SHIP-1 Deficiency in AID+ B Cells Leads to the Impaired Function of B10 Cells with Spontaneous Autoimmunity

Chen, Yingjia; Hu, Fanlei; Dong, Xuejiao; Zhao, Meng; Wang, Jing; Sun, Xiaolin; Kim, Tae Jin; Li, Zhanguo; Liu, Wanli

doi:10.4049/jimmunol.1700138

Cited by 12 publications

(9 citation statements)

References 55 publications

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“…FcγRI-mediated activation has been implicated in murine macrophage IL-10 production downstream of Ic ( 39 ). The FcγRIIB ITIM recruits the Src homology region 2 domain-containing phosphatase-1 and 2 (SHP-1 and 2) and the lipid phosphatase, SH2–containing inositol polyphosphate phosphatase (SHIP), to the cell membrane, the latter of which has been implicated in IL-10 production by regulatory B cells ( 40 ). Thus activating and inhibitory FcγRs may cooperate in human monocytes to promote anti-inflammatory (IVIg + LPS)-induced IL-10 production.…”

Section: Discussionmentioning

confidence: 99%

IVIg and LPS Co-stimulation Induces IL-10 Production by Human Monocytes, Which Is Compromised by an FcγRIIA Disease-Associated Gene Variant

et al. 2018

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Intravenous Immunoglobulin (IVIg) is used to treat autoimmune or inflammatory diseases, but its mechanism of action is not completely understood. We asked whether IVIg can induce interleukin-10 (IL-10) and reduce pro-inflammatory cytokine production in human monocytes, and whether this response is reduced in monocytes from people with an Fcγ receptor IIA (FcγRIIA) gene variant, which is associated with increased risk of inflammatory diseases and poor response to antibody-based biological therapy. IVIg increased IL-10 production and reduced pro-inflammatory cytokine production in response to bacterial lipopolysaccharide (LPS), which required FcγRI and FcγRIIB and activation of MAPKs, extracellular signal-regulated kinase 1/2 (ERK1/2), and p38. IL-10 production was lower and pro-inflammatory cytokine production was higher in monocytes from people with the FcγRIIA risk variant and the risk variant prevented IL-10 production in response to (IVIg+LPS). Finally, we show that IVIg did not induce MAPK activation in monocytes from people with the risk variant. Our results demonstrate that IVIg can skew human monocytes to an anti-inflammatory, IL-10-producing activation state, which is compromised in monocytes from people with the FcγRIIA risk variant. This research has profound implications for the use of IVIg because 25% of the population is homozygous for the FcγRIIA risk variant and its efficacy may be reduced in those individuals. In addition, this research may be useful to develop new therapeutic strategies to replace IVIg by cross-linking FcγRIs and FcγRIIBs to promote anti-inflammatory macrophage activation, independent of the FcγRIIA genotype.

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Section: Discussionmentioning

confidence: 99%

IVIg and LPS Co-stimulation Induces IL-10 Production by Human Monocytes, Which Is Compromised by an FcγRIIA Disease-Associated Gene Variant

et al. 2018

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“…Hyperproliferation of CD25-deficient mature B-cells in transplant recipient mice was paralleled by production of antinuclear autoantibodies ( Figure 2f ). These lupus-like features of B-cell-specific CD25-deletion phenocopied outcomes of germinal center-specific ( Aicda -Cre) deletion of the inhibitory SHIP1-phosphatase 45 . A closer examination of immunization experiments revealed that, NP-specific IgM serum levels were substantially increased upon B-cell-specific ablation of CD25, whereas NP-specific serum IgG levels were decreased compared to mice with CD25 +/+ B-cells ( Figure 2d ).…”

Section: Cd25 Surface Expression Marks Milestones Of B-cell Developme...mentioning

confidence: 93%

Dynamic phosphatase-recruitment controls B-cell selection and oncogenic signaling

