Publications by authors named "Ji-Yang Wang"

66 Publications

CTLA-4 expression by B-1a B cells is essential for immune tolerance.

Nat Commun 2021 01 22;12(1):525. Epub 2021 Jan 22.

Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.

CTLA-4 is an important regulator of T-cell function. Here, we report that expression of this immune-regulator in mouse B-1a cells has a critical function in maintaining self-tolerance by regulating these early-developing B cells that express a repertoire enriched for auto-reactivity. Selective deletion of CTLA-4 from B cells results in mice that spontaneously develop autoantibodies, T follicular helper (Tfh) cells and germinal centers (GCs) in the spleen, and autoimmune pathology later in life. This impaired immune homeostasis results from B-1a cell dysfunction upon loss of CTLA-4. Therefore, CTLA-4-deficient B-1a cells up-regulate epigenetic and transcriptional activation programs and show increased self-replenishment. These activated cells further internalize surface IgM, differentiate into antigen-presenting cells and, when reconstituted in normal IgH-allotype congenic recipient mice, induce GCs and Tfh cells expressing a highly selected repertoire. These findings show that CTLA-4 regulation of B-1a cells is a crucial immune-regulatory mechanism.
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http://dx.doi.org/10.1038/s41467-020-20874-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822855PMC
January 2021

The role of GtxA during Gallibacterium anatis infection of primary chicken oviduct epithelial cells.

Mol Cell Probes 2020 10 28;53:101641. Epub 2020 Jul 28.

College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zhengzhou, 450002, China.

Gallibacterium anatis (G. anatis), one of the major pathogens causing reproductive tract disorders in laying hens, leads to a reduction in egg production and increased mortality, caused by either single or mixed infections with other pathogens. As a specific virulence factor of G. anatis, the role of GtxA in layers' salpingitis remains unclear. In this study, we explored the effect of GtxA on G. anatis infection by comparing wild strain Yu-PDS-RZ-1-SLG (RZ) and its GtxA deleted counterpart RZΔgtxA in primary chicken oviduct epithelial cells (COEC). Their adherence, invasion, cytoxicity, and ability to induce apoptosis and and cytokine secretion were evaluated and the cytotoxicity and cytokine secretion of the recombinant GtxA protein and its N-terminal adenylate cyclase and C-terminal RTX hemolysin domain were also analyzed. We found that the adhesion ability of RZΔgtxA was significantly lower than that of parental strain RZ, and its toxicity to COEC was weakened; Meanwhile, apoptosis was inhibited and the expression of IL-6, IL-2, TNF-α and IFN-γ were dramatically reduced in COEC infected by RZΔgtxA. In contrast, the recombinant protein GtxA inhibited the proliferation of oviduct cells and induced obvious cytotoxicity, and the expression of IL-6, TNF-α and IFN-γ were up-regulated in COEC interacted with recombinant proteins. Our study indicates that GtxA promotes G. anatis adherence to cells, changes cells permeability and expression of inflammatory factors, resulting in cell damage and apoptosis.
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http://dx.doi.org/10.1016/j.mcp.2020.101641DOI Listing
October 2020

SAMHD1-mediated dNTP degradation is required for efficient DNA repair during antibody class switch recombination.

EMBO J 2020 Aug 8;39(15):e102931. Epub 2020 Jun 8.

Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Sterile alpha motif and histidine-aspartic acid domain-containing protein 1 (SAMHD1), a dNTP triphosphohydrolase, regulates the levels of cellular dNTPs through their hydrolysis. SAMHD1 protects cells from invading viruses that depend on dNTPs to replicate and is frequently mutated in cancers and Aicardi-Goutières syndrome, a hereditary autoimmune encephalopathy. We discovered that SAMHD1 localizes at the immunoglobulin (Ig) switch region, and serves as a novel DNA repair regulator of Ig class switch recombination (CSR). Depletion of SAMHD1 impaired not only CSR but also IgH/c-Myc translocation. Consistently, we could inhibit these two processes by elevating the cellular nucleotide pool. A high frequency of nucleotide insertion at the break-point junctions is a notable feature in SAMHD1 deficiency during activation-induced cytidine deaminase-mediated genomic instability. Interestingly, CSR induced by staggered but not blunt, double-stranded DNA breaks was impaired by SAMHD1 depletion, which was accompanied by enhanced nucleotide insertions at recombination junctions. We propose that SAMHD1-mediated dNTP balance regulates dNTP-sensitive DNA end-processing enzyme and promotes CSR and aberrant genomic rearrangements by suppressing the insertional DNA repair pathway.
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http://dx.doi.org/10.15252/embj.2019102931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396875PMC
August 2020

B Cell Lymphoma.

Adv Exp Med Biol 2020 ;1254:161-181

Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.

