Continuous inhibitory signaling by both SHP-1 and SHIP-1 pathways is required to maintain unresponsiveness of anergic B cells

Getahun, Andrew; Beavers, Nicole A.; Larson, Sandy; Shlomchik, Mark J.; Cambier, John C.

doi:10.1084/jem.20150537

Cited by 92 publications

(134 citation statements)

References 75 publications

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“…Like most cancers, CLL is heterogeneous and the outcome of BCR signalling ranges from enhanced B cell activation to B cell anergy 81,82 . The main pathways that lead to cell survival and proliferation downstream of the BCR are shown in FIG.…”

Section: Mechanisms/pathophysiologymentioning

confidence: 99%

“…One important molecule that may be involved is the inositol lipid phosphatase SHIP1. SHIP1 is activated by the tyrosine-protein kinase LYN and may limit B cell activation by counteracting phosphoinositide 3-kinase (PI3K) activity at both chronically engaged receptors and distant non-ligated BCRs, rendering them insensitive to stimulation 82,83 .…”

Section: Mechanisms/pathophysiologymentioning

confidence: 99%

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Chronic lymphocytic leukaemia

Kipps

Stevenson

et al. 2017

Nat Rev Dis Primers

416

437

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Chronic lymphocytic leukaemia (CLL) is a malignancy of CD5+ B cells that is characterized by the accumulation of small, mature-appearing lymphocytes in the blood, marrow and lymphoid tissues. Signalling via surface immunoglobulin, which constitutes the major part of the B cell receptor, and several genetic alterations play a part in CLL pathogenesis, in addition to interactions between CLL cells and other cell types, such as stromal cells, T cells and nurse-like cells in the lymph nodes. The clinical progression of CLL is heterogeneous and ranges from patients who require treatment soon after diagnosis to others who do not require therapy for many years, if at all. Several factors, including the immunoglobulin heavy-chain variable region gene (IGHV) mutational status, genomic changes, patient age and the presence of comorbidities, should be considered when defining the optimal management strategies, which include chemotherapy, chemoimmunotherapy and/or drugs targeting B cell receptor signalling or inhibitors of apoptosis, such as BCL-2. Research on the biology of CLL has profoundly enhanced our ability to identify patients who are at higher risk for disease progression and our capacity to treat patients with drugs that selectively target distinctive phenotypic or physiological features of CLL. How these and other advances have shaped our current understanding and treatment of patients with CLL is the subject of this Primer.

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Section: Mechanisms/pathophysiologymentioning

confidence: 99%

Section: Mechanisms/pathophysiologymentioning

confidence: 99%

Chronic lymphocytic leukaemia

Kipps

Stevenson

et al. 2017

Nat Rev Dis Primers

416

437

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“…1a,b) is the most obvious explanation to their unresponsiveness to antigen triggering but it must be balanced with the fact that IgG is also able to elicit stronger responses than IgM, at least partly due to the additional signalling motifs of its cytoplasmic tail29. Because increased activity of phosphatases such as SHP-1 and SHIP, known to regulate BCR signalling, has been described to impair responsiveness of germinal centre30 or anergic31 B cells to antigenic stimulation, the possibility of an active silencing of the signalling function of IgG BCR in plasma cells cannot be excluded. Conversely, the loss of IgD and CD22 expression by IgM + plasma cells suggest that they could display an enhanced susceptibility to antigenic stimuli.…”

Section: Discussionmentioning

confidence: 99%

Mature IgM-expressing plasma cells sense antigen and develop competence for cytokine production upon antigenic challenge

et al. 2016

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Dogma holds that plasma cells, as opposed to B cells, cannot bind antigen because they have switched from expression of membrane-bound immunoglobulins (Ig) that constitute the B-cell receptor (BCR) to production of the secreted form of immunoglobulins. Here we compare the phenotypical and functional attributes of plasma cells generated by the T-cell-dependent and T-cell-independent forms of the hapten NP. We show that the nature of the secreted Ig isotype, rather than the chemical structure of the immunizing antigen, defines two functionally distinct populations of plasma cells. Fully mature IgM-expressing plasma cells resident in the bone marrow retain expression of a functional BCR, whereas their IgG+ counterparts do not. Antigen boost modifies the gene expression profile of IgM+ plasma cells and initiates a cytokine production program, characterized by upregulation of CCL5 and IL-10. Our results demonstrate that IgM-expressing plasma cells can sense antigen and acquire competence for cytokine production upon antigenic challenge.

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“…The lipid phosphatase SHIP-1 and the non-receptor type protein tyrosine phosphatases (PTPs) SHP-1 and LYB/PEP regulate B-cell tolerance and the development of autoimmune diseases 47, 48 . A recent study by Getahun et al .…”

Section: Regulation Of Central Tolerance and Clonal Anergy By Apoptosmentioning

confidence: 99%

“…A recent study by Getahun et al . 48 demonstrated that inducible deletion of either SHP-1 or SHIP-1 reverses anergy of DNA-reactive B cells and allows spontaneous differentiation of these self-reactive B cells to plasma cells. This result clearly indicates that anergy of self-reactive B cells is reversible and that both SHP-1 and SHIP-1 are required for maintenance of anergy.…”

Section: Regulation Of Central Tolerance and Clonal Anergy By Apoptosmentioning

confidence: 99%

B-cell tolerance and autoimmunity

Tsubata

2017

F1000Res

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Self-reactive B cells are tolerized at various stages of B-cell development and differentiation, including the immature B-cell stage (central tolerance) and the germinal center (GC) B-cell stage, and B-cell tolerance involves various mechanisms such as deletion, anergy, and receptor editing. Self-reactive B cells generated by random immunoglobulin variable gene rearrangements are tolerized by central tolerance and anergy in the periphery, and these processes involve apoptosis regulated by Bim, a pro-apoptotic member of the Bcl-2 family, and regulation of B-cell signaling by various phosphatases, including SHIP-1 and SHP-1. Self-reactive B cells generated by somatic mutations during GC reaction are also eliminated. Fas is not directly involved in this process but prevents persistence of GC reaction that allows generation of less stringently regulated B cells, including self-reactive B cells. Defects in self-tolerance preferentially cause lupus-like disease with production of anti-nuclear antibodies, probably due to the presence of a large potential B-cell repertoire reactive to nucleic acids and the presence of nucleic acid-induced activation mechanisms in various immune cells, including B cells and dendritic cells. A feed-forward loop composed of anti-nuclear antibodies produced by B cells and type 1 interferons secreted from nucleic acid-activated dendritic cells plays a crucial role in the development of systemic lupus erythematosus.

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Continuous inhibitory signaling by both SHP-1 and SHIP-1 pathways is required to maintain unresponsiveness of anergic B cells

Abstract: Cambier et al. show that the tyrosine phosphatase SHP-1 and the inositol phosphatase SHIP-1 are required to maintain B cell anergy.

Cited by 92 publications

References 75 publications

Chronic lymphocytic leukaemia

Chronic lymphocytic leukaemia

Mature IgM-expressing plasma cells sense antigen and develop competence for cytokine production upon antigenic challenge

B-cell tolerance and autoimmunity

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