scholarly journals B cell–intrinsic TLR signals amplify but are not required for humoral immunity

2007 ◽  
Vol 204 (13) ◽  
pp. 3095-3101 ◽  
Author(s):  
Almut Meyer-Bahlburg ◽  
Socheath Khim ◽  
David J. Rawlings
Keyword(s):  
B Cells ◽  
B Cell ◽  
Long Term Memory ◽  
Altered Expression ◽  
Intrinsic Signals ◽  
Antibody Titers ◽  
Specific Igg ◽  
B Cell Subsets

Although innate signals driven by Toll-like receptors (TLRs) play a crucial role in T-dependent immune responses and serological memory, the precise cellular and time-dependent requirements for such signals remain poorly defined. To directly address the role for B cell–intrinsic TLR signals in these events, we compared the TLR response profile of germinal center (GC) versus naive mature B cell subsets. TLR responsiveness was markedly up-regulated during the GC reaction, and this change correlated with altered expression of the key adaptors MyD88, Mal, and IRAK-M. To assess the role for B cell–intrinsic signals in vivo, we transferred MyD88 wild-type or knockout B cells into B cell–deficient μMT mice and immunized recipient animals with 4-hydroxy-3-nitrophenylacetyl (NP) chicken gamma globulin. All recipients exhibited similar increases in NP-specific antibody titers during primary, secondary, and long-term memory responses. The addition of lipopolysaccharide to the immunogen enhanced B cell-intrinsic, MyD88-dependent NP-specific immunoglobulin (Ig)M production, whereas NP-specific IgG increased independently of TLR signaling in B cells. Our data demonstrate that B cell–intrinsic TLR responses are up-regulated during the GC reaction, and that this change significantly promotes antigen-specific IgM production in association with TLR ligands. However, B cell–intrinsic TLR signals are not required for antibody production or maintenance.

Serial analysis of the effects of methimazole therapy on circulating B cell subsets in Graves' disease

1996 ◽  
Vol 151 (2) ◽  
pp. 231-240 ◽  
Author(s):  
J J Corrales ◽  
A Orfao ◽  
A López ◽  
J Ciudad ◽  
M T Mories
Keyword(s):  
B Cells ◽  
B Cell ◽  
Antithyroid Drug ◽  
Graves Disease ◽  
Cellular Mechanisms ◽  
Stable Pattern ◽  
Antithyroid Drug Therapy ◽  
B Cell Subsets

Abstract The immunosuppressive effects of antithyroid drug therapy are well recognized; however, the cellular mechanisms underlying their action remain largely unknown. In the present paper we have prospectively analyzed the in vivo effects of methimazole treatment on a large number of circulating B cell subsets, involved in the effector phase of the immune response, in a group of 18 hyperthyroid patients with Graves' disease (GD). The patients were sequentially studied before (day 0) and 7, 14, 30, 90 and 180 days after methimazole therapy. The results were compared with both a group of 19 age- and sex-matched healthy controls and a group of 20 untreated/euthyroid GD patients in long-term remission. The combination of flow cytometry and three colour immunofluorescence revealed a clear increase (P<0·001) in the numbers of circulating total B cells (CD19+) due to a significant increase (P<0·001) in the CD5+, FMC7+, CD5+/FMC7+ and CD23+ B cell subsets in hyperthyroid GD patients with respect to both healthy individuals and to GD patients in long-term remission. The absolute numbers of all these B cell subsets analyzed before treatment, although abnormal, were not statistically different from those observed during the whole period of therapy. When comparing the percentages of these B cell subsets during treatment, significant changes (P<0·001) were only observed in the proportion of CD5+, CD5+/FMC7+ and CD5 −B cells at the end of the follow-up period with respect to those found both before and during the first month of therapy. Whereas CD5+ and CD5+/FMC7+ B cells decreased (P<0·001) after 3 months of therapy, CD5 − B cells showed a significant increase (P<0·001) at the end of therapy. It is remarkable that the percentage of CD5+, CD5+/FMC7+, CD5 − and CD23+ B cell subsets were abnormal during the whole period of treatment and that they never reached normal values. These results show that, in vivo, GD patients treated with methimazole exhibited an abnormal but rather stable pattern of B cell distribution, similar to that present in hyperthyroid untreated GD patients, except for the CD5+ and CD5 − B cell populations. Our findings suggest that in vivo methimazole therapy would not directly have an important influence on circulating B cell subsets. Journal of Endocrinology (1996) 151, 231–240

scholarly journals Antigen-Specific B Cell Memory

2000 ◽  
Vol 191 (7) ◽  
pp. 1149-1166 ◽  
Author(s):  
Louise J. McHeyzer-Williams ◽  
Melinda Cool ◽  
Michael G. McHeyzer-Williams
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Memory B Cells ◽  
Cell Memory ◽  
Specific Memory ◽  
B Cell Memory ◽  
Cellular Components

