory (p<0.0001, r=0.8556) and CD20lowCD27high (p<0.0001, r=0.9396) B cells from SLE patients with (A) Siglec-1 (CD169) expression on CD14+ cells as parameter of type I IFN signature and (B) lupus disease activity (SLEDAI score). Spearman rank coefficient (r) was calculated to identify correlations between these parameters. *p≤0.05, **p≤0.01. (C) STAT1 expression in B cell subsets of a previously undiagnosed, active SLE patient who was subsequently treated with two dosages of prednisolone and reanalyzed.Conclusion:Enhanced expression of STAT1 by B-cells candidates as key node of two immunopathogenic signatures (type I IFN and B-cells) related to important immunopathogenic pathways and lupus activity. We show that STAT1 is activated upon IFNα exposure in SLE plasmablasts. Thus, Jak inhibitors, targeting JAK-STAT pathways, hold promise to block STAT1 expression and control plasmablast induction in SLE.References:[1]Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Ortmann WA, Espe KJ, et al. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci U S A. 2003;100(5):2610-5.[2]Lino AC, Dorner T, Bar-Or A, Fillatreau S. Cytokine-producing B cells: a translational view on their roles in human and mouse autoimmune diseases. Immunol Rev. 2016;269(1):130-44.[3]Dorner T, Lipsky PE. Beyond pan-B-cell-directed therapy - new avenues and insights into the pathogenesis of SLE. Nat Rev Rheumatol. 2016;12(11):645-57.[4]Biesen R, Demir C, Barkhudarova F, Grun JR, Steinbrich-Zollner M, Backhaus M, et al. Sialic acid-binding Ig-like lectin 1 expression in inflammatory and resident monocytes is a potential biomarker for monitoring disease activity and success of therapy in systemic lupus erythematosus. Arthritis Rheum. 2008;58(4):1136-45.Disclosure of Interests:Arman Aue: None declared, Franziska Szelinski: None declared, Sarah Weißenberg: None declared, Annika Wiedemann: None declared, Thomas Rose: None declared, Andreia Lino: None declared, Thomas Dörner Grant/research support from: Janssen, Novartis, Roche, UCB, Consultant of: Abbvie, Celgene, Eli Lilly, Roche, Janssen, EMD, Speakers bureau: Eli Lilly, Roche, Samsung, Janssen

scholarly journals B cell depletion impairs vaccination-induced CD8+ T cell responses in a type I interferon-dependent manner

2021 ◽  
pp. annrheumdis-2021-220435
Author(s):  
Theresa Graalmann ◽  
Katharina Borst ◽  
Himanshu Manchanda ◽  
Lea Vaas ◽  
Matthias Bruhn ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Expansion ◽  
De Novo ◽  
T Cell Responses ◽  
Type I ◽  
Cell Responses ◽  
T Cell Expansion

ObjectivesThe monoclonal anti-CD20 antibody rituximab is frequently applied in the treatment of lymphoma as well as autoimmune diseases and confers efficient depletion of recirculating B cells. Correspondingly, B cell-depleted patients barely mount de novo antibody responses during infections or vaccinations. Therefore, efficient immune responses of B cell-depleted patients largely depend on protective T cell responses.MethodsCD8+ T cell expansion was studied in rituximab-treated rheumatoid arthritis (RA) patients and B cell-deficient mice on vaccination/infection with different vaccines/pathogens.ResultsRituximab-treated RA patients vaccinated with Influvac showed reduced expansion of influenza-specific CD8+ T cells when compared with healthy controls. Moreover, B cell-deficient JHT mice infected with mouse-adapted Influenza or modified vaccinia virus Ankara showed less vigorous expansion of virus-specific CD8+ T cells than wild type mice. Of note, JHT mice do not have an intrinsic impairment of CD8+ T cell expansion, since infection with vaccinia virus induced similar T cell expansion in JHT and wild type mice. Direct type I interferon receptor signalling of B cells was necessary to induce several chemokines in B cells and to support T cell help by enhancing the expression of MHC-I.ConclusionsDepending on the stimulus, B cells can modulate CD8+ T cell responses. Thus, B cell depletion causes a deficiency of de novo antibody responses and affects the efficacy of cellular response including cytotoxic T cells. The choice of the appropriate vaccine to vaccinate B cell-depleted patients has to be re-evaluated in order to efficiently induce protective CD8+ T cell responses.

