Evidence of Marginal-Zone B Cell- Positive Selection in Spleen

Wen, Li; Brill-Dashoff, Joni; Shinton, Susan A.; Asano, Masanao; Hardy, Richard R.; Hayakawa, Kyoko

doi:10.1016/j.immuni.2005.08.007

Cited by 150 publications

(178 citation statements)

References 61 publications

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“…Similarly, it has been demonstrated Our finding of significantly increased anti-nucleosome IgM serum levels in E-Btk-2 Tg mice does not appear to reflect an increase in natural antibodies due to higher numbers of B-1 cells. This might be a possibility, as natural autoreactive B-1 B cells are positively selected by self-antigen [6,7]. But, in contrast to our E-Btk-2 mice, autoreactive B-1 cells are normally not efficiently driven into autoreactive IgM plasma cell formation: Tg mice that produce B cells specific for the Sm ribonucleoprotein, which is unique target in lupus, remain tolerant.…”

Section: Discussionmentioning

confidence: 84%

“…Similarly, it has been demonstrated that a natural serum autoantibody specific for the Thy-1 glycoprotein was produced in mice by B-1 cells that are positively selected by self-antigen [6]. Whereas lack of Thy-1 engagement in Thy-1 À/À mice permitted B cells specific for the Thy-1 glycoprotein to proceed to the follicular B-cell subset [32], increases in BCR signaling strength, induced by low-dose self-antigen, directed naive immature B cells to mature instead into the marginalzone B-cell subset [7]. It is therefore conceivable that LMP2A or Thy-1 antigen-mediated signals direct differentiation into B-cell subsets, whereas isolated Btk-mediated signals primarily affect cellular survival.…”

Section: Discussionmentioning

confidence: 99%

“…BCR signal strength is also a key factor in deciding between the three functionally distinct mature B-cell compartments of follicular, marginal zone (MZ) and B-1 B cells. Increases in BCR signaling strength, induced by low-dose selfantigen, direct maturation of naive immature B cells from the follicular into the B-1 or MZ B-cell fate [6,7]. Eur.…”

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confidence: 99%

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Constitutive activation of Bruton's tyrosine kinase induces the formation of autoreactive IgM plasma cells

et al. 2010

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B-cell receptor (BCR)-mediated signals provide the basis for B-cell differentiation in the BM and subsequently into follicular, marginal zone, or B-1 B-cell subsets. We have previously shown that B-cell-specific expression of the constitutive active E41K mutant of the BCR-associated molecule Bruton's tyrosine kinase (Btk) leads to an almost complete deletion of immature B cells in the BM. Here, we report that low-level expression of the E41K or E41K-Y223F Btk mutants was associated with reduced follicular B-cell numbers and significantly increased proportions of B-1 cells in the spleen. Crosses with 3-83md and VH81X BCR Tg mice showed that constitutive active Btk expression did not change follicular, marginal zone, or B-1 B-cell fate choice, but resulted in selective expansion or survival of B-1 cells. Residual B cells were hyperresponsive and manifested sustained Ca 21 mobilization. They were spontaneously driven into germinal center-independent plasma cell differentiation, as evidenced by increased numbers of IgM 1 plasma cells in spleen and BM and significantly elevated serum IgM. Because anti-nucleosome autoantibodies and glomerular IgM deposition were present, we conclude that constitutive Btk activation causes defective B-cell tolerance, emphasizing that Btk signals are essential for appropriate regulation of B-cell activation. IntroductionSignals transmitted by the B-cell receptor (BCR) control the antigen response of B cells and are also essential regulators of survival, tolerance and differentiation (reviewed in [1,2]). Inducible and stage-specific targeting experiments demonstrated that mature B cells undergo apoptosis upon in vivo BCR ablation or mutation of one of its signaling units, Ig-a, and consequently disappear from the circulation [3,4]. A critical survival signal is provided by PI3K [5], but how this signaling is initiated in resting mature B cells is not fully understood. BCR signal strength is also a key factor in deciding between the three functionally distinct mature B-cell compartments of follicular, marginal zone (MZ) and B-1 B cells. Increases in BCR signaling strength, induced by low-dose selfantigen, direct maturation of naive immature B cells from the follicular into the B-1 or MZ B-cell fate [6,7]. Eur. J. Immunol. 2010. 40: 2643-2654 DOI 10.1002 Leukocyte signaling 2643In mature B cells, BCR engagement induces phosphorylation of Ig-a and Ig-b and the formation of a lipid raft-associated calcium-signaling module. In this complex Syk phosphorylates the adapter molecule Slp65, thereby providing docking sites for Bruton's tyrosine kinase (Btk) and phospholipase Cg2 (Plcg2). Activation of Plcg2 by Btk results in the generation of the Ca 21 -releasing factors inositol-1,4,5-trisphosphate and diacylglycerol (reviewed in [8,9]). During these events various co-receptors modulate BCR signaling either positively or negatively [10].Deficiencies of BCR signaling molecules, such as Btk, Slp65 or Plcg2 or the excitatory co-receptor CD19 result in a hyporesponsive phenotype, mainly characterize...