Lee

Robinson

Sun

et al. 2023

Preprint

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Initiation of B-cell receptor (BCR)1 signaling, and subsequent antigen-encounter in germinal centers2,3 represent milestones of B-lymphocyte development that are both marked by sharp increases of CD25 surface-expression. Oncogenic signaling in B-cell leukemia (B-ALL)4 and lymphoma (5) also induced CD25-surface expression. While CD25 is known as an IL2-receptor chain on T- and NK-cells (6-9), the significance of its expression on B-cells was unclear. Our experiments based on genetic mouse models and engineered patient-derived xenografts revealed that, rather than functioning as an IL2-receptor chain, CD25 expressed on B-cells assembled an inhibitory complex including PKCD and SHIP1 and SHP1 phosphatases for feedback control of BCR-signaling or its oncogenic mimics. Recapitulating phenotypes of genetic ablation of PKCD (10-12),SHIP1 (13,14) and SHP1 (14-16), conditional CD25-deletion decimated early B-cell subsets but expanded mature B-cell populations and induced autoimmunity. In B-cell malignancies arising from early (B-ALL) and late (lymphoma) stages of B-cell development, CD25-loss induced cell death in the former and accelerated proliferation in the latter. Clinical outcome annotations mirrored opposite effects of CD25-deletion: high CD25 expression levels predicted poor clinical outcomes for patients with B-ALL, in contrast to favorable outcomes for lymphoma-patients. Biochemical and interactome studies revealed a critical role of CD25 in BCR-feedback regulation: BCR-signaling induced PKCD-mediated phosphorylation of CD25 on its cytoplasmic tail (S268, T271). Genetic rescue experiments identified CD25-S268/T271 tail-phosphorylation as central structural requirement to recruit SHIP1 and SHP1 phosphatases to curb BCR-signaling. A single point mutation CD25-S268A abolished recruitment and activation of SHIP1 and SHP1 to limit duration and strength of BCR-signaling. Loss of phosphatase-function, autonomous BCR-signaling and Ca2+-oscillations induced anergy and negative selection during early B-cell development, as opposed to excessive proliferation and autoantibody production in mature B-cells. These findings highlight the previously unrecognized role of CD25 in assembling inhibitory phosphatases to control oncogenic signaling in B-cell malignancies and negative selection to prevent autoimmune disease.

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“…When SHIP-1 is deleted in activated B cells using Aicda-cre, IL-10 expressing B cells are reduced. This may contribute to the observed autoantibody production in these animals ( 53 ). CD19-cre.SHIPf/f mice demonstrate an increase in CD11c+T-bet+ age associated B cells (ABCs), which are similar to the DN2 B cells that accumulate in SLE patients ( 54 ).…”

Section: Pi3k Signaling In the Loss Of B Cell Tolerancementioning

confidence: 95%

Recent Advances in Lupus B Cell Biology: PI3K, IFNγ, and Chromatin

Bacalao

Satterthwaite

2021

Front. Immunol.

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In the autoimmune disease Systemic Lupus Erythematosus (SLE), autoantibodies are formed that promote inflammation and tissue damage. There has been significant interest in understanding the B cell derangements involved in SLE pathogenesis. The past few years have been particularly fruitful in three domains: the role of PI3K signaling in loss of B cell tolerance, the role of IFNγ signaling in the development of autoimmunity, and the characterization of changes in chromatin accessibility in SLE B cells. The PI3K pathway coordinates various downstream signaling molecules involved in B cell development and activation. It is governed by the phosphatases PTEN and SHIP-1. Murine models lacking either of these phosphatases in B cells develop autoimmune disease and exhibit defects in B cell tolerance. Limited studies of human SLE B cells demonstrate reduced expression of PTEN or increased signaling events downstream of PI3K in some patients. IFNγ has long been known to be elevated in both SLE patients and mouse models of lupus. New data suggests that IFNγR expression on B cells is required to develop autoreactive germinal centers (GC) and autoantibodies in murine lupus. Furthermore, IFNγ promotes increased transcription of BCL6, IL-6 and T-bet in B cells, which also promote GC and autoantibody formation. IFNγ also induces epigenetic changes in human B cells. SLE B cells demonstrate significant epigenetic reprogramming, including enhanced chromatin accessibility at transcription factor motifs involved in B cell activation and plasma cell (PC) differentiation as well as alterations in DNA methylation and histone modifications. Histone deacetylase inhibitors limit disease development in murine lupus models, at least in part via their ability to prevent B cell class switching and differentiation into plasma cells. This review will discuss relevant discoveries of the past several years pertaining to these areas of SLE B cell biology.

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SHIP-1 Deficiency in AID+ B Cells Leads to the Impaired Function of B10 Cells with Spontaneous Autoimmunity

Cited by 12 publications

References 55 publications

IVIg and LPS Co-stimulation Induces IL-10 Production by Human Monocytes, Which Is Compromised by an FcγRIIA Disease-Associated Gene Variant

IVIg and LPS Co-stimulation Induces IL-10 Production by Human Monocytes, Which Is Compromised by an FcγRIIA Disease-Associated Gene Variant

Dynamic phosphatase-recruitment controls B-cell selection and oncogenic signaling

Recent Advances in Lupus B Cell Biology: PI3K, IFNγ, and Chromatin

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