FcγRIIb controls bone marrow plasma cell persistence and apoptosis

Zou, Xiang; Cutler, Antony J.; Brownlie, Rebecca J.; Fairfax, Kirsten; Lawlor, Kate E.; Severinson, Eva; Walker, Elizabeth; Manz, Rudolf A.; Tarlinton, David M.; Smith, Kenneth G. C.

doi:10.1038/ni1440

Cited by 276 publications

(270 citation statements)

References 58 publications

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“…We have found, however, that B6.Sle1(111-148) mice produced significantly more anti-SRBC IgG and total IgG, which was correlated with a greater number of primary AFCs that downregulated surface and intracellular IgM in favor of IgG. We have confirmed recent results showing FcgRIIB expression on PC, 21 but contrary to the other autoimmune strains NZB and MRL in which FcgRIIB is virtually absent on the PC surface, the NZW allele is associated with only a modest reduction of expression on PCs. Future experiments will have to be performed to assess whether this modest reduction is sufficient to decrease PC turnover through decreased apoptosis in Fcgr2b NZW -carrying mice, as it has been shown for Fcgr2b-deficient mice.…”

Section: Resultssupporting

confidence: 88%

“…Future experiments will have to be performed to assess whether this modest reduction is sufficient to decrease PC turnover through decreased apoptosis in Fcgr2b NZW -carrying mice, as it has been shown for Fcgr2b-deficient mice. 21 Interestingly, the kinetics of FcgRIIB expression on PC as well as the absence of Fcgr2b NZW -specific phenotype in secondary immune responses corroborates Fcgr2b NZW allele contribution to autoimmunity ZSM Rahman et al our previous findings 15 that this receptor regulates primary T-dependent immune responses. Overall, our results indicate that Fcgr2b NZW functions as an Fcgr2b hypomorph in regulating AFC numbers and class switching independent of GC reactions.…”

Section: Resultssupporting

confidence: 56%

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Expression of the autoimmune Fcgr2b NZW allele fails to be upregulated in germinal center B cells and is associated with increased IgG production

et al. 2007

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The inhibitory receptor FcgRIIb regulates B-cell functions. Genetic studies have associated Fcgr2b polymorphisms and lupus susceptibility in both humans and murine models, in which B cells express reduced FcgRIIb levels. Furthermore, FcgRIIb absence results in lupus on the appropriate genetic background, and lentiviral-mediated FcgRIIb overexpression prevents disease in the NZM2410 lupus mouse. The NZM2410/NZW allele Fcgr2b is, however, located in-between Sle1a and Sle1b, two potent susceptibility loci, making it difficult to evaluate Fcr2b NZW independent contribution. By using two congenic strains that each carries only Sle1a (B6.Sle1a(15-353)), or Fcr2b NZW in the absence of Sle1a or Sle1b (B6.Sle1(111-148)), we show that the Fcr2b NZW allele does not upregulate its expression on germinal center B cells and plasma cells, as does the C57BL/6 allele on B6.Sle1a(15-353) B cells. Furthermore, in the absence of the flanking Sle1a and Sle1b, Fcr2b NZW does not produce an autoimmune phenotype, but is associated with an increased number of class-switched plasma cells. These results show that while a lower level of FcgRIIb does not by itself induce the development of autoreactive B cells, it has the potential to amplify the contribution of autoreactive B cells induced by other lupus-susceptibility loci by enhancing the production of class-switched plasma cells.

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Section: Resultssupporting

confidence: 88%

Section: Resultssupporting

confidence: 56%

Expression of the autoimmune Fcgr2b NZW allele fails to be upregulated in germinal center B cells and is associated with increased IgG production

et al. 2007

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“…Because a significant fraction of circulating mature B cells is thought to be auto-or poly-reactive [36], such B cells may become activated because constitutive active Btk suppresses inhibitory effects of FcgRIIb or SHIP (as was previously shown for a membrane-associated Btk chimera, which led to sustained elevation of intracellular calcium [37]). In this context, it is conceivable that the E-Btk-2 Tg can also counteract inhibitory signals generated by FcgRIIb crosslinking that were recently found to induce apoptosis and thereby govern differentiation and maintenance of plasma cells [38]. Persistence of plasma cells in E-Btk-2 Tg mice would be supported by our finding of increased numbers of these cells in the BM.…”

Section: Discussionsupporting

confidence: 64%

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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“…It is the most broadly expressed, being found on most cells of myeloid lineage, and it is the only FcgR found on B cells. On B cells, cross-linking of FcgRIIb and the BCR activates a distinct pathway that inhibits cell proliferation, maturation, and the production of cytokines (1); however, cross-linking of FcgRIIb in the absence of the BCR initiates a bim-dependent apoptosis pathway (2). Reduced expression of FcgRIIb is associated with enhanced activation and proliferation of B cells and plasma cells (3), as well as increased Ab production to T-dependent Ags (3,4) and increased macrophage activation by immune complexes (4)(5)(6).…”

mentioning

confidence: 99%

FcγRIIb on Myeloid Cells and Intrinsic Renal Cells Rather than B Cells Protects from Nephrotoxic Nephritis

Sharp

Martín-Ramírez

Mangsbo

et al. 2013

The Journal of Immunology

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FcγRIIb is the sole inhibitory FcR for IgG in humans and mice, where it is involved in the negative regulation of Ab production and cellular activation. FcγRIIb-deficient mice show exacerbated disease following the induction of nephrotoxic nephritis (NTN). In this study, we determined the cellular origin of the FcγRIIb-knockout phenotype by inducing NTN in mice with a deficiency of FcγRIIb on either B cells alone (FcγRIIBfl/fl/CD19Cre+) or myeloid cells (FcγRIIBfl/fl/CEBPαCre+). Deletion of FcγRIIb from B cells did not increase susceptibility to NTN, compared with wild-type (WT) mice, despite higher Ab titers in the FcγRIIBfl/fl/CD19Cre+ mice compared with the WT littermate controls. In contrast, mice lacking FcγRIIb on myeloid cells had exacerbated disease as measured by increased glomerular thrombosis, glomerular crescents, albuminuria, serum urea, and glomerular neutrophil infiltration when compared with WT littermate controls. The role for FcγRIIb expression on radioresistant intrinsic renal cells in the protection from NTN was then investigated using bone marrow chimeric mice. FcγRIIb−/− mice transplanted with FcγRIIb−/− bone marrow were more susceptible to NTN than WT mice transplanted with FcγRIIb−/− bone marrow, indicating that the presence of WT intrinsic renal cells protects from NTN. These results demonstrate that FcγRIIb on myeloid cells plays a major role in protection from NTN, and therefore, augmentation of FcγRIIb on these cells could be a therapeutic target in human Ab-mediated glomerulonephritis. Where there was a lack of FcγRIIb on circulating myeloid cells, expression of FcγRIIb on intrinsic renal cells provided an additional level of protection from Ab-mediated glomerulonephritis.

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FcγRIIb controls bone marrow plasma cell persistence and apoptosis

Cited by 276 publications

References 58 publications

Expression of the autoimmune Fcgr2b NZW allele fails to be upregulated in germinal center B cells and is associated with increased IgG production

Expression of the autoimmune Fcgr2b NZW allele fails to be upregulated in germinal center B cells and is associated with increased IgG production

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

FcγRIIb on Myeloid Cells and Intrinsic Renal Cells Rather than B Cells Protects from Nephrotoxic Nephritis

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