B cell development and activation are accompanied by dynamic genetic alterations including V(D)J rearrangements and immunoglobulin-gene somatic hypermutation and class-switch recombination. Abnormalities in these genetic events can cause chromosomal translocations and genomic mutations, leading to altered expression and function of genes involved in B cell survival or proliferation and consequently B lymphomagenesis. In fact, B cell lymphoma accounts for 95% of the lymphomas. In this chapter, we summarize the morphology, immunophenotypes, clinical features, genetic defects that cause the malignancies, treatments, and prognosis of the most prevalent types of B cell lymphomas, including typical precursor B cell malignance (B-ALL/LBL) and mature B cell lymphoma (Hodgkin lymphoma and B cell non-Hodgkin lymphoma).
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http://dx.doi.org/10.1007/978-981-15-3532-1_12DOI Listing
July 2020

Primary Antibody Deficiencies.

Adv Exp Med Biol 2020 ;1254:117-144

Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.

Primary antibody deficiencies (PADs) are the most common types of inherited primary immunodeficiency diseases (PIDs) presenting at any age, with a broad spectrum of clinical manifestations including susceptibility to infections, autoimmunity and cancer. Antibodies are produced by B cells, and consequently, genetic defects affecting B cell development, activation, differentiation or antibody secretion can all lead to PADs. Whole exome and whole genome sequencing approaches have helped identify genetic defects that are involved in the pathogenesis of PADs. Here, we summarize the clinical manifestations, causal genes, disease mechanisms and clinical treatments of different types of PADs.
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http://dx.doi.org/10.1007/978-981-15-3532-1_10DOI Listing
July 2020

Regulation of Humoral Immune Responses and B Cell Tolerance by the IgM Fc Receptor (FcμR).

Adv Exp Med Biol 2020 ;1254:75-86

Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.

Immunoglobulin (Ig) M is the first antibody isotype produced during an immune response and is critical for host defense against infections. Recent studies have revealed that IgM also plays an important role in immune regulation and immunological tolerance. Mice lacking secretory IgM not only exhibit impaired production of antigen-specific IgG and are more susceptible to bacterial and viral infections, but also produce autoantibodies and are prone to develop autoimmune diseases. For many years, IgM has been thought to function predominantly by binding to antigen and activating complement (C') system. It is now clear that IgM can also elicit its function through the IgM Fc receptor (FcμR). In this chapter, we will review the role of FcμR in B cell development, maturation, survival and activation, antibody production, host defense against bacterial and viral infections, and B cell tolerance. We will also discuss the relative contribution of IgM-C' and IgM-FcμR pathways in humoral immune responses. Finally, we will discuss the possible involvement of FcμR in human chronic lymphocytic leukemia.
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http://dx.doi.org/10.1007/978-981-15-3532-1_7DOI Listing
July 2020

B Cell Development and Maturation.

Adv Exp Med Biol 2020 ;1254:1-22

Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.

Since the identification of B cells in 1965 (Cooper  et al. 1965), three has been tremendous progress in our understanding of B cell development, maturation and function. A number of B cell subpopulations, including B-1, B-2 and regulatory B cells, have been identified. B-1 cells mainly originate from the fetal liver and contain B-1a and B-1b subsets. B-2 cells are derived from the bone marrow (BM) and can be further classified into follicular B (FOB) and marginal zone B (MZB) cells. Regulatory B cells (Bregs) function to suppress immune responses, primarily by production of the anti-inflammatory cytokine IL-10. B cell tolerance is established at several checkpoints, during B cell development in the BM (central tolerance) as well as during B cell maturation and activation in the periphery (peripheral tolerance). This chapter will focus on the regulation of important processes during the development and maturation of B-1 and B-2 cells.
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http://dx.doi.org/10.1007/978-981-15-3532-1_1DOI Listing
July 2020

Aortic intimal intussusception during acute type B aortic dissection endovascular repair.

Ann Transl Med 2019 Nov;7(22):700

Department of Vascular Surgery, Beijing Hospital, National Center of Gerontology, Beijing 100730, China.

Aortic intimal intussusception (AoII) is rare, especially during the endovascular repair of acute uncomplicated type B aortic dissection. Here we present a case of 47-year-old man who suffered AoII during the endovascular repair of type B aortic dissection. An abdominal aortic stent was inserted to recanalize the aorta, but failed. He was immediately transferred to our department from the local hospital. Computed tomography angiography confirmed the AoII and showed thrombus in the abdominal aortic stent. Hybrid operation was performed. Final angiography showed patency of the aorta. His postoperative period was uneventful and was discharged on the postoperative 8 day. No complications happened during the 6 month follow-up.
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http://dx.doi.org/10.21037/atm.2019.10.52DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944591PMC
November 2019

Effective and safe treatment of a novel IL2RA deficiency with rapamycin.

J Allergy Clin Immunol Pract 2020 03 9;8(3):1132-1135.e4. Epub 2019 Oct 9.

Department of Clinical Immunology, Children's Hospital of Fudan University, Shanghai, China. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2019.09.027DOI Listing
March 2020

Distinct roles of BCNP1 in B-cell development and activation.

Int Immunol 2020 01;32(1):17-26

Department of Immunology, School of Basic Medical Sciences.