The mechanisms that regulate B cell memory and the rapid recall response to antigen remain poorly defined. This study focuses on the rapid expression of B cell memory upon antigen recall in vivo, and the replenishment of quiescent B cell memory that follows. Based on expression of CD138 and B220, we reveal a unique and major subtype of antigen-specific memory B cells (B220−CD138−) that are distinct from antibody-secreting B cells (B220+/−CD138+) and B220+CD138− memory B cells. These nonsecreting somatically mutated B220− memory responders rapidly dominate the splenic response and comprise &gt;95% of antigen-specific memory B cells that migrate to the bone marrow. By day 42 after recall, the predominant quiescent memory B cell population in the spleen (75–85%) and the bone marrow (&gt;95%) expresses the B220− phenotype. Upon adoptive transfer, B220− memory B cells proliferate to a lesser degree but produce greater amounts of antibody than their B220+ counterparts. The pattern of cellular differentiation after transfer indicates that B220− memory B cells act as stable self-replenishing intermediates that arise from B220+ memory B cells and produce antibody-secreting cells on rechallenge with antigen. Cell surface phenotype and Ig isotype expression divide the B220− compartment into two main subsets with distinct patterns of integrin and coreceptor expression. Thus, we identify new cellular components of B cell memory and propose a model for long-term protective immunity that is regulated by a complex balance of committed memory B cells with subspecialized immune function.

scholarly journals Specific In Vivo Deletion of B-Cell Subpopulations Expressing Human Immunoglobulins by the B-Cell Superantigen Protein L

2004 ◽  
Vol 72 (6) ◽  
pp. 3515-3523 ◽  
Author(s):  
Muriel Viau ◽  
Nancy S. Longo ◽  
Peter E. Lipsky ◽  
Lars Björck ◽  
Moncef Zouali
Keyword(s):  
B Cells ◽  
B Cell ◽  
Immune Defense ◽  
Protein L ◽  
Variable Regions ◽  
Marginal Zone B Cells ◽  
Human Immunoglobulins ◽  
Cell Immunity ◽  
B Cell Subsets

ABSTRACT Some pathogens have evolved to produce proteins, called B-cell superantigens, that can interact with human immunoglobulin variable regions, independently of the combining site, and activate B lymphocytes that express the target immunoglobulins. However, the in vivo consequences of these interactions on human B-cell numbers and function are largely unknown. Using transgenic mice expressing fully human immunoglobulins, we studied the consequences of in vivo exposure of protein L of Peptostreptococcus magnus with human immunoglobulins. In the mature pool of B cells, protein L exposure resulted in a specific reduction of splenic marginal-zone B cells and peritoneal B-1 cells. Splenic B cells exhibited a skewed light-chain repertoire consistent with the capacity of protein L to bind specific kappa gene products. Remarkably, these two B-cell subsets are implicated in innate B-cell immunity, allowing rapid clearance of pathogens. Thus, the present study reveals a novel mechanism that may be used by some infectious agents to subvert a first line of the host's immune defense.

Bcl-2 Antagonist ApoGossypol (NSC736630) Displays Single-Agent Activity in Bcl-2 Transgenic Mice and Has Superior Efficacy and Pharmacology with Less Toxicity Compared to Gossypol (NSC19048).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2487-2487
Author(s):  
Shinichi Kitada ◽  
Lee Jia ◽  
Lori C. Coward ◽  
Greg S. Gorman ◽  
Patricia Noker ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Parent Compound ◽  
Single Agent ◽  
Pharmacokinetic Studies ◽  
Synthetic Analog ◽  
Low Grade ◽  
Altered Expression ◽  
Cell Counts

