Lupus-Specific Antiribonucleoprotein B Cell Tolerance in Nonautoimmune Mice Is Maintained by Differentiation to B-1 and Governed by B Cell Receptor Signaling Thresholds

Qian, Yuping; Santiago, Carlos; Borrero, Michelle; Tedder, Thomas F.; Clarke, Stephen H.

doi:10.4049/jimmunol.166.4.2412

Cited by 78 publications

(86 citation statements)

References 55 publications

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“…Taken together with other studies [4, 31,32], our results support the hypothesis that peritoneal B-2 cells can acquire a B-1b-like phenotype under the appropriate conditions. This may reflect the ability of peritoneal B-2 cells to directly differentiate into B-1 cells as has been postulated by several investigators [38,39].…”

Section: Discussionsupporting

confidence: 91%

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Peritoneal B‐2 cells comprise a distinct B‐2 cell population with B‐1b‐like characteristics

et al. 2006

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B‐1 and B‐2 cells are lymphocyte populations that differ in development, surface marker expression, tissue localization, and function. Though mainly found in the spleen, lymph nodes, and circulation of mice, small numbers of B‐2 cells are found in the peritoneal cavity, a site predominantly populated by B‐1 cells. Here, we characterized peritoneal B‐2 cells, and determined their relationship to B‐1 cells. We found that peritoneal B‐2 cells appear to be intermediate between splenic B‐2 and peritoneal B‐1 cells in terms of surface marker expression of B220, CD80, and CD43, expression of several marker genes, and in vitro viability and IgM secretion. Adoptive transfer of peritoneal B‐2 cells into severe combined immunodeficiency mice resulted in the acquisition of a phenotype reminiscent of B‐1b cells, as shown by up‐regulation of Mac‐1 and CD43, and down‐regulation of CD23. Moreover, adoptively transferred peritoneal B‐2 cells recapitulated B‐1 cell function by producing natural IgM in recipient mice. These data suggest that peritoneal B‐2 cells express some characteristics of B‐1b cells and that this similarity increases with additional time in the peritoneal cavity.

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Section: Discussionsupporting

confidence: 91%

“…The induction of B-1 cell phenotypic characteristics in (splenic) B-2 cells has been reported before [4, 31,32]. However, the current work differs from these previous reports in two key respects.…”

Section: Discussionmentioning

confidence: 46%

Peritoneal B‐2 cells comprise a distinct B‐2 cell population with B‐1b‐like characteristics

et al. 2006

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“…These 2-12H mice have high numbers of anti-Sm B-1 B cells in spleen and peritoneum, but do not have higher serum anti-Sm relative to non-Tg littermates [34]. Only manipulations of the BCR co-receptors CD19 and CD22 resulted in increased anti-Sm autoantibody production [34]. Therefore, we conclude that tolerance is lost in E-Btk-2 Tg mice and that in this respect these mice resemble CD19-overexpressing or CD22-deficient mice.…”

Section: Discussionmentioning

confidence: 94%

“…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. These 2-12H mice have high numbers of anti-Sm B-1 B cells in spleen and peritoneum, but do not have higher serum anti-Sm relative to non-Tg littermates [34]. Only manipulations of the BCR co-receptors CD19 and CD22 resulted in increased anti-Sm autoantibody production [34].…”

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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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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Strong antigenic selection shaping the immunoglobulin heavy chain repertoire of B-1a lymphocytes in λ2315 transgenic mice

2002

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The B lymphocyte compartment of the recombinant mouse line L2 consists predominantly of CD5+ B‐1 cells that exclusively express the transgenic (Tg) λ2 L chain of the plasmacytoma MOPC315. Using such Tg mice as a simplified model to study positive selection processes, we show that restriction to a single L chain results in a strongly oligoclonal IgH chain repertoire in fetal and neonatal liver‐derived B cells, as well as in peritoneal CD5+ B‐1 lymphocytes from adult mice. In contrast, in vitro differentiated fetal liver Pro/PreB‐I cells from L2 embryosshow a clear increase of complementarity determining region three (CDR3) diversity. These data suggest that the antibody repertoire of B‐1a cells is strongly selected by antigen during fetal as well as adult peritoneal phase.

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Lupus-Specific Antiribonucleoprotein B Cell Tolerance in Nonautoimmune Mice Is Maintained by Differentiation to B-1 and Governed by B Cell Receptor Signaling Thresholds

Cited by 78 publications

References 55 publications

Peritoneal B‐2 cells comprise a distinct B‐2 cell population with B‐1b‐like characteristics

Peritoneal B‐2 cells comprise a distinct B‐2 cell population with B‐1b‐like characteristics

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

Strong antigenic selection shaping the immunoglobulin heavy chain repertoire of B-1a lymphocytes in λ2315 transgenic mice

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