B-cell novel protein 1 (BCNP1) has recently been identified as a new B-cell receptor (BCR) signaling molecule but its physiological function remains unknown. Here, we demonstrate that mice deficient in BCNP1 exhibit impaired B-cell maturation and a reduction of B-1a cells. BCNP1-deficient spleen B cells show enhanced survival, proliferation and Ca2+ influx in response to BCR cross-linking as compared with wild-type spleen B cells. Consistently, mutant B cells show elevated phosphorylation of SYK, B-cell linker protein (BLNK) and PLCγ2 upon BCR cross-linking. In vivo, BCNP1-deficient mice exhibit enhanced humoral immune responses to T-independent and T-dependent antigens. Moreover, aged mutant mice contain elevated levels of serum IgM and IgG3 antibodies and exhibit polyclonal and monoclonal B-cell expansion in lymphoid organs. These results reveal distinct roles for BCNP1 in B-cell development, activation and homeostasis.
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http://dx.doi.org/10.1093/intimm/dxz055DOI Listing
January 2020

MZB1 promotes the secretion of J-chain-containing dimeric IgA and is critical for the suppression of gut inflammation.

Proc Natl Acad Sci U S A 2019 07 24;116(27):13480-13489. Epub 2019 May 24.

Department of Immunology, School of Basic Medical Sciences, Fudan University, 200032 Shanghai, China;

IgA is the most abundantly produced antibody in the body and plays a crucial role in gut homeostasis and mucosal immunity. IgA forms a dimer that covalently associates with the joining (J) chain, which is essential for IgA transport into the mucosa. Here, we demonstrate that the marginal zone B and B-1 cell-specific protein (MZB1) interacts with IgA through the α-heavy-chain tailpiece dependent on the penultimate cysteine residue and prevents the intracellular degradation of α-light-chain complexes. Moreover, MZB1 promotes J-chain binding to IgA and the secretion of dimeric IgA. MZB1-deficient mice are impaired in secreting large amounts of IgA into the gut in response to acute inflammation and develop severe colitis. Oral administration of a monoclonal IgA significantly ameliorated the colitis, accompanied by normalization of the gut microbiota composition. The present study identifies a molecular chaperone that promotes J-chain binding to IgA and reveals an important mechanism that controls the quantity, quality, and function of IgA.
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http://dx.doi.org/10.1073/pnas.1904204116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613140PMC
July 2019

Role of the IgM Fc Receptor in Immunity and Tolerance.

Front Immunol 2019 22;10:529. Epub 2019 Mar 22.

Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.

Immunoglobulin (Ig) M is the first antibody isotype to appear during evolution, ontogeny and immune responses. IgM not only serves as the first line of host defense against infections but also plays an important role in immune regulation and immunological tolerance. For many years, IgM is thought to function by binding to antigen and activating complement system. With the discovery of the IgM Fc receptor (FcμR), it is now clear that IgM can also elicit its function through FcμR. In this review, we will describe the molecular characteristics of FcμR, its role in B cell development, maturation and activation, humoral immune responses, host defense, and immunological tolerance. We will also discuss the functional relationship between IgM-complement and IgM-FcμR pathways in regulating immunity and tolerance. Finally, we will discuss the potential involvement of FcμR in human diseases.
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http://dx.doi.org/10.3389/fimmu.2019.00529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6438924PMC
September 2020

The B cell novel protein 1 (BCNP1) regulates BCR signaling and B cell apoptosis.

Eur J Immunol 2019 06 28;49(6):911-917. Epub 2019 Mar 28.

Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.

The BCR plays a central role in B cell development, survival, activation, and differentiation. We have identified the B cell novel protein 1 (BCNP1) as a new regulator of BCR signaling. BCNP1 contains a pleckstrin homology domain, three proline-rich motifs, and a potential SH2 binding site, and is predominantly expressed by B cells. We found that BCNP1 overexpression in WEHI231 immature B cells potentiated α-IgM-induced apoptosis. Conversely, BCNP1-deficient WEHI231 cells, generated by CRISPR-Cas9-mediated genome editing, exhibited reduced apoptosis after BCR crosslinking. Biochemical analyses revealed that BCNP1 physically interacted with the B cell linker protein (BLNK), Grb2, and PLCγ2. Moreover, absence of BCNP1 resulted in accelerated dephosphorylation of BLNK, reduced phosphorylation of SYK and PLCγ2, and decreased Ca influx after BCR crosslinking. These results demonstrate that BCNP1 promotes BCR signaling by modulating the phosphorylation of BLNK, SYK, and PLCγ2.
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http://dx.doi.org/10.1002/eji.201847985DOI Listing
June 2019

Essential Role of NADPH Oxidase-Dependent Production of Reactive Oxygen Species in Maintenance of Sustained B Cell Receptor Signaling and B Cell Proliferation.

J Immunol 2019 05 13;202(9):2546-2557. Epub 2019 Mar 13.