Abstract Altered expression of Bcl-2-family proteins plays a central role in apoptosis dysregulation in cancer and leukemia, promoting malignant cell expansion and contributing to chemoresistance. In this study, we compared the toxicity, pharmacology, and efficacy in mice of Gossypol (NSC19048) and ApoGossypol (NSC736630), a semi-synthetic analog of natural product Gossypol, in which two reactive aldehydes were eliminated from the compound (Becattini, et al Chem & Biol 11(3):389-95, 2004 Mar.). Gossypol and ApoGossypol mimic endogenous BH3 peptide-containing antagonists of anti-apoptotic Bcl-2-family proteins, competing with the BH3 peptide binding sites on Bcl-2, Bcl-XL, Mcl-1, Bcl-W, and Bcl-B, but not Bfl-1, with IC 50 of 0.5-2 M (Zhai, et al. Cell Death & Differ 13:1419-21, 2006). These compounds thus represent broad-spectrum antagonists of anti-apoptotic Bcl-2-family proteins. ApoGossypol displayed biostability comparable to Gossypol in plasma from mice, rats, dogs, and humans. Liver microsome analysis demonstrated no metabolites of either ApoGossypol or Gossypol, though both compounds underwent some glucuronidation. Apogossypol appeared more stable in human and mouse liver microsomal preparations than gossypol. Pharmacokinetic studies of i.v. and orally delivered Gossypol and ApoGossypol in mice showed that ApoGossypol has improved AUC (50–75% higher) due principally to reduced clearance rate. Both Gossypol and ApoGossypol exhibited similar oral bioavailability (10–13%) and have similar Cmax (10-20 M). Toxicity studies of i.p. and orally administered compounds showed that ApoGossypol is far less toxic than Gossypol. Daily dosing studies showed that mice tolerate doses of ApoGossypol 2–4-times higher than Gossypol. Hepatotoxicity and gastrointestinal toxicity (intestinal edema and ileus) represented the major adverse activities of these compounds, with ApoGossypol far less toxic than Gossypol. Efficacy of Gossypol and ApoGossypol was compared in a transgenic mouse model of Bcl-2-driven disease, where a human Bcl-2 gene from a t(14;18)-containing lymphoma drives continuous Bcl-2 expression in B-cells (Katsumata, et al. Proc Natl Acad Sci89: 11376; 1992). These mice develop splenomegally and have expanded populations of mature non-cycling B-cells in lymph nodes, resembling low-grade follicular lymphoma in humans. In vitro, Bcl-2-expressing B-cells were more sensitive to ApoGossypol than Gossypol, with LD50 values of 3–5 M and 7.5–10 M, respectively. In vivo, using the maximum tolerated dose of Gossypol (0.06 mmoles/kg) for sequential daily dosing (daily × 5 days × 3 weeks), ApoGossypol displayed superior activity to Gossypol in terms of reducing splenomegally and reducing B-cell counts in spleen. At higher does (0.12–0.24 mmole/kg), ApoGossypol showed still greater in vivo activity, producing larger reductions in splenomegally and in B-cell counts in spleen. Taken together, these studies indicate that ApoGossypol is superior to parent compound Gossypol with respect to pharmacology, toxicology, and efficacy, suggesting that further development of this compound for cancer therapy is warranted. (Supported by NCI-RAID and NCI contract funds N01-CM-07110 and N01-CM-52205, and by a grant to the CLL Research Consortium P01-CA081534).

Autoantibody Production during Chronic Graft-Versus-Host Disease Does Not Associate with Long-Term Persistence of Host B Cells in Humans

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1180-1180
Author(s):  
Simona Piemontese ◽  
Zulma Magnani ◽  
Jacopo Peccatori ◽  
Claudio Bordignon ◽  
Chiara Bonini ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
Graft Versus Host Disease ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Autoantibody Production ◽  
Graft Versus Host

