Peripheral deletion of self-reactive B cells

Russell, D. M.; Dembić, Zlatko; Morahan, Grant; Miller, J. F. A. P.; Bürki, Kurt; Nemazee, David

doi:10.1038/354308a0

Cited by 336 publications

(261 citation statements)

References 28 publications

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“…To distinguish between these two possibilities, we directly investigated whether constitutive activation of Btk had the capacity to change the B-cell fate in the 3-83md Tg system. The 3-83md Tg encodes an antibody specific for MHC class I of the H-2K k,b haplotype [29]. On a non-autoreactive background, the expression of the 3-83md BCR commits B cells to the follicular or MZ subsets in the spleen.…”

Section: Constitutive Activation Of Btk Does Not Change the Folliculamentioning

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: Constitutive Activation Of Btk Does Not Change the Folliculamentioning

confidence: 99%

“…Btk-deficient, Slp65-deficient, VH81X or 3-83md Tg mice have been described [8,24,29,30]. We previously reported CD19-driven E41K-Btk and E41K-Y223F-Btk mice [28,40].…”

Section: Mice and Genotypingmentioning

confidence: 99%

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

et al. 2010

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“…They could be functionally inactivated by clonal anergy, as was demonstrated for high-affinity anti-hen egg lysozyme (HEL) antibodies and soluble HEL [56], or eliminated by clonal deletion as shown in the same Tg model for membrane-bound HEL [57], and further demonstrated in the case of Tg anti-class I autoantibodies that encounter the cognate class I antigen at a post-BM stage of development [58]. If activated, they could also be eliminated during GC immune responses [59,60].…”

Section: Discussionmentioning

confidence: 93%

Peripheral B cell receptor editing may promote the production of high‐affinity autoantibodies in CD22‐deficient mice

et al. 2006

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CD22-deficient mice are characterized by B cell hyperactivity and autoimmunity. We have constructed knock-in CD22 -/-mice, expressing an anti-DNA heavy (H) chain (D42), alone or combined with Vj1-Jj1 or Vj8-Jj5 light (L) chains. The Ig-targeted mice produced a lupus-like serology that was age-and sex-dependent. High-affinity IgG autoantibodies were largely dependent on the selection of B cells with a particular H/L combination, in which a non-transgenic, endogenous L chain was assembled by secondary rearrangements through the mechanism of receptor editing. Moreover, we present evidence that these secondary rearrangements are very prominent in splenic peripheral B cells. Since CD22 is primarily expressed on the surface of peripheral B cells, we propose a model for the development of a lupus-like autoimmune disease by a combination of peripheral receptor editing and abnormal B cell activation. IntroductionSystemic lupus erythematosus (SLE) is a rheumatic disease of unknown etiology, usually occurring in young women of childbearing age. The presence of serum antibodies to a variety of self components and their possible involvement in the development of severe kidney disease (glomerulonephritis) has made SLE a prototype of systemic autoimmune diseases [1]. The autoantibodies in lupus sera react with a large variety of nuclear antigens, including DNA, RNA and nuclear proteins. The antibodies to dsDNA are mostly highaffinity IgG that appear almost exclusively in SLE and very rarely in other diseases [2, 3].Several mouse models which spontaneously develop a lupus-like disease have been studied extensively [4]. The NZB/NZW F1 mouse is considered to be the murine model most closely resembling human SLE [5]. The lupus-like disease in these mice is more severe in females and is accompanied by high-affinity IgG anti-dsDNA autoantibodies. Both NZB and NZW parents contribute multiple susceptibility genes to the immune abnormalities of the F1 hybrid mouse [6]. Additional mouse models of SLE include mouse strains with deficiencies in antigen disposal mechanisms and mice that are deficient in proteins regulating the thresholds for tolerance and activation of B and T lymphocytes [7].CD22 is a B cell-specific surface glycoprotein of the Ig superfamily expressed on mature B cells [8, 9]. It functions as an adhesion molecule, as a signal-transducing molecule and as a modulator of intracellular signaling through the B cell receptor (BCR) complex. Negative regulatory roles for CD22 in BCR signaling are proposed to be critical for normal B cell activation, since immunoreceptor tyrosine-based inhibitory motifs with- in CD22 recruit SHP-1, a potent intracellular phosphatase with inhibitory functions in BCR signaling [10,11]. CD22-deficient mice [12][13][14][15] were reported to have decreased numbers of circulating B cells and slightly increased numbers of peritoneal B-1 cells, as well as higher levels of serum IgM [12,14]. Significantly, mature B cells from CD22-deficient mice had decreased expression of cell surface IgM and augmented i...

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“…As new emigrant B cells mature and become incorporated into the naive B cell pools responsive to antigens, the frequency of autoreactive BCRs is reduced again by one-half (to ϳ20% autoreactive and 5% polyreactive) (10,11). In contrast to the well-described mechanisms of central (first checkpoint) tolerance (4-7), the mechanisms of enforcement of B cell tolerance in the periphery are less clear (24)(25)(26)(27). Nonetheless, the primary B cell repertoire in humans is effectively censored by these 2 tolerance checkpoints, with the result that the substantial majority of autoreactive B cells and virtually all polyreactive B cells are lost during lymphocyte development and maturation.…”

Section: Garnett Kelsoementioning

confidence: 99%

B cell tolerance: Putting the horse before the cart

Kelsoe¹

2011

Arthritis & Rheumatism

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Peripheral deletion of self-reactive B cells

Cited by 336 publications

References 28 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

Peripheral B cell receptor editing may promote the production of high‐affinity autoantibodies in CD22‐deficient mice

B cell tolerance: Putting the horse before the cart

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