Level of B Cell Antigen Receptor Surface Expression Influences Both Positive and Negative Selection of B Cells During Primary Development

Heltemes, Lynn; Manser, Tim

doi:10.4049/jimmunol.169.3.1283

Cited by 42 publications

(42 citation statements)

References 54 publications

(54 reference statements)

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“…Taken as a whole, our data support a model, first suggested by Nemazee (11) and later on confirmed by studies from other investigators (10,56,57), in which a threshold of tonic BCR signaling is required to prevent receptor editing and lead to positive selection of immature B cells. Behrens and coworkers extended this model, suggesting that autoreactive immature B cells undergo editing because they lack tonic BCR signaling and not because they experience antigen-induced BCR signaling (28).…”

Section: Discussionsupporting

confidence: 76%

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: Discussionsupporting

confidence: 76%

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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“…Nonetheless, these ANA B cells are characterized by substantially reduced levels of BCR (20). These data led us to suggest that during their primary development, such B cells avoid central tolerance and peripheral anergy by reducing their cellular avidity for autoantigen via BCR down-regulation (20,21). However, this hypothesis was incompatible with other studies showing that reduced BCR levels, particularly of surface IgM (sIgM) are a common characteristic of anergy (1).…”

contrasting

confidence: 52%

Quantitatively Reduced Participation of Anti-Nuclear Antigen B Cells That Down-Regulate B Cell Receptor during Primary Development in the Germinal Center/Memory B Cell Response to Foreign Antigen

Alabyev

Rahman

Manser

2007

The Journal of Immunology

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The peripheral B cell compartment contains high levels of “polyreactivity” including autospecificities. We have described a pathway that certain autoreactive B cells may take in gaining stable access to the foreign Ag-responsive peripheral compartment. This pathway was revealed in mice expressing a targeted Ig H chain transgene encoding BCRs with “multireactivity” for the hapten arsonate and DNA-based autoantigens. B cells expressing such BCRs develop to mature follicular phenotype and locale, and are not short-lived. These B cells express very low levels of BCR, indicating that they are not “ignorant” of self Ag, but do not display features of anergy in in vitro assays. Nonetheless, a variety of states of lymphocyte anergy has been described, and some may only be manifested in vivo. As such, we analyzed the ability of these B cells to participate in a T cell-dependent immune response to arsonate in vivo. These B cells mount an early primary response similar to control B cells, including homing to follicles, migration to the T-B interface, and induction of costimulatory molecules, proliferation, differentiation to AFCs, class switching, and entry into GCs and somatic hypermutation. Nonetheless, these B cells display reduced participation in the latter stages of the GC response and in the anamnestic AFC response. In total, these data suggest that while the autoreactivity of this type of B cell does not result in anergy, the ability of such B cells to participate in a cross-reactive immune response to foreign Ag is compromised.

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“…6 and 7). Likewise, the gene dose-dependent increase of MZ B cells has been reported in anti-RBC or anti-p-azophenylarsonate IgH Tg mouse line (41,48). Thus, when the V H T gene was made homozygous, it is possible that the intensity of the augmented signals delivered by the homozygous BCR was within the optimal range for the development of MZ B cells, but did not exceed a threshold level required for negative selection.…”

Section: Discussionmentioning

confidence: 99%

Analysis of Marginal Zone B Cell Development in the Mouse with Limited B Cell Diversity: Role of the Antigen Receptor Signals in the Recruitment of B Cells to the Marginal Zone

Kanayama

Cascalho

Ohmori

2005

The Journal of Immunology

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The quasimonoclonal (QM) mouse provides an intelligible model to analyze the B cell selection as the competition between two major 4-hydroxy-3-nitrophenylacetyl-specific B cell populations whose BCR are comprised of the knockin VH17.2.25 (VHT)-encoded H chain and the λ1 or λ2 L chain. In this study, we show the QM system is useful to examine how BCR signals guide a subset of B cells to the marginal zone (MZ). Compared with the control C57BL/6 mice, the QM mice had ∼2.7-fold increased number of B cells exhibiting the MZ B cell phenotype and a larger MZ area in the spleen. Interestingly, VHT/λ2 B cells significantly predominated over VHT/λ1 B cells in MZ-(VHT/λ1:VHT/λ2 ≈ 3:7) and transitional 2-B cell subsets, while these two populations were comparable in immature, transitional 1, and mature counterparts. Thus, the biased use of λ2 in the MZ B cells may be the result of selection in the periphery. The enlargement of MZ B cell compartment and the preferred recruitment of the VHT/λ2 B cells were further augmented by doubling the VHT gene, but dampened by the dysfunction of Bruton’s tyrosine kinase, suggesting a positive role of BCR signaling in this selection. Comparison of Ag specificity between VHT/λ1 and VHT/λ2 IgM mAbs revealed a polyreactive nature of the VHT/λ2 BCR, including the reactivity with ssDNA. Taken together, it is suggested that polyreactivity (including self-reactivity) of BCR is crucial in driving B cells to differentiate into the MZ phenotype.

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Level of B Cell Antigen Receptor Surface Expression Influences Both Positive and Negative Selection of B Cells During Primary Development

Cited by 42 publications

References 54 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

Quantitatively Reduced Participation of Anti-Nuclear Antigen B Cells That Down-Regulate B Cell Receptor during Primary Development in the Germinal Center/Memory B Cell Response to Foreign Antigen

Analysis of Marginal Zone B Cell Development in the Mouse with Limited B Cell Diversity: Role of the Antigen Receptor Signals in the Recruitment of B Cells to the Marginal Zone

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