Evidence for a preformed transducer complex organized by the B cell antigen receptor.

Wienands, Jürgen; Larbolette, Oliver; Reth, Michael

doi:10.1073/pnas.93.15.7865

Cited by 162 publications

(157 citation statements)

References 41 publications

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“…S1A). The effect of pervanadate in B cells is for the most part dependent on BCR expression and its ligand-independent activity (36,37). Thus, we identify the pErk detected in immature B cells as basal, although the absolute level measured after pervanadate treatment is inflated.…”

Section: Resultsmentioning

confidence: 90%

Activation of Ras overcomes B-cell tolerance to promote differentiation of autoreactive B cells and production of autoantibodies

Teodorovic

Babolin

Rowland

et al. 2014

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

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Newly generated immature B cells are selected to enter the peripheral mature B-cell pool only if they do not bind (or bind limited amount of) self-antigen. We previously suggested that this selection relies on basal extracellular signal-regulated kinase (Erk) activation mediated by tonic B-cell antigen receptor (BCR) signaling and that this signal can be replaced by an active rat sarcoma (Ras), which are small GTPase proteins. In this study we compared the activity of Ras and Erk in nonautoreactive and autoreactive immature B cells and investigated whether activation of Ras can break tolerance. Our results demonstrate lower levels of active Erk and Ras in autoreactive immature B cells, although this is evident only when these cells display medium/high avidity for self-antigen. Basal activation of Erk in immature B cells is proportional to surface IgM and dependent on sarcoma family kinases, whereas it is independent of B-cell activating factor, IFN, and Tolllike receptor signaling. Ectopic expression of the constitutively active mutant Ras form N-RasD12 in autoreactive cells raises active Erk, halts receptor editing via PI3 kinase, and promotes differentiation via Erk, breaking central tolerance. Moreover, when B cells coexpress autoreactive and nonautoreactive BCRs, N-RasD12 leads also to a break in peripheral tolerance with the production of autoantibodies. Our findings indicate that in immature B cells, basal activation of Ras and Erk are controlled by tonic BCR signaling, and that positive changes in Ras activity can lead to a break in both central and peripheral B-cell tolerance.Src | BAFF

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Section: Resultsmentioning

confidence: 90%

Activation of Ras overcomes B-cell tolerance to promote differentiation of autoreactive B cells and production of autoantibodies

Teodorovic

Babolin

Rowland

et al. 2014

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

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“…In support of this view, it has been suggested that the mitogenic effects of an oncogenic truncated mutant of the epidermal growth factor receptor are due to low constitutive activation, amplified by failure to attenuate signaling (36). Interestingly, it has been proposed that a normal BCR might possess constitutive activity (11,12), and therefore this constitutive activity might be exacerbated by the absence of feedback. The mechanism leading to the absence of down-regulation is unknown.…”

Section: Discussionmentioning

confidence: 84%

“…Although there is evidence for self-aggregation of ⌬V -bearing receptors (7), it is not known whether this is required for the constitutive activity of these truncated BCR. Recently, biochemical and biological evidence has led to the suggestion that the normal BCR itself might possess constitutive activity (11,12). Constitutive activity of unligated receptors has also been postulated to explain the effects of a transgenic truncated mouse H chain and of a truncated pre-TCR (13,14), prompting us to determine whether the H chain disease protein containing BCR behaves as a normal BCR or whether the activity of the truncated BCR mimics that induced upon Ag binding.…”

mentioning

confidence: 99%

Expression of a V Region-Less B Cell Receptor Confers a Tolerance-Like Phenotype on Transgenic B Cells

Corcos

Grandien

Vázquez

et al. 2001

The Journal of Immunology

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Neoplastic B cells from H chain disease patients express a truncated B cell receptor (BCR), comprising a membrane Ig that lacks part of its extracellular domain. It has been speculated that deletion of the Ag binding domain would confer a constitutive activity on the BCR, as it has been shown for oncogenic growth factor receptors. A V region-less BCR has constitutive activity, because in transgenic mice it causes inhibition of endogenous H chain gene rearrangements and relieves the requirement for surrogate L chain in pre-B cell development. However, it has been speculated that normal Ag receptors also display constitutive activity. Here we show that transgenic B cells expressing a membrane H chain disease protein on their surface are phenotypically and functionally similar to B cells developing in the presence of their cognate Ag and that cells with normal levels of mutant BCR are eliminated in spleen via a bcl-2 sensitive pathway while progressing toward the mature stage. In contrast, cells with lower levels of mutant receptors develop as mature B cells. These findings support the view that the truncated BCR has a constitutive activity that mimics ligand binding, in analogy to what has been shown for oncogenic growth factor receptors.

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“…It is possible that tonic signals through the FcRγ-chain are required to make cells permissive to stimulation. A similar concept is illustrated by a requirement for antigen-independent tonic signals through the B-cell receptor for B-cell development (41)(42)(43). It has been suggested that isotype-switched antibodies and FcRγ expression play a role in supporting Heligmosomoides polygyrus-induced expansion of basophils (44).…”

Section: Discussionmentioning

confidence: 99%

Signaling pathways activated by a protease allergen in basophils

Rosenstein

Bezbradica

et al. 2014

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

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Allergic diseases represent a significant burden in industrialized countries, but why and how the immune system responds to allergens remain largely unknown. Because many clinically significant allergens have proteolytic activity, and many helminths express proteases that are necessary for their life cycles, host mechanisms likely have evolved to detect the proteolytic activity of helminth proteases, which may be incidentally activated by protease allergens. A cysteine protease, papain, is a prototypic protease allergen that can directly activate basophils and mast cells, leading to the production of cytokines, including IL-4, characteristic of the type 2 immune response. The mechanism of papain's immunogenic activity remains unknown. Here we have characterized the cellular response activated by papain in basophils. We find that papain-induced IL-4 production requires calcium flux and activation of PI3K and nuclear factor of activated T cells. Interestingly, papain-induced IL-4 production was dependent on the immunoreceptor tyrosine-based activation motif (ITAM) adaptor protein Fc receptor γ-chain, even though the canonical ITAM signaling was not activated by papain. Collectively, these data characterize the downstream signaling pathway activated by a protease allergen in basophils.allergen | basophil | signaling

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Evidence for a preformed transducer complex organized by the B cell antigen receptor.

Cited by 162 publications

References 41 publications

Activation of Ras overcomes B-cell tolerance to promote differentiation of autoreactive B cells and production of autoantibodies

Activation of Ras overcomes B-cell tolerance to promote differentiation of autoreactive B cells and production of autoantibodies

Expression of a V Region-Less B Cell Receptor Confers a Tolerance-Like Phenotype on Transgenic B Cells

Signaling pathways activated by a protease allergen in basophils

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