Positive Selection of Natural Autoreactive B Cells

Hayakawa, Kyoko; Asano, Masanao; Shinton, Susan A.; Gui, Ming; Allman, David; Stewart, Colin L.; Silver, Jack; Hardy, Richard R.

doi:10.1126/science.285.5424.113

Cited by 539 publications

(476 citation statements)

References 29 publications

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“…LMP2A expression allows the generation of BCR-negative B cells, and therefore provides a model where BCR signaling strength could be evaluated independently of BCR specificity. 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].…”

Section: Discussionmentioning

confidence: 97%

“…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.…”

mentioning

confidence: 84%

“…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: 97%

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confidence: 84%

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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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“…An increase in CD5+ B cells in mice with myocarditis suggests role of autoreactive B cells in pathogenesis. CD5+ B220+ cells represent B1 cells which have been shown to be positively selected on self-antigen [33]. Self-antigen has been shown to promote accumulation of B-1 cells and serum autoantibody [34].…”

Section: Discussionmentioning

confidence: 99%

Spontaneous myocarditis mimicking human disease occurs in the presence of an appropriate MHC and non-MHC background in transgenic mice

Taneja

Behrens

Cooper

et al. 2007

Journal of Molecular and Cellular Cardiology

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Most individuals have viral infections at some point in their life, however, only few develop autoreactivity to cardiac myosin following infection resulting in myocarditis suggesting a genetic predisposition. Most mouse models of myocarditis are induced by viral infection or by immunization with cardiac myosin. We generated HLA-DR3.Aβo and HLA-DQ8.Aβo transgenic mice in NOD and HLA-DQ8.Aβo in B10 background to study spontaneous autoimmunity. A high mortality was observed in NOD.DQ8 female mice 16 weeks or older. Echocardiography showed marked systolic dysfunction. Histopathology of various organs revealed an enlarged heart with mononuclear infiltrate consisting of CD4 and Mac-1+ cells and myocyte necrosis. The autoimmunity was associated with the presence of spontaneous autoreactive T cells and antibodies to cardiac myosin. Serologically, mice were negative for all known mouse viruses. NOD.DR3.Aβo, the transgene negative littermates, NOD, and B10.DQ8 Aβo mice had no gross or microscopic cardiac pathology. Spontaneous cellular and humoral response to cardiac myosin suggest that NOD.DQ8 may harbor autoreative cells that can lead to spontaneous myocarditis and dilated cardiomyopathy. HLA-DQ8 is required for predisposition to the spontaneous autoreactivity while NOD background influences onset and progression of disease. This model of myocarditis occurs predominantly in female mice and may provide insight into the pathogenesis of heart disease in women.

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“…Indeed, positive selection of developing T cells [13] and B cells [14] by self antigens seems to be critical in the development of the adaptive immune repertoire. Natural autoimmunity appears to perform a variety of positive functions [11]; autoimmune T cells, for example, have been shown experimentally to protect organs like the brain from secondary degeneration following trauma [15].…”

Section: Immune Attention To the Selfmentioning

confidence: 99%

Regulatory T cells and immune computation

Quintana

Cohen

2008

Eur J Immunol

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The role of Treg in immune regulation is the topic of this Viewpoint series in the European Journal of Immunology (EJI); the question to be discussed in this section is the effector function of Treg in immune regulation. In this manuscript, we take on the following three postulates outlined by Rolf Zinkernagel on the role of Treg in the control of immunity. First, the immune response is regulated primarily by the antigen and not by Treg. Second, immune non‐responsiveness results from the deletion of specific receptor‐bearing T cells. Third, there is no definitive proof of the existence of specialized Treg that know what is needed for an equilibrated immune response. Herein, we discuss data demonstrating the existence of specialized Treg and therefore arguing against the validity of the first two postulates. However, based on the reactive nature of the immune system, we agree with Rolf’s third postulate in that Treg cannot know ahead of time an ideal set‐point for immune homeostasis. See accompanying commentary:

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Positive Selection of Natural Autoreactive B Cells

Cited by 539 publications

References 29 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

Spontaneous myocarditis mimicking human disease occurs in the presence of an appropriate MHC and non-MHC background in transgenic mice

Regulatory T cells and immune computation

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