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

Yarkoni, Yuval; Fischel, Ruth; Kat, Inbal; Yachimovich-Cohen, Nurit; Eilat, Dan

doi:10.1002/eji.200636190

Cited by 12 publications

(14 citation statements)

References 69 publications

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“…Whether receptor editing in transitional B cells normally occurs is uncertain. Although receptor editing in mature and germinal center B cells is well documented, these studies were conducted under special circumstances, such as immunization, ongoing autoimmune responses, or in cells with mutant BCR signaling molecules (11)(12)(13)(14)(15). This type of peripheral receptor editing, also known as "receptor revision", is purported to generate high-affinity Abs rather than to silence autoreactive B cell clones.…”

Section: B Cell Development In Bone Marrow (Bm)mentioning

confidence: 99%

Transitional B Cells Lose Their Ability to Receptor Edit but Retain Their Potential for Positive and Negative Selection

Wang

Feng

et al. 2007

The Journal of Immunology

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Ligation of B cell receptors on immature bone marrow B cells, either by an endogenous Ag or by an anti-B cell receptor Ab induces secondary V(D)J gene rearrangements, termed receptor editing. Whether the same signal induces receptor editing in transitional B cells is not clear. In this study, we examined the responses of immature and transitional B cells from VH12Vκ1A Ig transgenic mice to stimulation with an anti-Igβ Ab. Our results demonstrated that immature B cells stimulated with a low concentration of anti-Igβ Ab, mimicking Ag stimulation, underwent receptor editing both in vivo and in vitro, as evidenced by the detection of dsDNA breaks at Jκ recombination signal sequences, whereas transitional B cells did not. The lack of dsDNA breaks in transitional B cells contrasts with their increased expression of RAG1 and RAG2, suggesting a novel mechanism that may prevent rearrangements. Furthermore, treatment of transitional B cells with high concentrations of anti-Igβ Abs induced apoptosis, whereas low concentrations induced differentiation. Our results support the idea that transitional B cells lose the capacity to edit, but are sensitive to positive and negative selection.

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Section: B Cell Development In Bone Marrow (Bm)mentioning

confidence: 99%

Transitional B Cells Lose Their Ability to Receptor Edit but Retain Their Potential for Positive and Negative Selection

Wang

Feng

et al. 2007

The Journal of Immunology

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“…Studies in BCR Tg models have demonstrated that B cells with strong self-reactivity are censored in the bone marrow largely through receptor editing and deletion (1)(2)(3)(4)(5). Elegant work by several investigators has shown that secondary rearrangement at the L chain (LC) locus is a particularly effective mechanism that B cells commonly use to veto self-reactivity (6 -9).…”

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confidence: 99%

The Role of Rearrangement at the Second Ig Heavy Chain Locus in Maintaining B Cell Tolerance to DNA

Liu

Mohan

2008

The Journal of Immunology

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In recently generated B6.56R anti-DNA autoantibody-transgenic mice, it was noted that a substantial fraction of the B cells that had avoided DNA reactivity had done so through the rearrangement and usage of the endogenous, nontargeted H chain (HC) allele. This suggested that rearrangement at the second HC locus might be an important mechanism through which self-reactive B cells might successfully revise their initial Ag specificity. To test the importance of this mechanism in B cell tolerance, we generated B6.56R/56R mice that possessed the 56R anti-DNA H chain transgene inserted into both HC loci. These transgenic homozygotes developed higher titers of anti-DNA Abs, with an expanded population of B220lowMHC class IIlow B cells, enriched for CD21lowCD23low preplasmablasts. The analysis of hybridomas from these mice revealed that the only avenue by which these B cells could avoid DNA reactivity was through the use of the editor L chains, Vk20 or Vk21. Hence, in addition to LC editing, rearrangement and usage of the second HC locus/allele constitutes an important safety valve for B cells the primary BCR of which confers DNA reactivity. In contrast to these tolerance mechanisms, editing the first rearranged HC locus (through HC replacement) and somatic mutations appear to be less frequently used to edit/revise self-reactive B cells.