Department of Immunology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan;

Reactive oxygen species (ROS) are not only toxic substances inducing oxidative stress but also play a role as a second messenger in signal transduction through various receptors. Previously, B cell activation was shown to involve prolonged ROS production induced by ligation of BCR. However, the mechanisms for ROS production and ROS-mediated activation in B cells are still poorly understood. In this study, we demonstrate that BCR ligation induces biphasic ROS production in both mouse spleen B cells and the mouse B cell line BAL17; transient and modest ROS production is followed by sustained and robust ROS production at 2-6 h after BCR ligation. ROS production in the late phase but not in the early phase augments activation of signaling pathways, such as the NF-κB and PI3K pathways, and is essential for B cell proliferation. ROS production in the late phase appears to be mediated by NADPH oxidases (NOXes) because prolonged ROS production is inhibited by various NOX inhibitors, including the specific inhibitor VAS2870. BCR ligation-induced ROS production is also inhibited by CRISPR/Cas9-mediated deletion of either the gene encoding p22, the regulator of NOX1-4 required for their activation, or , whereas ROS production is not affected by double deficiency of the and genes essential for the activation of the NOX isoforms DUOX1 and DUOX2. These results indicate that NOXes play a crucial role in sustained but not early BCR signaling and suggest an essential role of NOX-dependent sustained BCR signaling in B cell activation.
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http://dx.doi.org/10.4049/jimmunol.1800443DOI Listing
May 2019

Long noncoding RNA MEG3 prevents vascular endothelial cell senescence by impairing miR-128-dependent Girdin downregulation.

Am J Physiol Cell Physiol 2019 06 21;316(6):C830-C843. Epub 2018 Dec 21.

Beijing Neurosurgical Institute, Capital Medical University , Beijing , People's Republic of China.

Long noncoding RNAs (lncRNAs) are commonly associated with various biological functions, in which the function of lncRNA maternally expressed gene 3 (MEG3) has been identified in various cancers. Strikingly, an association between MEG3 with microRNAs (miRNAs), mRNAs, and proteins has been reported. This study investigates the role of MEG3 in vascular endothelial cell (VEC) senescence. Expression of Girdin and miR-128 was monitored in the blood vessel samples of young and old mice/healthy volunteers, along with the measurement of human umbilical vein endothelial cells (HUVECs). The relationship between MEG3/Girdin and miR-128 was determined and verified. Loss- and gain-of-function approaches were applied to analyze the regulatory effects of MEG3 on platelet phagocytosis and lipoprotein oxidation of HUVEC membrane. In addition, the effect of MEG3 on HUVEC senescence was evaluated by detection of the reactive oxygen species, telomerase activity, and telomere length. To further analyze the MEG3-mediated regulatory mechanism, miR-128 upregulation and inhibition were introduced into the HUVECs. Downregulated Girdin and upregulated miR-128 were found in the blood vessels of old individuals and old mice, as well as in senescent HUVECs. MEG3 downregulation was found to be capable of inhibiting Girdin but enhancing miR-128 expression. It was also indicated to inhibit platelet phagocytosis and reduce telomerase activity and telomere length, while enhancing lipoprotein oxidation and reactive oxygen species production, which ultimately contributed in preventing and protecting HUEVCs from senescence. These findings provide evidence supporting that MEG3 leads to miR-128 downregulation and Girdin upregulation, which promotes platelet phagocytosis, thus protecting VECs from senescence.
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http://dx.doi.org/10.1152/ajpcell.00262.2018DOI Listing
June 2019

A tetrameric form of CD40 ligand with potent biological activities in both mouse and human primary B cells.

Mol Immunol 2019 01 6;105:173-180. Epub 2018 Dec 6.

Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China. Electronic address:

CD40 ligand (CD40 L) expressed by activated T cells interacts with CD40 on B cells and triggers B cell survival, proliferation and differentiation. Deficiency in CD40 L or CD40 in humans causes hyper IgM syndrome due to a defect in T-B interaction that is essential for Ig gene class switch recombination (CSR). CD40 L belongs to the tumor necrosis factor family and normally forms a homotrimer on the cell surface, which is important for its biological activity. To generate a multimeric CD40 L that can be used to stimulate both mouse and human B cells, we fused the extracellular domain of mouse CD40 L, which is known to also bind human CD40, with streptavidin (SA) that forms a stable tetramer under physiological conditions. As expected, 293 T cells transiently transfected with an SA-CD40 L expression vector secreted tetrameric SA-CD40 L in the culture supernatant. The secreted SA-CD40 L exhibited > 25-fold stronger activities in inducing the survival, activation and proliferation of both mouse and human primary B cells than did an agonistic anti-mouse or anti-human CD40 antibody. In the presence of IL-4, SA-CD40 L also induced efficient CSR and plasma cell differentiation in both mouse and human B cells. Moreover, administration of SA-CD40 L in mice induced activation and proliferation of spleen B cells in vivo. These results demonstrate that the SA-CD40 L fusion protein generated in the present study recapitulates the function of membrane-bound trimeric CD40 L and has potent biological activities in both mouse and human primary B cells.
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http://dx.doi.org/10.1016/j.molimm.2018.11.018DOI Listing
January 2019

TLR2 Promotes Glioma Immune Evasion by Downregulating MHC Class II Molecules in Microglia.

Cancer Immunol Res 2018 10 21;6(10):1220-1233. Epub 2018 Aug 21.