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 Cd5 Maintains Tolerance in Anergic B Cells

2000 ◽  
Vol 191 (5) ◽  
pp. 883-890 ◽  
Author(s):  
Keli L. Hippen ◽  
Lina E. Tze ◽  
Timothy W. Behrens
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Receptor ◽  
Immunoglobulin M ◽  
B Cell Tolerance ◽  
Cell Responses ◽  
B Cell Anergy ◽  
Clonal Anergy

Clonal anergy of autoreactive B cells is a key mechanism regulating tolerance. Here, we show that anergic B cells express significant surface levels of CD5, a molecule normally found on T cells and a subset of B-1 cells. Breeding of the hen egg lysozyme (HEL) transgenic model for B cell anergy onto the CD5 null background resulted in a spontaneous loss of B cell tolerance in vivo. Evidence for this included elevated levels of anti-HEL immunoglobulin M (IgM) antibodies in the serum of CD5−/− mice transgenic for both an HEL-specific B cell receptor (BCR) and soluble lysozyme. “Anergic” B cells lacking CD5 also showed enhanced proliferative responses in vitro and elevated intracellular Ca2+ levels at rest and after IgM cross-linking. These data support the hypothesis that CD5 negatively regulates Ig receptor signaling in anergic B cells and functions to inhibit autoimmune B cell responses.

Agonist for Toll-Like Receptor (TLR) 9 Amplifies as Well as Inhibits the Differentiation of FVIII-Specific Memory B Cells into Antibody-Producing Plasma Cells in Vitro and in Vivo.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3382-3382
Author(s):  
Peter Allacher ◽  
Christina Hausl ◽  
Aniko Ginta Pordes ◽  
Rafi Uddin Ahmad ◽  
Hartmut J Ehrlich ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Memory B Cells ◽  
Memory B Cell ◽  
Cpg Dna ◽  
Cell Responses ◽  
Specific Memory ◽  
B Cell Responses

Abstract Memory B cells are essential for maintaining long-term antibody responses. They can persist for years even in the absence of antigen and are rapidly re-stimulated to differentiate into antibody-producing plasma cells when they encounter their specific antigen. Previously we demonstrated that ligands for TLR 7 and 9 amplify the differentiation of FVIII-specific memory B cells into anti-FVIII antibody-producing plasma cells at low concentrations of FVIII and prevent the inhibition of memory-B-cell differentiation at high concentrations of FVIII. The modulation of FVIII-specific memory-B-cell responses by agonists for TLR is highly relevant for the design of new immunotherapeutic approaches in patients with FVIII inhibitors because TLR are activated by a range of different viral and bacterial components. Specifically, TLR 7 is triggered by single-stranded RNA derived from viruses and TLR 9 is triggered by bacterial DNA containing unmethylated CpG motifs. We further explored the modulation of FVIII-specific memory-B-cell responses by agonists for TLRs by studying a broad range of concentrations of CpG DNA, a ligand for TLR 9, both in vitro and in vivo using the murine E17 model of hemophilia A. We used CpG-DNA in concentrations ranging from 0.1 to 10,000 ng/ml to study the modulation of FVIII-specific memory-B-cell responses in vitro and verified the specificity of the effects observed by including a blocking agent for TLR 9 and GpC-DNA, a non-stimulating negative control for CpG DNA. Furthermore, we used doses of CpG DNA ranging from 10 to 50,000 ng per dose to study the modulation of FVIII-specific memory-B-cell responses in vivo. E17 hemophilic mice were treated with a single intravenous dose of 200 ng FVIII to stimulate the generation of FVIII-specific memory B cells and were subsequently treated with another dose of FVIII that was given together with CpG DNA. We analyzed titers of anti-FVIII antibodies in the circulation of these mice one week after the second dose of FVIII. Previously we had shown that a single dose of 200 ng FVIII, given intravenously to E17 hemophilic mice, stimulates the formation of FVIII-specific memory B cells but is not sufficient to induce anti-FVIII antibodies that would be detectable in the circulation. Our results demonstrate a biphasic effect of CpG DNA on the re-stimulation of FVIII-specific memory B cells and their differentiation into antibody-producing plasma cells. Both in vitro and in vivo studies show that CpG DNA at high doses inhibits the re-stimulation and differentiation of FVIII-specific memory B cells. However, CpG DNA at low doses amplifies these processes. Amplification and inhibition of memory-B-cell responses are due to specific interactions of CpG DNA with TLR 9. Both effects are blocked by addition of a blocking agent for TLR 9 in vitro. We conclude that triggering of TLR 9 by bacterial DNA has a substantial influence on FVIII-specific memory-B-cell responses. The consequence of TLR 9 triggering can be inhibitory or stimulatory, depending on the actual concentration of the bacterial DNA. Our findings demonstrate the potential modulatory effects of bacterial infections on the regulation of FVIII inhibitor development.

scholarly journals Enhanced B Cell Expansion, Survival, and Humoral Responses by Targeting Death Receptor 6