Abstract Background. Chronic graft-versus-host disease (cGvHD) is a common complication of allogeneic hemopoietic cell transplantation (allo-HCT). The pathogenesis of cGvHD is poorly understood. In cGvHD, the homeostasis of B lymphocytes is perturbed, as demonstrated by the production of autoantibodies. B-cell depletion with monoclonal antibodies (mAb) interferes with autoantibody production and ameliorates signs and symptoms of cGvHD. In mouse models, cGvHD and autoantibodies associate with the long-term persistence of host B cells after allo-HCT (Sylvain Perruche et al., Transplantation 2006). It has been postulated that host B cells may present alloantigens to donor T cells and, in turn, receive help for autoantibody production. This could be crucial to the pathogenesis of cGvHD. Aim. To investigate whether the long-term persistence of host B lymphocytes is associated with cGvHD and autoantibodies in humans. Patients and methods. We recruited 13 consecutive patients with active cGvHD (4 mild, 5 moderate, 4 severe according to NIH classification) with a median time of onset of 6 months (range 3–36) from HLA-identical sibling (9 patients) and HLA-matched unrelated (4) allo-HCT. As controls, we chose 10 patients that underwent HLAidentical sibling (2), HLA-matched unrelated (5) or haploidentical (3) allo-HCT and never experienced cGvHD. In the two groups, we studied: circulating autoantibodies, including anti-nuclear (ANA), anti-DNA, anti-extractable nuclear antigen, anti-beta2 glycoprotein, anti-neutrophil cytoplasm, anti-thyroid, anti-mytocondria antibodies, rheumatoid factor, absolute numbers of T (CD3+, CD4+, CD8+), conventional B (CD19+), B1 (CD5+/CD19+) and NK cells (CD16+/CD56+) in the graft and in the peripheral blood, microchimerism by short-tandem repeats (STR) on B, T and myeloid cells purified by immunomagnetic cell sorting (sensitivity 0,01%). Results. Patients with cGvHD had high-titer circulating ANA (&gt;1:160) more frequently than controls (54% versus 10%, P&lt;0,05). All other autoantibodies were negative. Peripheral T-cell counts were lower in patients with cGvHD than in controls (for CD8+ cells P&lt;0,05). This was not due to a difference in the absolute numbers of T lymphocytes within the graft between the two groups. Peripheral counts of conventional B and B1 cells in patients with cGvHD were similar to controls. Autoantibodies and cGvHD were not associated with the persistence of host B lymphocytes, since the analysis of STR on purified B cells revealed that they were all of donor origin. T and myeloid cells were also of donor origin. Of interest, in univariate analysis, in vivo B-cell depletion with mAb for the prophylaxis against Epstein-Barr virus-related lymphoproliferative disease showed a trend towards a lower risk of cGvHD (P=0,06). Conclusions. This study indicates that autoantibody production during cGvHD does not associate with long-term persistence of host B cells in humans. Moreover, it suggests that the early depletion of donor B lymphocytes in vivo may be effective for GvHD prophylaxis

scholarly journals Changes in the T and B- Cell Subsets Following Treatment with a CD25-Antibody in Patients with Steroid Refractory GvHD

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2497-2497
Author(s):  
Geothy Chakupurakal ◽  
Maria Garcia- Marquez ◽  
Alexander Shimabukuro- Vornhagen ◽  
Hans Anton Schloesser ◽  
Udo Holtick ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Interleukin 2 ◽  
Unrelated Donors ◽  
B Cell Subsets ◽  
Regulatory Type ◽  
Steroid Refractory

