B‐cell stage and context‐dependent requirements for survival signals from BAFF and the B‐cell receptor

Mackay, Fabienne; Figgett, William A.; Saulep, Damien; LePage, Mélanie; Hibbs, Margaret L.

doi:10.1111/j.1600-065x.2010.00944.x

Cited by 162 publications

(173 citation statements)

References 254 publications

(405 reference statements)

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“…Mice deficient for either BAFF or BAFFR lack late transitional (T2) and mature follicular and marginal zone (MZ) B cells (9,10). BAFFR delivers critical cell growth and survival signals to B cells through the phosphoinositide-3 kinase (PI3K) and noncanonical NF-κB pathways (2,3,11). In addition, through an as-yet unclear mechanism, BAFF promotes survival by suppressing protein kinase C-δ function (12).…”

mentioning

confidence: 99%

“…Critical tolerance checkpoints throughout B-cell development normally account for editing, deletion, or unresponsiveness of such autoreactive clones within the mature repertoire (1). Autoreactive B-cell clones are progressively selected out of the developing B-cell pool in a manner that depends on the magnitude and duration of B-cell receptor (BCR) and B-cell activating factor receptor (BAFFR) signals that serve to enforce these checkpoints (2)(3)(4). Each pathway is independently required for normal B-cell development and survival, and dysregulation of either signaling pathway can cause devastating autoimmune disease (5)(6)(7)(8)(9)(10).…”

mentioning

confidence: 99%

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Quantitative differences in CD45 expression unmask functions for CD45 in B-cell development, tolerance, and survival

Zikherman

Doan

Parameswaran

et al. 2011

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

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The receptor-like tyrosine phosphatase CD45 positively regulates antigen receptor signaling by dephosphorylating the inhibitory tyrosine of the src family kinases. CD45-deficient mice fail to fully unmask the role of CD45 in B cells because of the expression of a partially redundant tyrosine phosphatase, CD148. However, mice that are doubly deficient in CD45 and CD148 exhibit a very early block in B-cell development, thereby obscuring later roles for CD45. To overcome these limitations, here we take advantage of an allelic series of mice in which CD45 expression is titrated broadly (0-180%). Although high expression of CD45 inhibits T-cell receptor (TCR) signaling, we show that CD45 plays a purely positive regulatory role during B-cell receptor (BCR) signaling. In concert with exaggerated BCR signaling, increasing CD45 expression drives enhanced receptor editing in the bone marrow and profound loss of follicular and marginal zone B cells in the spleen. In the context of the IgHEL/sHEL model of B-cell tolerance, such high CD45 expression transforms anergy into deletion. Unexpectedly, elimination of the autoantigen sHEL in this model system in order to block clonal deletion fails to rescue survival of mature B cells. Rather, high CD45 expression reduces B-cell activating factor receptor (BAFFR) expression and inhibits B-cell activating factor (BAFF)-induced B-cell survival in a cell-intrinsic manner. Taken together, our findings reveal how CD45 function diverges in T cells and B cells, as well as how autoreactive B cells are censored as they transit development.antigen receptor signaling | Lyn

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confidence: 99%

mentioning

confidence: 99%

Quantitative differences in CD45 expression unmask functions for CD45 in B-cell development, tolerance, and survival

Zikherman

Doan

Parameswaran

et al. 2011

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

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“…However, BAFF-R is the only receptor that receives signals uniquely from BAFF, whereas another homologous TNF-family member, APRIL, also signals through BCMA and TACI (12). The mAb Belimumab is able to bind to soluble, but not membrane-bound BAFF (13), and as such the only mechanism of action is a reduction of signaling through the BAFF receptors by ''mopping up'' soluble BAFF in circulation.…”

Section: Introductionmentioning

confidence: 99%

BAFF/BLyS inhibitors: A new prospect for treatment of systemic lupus erythematosus

Fairfax

Mackay

2012

IUBMB Life

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In November 2009, Human Genome Sciences and Glaxo‐Smith Kline [HGS (Rockville, Maryland) and GSK, respectively] announced that Belimumab, a neutralizing antibody to the tumour necrosis factor (TNF)‐like ligand, B‐cell activating factor (BAFF belonging to the TNF family, also named BLyS), met the primary endpoints in two phase III clinical trials in systemic lupus erythematosus (SLE, lupus). In March 2011, Belimumab was approved by the US Federal Drug Agency for treatment of SLE patients; this was followed in May with approval by the European Medicines Agency for use in the European Union. This is an exciting development as it is the first successful late‐stage clinical trial in SLE in over 40 years. In the light of this breakthrough, we review the key data and research outcomes and examine how blocking BAFF in patients with SLE significantly improves clinical outcomes. © 2012 IUBMB IUBMB Life, 64(7): 595–602, 2012

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“…2 T cell-independent mechanisms are mainly triggered by the TNF family cytokines, BAFF and APRIL. 25,82 In this section, we describe the molecular pathways of B cell activation.…”

Section: Activation -Molecular Pathways and Regulatorsmentioning

confidence: 99%

B-lymphocyte lineage cells and the respiratory system

2013

Journal of Allergy and Clinical Immunology

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Adaptive humoral immune responses in the airways are mediated by B cells and plasma cells that express highly evolved and specific receptors and produce immunoglobulins of most isotypes. In some cases, such as autoimmune diseases or inflammatory diseases caused by excessive exposure to foreign antigens, these same immune cells can cause disease by virtue of overly vigorous responses. This review discusses the generation, differentiation, signaling, activation and recruitment pathways of B cells and plasma cells, with special emphasis on unique characteristics of subsets of these cells functioning within the respiratory system. The primary sensitization events that generate B cells responsible for effector responses throughout the airways usually occur in the upper airways, in tonsils and adenoid structures that make up Waldeyer's Ring. Upon secondary exposure to antigen in the airways, antigen-processing dendritic cells migrate into secondary lymphoid organs such as lymph nodes that drain the upper and lower airways and further B cell expansion takes place at those sites. Antigen exposure in the upper or lower airways can also drive expansion of B lineage cells in the airway mucosal tissue and lead to the formation of inducible lymphoid follicles or aggregates that can mediate local immunity or disease.

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B‐cell stage and context‐dependent requirements for survival signals from BAFF and the B‐cell receptor

Cited by 162 publications

References 254 publications

Quantitative differences in CD45 expression unmask functions for CD45 in B-cell development, tolerance, and survival

Quantitative differences in CD45 expression unmask functions for CD45 in B-cell development, tolerance, and survival

BAFF/BLyS inhibitors: A new prospect for treatment of systemic lupus erythematosus

B-lymphocyte lineage cells and the respiratory system

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