2002 ◽  
Vol 197 (1) ◽  
pp. 51-62 ◽  
Author(s):  
Clint S. Schmidt ◽  
Jinqi Liu ◽  
Tonghai Zhang ◽  
Ho Yeong Song ◽  
George Sandusky ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Expansion ◽  
Death Receptor ◽  
Immunoglobulin M ◽  
Type I ◽  
Factor C

Targeted disruption of death receptor (DR)6 results in enhanced CD4+ T cell expansion and T helper cell type 2 differentiation after stimulation. Similar to T cells, DR6 is expressed on resting B cells but is down-regulated upon activation. We examined DR6−/− B cell responses both in vitro and in vivo. In vitro, DR6−/− B cells undergo increased proliferation in response to anti–immunoglobulin M, anti-CD40, and lipopolysaccharide. This hyperproliferative response was due, at least in part, to both increased cell division and reduced cell apoptosis when compared with wild-type B cells. Consistent with these observations, increased nuclear levels and activity of nuclear factor κB transcription factor, c-Rel, and elevated Bcl-xl expression were observed in DR6−/− B cells upon stimulation. In addition, DR6−/− B cells exhibited higher surface levels of CD86 upon activation and were more effective as antigen-presenting cells in an allogeneic T cell proliferation response. DR6−/− mice exhibited enhanced germinal center formation and increased titers of immunoglobulins to T-dependent as well as T-independent type I and II antigens. This is the first demonstration of a regulatory role of DR6 in the activation and function of B cells.

scholarly journals Artemisinin derivative SM934, influences the activation, proliferation, differentiation and antibody-secreting capacity of β-cells in systemic lupus erythematosus mice via inhibition of TLR7/9 signaling pathway

2021 ◽  
Vol 18 (7) ◽  
pp. 1391-1396
Author(s):  
Yajuan Li ◽  
Lixin Zhao ◽  
Xuehui Yang ◽  
Jing Chen ◽  
Wenjing Xu ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
B Cells ◽  
B Cell ◽  
Lupus Erythematosus ◽  
B Lymphocyte ◽  
Underlying Mechanism ◽  
Dependent Manner ◽  
Artemisinin Derivative ◽  
Systemic Lupus ◽  
Dose Dependent

Purpose: To study the influence of artemisinin derivative, SM934 on activation, proliferation, differentiation and antibody-secreting capacity of B cells of systemic lupus erythematosus (SLE) mice, and the underlying mechanism. Methods: Female MRL/lpr mice (n = 60) were randomly assigned to four groups of 15 mice each: SLE, 2.5 mg/kg SM934; 5 mg/kg SM934, and 10 mg/kg SM934 groups. Serum levels of interleukins 6, 10, 17 and 21 (IL-6, IL-17, IL-10 and IL-21) were determined. The secretions of immunoglobulins G and M (IgG and IgM) by B cells were determined. The population of B lymphocyte subtypes was determined flow cytometrically. The expressions of Blimp-1 and Bcl-6, Toll-like receptors 7 and 9 (TLR7 and TLR9) mRNAs were determined. Results: SLE-induced upregulation of serum IL-10, IL-6, IL-17 and IL-21 was significantly and dosedependently reduced following a 2-month treatment with SM934 (p < 0.01). Treatment with SM934 significantly and dose-dependently accentuated B cell germinal center B cell populations, but significantly and dose-dependently decreased the populations of plasma and activated B cells (p < 0.01). The splenic levels of IgG and IgM were decreased in a dose-dependent fashion after 8 weeks of treatment (p < 0.01). Artemisinin derivative SM934 decreased the expression of Blimp-1, and upregulated the expression of Bcl-6, both in a dose-dependent manner (p < 0.01). Moreover, SM934 decreased the mRNA expressions of TLR7 and TLR9 in a dose-based manner (p < 0.01). Conclusion: Artemisinin derivative SM934 mitigates LSE syndromes by suppressing the TLR-induced B-cell stimulation and plasma cell generation

scholarly journals B Cell Intrinsic STING Signaling Is Not Required for Autoreactive Germinal Center Participation

2021 ◽  
Vol 12 ◽  
Author(s):  
Kenneth Green ◽  
Thomas R. Wittenborn ◽  
Cecilia Fahlquist-Hagert ◽  
Ewa Terczynska-Dyla ◽  
Nina van Campen ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Type I Interferon ◽  
Affinity Maturation ◽  
Antibody Responses ◽  
Type I ◽  
Cell Responses ◽  
B Cell Responses ◽  
Sting Pathway ◽  
Humoral Responses