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“…Engagement of SHIP via FcγRII is known to inhibit B-cell proliferation, Akt activation, and survival [37][38][39] Even in mice bearing an anti-DNA transgene and deregulation of BCR signaling by CD22 mutation show a sex bias in development of autoimmunity [43], suggesting additional sex-dependant factors contribute beyond initial B-cell dysfunction. The mechanisms contributing to female bias in autoantibody-mediated diseases are not completely understood but may involve mechanisms related to sex hormones since some studies find blocking sex hormone signaling in autoimmune female mice led to amelioration of disease [44,45].…”

Section: Discussionmentioning

confidence: 99%

“…Thus, another contributing factor might be that mutation of TAPP1-and TAPP2-binding sites for PI(3,4)P2 increases that amount of this PI available for recruiting Akt to the plasma membrane, where it can be phosphorylated and activated by PDK1. It should be noted that while PI(3,4)P2 has been implicated in Akt phosphorylation and activation, other studies suggest that PIP3 is the limiting factor for Akt membrane recruitment and activation [20,22,32].Engagement of SHIP via FcγRII is known to inhibit B-cell proliferation, Akt activation, and survival [37][38][39] Even in mice bearing an anti-DNA transgene and deregulation of BCR signaling by CD22 mutation show a sex bias in development of autoimmunity [43], suggesting additional sex-dependant factors contribute beyond initial B-cell dysfunction. The mechanisms contributing to female bias in autoantibody-mediated diseases are not completely understood but may involve mechanisms related to sex hormones since some studies find blocking sex hormone signaling in autoimmune female mice led to amelioration of disease [44,45].…”

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confidence: 99%

Interaction of TAPP adapter proteins with phosphatidylinositol (3,4)‐bisphosphate regulates B‐cell activation and autoantibody production

et al. 2012

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TAPP1 and TAPP2 (where TAPP is tandem PH domain containing protein) are dual PH domain adaptors that selectively bind PI(3,4)P2 (phosphatidylinositol (3,4)-bisphosphate). PI(3,4)P2 is a lipid messenger generated by phosphoinositide 3-kinase (PI3K)and IntroductionThe phosphoinositide 3-kinase (PI3K) signaling pathway is linked to a number of key cellular processes including lymphocyte cell survival, proliferation, differentiation, and motility [1][2][3].Correspondence: Dr. Aaron J. Marshall e-mail: marshall@ms.umanitoba.ca PI3K functions by phosphorylating the D3 position of membrane phosphoinositides (PIs) generating PI(3)P, PI(3,4)P2, and PI(3,4,5)P3. These D3 PIs regulate various cellular processes through the recruitment of effector proteins containing PI-binding domains [4][5][6]. Regulation of this pathway in immune cells is crucial for prevention of leukocyte-derived cancers as well as development of autoimmune diseases [7][8][9][10].The B-cell antigen receptor (BCR) activates PI3K [11] and this pathway plays critical roles in B lymphocyte development and function [12,13]. The PI3K pathway is critical for C 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2012. 42: 2760-2770 Leukocyte signaling 2761"tonic" signaling through the BCR, which is required to maintain the survival of mature B cells [14]. PI phosphatases such as PTEN and SHIP function to restrain PI3K signaling by limiting the amount of PI(3,4,5)P3 available for binding [15,16]. In B cells, inhibitory signaling via the receptor FcγRIIB requires binding of SHIP to an ITIM motif in its cytoplasmic tail [17]. SHIP-deficient mice show elevated immunoglobulin levels and increased B-cell proliferation upon BCR-FcγRIIB cross-linking, indicating that SHIP functions as a negative regulator in B cells [18]. PI second messengers regulate various cellular activities by functioning as membrane docking sites for proteins containing PIbinding modules such as PH, PX, or FYVE domains [19]. While PI(3,4,5)P3 is clearly implicated in activation of signaling pathways, the signaling events downstream of PI(3,4)P2 are not well understood. A key PI-dependant protein kinase Akt/PKB can bind both PI(3,4,5)P3 and PI(3,4)P2, and the latter lipid has been suggested to contribute to Akt activation [20,21]; however the direct versus indirect effects of PI(3,4)P2 on Akt activity remains controversial. SHIP, which hydrolyzes PIP3 to generate PI(3,4)P2, has been found in several systems to inhibit Akt activation [18,22], suggesting that PIP3 levels may often be the limiting factor regulating Akt activity.A few proteins are known to selectively bind to PI(3,4)P2, but not PIP3, including PX domain proteins involved in NADPH oxidase regulation [23] and TAPP1 and TAPP2 (where TAPP is tandem PH domain containing proteins) [24]. We previously found that TAPP adapters are expressed in B cells and are recruited to the plasma membrane in response to BCR cross-linking, in a delayed and sustained manner correlating with PI(3,4)P2 levels [25]. TAPP2 membra...

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

Cited by 12 publications

References 69 publications

Transitional B Cells Lose Their Ability to Receptor Edit but Retain Their Potential for Positive and Negative Selection

Transitional B Cells Lose Their Ability to Receptor Edit but Retain Their Potential for Positive and Negative Selection

The Role of Rearrangement at the Second Ig Heavy Chain Locus in Maintaining B Cell Tolerance to DNA

Interaction of TAPP adapter proteins with phosphatidylinositol (3,4)‐bisphosphate regulates B‐cell activation and autoantibody production

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