Department of Immunology, School of Basic Medical Sciences, and Institute of Biomedical Sciences, Fudan University, Shanghai, P.R. China.

Gliomas, the most common primary neoplasms in the brain, are notorious for their ability to evade the immune response. Despite microglial infiltration in gliomas, expression of MHC class II molecules in those microglia is compromised. Here, we report that Toll-like receptor 2 (TLR2) activation downregulated expression of MHC class II molecules in microglia in an orthotopic murine glioma model. TLR2-induced microglial impairment hindered the proliferation and activation of CD4 T cells, which facilitated glioma immune evasion. TLR2-induced downregulation of MHC class II molecules was caused by suppression of the master regulator of MHC class II molecule transcription, TLR2 activation triggered downstream MAPK/ERK1/2 signaling and loss of histone H3 acetylation at promoters, which in turn inhibited expression. In glioblastoma tissues, various endogenous TLR2 ligands, including the heat shock proteins that are endogenous TLR2 ligands, were upregulated, a response that correlated with inhibition. Thus, TLR2 promotes glioma immune-system evasion. These results advance our understanding of microglia as antigen-presenting cells in the context of glioma. In the glioma tumor microenvironment, TLR2 activation of microglia induces downregulation of microglial MHC class II expression. Impaired MHC class II expression limits T-cell-dependent antitumor immunity. .
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http://dx.doi.org/10.1158/2326-6066.CIR-18-0020DOI Listing
October 2018

Opposing roles of IgM and IgD in BCR-induced B-cell survival.

Genes Cells 2018 Oct 26;23(10):868-879. Epub 2018 Sep 26.

Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.

The B-cell receptor (BCR) transmits a tonic survival signal in the absence of antigen stimulation and an antigen-triggered survival signal. Mature B cells express two types of BCR, IgM and IgD, but it remains unclear how B-cell survival is differentially regulated by these two receptors. We found that, whereas cross-linking IgM on spleen B cells greatly enhanced their survival, cross-linking IgD did not enhance, but rather decreased, their survival. Consistently, cross-linking both IgM and IgD only moderately enhanced B-cell survival, suggesting that IgM and IgD play opposing roles in B-cell survival induced by BCR stimulation. Based on these and additional experimental results, we present a mathematical model integrating IgM- and IgD-mediated survival signals. Our model shows that IgD can transmit a tonic survival signal in the absence of antigen stimulation but cross-linking IgD not only does not generate a survival signal but also disrupts its tonic signal, resulting in inhibition of B-cell survival. These results suggest that IgD attenuates BCR-induced survival in mature B cells, presumably to restrain B-cell response to weak and/or self-antigens and prevent nonspecific B-cell activation and autoimmunity.
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http://dx.doi.org/10.1111/gtc.12635DOI Listing
October 2018

Kelch-like protein 14 promotes B-1a but suppresses B-1b cell development.

Int Immunol 2018 06;30(7):311-318

Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.

B-1 cells are innate-like B-cell population and produce natural antibodies that contribute to the first line of host defense. There are two subsets of B-1 cells: B-1a and B-1b. B-1a cells are the main producer of poly-reactive and autoreactive natural IgM antibodies, whereas B-1b cells can respond specifically to T-cell-independent antigens. Despite the functional significance of B-1a and B-1b cells, little information is available about what regulates the development of these two subsets. We found that Kelch-like protein 14 (KLHL14) was expressed at high levels in B cells but only at low levels in a few non-lymphoid tissues. Although mice lacking KLHL14 died right after birth, the heterozygotes developed normally with no gross abnormalities by appearance. B-cell development in the bone marrow and maturation and activation in the spleen were not affected in the heterozygous mice. However, the number of peritoneal B-1a cells was significantly reduced while B-1b cells were increased in Klhl14 heterozygous mice compared with wild-type (WT) mice. Consistently, Rag1-/- mice reconstituted with Klhl14-/- fetal liver cells had a more severe reduction of B-1a and an increase of B-1b cells in the peritoneal cavity. KLHL14 did not affect the turnover or apoptosis of B-1a and B-1b cells in vivo. Moreover, Klhl14-/- fetal liver contained a similar proportion and absolute numbers of the B-1 progenitor cells as did WT fetal liver. These results suggest that KLHL14 promotes B-1a development in mice.
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http://dx.doi.org/10.1093/intimm/dxy033DOI Listing
June 2018

Fcµ Receptor Promotes the Survival and Activation of Marginal Zone B Cells and Protects Mice against Bacterial Sepsis.

Front Immunol 2018 5;9:160. Epub 2018 Feb 5.

Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.