Abstract Allogeneic stem cell transplantation is the therapeutic option for a variety of malignant and non-malignant haematological diseases. Graft versus Host Disease (GvHD) is a common post transplant complication. In 40% of these patients, GvHD is steroid refractory and associated with a mortality of around 60%. Basiliximab is a chimeric murine –human antibody also selective for interleukin -2 receptor (IL-2R) with a half life of 7 days. It is routinely used as part of the induction therapy in renal transplant recipients to prevent acute rejection following successful phase III studies. Phase 2 studies have demonstrated its superior efficacy in treating patients with steroid refractory GvHD (1). We administered Basiliximab in 14 patients with steroid refractory GvHD with a median age of 41 (range 20-69). M: F 7:7. All patients but one 13/14 received PBSC from unrelated donors and 6/13 had mismatched unrelated donors. Overall response was in the order of 12/14 (85%). One patient could not be assessed. 7/14 (50%) achieved a complete response to treatment. We aimed to study the in vivo T- and B-cell changes following Basiliximab administration as this would be an ideal platform to monitor the alterations in the regulatory T and B-cell compartment. PBMCs were obtained from all donors after informed consent, Immucan (Nr 11-116) approved by our local ethics committee, prior to and after weekly administration of Basiliximab 40mg for 4 weeks. Control samples were obtained from patients with steroid responsive acute GvHD. The total number of CD3+ as well as CD4+ and CD8+ T-cells remained constant during treatment and no change was observed on comparison with the controls. Gagliani et al (2) demonstrated that regulatory type 1 T-cells can be identified by the co-expression of CD49b and Lag3. No difference was observed between the % CD49d+, Lag3+ T-cells in the control cohort and the treatment cohort prior to therapy, ie day 0. The % CD49d+, Lag3+ T-cells decreased during the treatment period (statistically significant) in comparison to the control cohort. Despite the use of the CD25-antibody, a small population of CD25+, CD127+ cells could be detected and this population correlated to the % CD49d+, Lag3+ T-cells. Figure 1 Figure 1. Figure 2 Figure 2. The % CD19+, CD20+ B-cells were similar prior to treatment in the treatment group and control. Following the first administration a rise was observed followed by a decline over the next 3 weeks. No changes were seen in the activated (CD20+, CD86+) and anergic B-cell subsets (CD20+, CD21-) during the observation period. The % of CD24high, CD27+ regulatory B-cells were found to be twice that seen in the controls. With treatment a decrease was seen in this population. The CD24high, CD38high transitional B-cells were also found to be higher than that seen in the controls. No change was observed in this subset with treatment. Figure 3 Figure 3. This is the first attempt to study the in-vivo changes induced by a CD25 antibody in patients with steroid refractory GvHD. We conclude that this antibody not only depletes the alloreactive CD25+ T and B-cell population but also alters the regulatory T and B-cell subsets in comparison to patients with steroid responsive GvHD. Our clinical data supports the efficacy of this drug in patients with steroid refractory GvHD. Contrary to the current knowledge that regulatory T-cells are required for GvHD suppression our data suggests that Basiliximab facilitates regulatory T-cell depletion. The reduction of the regulatory T-cell subset observed in patients responding to anti CD25 treatment suggests a complex regulation and potential dichotomous role of these cells in acute GvHD. Schmidt-Hieber M, Fietz T, Knauf W, Uharek L, Hopfenmuller W, Thiel E, et al. Efficacy of the interleukin-2 receptor antagonist basiliximab in steroid-refractory acute graft-versus-host disease. Br J Haematol. 2005 Aug;130(4):568-74.Gagliani N, Magnani CF, Huber S, Gianolini ME, Pala M, Licona-Limon P, et al.Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells. Nat Med. 2013 Jun;19(6):739-46 Disclosures No relevant conflicts of interest to declare.

Extensive in vivo self-renewal, long-term reconstitution capacity, and hematopoietic multipotency of Pax5-deficient precursor B-cell clones

Blood ◽  
2002 ◽  
Vol 99 (8) ◽  
pp. 2760-2766 ◽  
Author(s):  
Christoph Schaniel ◽  
Marie Gottar ◽  
Eddy Roosnek ◽  
Fritz Melchers ◽  
Antonius G. Rolink
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Telomerase Activity ◽  
Self Renewal ◽  
Cell Clones ◽  
Precursor B Cells

Abstract Self-renewal, pluripotency, and long-term reconstitution are defining characteristics of single hematopoietic stem cells.Pax5−/− precursor B cells apparently possess similar characteristics. Here, using serial transplantations, with in vitro recloning and growth of the bone marrow–homed donor cells occurring after all transplantations, we analyzed the extent of self-renewal and hematopoietic multipotency ofPax5−/− precursor B-cell clones. Moreover, telomere length and telomerase activity in these clones was analyzed at various time points. Thus far, 5 successive transplantations have been performed. Clones transplanted for the fifth time, which have proliferated for more than 150 cell divisions in vitro, still repopulate the bone marrow with precursor B cells and reconstitute these recipients with lymphoid and myeloid cells. During this extensive proliferation, Pax5−/− precursor B cells shorten their telomeres at 70 to 90 base pairs per division. Their telomerase activity remains at 3% of that of HEK293 cancer cells during all serial in vivo transplantations/in vitro expansions. Together, these data show thatPax5−/− precursor B-cell clones possess extensive in vivo self-renewal capacity, long-term reconstitution capacity, and hematopoietic multipotency, with their telomeres shortening at the normal rate.