Germinal centers (GCs) are induced microanatomical structures wherein B cells undergo affinity maturation to improve the quality of the antibody response. Although GCs are crucial to appropriate humoral responses to infectious challenges and vaccines, many questions remain about the molecular signals driving B cell participation in GC responses. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is an important mediator of type I interferon and proinflammatory cytokine responses during infection and cellular stress. Recent studies have reported important roles for STING in B cell responses, including an impact on GC B cells and downstream antibody responses, which could have great consequences for vaccine design and understanding STING-associated interferonopathies. GCs are also involved in untoward reactions to autoantigens in a plethora of autoimmune disorders, and it is generally thought that these responses coopt the mechanisms used in foreign antigen-directed GCs. Here, we set out to investigate the importance of the cGAS-STING pathway in autoreactive B cell responses. In a direct competition scenario in a murine mixed bone marrow chimera model of autoreactive GCs, we find that B cell intrinsic deficiency of cGAS, STING, or the type I interferon receptor IFNAR, does not impair GC participation, whereas Toll-like receptor (TLR)-7 deficiency mediates a near-complete block. Our findings suggest that physiological B cell responses are strictly sustained by signals linked to BCR-mediated endocytosis. This wiring of B cell signals may enable appropriate antibody responses, while at the same time restricting aberrant antibody responses during infections and in autoimmune or autoinflammatory settings.

scholarly journals Type 1 interferon supports B cell responses to polysaccharide antigens but is not required for MPL/TDCM adjuvant effects on innate B cells

2021 ◽  
Author(s):  
Ariel Spurrier ◽  
Jamie Jennings-Gee ◽  
Karen Haas
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Lipid A ◽  
Type I ◽  
Type I Ifn ◽  
Cell Responses ◽  
Monophosphoryl Lipid A ◽  
B Cell Responses ◽  
Adjuvant Effects

We previously described monophosphoryl lipid A (MPL) and synthetic cord factor, trehalose-6,6-dicorynomycolate (TDCM) significantly increases antibody (Ab) responses to T cell independent type 2 antigens (TI-2 Ags) in a manner dependent on B cell-intrinsic TLR4 expression as well as MyD88 and TRIF adapter proteins. Given the requirement for TRIF in optimal MPL/TDCM adjuvant effects and the capacity of MPL to drive type I IFN production, we aimed to investigate the extent to which adjuvant effects on TI-2 Ab responses depend on type I IFN receptor (IFNAR) signaling. We found IFNAR-/- mice had impaired early TI-2 Ag-induced B cell activation and expansion and that B cell-intrinsic type I IFN signaling on B cells was essential for normal antibody responses to TI-2 Ags, including haptenated Ficoll and the pneumococcal vaccine, Pneumovax23. However, MPL/TDCM significantly increased TI-2 IgM and IgG responses in IFNAR-/- mice. MPL/TDCM enhanced TI-2 Ab production primarily by activating innate B cells (B-1b and splenic CD23- B cells) as opposed to CD23+ enriched follicular B cells. In summary, our study highlights an important role for type I IFN in supporting early B cell responses to TI-2 Ags through B cell-expressed IFNAR, but nonetheless demonstrates an MPL/TDCM adjuvant significantly increases TI-2 Ab responses independently of type I IFN signaling and does so by predominantly supporting increased polysaccharide-specific Ab production by innate B cell populations.

scholarly journals Blimp-1-Dependent Repression of Pax-5 Is Required for Differentiation of B Cells to Immunoglobulin M-Secreting Plasma Cells

2002 ◽  
Vol 22 (13) ◽  
pp. 4771-4780 ◽  
Author(s):  
Kuo-I Lin ◽  
Cristina Angelin-Duclos ◽  
Tracy C. Kuo ◽  
Kathryn Calame
Keyword(s):  
B Cells ◽  
B Cell ◽  
B Lymphocyte ◽  
Critical Role ◽  
Cell Lineage ◽  
Immunoglobulin M ◽  
Dependent Manner ◽  
Plasmacytic Differentiation

ABSTRACT B-cell lineage-specific activator protein (BSAP), encoded by the Pax-5 gene, is critical for B-cell lineage commitment and B-cell development but is not expressed in terminally differentiated B cells. We demonstrate a direct connection between BSAP and B-lymphocyte-induced maturation protein 1 (Blimp-1), a transcriptional repressor that is sufficient to drive plasmacytic differentiation. Blimp-1 binds a site on the Pax-5 promoter in vitro and in vivo and represses the Pax-5 promoter in a binding-site-dependent manner. By ectopically expressing Blimp-1 or a competitive inhibitor of Blimp-1, we show that Blimp-1 is both necessary and sufficient to repress Pax-5 during plasmacytic differentiation of primary splenic B cells. Blimp-1-dependent repression of Pax-5 is sufficient to regulate BSAP targets CD19 and J chain and is necessary but not sufficient to induce XBP-1. We further show that repression of Pax-5 is required for Blimp-1 to drive differentiation of splenocytes to immunoglobulin M-secreting cells. Thus, repression of Pax-5 plays a critical role in the Blimp-1-dependent program of plasmacytic differentiation.

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