The marginal zone B cells (MZB) are located at the interface between the circulation and lymphoid tissue and as a gatekeeper play important roles in both innate and adaptive immune responses. We have previously found that MZB are significantly reduced in mice deficient in the IgM Fc receptor (FcμR) but how FcμR regulates the development and function of MZB remains unknown. In this study, we found that both marginal zone precursor (MZP) and MZB were decreased in mice. The reduction of MZP and MZB was not due to impaired proliferation of these cells but rather due to their increased death. Further analysis revealed that MZB had reduced tonic BCR signal, as evidenced by their decreased levels of phosphorylated SYK and AKT relative to WT MZB. MZB in mice responded poorly to LPS when compared with MZB in WT mice. Consistent with the reduced proportion of MZB and their impaired response to LPS, antibody production against the type 1 T-independent Ag, NP-LPS, was significantly reduced in mice. Moreover, mice were highly susceptible to -induced sepsis. These results reveal a critical role for FcμR in the survival and activation of MZB and in protection against acute bacterial infection.
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http://dx.doi.org/10.3389/fimmu.2018.00160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5807594PMC
April 2019

A model integrating tonic and antigen-triggered BCR signals to predict the survival of primary B cells.

Sci Rep 2017 11 2;7(1):14888. Epub 2017 Nov 2.

Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.

The BCR constitutively transmits a "tonic" survival signal in the absence of exogenous antigen-binding. However, the strength of tonic BCR signal and its relationship with antigen-triggered survival signal are poorly understood. We found that primary B cells expressing high levels of BCR had elevated BCR tonic signal and increased survival compared with those expressing low levels of BCR. In addition, we found that crosslinking BCR with low doses of F(ab') α-IgM antibodies did not enhance, but rather decreased, B cell survival and that only when most of the BCR were occupied by F(ab') α-IgM antibodies was B cell survival enhanced. Based on these experimental results, we present a mathematical model integrating tonic and antigen-triggered BCR signals. Our model indicates that the signal generated from crosslinked BCR is 4.3 times as strong as the tonic signal generated from free BCR and that the threshold of B cell activation corresponds to the signal generated by crosslinking 61% of the surface BCR. This model also allows the prediction of the survival probability of a B cell based on its initial BCR level and the strength and duration of antigen stimulation, and fits with the mechanism of B cell tolerance.
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http://dx.doi.org/10.1038/s41598-017-13993-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5668375PMC
November 2017

Efficient Induction of Ig Gene Hypermutation in Ex Vivo-Activated Primary B Cells.

J Immunol 2017 11 22;199(9):3023-3030. Epub 2017 Sep 22.

Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China;

Activation-induced cytidine deaminase (AID) initiates both somatic hypermutation (SHM) and class switch recombination (CSR) of Ig genes. How AID is targeted to the Ig V gene and switch region to trigger SHM and CSR remains elusive. Primary B cells stimulated with CD40L plus IL-4 or LPS plus IL-4 undergo efficient CSR, but it has been difficult to induce SHM in these cells. In the current study, we used B cells from B1-8 mice carrying a prerecombined V186.2DFL16.1J2 Ab gene to investigate the induction of SHM under in vitro culture conditions. B1-8 splenic B cells stimulated with CD40L plus IL-4 or LPS plus IL-4 underwent robust CSR to IgG, but failed to generate SHM in the V186.2 gene. Remarkably, ectopic expression of AID in AID-deficient, but not wild-type, B1-8 B cells induced efficient SHM at a rate close to that observed in germinal center B cells. We further established an AID-deficient CH12 B lymphoma line and found that ectopic expression of AID in the mutant line, but not in AID-sufficient CH12 cells, induced efficient point mutations and deletions in the V gene. These results demonstrate that the endogenous AID in ex vivo-activated primary B and B lymphoma cells not only cannot induce SHM but also inhibit the induction of SHM by the exogenous AID. Our results further suggest that the spatiotemporal distribution and/or posttranslational modification of AID strongly affects the induction of SHM in ex vivo-activated primary B cells.
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http://dx.doi.org/10.4049/jimmunol.1700868DOI Listing
November 2017

EAF2 mediates germinal centre B-cell apoptosis to suppress excessive immune responses and prevent autoimmunity.

Nat Commun 2016 Mar 3;7:10836. Epub 2016 Mar 3.

Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.

Regulated apoptosis of germinal centre (GC) B cells is critical for normal humoral immune responses. ELL-associated factor 2 (EAF2) regulates transcription elongation and has been shown to be an androgen-responsive potential tumour suppressor in prostate by inducing apoptosis. Here we show that EAF2 is selectively upregulated in GC B cells among various immune cell types and promotes apoptosis of GC B cells both in vitro and in vivo. EAF2 deficiency results in enlarged GCs and elevated antibody production during a T-dependent immune response. After immunization with type II collagen, mice lacking EAF2 produce high levels of collagen-specific autoantibodies and rapidly develop severe arthritis. Moreover, the mutant mice spontaneously produce anti-dsDNA, rheumatoid factor and anti-nuclear antibodies as they age. These results demonstrate that EAF2-mediated apoptosis in GC B cells limits excessive humoral immune responses and is important for maintaining self-tolerance.
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http://dx.doi.org/10.1038/ncomms10836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4782062PMC
March 2016

Q-switched 1329  nm Nd:CNGG laser.

