CD22 × Siglec-G Double-Deficient Mice Have Massively Increased B1 Cell Numbers and Develop Systemic Autoimmunity

Jellusova, Julia; Wellmann, Ute; Amann, Kerstin; Winkler, Thomas; Nitschke, Lars

doi:10.4049/jimmunol.0902711

Cited by 129 publications

(153 citation statements)

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“…These findings are of importance and explain the mechanism of the inhibitory receptor Siglec-G in the mouse and potentially also its counterpart in the human, Siglec-10. Both CD22 and Siglec-G have been shown to be involved in B cell tolerance induction (11), and a deficiency in both of these receptors together leads to autoimmunity (22). Our findings are therefore highly relevant for the better understanding of B cell-driven autoimmune diseases and offer new treatment concepts for patients with these diseases.…”

Section: Discussionmentioning

confidence: 93%

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: Discussionmentioning

confidence: 93%

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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“…Thus, it is possible that bone marrow progenitors play a larger role in NOD B1a cell ontogeny, conditioning a higher B220 expression. Additionally, increased B220 expression is associated with a lower threshold of activation [38,39] and possibly underlies the surface immunophenotypes observed in NOD peritoneal B1a cells. This B1a B cell surface profile was also observed in male NOD mice, strengthening the suggestion that such NOD phenotypes are genetically determined and not affected by the degree of beta cell destruction (ESM Fig.…”

Section: Discussionmentioning

confidence: 99%

Innate stimulation of B1a cells enhances the autoreactive IgM repertoire in the NOD mouse: implications for type 1 diabetes

Côrte‐Real

Duarte

Tavares³

et al. 2012

Diabetologia

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Aims/hypothesis We sought to determine whether the presence of natural autoreactive antibodies of B1a cell origin would play a role in the initiation of type 1 diabetes. Methods We compared IgM repertoires and B1a cell compartments in NOD and C57BL/6 mice. Serum IgM autoreactivity profiles were determined by ELISA and the secretory properties and activation status of B1a cells were characterised by enzyme-linked immunosorbent spot (ELI-SPOT) assay and flow cytometry. B1a cell response to innate activation was analysed by gene expression assays, ELISA and [ 3 H]thymidine incorporation. The effect of NOD IgM produced by B1a cells on NOD.severe combined immunodeficient (SCID) beta cells was examined in cocultures: IgM binding was measured by flow cytometry and real-time PCR was used to study oxidative stress responses.Results NOD mice displayed increased levels of serum antiinsulin IgM that were independent of the H2 locus, that were maintained up to prediabetic stages and that correlated with the NOD B1a cell secretion profile. NOD B1a cells had a naturally increased pattern of activation, expressed higher levels of toll-like-receptors (Tlrs) and responded to TLR stimulation in vitro with higher proliferation and increased capacity to secrete anti-type-1-diabetes-related IgM, but produced lower amounts of IL10. IgM of NOD B1a cell origin was able to bind to pancreatic beta cells in vitro and induce expression of inducible nitric oxide synthase (Nos2). Conclusions/interpretation NOD B1a cells had a lower innate activation threshold for secretion of autoreactive IgM capable of triggering oxidative stress responses on binding to pancreatic beta cells; this provides an early mechanism that contributes to diabetes in a mouse model of type 1 diabetes.

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“…This is different on a mixed 129 × C57BL/6 background (23) or when CD22 −/− mice are crossed to Siglec-G −/− mice, which suggests some redundancy, as Siglec-G is a similar inhibitory receptor on B cells (3). One study showed that mice with a mutated CD22 ligand-binding domain had similar phenotypes to the CD22-deficient mice, without affecting Ca 2+ signaling.…”

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confidence: 99%

“…How ligand recognition of the Siglecs is mechanistically linked to the inhibitory function of these molecules is not clear. Loss of both CD22 and Siglec-G in B cells leads to spontaneous autoimmunity in mice (3). Additionally, mutations in an acetyl sialic acid esterase gene, coding for an enzyme, which modifies Siglec ligands, lead to autoimmunity (4).…”

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confidence: 99%

CD22 ligand-binding and signaling domains reciprocally regulate B-cell Ca ²⁺ signaling

Müller

Ingrid

Wöhner

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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A high proportion of human B cells carry B-cell receptors (BCRs) that are autoreactive. Inhibitory receptors such as CD22 can downmodulate autoreactive BCR responses. With its extracellular domain, CD22 binds to sialic acids in α2,6 linkages in cis, on the surface of the same B cell or in trans, on other cells. Sialic acids are self ligands, as they are abundant in vertebrates, but are usually not expressed by pathogens. We show that cis-ligand binding of CD22 is crucial for the regulation of B-cell Ca 2+ signaling by controlling the CD22 association to the BCR. Mice with a mutated CD22 ligand-binding domain of CD22 showed strongly reduced Ca 2+ signaling. In contrast, mice with mutated CD22 immunoreceptor tyrosine-based inhibition motifs have increased B-cell Ca 2+ responses, increased B-cell turnover, and impaired survival of the B cells. Thus, the CD22 ligand-binding domain has a crucial function in regulating BCR signaling, which is relevant for controlling autoimmunity.

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CD22 × Siglec-G Double-Deficient Mice Have Massively Increased B1 Cell Numbers and Develop Systemic Autoimmunity

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Cited by 129 publications

References 51 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

Innate stimulation of B1a cells enhances the autoreactive IgM repertoire in the NOD mouse: implications for type 1 diabetes

CD22 ligand-binding and signaling domains reciprocally regulate B-cell Ca ²⁺ signaling

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CD22 × Siglec-G Double-Deficient Mice Have Massively Increased B1 Cell Numbers and Develop Systemic Autoimmunity

Abstract: Material

Cited by 129 publications

References 51 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

Innate stimulation of B1a cells enhances the autoreactive IgM repertoire in the NOD mouse: implications for type 1 diabetes

CD22 ligand-binding and signaling domains reciprocally regulate B-cell Ca 2+ signaling

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CD22 ligand-binding and signaling domains reciprocally regulate B-cell Ca ²⁺ signaling