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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

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Constitutive activation of Bruton's tyrosine kinase induces the formation of autoreactive IgM plasma cells

et al. 2010

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“…Our studies suggest that the intact BCR-NF-jB signaling pathway is required for maintenance and responsiveness of mature MZ B cell pool. During the preparation of this manuscript, a study by Wen et al [58] demonstrated that low-dose antigen signaling is required for the positive selection of MZ B cells in the spleen. This study further supports our conclusion that CARMA1 may be involved in constitutive BCR signaling required for the maturation of different splenic B cell subsets.…”

Section: Discussionmentioning

confidence: 99%

Potential role of CARMA1 in CD40‐induced splenic B cell proliferation and marginal zone B cell maturation

Pappu¹,

Lin²

2006

Eur J Immunol

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NF‐κB activation through B cell receptor (BCR) ligation is critical for B cell development, survival and antigen‐mediated activation of B cells. CARD domain and MAGUK‐domain containing protein‐1 (CARMA1), recently identified adaptor molecule, has been shown to play an essential role in BCR‐induced NF‐κB activation. CARMA1‐deficient B cells fail to proliferate upon BCR stimulation, leading to defective humoral responses. Surprisingly, CARMA1‐deficient B cells are also defective in CD40‐induced proliferation. The mechanisms responsible for CD40‐induced proliferation defect have not yet been characterized. In this study, we show that signaling cascades activated by CD40 stimulation are largely unaffected in CARMA1‐deficient B cells. Instead, we have found that the defective proliferation of CARMA1‐deficient B cells is due to two events. First, CARMA1‐deficient B cells show defective cell‐cycle progression. Secondly, the numbers of marginal zone (MZ) B cells, which are the main responders upon CD40 stimulation, are greatly diminished in CARMA1‐deficient mice. Since B cell maturation requires basal signaling through BCR and NF‐κB activation, we propose that impaired BCR signaling in CARMA1‐deficient mice leads to defective maturation of MZ B cell population, which in turn, contributes to impaired proliferation upon CD40 stimulation.

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“…However, recent studies have shown that BCR signal strength plays an important role in deciding B cell fate. B cells expressing a typical B1 BCR can be directed to MZ differentiation when Ag dose is reduced (43). Likewise, mutations that impair BCR signaling prevent B1 and FO but favor MZ B cell development, and mutations that enhance BCR signaling are associated with increased FO and decreased MZ B cells (26,76).…”

Section: The Cellular Origin Of Naamentioning

confidence: 99%

B Cells Expressing a Natural Polyreactive Autoantibody Have a Distinct Phenotype and Are Overrepresented in Immunoglobulin Heavy Chain Transgenic Mice

Tian¹,

Beardall²,

Xu³

et al. 2006

The Journal of Immunology

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Despite stringent regulation of disease-associated autoantibodies, a substantial proportion of circulating Abs in sera of healthy individuals exhibit self-reactivity. These Abs are referred to as naturally occurring or natural autoantibodies (NAAs). To understand the origin and function of NAAs, we have generated a new site-directed transgenic mouse model in which a prerearranged VDJ gene coding for the H chain of a typical polyreactive NAA, ppc1-5, is inserted into the IgH locus. This H chain, when combined with its original L chain, the λ1 L chain, yields a NAA that characteristically binds a variety of self and non-self Ags including ssDNA, actin, ubiquitin, and nitrophenyl phosphocholine. Despite their autoreactivity, B cells expressing ppc1-5H/λ1 NAA are not negatively selected, but rather are overrepresented in the transgenic mice. The shift toward λ1 expression mainly occurs during the transition of immature to mature B cells in the spleen, suggesting a BCR selection process. The ppc1-5H/λ1 B cells exhibit a phenotype that is different from those of the known mature B cell populations, and they are located predominantly in the lymphoid follicles of the spleen and the lymph nodes. These B cells are functionally active, producing high levels of Abs in vivo and responding well to BCR stimulation in vitro. The findings indicate that the ppc1-5/λ1 natural autoantibodies originate from a distinct B cell subset that may be positively selected by virtue of its poly/autoreactivity.

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Evidence of Marginal-Zone B Cell- Positive Selection in Spleen

Cited by 150 publications

References 61 publications

Constitutive activation of Bruton's tyrosine kinase induces the formation of autoreactive IgM plasma cells

Constitutive activation of Bruton's tyrosine kinase induces the formation of autoreactive IgM plasma cells

Potential role of CARMA1 in CD40‐induced splenic B cell proliferation and marginal zone B cell maturation

B Cells Expressing a Natural Polyreactive Autoantibody Have a Distinct Phenotype and Are Overrepresented in Immunoglobulin Heavy Chain Transgenic Mice

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