Siglecg Limits the Size of B1a B Cell Lineage by Down-Regulating NFκB Activation

Ding, Cheng; Liu, Yan; Wang, Yin; Park, Bae Keun; Wang, Cun‐Yu; Zheng, Pan; Liu, Yang

doi:10.1371/journal.pone.0000997

Cited by 51 publications

(72 citation statements)

References 27 publications

(49 reference statements)

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“…mRNA and intracellular protein expression analysis showed a Siglec-G expression pattern during all stages of B cell development, with higher intracellular mRNA and protein levels in B1 cells than in B2 cells (3). A Siglec-G-GFP knockin mouse suggested a broader Siglec-G expression pattern in B cells and several myeloid cell types (8). A functional role of Siglec-G expression on DCs was postulated to be responsible for a Siglec-Gdependent protective effect in a liver injury model and in antibacterial defense (9,10).…”

Section: The Journal Of Immunologymentioning

confidence: 95%

The Ligand-Binding Domain of Siglec-G Is Crucial for Its Selective Inhibitory Function on B1 Cells

Hutzler

Özgör

Naito-Matsui

et al. 2014

The Journal of Immunology

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Siglec-G is an inhibitory receptor on B1 cells. Siglec-G–deficient mice show a large B1 cell expansion, owing to higher BCR-induced Ca2+ signaling and enhanced cellular survival. It was unknown why Siglec-G shows a B1 cell–restricted inhibitory function. With a new mAb we could show a comparable Siglec-G expression on B1 cells and conventional B2 cells. However, Siglec-G has a different ligand sialic acid–binding pattern on peritoneal B1 cells than on splenic B cells, and its sialic acid ligands are expressed differentially on these two B cell populations, suggesting that cis-ligand binding plays a crucial role on B1 cells. This observation was further studied by generation of Siglec-G knockin mice with a mutated ligand-binding domain. These mice show increased B1 cell numbers, increased B1 cell Ca2+ signaling, better B1 cell survival, and changes in the B1 cell Ig repertoire. These phenotypes are very similar to Siglec-G–deficient mice. The mutation of the ligand-binding domain of Siglec-G strongly reduces the Siglec-G–IgM association on the B cell surface. Thus, Siglec-G sialic acid–dependent binding to the BCR is crucial for the B1 cell–restricted inhibitory function of Siglec-G and is regulated in an opposite way to that of the related protein CD22 (Siglec-2) on B cells.

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Section: The Journal Of Immunologymentioning

confidence: 95%

The Ligand-Binding Domain of Siglec-G Is Crucial for Its Selective Inhibitory Function on B1 Cells

Hutzler

Özgör

Naito-Matsui

et al. 2014

The Journal of Immunology

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“…Siglec-G is expressed throughout the B cell lineage, with the highest expression levels in B1a cells (1)(2)(3). Although Siglec-G is a potent inhibitor of BCR-induced Ca 2+ signaling when overexpressed in a B cell line, in mice it seems to play a dominant role only in B1a cells and not in conventional B2 cells.…”

mentioning

confidence: 99%

Siglec-G Regulates B1 Cell Survival and Selection

Jellusova

Düber

Gückel

et al. 2010

The Journal of Immunology

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Siglec-G is a negative regulator of BCR-mediated signaling in B1a cells. This population of B cells is highly increased in Siglec-G–deficient mice, but the mechanism of this expansion is not known so far. In this study, we demonstrate that Siglecg−/− B1a cells show a lower level of spontaneous apoptosis and a prolonged life span. Mechanistically, the lower apoptosis could result from higher expression levels of the transcription factor NFATc1 in Siglec-G–deficient B1a cells. Interestingly, Siglecg−/− B1a cells display an altered BCR repertoire compared with wild-type B1a cells. As the BCR repertoire and the VDJ composition of Igs of Siglecg−/− B1a cells resembles more the Abs produced by adult bone marrow-derived B cells rather than canonical fetal liver-derived B1a cells, this suggest that the selection into the B1a cell population is altered in Siglec-G–deficient mice.

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“…1,11 The possibility that the accumulation of Siglecg B-1a cells, the major source of natural antibodies, might lead to an autoimmune disease has been ruled out. 1,3 We aimed to investigate whether the Siglecg −/− phenotype might favor a monoclonal expansion or even the development of an overt lymphoid malignancy.…”

Section: Discussionmentioning

confidence: 99%

“…+ polyclonal B-cell population in the spleen and especially in the peritoneal cavity. 1,11 Siglecg −/− peritoneal B-1a cells injected into chimeric mice have both an increased rate of proliferation and an improved capacity for survival as compared to wild-type B-1a cells. 2 In addition, Siglecg −/− mice have a higher titer of serum IgM and with age have an increased production of autoantibodies, 1 although they do not develop an overt autoimmune disease.…”

Section: Introductionmentioning

confidence: 99%

SIGLEC-G deficiency increases susceptibility to develop B-cell lymphoproliferative disorders

et al. 2014

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The sialic-acid-binding immunoglobulin-like lectin SIGLEC-G is a negative regulator of B-cell receptor-mediated calcium signaling. Its deficiency leads to reduced turnover and increased proliferation and survival of murine B-1a cells. Siglecg −/− mice show a premature expansion of polyclonal CD5 + B cells in the spleen and the peritoneal cavity. Here we studied the fate of B lymphocytes in Siglecg −/− mice over time. We demonstrate that in aging animals SIGLEC-G deficiency promotes progressive accumulation of monoclonal B lymphocytes and increases the susceptibility to develop B-cell lymphoproliferative disorders. Lymphoid tumors arising in aged Siglecg −/− mice are monoclonal and histologically heterogeneous as they include diffuse large B-cell lymphoma, follicular lymphoma, and medium-to-large B-cell monomorphic lymphoma but surprisingly not chronic lymphocytic leukemia. The tumors express high levels of BCL-2 and are transplantable. In keeping with these findings we have also observed a remarkable down-regulation of the human ortholog SIGLEC10 in human B-cell lymphoma and leukemia cell lines. Taken together, these observations indicate that the down-regulation of negative B-cell receptor regulators such as SIGLEC-G/SIGLEC10 may represent another mechanism relevant to the pathogenesis of B-cell lymphomas.ABSTRACT nant clones are explained by the interplay of the transforming genetic lesions and the cellular and molecular interactions that occur in the tumor microenvironment. [17][18][19][20]

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Siglecg Limits the Size of B1a B Cell Lineage by Down-Regulating NFκB Activation

Cited by 51 publications

References 27 publications

The Ligand-Binding Domain of Siglec-G Is Crucial for Its Selective Inhibitory Function on B1 Cells

The Ligand-Binding Domain of Siglec-G Is Crucial for Its Selective Inhibitory Function on B1 Cells

Siglec-G Regulates B1 Cell Survival and Selection

SIGLEC-G deficiency increases susceptibility to develop B-cell lymphoproliferative disorders

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