Rap1 Signal Controls B Cell Receptor Repertoire and Generation of Self-Reactive B1a Cells

Ishida, Daisuke; Su, Li; Tamura, Akihisa; Katayama, Yoshinori; Kawai, Yohei; Wang, Shufang; Taniwaki, Masafumi; Hamazaki, Yoko; Hattori, Masao; Minato, Nagahiro

doi:10.1016/j.immuni.2006.02.007

Cited by 58 publications

(67 citation statements)

References 62 publications

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“…Our demonstration that blocking this pathway alters receptor editing in vitro and promotes autoreactivity in vivo is also consonant with the phenotype of mice lacking SPA, a regulator of MAP kinases, including Erk and p38 MAPK (40). SPA-1 Ϫ/Ϫ mice exhibited an expansion of autoreactive B cells, produced anti-dsDNA Abs, and developed a lupus-like syndrome (41). Their immature B cells showed ineffective receptor editing of V genes with a significantly altered repertoire, suggesting that this bias may have favored the generation of autoreactive immature B cells.…”

Section: Discussionsupporting

confidence: 70%

“…Their immature B cells showed ineffective receptor editing of V genes with a significantly altered repertoire, suggesting that this bias may have favored the generation of autoreactive immature B cells. Thus, absence of the SPA-1 signaling molecule (41) or partial blocking of the Raf-MEK-Erk signaling pathway (this report) alter V gene repertoire expression, impair receptor editing in immature B cells and give rise to self-reactive B cells in vivo.…”

Section: Discussionmentioning

confidence: 81%

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Subversion of B lymphocyte tolerance by hydralazine, a potential mechanism for drug-induced lupus

Mazari

Ouarzane

Zouali

2007

Proc. Natl. Acad. Sci. U.S.A.

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Accumulating evidence indicates that epigenetic alterations contribute to exacerbated activation or deregulation of the mechanisms that maintain tolerance to self-antigens in patients with lupus, a systemic autoimmune disease that can be triggered by medications taken to treat a variety of conditions. Here, we tested the effect of hydralazine, an antihypertensive drug that triggers lupus, on receptor editing, a chief mechanism of B lymphocyte tolerance to self-antigens. Using mice expressing transgenic human Igs, we found that hydralazine impairs up-regulation of RAG-2 gene expression and reduces secondary Ig gene rearrangements. Receptor editing was also partially abolished in a dose-dependent manner by a specific inhibitor of MEK1/2. Adoptive transfer of bone marrow B cells pretreated with hydralazine or with a MEK inhibitor to naïve syngeneic mice resulted in autoantibody production. We conclude that, by disrupting receptor editing, hydralazine subverts B lymphocyte tolerance to self and contributes to generation of pathogenic autoreactivity. We also postulate that inhibition of the Erk signaling pathway contributes to the pathogenesis of hydralazine-induced lupus and idiopathic human lupus.autoimmune disease ͉ receptor editing D rug-induced lupus (DIL) is a systemic autoimmune disease that can be induced by over 40 medications, including the antihypertensive drug hydralazine and the antiarrhythmic drug procainamide (1). In the patient, the drug reaches a steady-state concentration within a few hours, but the symptoms require several months to develop and fade with therapy discontinuation. Intriguingly, there is no apparent common chemical structure or pharmacologic property among the various medications that trigger similar laboratory and clinical features, and the disease is clinically indistinguishable from idiopathic lupus. Likewise, the mechanisms underlying the induction of DIL remain unclear.The ability of the immune system to distinguish self from non-self is central to its capacity to protect against pathogens and, at the same time, maintains tolerance to its own components. This seminal property is established at discrete nodes, both during early development and adulthood. In the B lymphocyte compartment, several mechanisms have been identified (2). They include clonal deletion of autoreactive lymphocytes, clonal anergy, which converts autoreactive cells to a state that precludes them from becoming activated, and receptor editing, a mechanism that modifies self-reactive B cells and renders them nonautoreactive (3, 4). This latter process can extinguish autoreactivity by displacing a productively rearranged Ig heavy (H)-or light (L)-chain gene by secondary gene rearrangements, forming edited antigen (Ag) receptors with no, or reduced autoreactivity. Importantly, it also represents a powerful mechanism by which autoreactive cells can be generated or fail to be eliminated (5, 6). Editing depends on the products of recombinase activator genes (RAG-1 and RAG-2), and uses the same recombination machinery ...