Appl Opt 2015 Aug;54(23):7071-5

We demonstrate a laser-diode-pumped Q-switched 1329 nm neodymium-doped calcium-niobium-gallium-garnet (Nd:CNGG) laser using a V:YAG crystal as a saturable absorber. An average output power of 353 mW and a repetition rate of 13.43 kHz for Q-switched pulses were obtained. The pulse width was from 124 to 151.4 ns under different pump powers. Output power of 685 mW was obtained without the V:YAG crystal inserted.
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http://dx.doi.org/10.1364/AO.54.007071DOI Listing
August 2015

B cells expressing CD11b effectively inhibit CD4+ T-cell responses and ameliorate experimental autoimmune hepatitis in mice.

Hepatology 2015 Nov 28;62(5):1563-75. Epub 2015 Sep 28.

Department of Immunology, Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences, Fudan University, Shanghai, China.

Unlabelled: Increasing evidence in recent years has suggested that B cells act as a crucial regulator in autoimmune diseases. However, little is known about their role in autoimmune hepatitis (AIH) and the underlying regulatory mechanisms. In this study, we show that B cells ameliorated experimental AIH (EAH) by suppressing CD4+ T-cell responses and that CD11b expression on B cells was required for the regulatory function of B cells. In vitro studies reveal that the suppressive function of CD11b was mediated by the impairment of T-cell antigen receptor (TCR) signaling transduction and the promotion of TCR down-regulation. Moreover, we show that the increased CD11b expression on B cells was interleukin (IL)-10 dependent and that additional IL-10 stimulation promoted CD11b expression on B cells, thereby enhancing B-cell regulatory effects.

Conclusion: These findings reveal a previously unrecognized role for CD11b in B-cell regulatory function and its protective effect on EAH.
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http://dx.doi.org/10.1002/hep.28001DOI Listing
November 2015

Expression of activation-induced cytidine deaminase is associated with a poor prognosis of diffuse large B cell lymphoma patients treated with CHOP-based chemotherapy.

J Cancer Res Clin Oncol 2016 Jan 16;142(1):27-36. Epub 2015 Jun 16.

Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuo-ku, Chiba, 260-8717, Japan.

Purpose: Activation-induced cytidine deaminase (AID) is involved in somatic hypermutation and class switch recombination processes in the antibody formation. The AID activity induces gene mutations and could be associated with transformation processes of B cells. Nevertheless, the relation between AID expression and the prognosis of B cell lymphoma patients remains uncharacterized.

Methods: We examined expression levels of the AID gene in 89 lymph node specimens from lymphoma and non-lymphoma patients with Northern blot analysis and investigated an association with their survival.

Results: The AID gene was preferentially expressed in B cell lymphoma in particular in diffuse large B cell lymphoma and follicular lymphoma. We confirmed AID protein expression in the mRNA-positive but not in the negative specimens with Western blot analysis and immunohistochemical staining. Survival of the patients treated with cyclophosphamide-/doxorubicin-/vincristine-/prednisone-based chemotherapy demonstrated that the prognosis of diffuse large B cell patients was unfavorable in the mRNA-positive group compared with the negative group, and that AID expression levels were correlated with the poor prognosis. In contrast, AID expression was not linked with the prognosis of follicular lymphoma patients.

Conclusions: AID expression is a predictive marker for an unfavorable outcome in DLBCL patients treated with the chemotherapy.
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http://dx.doi.org/10.1007/s00432-015-2001-7DOI Listing
January 2016

Nomenclature of Toso, Fas apoptosis inhibitory molecule 3, and IgM FcR.

J Immunol 2015 May;194(9):4055-7

Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852;

Hiromi Kubagawa and John E. Coligan coordinated an online meeting to define an appropriate nomenclature for the cell surface glycoprotein presently designated by different names: Toso, Fas apoptosis inhibitory molecule 3 (FAIM3), and IgM FcR (FcμR). FAIM3 and Faim3 are the currently approved symbols for the human and mouse genes, respectively, in the National Center for Biotechnology Information, Ensembl, and other databases. However, recent functional results reported by several groups of investigators strongly support a recommendation for renaming FAIM3/Faim3 as FCMR/Fcmr, a name better reflecting its physiological function as the FcR for IgM. Participants included 12 investigators involved in studying Toso/FAIM3(Faim3)/FμR, representatives from the Human Genome Nomenclature Committee (Ruth Seal) and the Mouse Genome Nomenclature Committee (Monica McAndrews), and an observer from the IgM research field (Michael Carroll). In this article, we provide a brief background of the key research on the Toso/FAIM3(Faim3)/FcμR proteins, focusing on the ligand specificity and functional activity, followed by a brief summary of discussion about adopting a single name for this molecule and its gene and a resulting recommendation for genome nomenclature committees.
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http://dx.doi.org/10.4049/jimmunol.1500222DOI Listing
May 2015

FcμR interacts and cooperates with the B cell receptor To promote B cell survival.

J Immunol 2015 Apr 2;194(7):3096-101. Epub 2015 Mar 2.

Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; Department of Immunology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan; Biotherapy Research Center, Fudan University, Shanghai 200032, China; and Immunobiology Institute, Fudan University, Shanghai 200032, China

The IgM FcR (FcμR) promotes B cell survival, but the molecular mechanism remains largely unknown. We show using FcμR(-/-) and wild-type mice that FcμR specifically enhanced B cell survival induced by BCR cross-linking with F(ab')2-anti-IgM Abs while having no effect on survival when the B cells were activated by CD40 ligation or LPS stimulation. FcμR expression was markedly upregulated by anti-IgM stimulation, which may promote enhanced FcμR signaling in these cells. Immunofluorescence and confocal microscopy analyses demonstrated that FcμR colocalized with the BCR on the plasma membrane of primary B cells. Coimmunoprecipitation analysis further revealed that FcμR physically interacted with the BCR complex. Because NF-κB plays a prominent role in B cell survival, we analyzed whether FcμR was involved in BCR-triggered NF-κB activation. FcμR did not affect BCR-triggered IκBα phosphorylation characteristic of the canonical NF-κB activation pathway but promoted the production of the noncanonical NF-κB pathway component p52. Consistent with the elevated p52 levels, FcμR enhanced BCR-triggered expression of the antiapoptotic protein BCL-xL. Importantly, FcμR stimulation alone in the absence of BCR signaling had no effect on either IκBα phosphorylation or the expression of p52 and BCL-xL. Therefore, FcμR relied on the BCR signal to activate the noncanonical NF-κB pathway and enhance B cell survival. These results reveal a cross-talk downstream of FcμR and BCR signaling and provide mechanistic insight into FcμR-mediated enhancement of B cell survival after BCR stimulation.
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http://dx.doi.org/10.4049/jimmunol.1402352DOI Listing
April 2015

Superior intrinsic thermoelectric performance with zT of 1.8 in single-crystal and melt-quenched highly dense Cu(2-x)Se bulks.

Sci Rep 2015 Jan 8;5:7671. Epub 2015 Jan 8.

Faculty of Engineering, Shandong Jianzhu University, Shandong, P.R. China.

Practical applications of the high temperature thermoelectric materials developed so far are partially obstructed by the costly and complicated fabrication process. In this work, we put forward two additional important properties for thermoelectric materials, high crystal symmetry and congruent melting. We propose that the recently discovered thermoelectric material Cu2-xSe, with figure of merit, zT, over 1.5 at T of ~ 1000 K, should meet these requirements, based on our analysis of its crystal structure and the Cu-Se binary phase diagram. We found that its excellent thermoelectric performance is intrinsic, and less dependent on grain size, while highly dense samples can be easily fabricated by a melt-quenching approach. Our results reveal that the melt-quenched samples and single crystals exhibit almost the same superior thermoelectric performance, with zT as high as 1.7-1.8 at T of ~973 K. Our findings not only provide a cheap and fast fabrication method for highly dense Cu(2-x)Se bulks with superior thermoelectric performance, paving the way for possible commercialization of Cu2-xSe as an outstanding component in practical thermoelectric modules, but also provide guidance in searching for new classes of thermoelectric systems with high crystal symmetry or further improving the cost performance of other existing congruent-melting thermoelectric materials.
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http://dx.doi.org/10.1038/srep07671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5378988PMC
January 2015

Self DNA from lymphocytes that have undergone activation-induced cell death enhances murine B cell proliferation and antibody production.

PLoS One 2014 8;9(10):e109095. Epub 2014 Oct 8.

Key Laboratory of Medical Molecular Virology of MOE/MOH, Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China; Biotherapy Research Center of Fudan University, Shanghai, China.

Systemic lupus erythematosus (SLE) is characterized by prominent autoinflammatory tissue damage associated with impaired removal of dying cells and DNA. Self DNA-containing immune complexes are able to activate both innate and adaptive immune responses and play an important role in the maintenance and exacerbation of autoimmunity in SLE. In this study, we used DNA from lymphocytes that have undergone activation-induced cell death (ALD-DNA) and analyzed its role on the activation and differentiation of B cells from normal BALB/c mice as well as lupus-prone MRL+/+ and MRL/lpr mice. We found that ALD-DNA directly increased the expression of costimulatory molecules and the survival of naïve B cells in vitro. Although ALD-DNA alone had little effect on the proliferation of naïve B cells, it enhanced LPS-activated B cell proliferation in vitro and in vivo. In addition, ALD-DNA increased plasma cell numbers and IgG production in LPS-stimulated cultures of naïve B cells, in part via enhancing IL-6 production. Importantly, B cells from lupus mice were hyperresponsive to ALD-DNA and/or LPS relative to normal control B cells in terminal plasma cell differentiation, as evidenced by increases in CD138+ cell numbers, IgM production, and mRNA levels of B lymphocyte-induced maturation protein-1 (Blimp-1) and the X-box binding protein 1 (XBP1). Furthermore, ALD-DNA enhanced CD40-activated naïve B cell proliferation. Collectively, these data indicate that self DNA can serve as a DAMP (damage-associated molecular pattern) that cooperates with signals from both innate and adaptive immunity to promote polyclonal B cell activation, a common characteristic of autoimmune diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0109095PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4189923PMC
June 2015