scholarly journals Intrathecal B-cell activation in LGI1 antibody encephalitis

2020 ◽  
Vol 7 (2) ◽  
pp. e669 ◽  
Author(s):  
Klaus Lehmann-Horn ◽  
Sarosh R. Irani ◽  
Shengzhi Wang ◽  
Arumugam Palanichamy ◽  
Sarah Jahn ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Cell Activity ◽  
Oligoclonal Bands ◽  
B Cell Activation ◽  
Cell Repertoire ◽  
Antibody Titers ◽  
B Cell Subsets

ObjectiveTo study intrathecal B-cell activity in leucine-rich, glioma-inactivated 1 (LGI1) antibody encephalitis. In patients with LGI1 antibodies, the lack of CSF lymphocytosis or oligoclonal bands and serum-predominant LGI1 antibodies suggests a peripherally initiated immune response. However, it is unknown whether B cells within the CNS contribute to the ongoing pathogenesis of LGI1 antibody encephalitis.MethodsPaired CSF and peripheral blood (PB) mononuclear cells were collected from 6 patients with LGI1 antibody encephalitis and 2 patients with other neurologic diseases. Deep B-cell immune repertoire sequencing was performed on immunoglobulin heavy chain transcripts from CSF B cells and sorted PB B-cell subsets. In addition, LGI1 antibody levels were determined in CSF and PB.ResultsSerum LGI1 antibody titers were on average 127-fold higher than CSF LGI1 antibody titers. Yet, deep B-cell repertoire analysis demonstrated a restricted CSF repertoire with frequent extensive clusters of clonally related B cells connected to mature PB B cells. These clusters showed intensive mutational activity of CSF B cells, providing strong evidence for an independent CNS-based antigen-driven response in patients with LGI1 antibody encephalitis but not in controls.ConclusionsOur results demonstrate that intrathecal immunoglobulin repertoire expansion is a feature of LGI1 antibody encephalitis and suggests a need for CNS-penetrant therapies.

scholarly journals Retinoic Acid and α-Galactosylceramide Differentially Regulate B Cell ActivationIn Vitroand Augment Antibody ProductionIn Vivo

2011 ◽  
Vol 18 (6) ◽  
pp. 1015-1020 ◽  
Author(s):  
Qiuyan Chen ◽  
Kara L. Mosovsky ◽  
A. Catharine Ross
Keyword(s):  
Cell Proliferation ◽  
Retinoic Acid ◽  
Cell Differentiation ◽  
B Cells ◽  
Antibody Response ◽  
B Cell ◽  
Secondary Response ◽  
Long Term Memory ◽  
B Cell Differentiation

ABSTRACTAll-trans-retinoic acid (RA) promotes the maturation and differentiation of B cells, which are known as a type of professional antigen-presenting cells. We show here that CD1d, a major histocompatibility complex class I-like molecule that presents lipid antigens, is expressed in the mouse spleen B cells and is increased by RA. Thus, we hypothesized that RA and the CD1d ligand, α-galactosylceramide (αGalCer), could interact to promote the differentiation, maturation, and antibody response of antigen-activated B cells. In isolated B cells, αGalCer alone markedly stimulated, and RA further increased B cell proliferation, synergizing with the B cell antigen receptor ligation via anti-μ antibody (P< 0.05). The significantly increased cell proliferation stimulated by αGalCer was abrogated in the B cells of CD1d-null mice. RA alone and combined with αGalCer also promoted B cell differentiation by the enrichment of sIgG1-, CD138-, and PNA/Fas-positive B cells (P< 0.05), suggesting a plasmacytic cell differentiation.In vivo, wild-type mice treated with RA and/or αGalCer during primary immunization with tetanus toxoid produced a higher serum anti-tetanus IgG response and had more bone marrow anti-tetanus antibody-secreting cells as determined by enzyme-linked immunospot assay (P< 0.05) in the secondary response, a finding indicative of heightened long-term memory; however, the increased antibody secretion after αGalCer treatment was abolished in CD1d-null mice. We provide evidence here that RA, together with αGalCer, can effectively regulate B cell proliferation and differentiation, ultimately promoting a more efficient antibody response to protein antigen. The results suggest that the combination of RA and αGalCer could be a useful adjuvant combination in vaccine strategies.

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