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 81%

Subversion of B lymphocyte tolerance by hydralazine, a potential mechanism for drug-induced lupus

Mazari

Ouarzane

Zouali

2007

Proc. Natl. Acad. Sci. U.S.A.

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“…4,5 B-1a cells are also associated with autoimmunity in murine models. 6 Furthermore, cells of B-1a lineage can undergo malignant transformation to produce B-cell chronic lymphocytic leukemia (B-CLL).…”

mentioning

confidence: 99%

Dermatan Sulfate Interacts with Dead Cells and Regulates CD5+ B-Cell Fate

Wang

Lee

Yan

et al. 2011

The American Journal of Pathology

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CD5 ؉ (B-1a) B cells play pivotal roles in autoimmunity through expression of autoreactive B-cell receptors and production of autoantibodies. The mechanism underlying their positive selection and expansion is currently unknown. This study demonstrates that dermatan sulfate (DS) expands the B-1a cell population and augments the specific antibody response to an antigen when it is in complex with DS. DS displays preferential affinity for apoptotic and dead cells, and DS-stimulated cell cultures produce antibodies to various known autoantigens. The companion article further illustrates that autoantigens can be identified by affinity to DS, suggesting that molecules with affinity to DS have a high propensity to become autoantigens. We thus propose that the association of antigens from dead cells with DS is a possible origin of autoantigens and that autoreactive B-1a cells are positively selected and expanded by DS•autoantigen complexes. This mechanism may also explain the clonal expansion of B-1a cells in certain B-cell malignancies.

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“…When ischemia-reperfusion injury or other types of tissue damage expose intracellular proteins, natural Abs against specific intracellular self-Ags can initiate acute complement-mediated inflammation (8 -10). Moreover, in chronic inflammatory diseases such as rheumatoid arthritis and lupus, there is expansion of B-1 and MZ B cell populations and increased production of self-reactive Abs that contribute to autoimmunity (11)(12)(13)(14)(15). Thus, modulating the activation of MZ and B-1 B cells could be a useful approach for treating Ab-mediated inflammation and autoimmune diseases.…”

mentioning

confidence: 99%

Phosphoinositide 3-Kinase p110δ Regulates Natural Antibody Production, Marginal Zone and B-1 B Cell Function, and Autoantibody Responses

Durand

Hartvigsen²,

Fogelstrand³

et al. 2009

The Journal of Immunology

118

103

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B-1 and marginal zone (MZ) B cells produce natural Abs, make Ab responses to microbial pathogens, and contribute to autoimmunity. Although the δ isoform of the PI3K p110 catalytic subunit is essential for development of these innate-like B cells, its role in the localization, activation, and function of normal B-1 and MZ B cells is not known. Using IC87114, a highly selective inhibitor of p110δ enzymatic activity, we show that p110δ is important for murine B-1 and MZ B cells to respond to BCR clustering, the TLR ligands LPS and CpG DNA, and the chemoattractants CXCL13 and sphingosine 1-phosphate. In these innate-like B cells, p110δ activity mediates BCR-, TLR- and chemoattractant-induced activation of the Akt prosurvival kinase, chemoattractant-induced migration, and TLR-induced proliferation. Moreover, we found that TLR-stimulated Ab responses by B-1 and MZ B cells, as well as the localization of MZ B cells in the spleen, depend on p110δ activity. Finally, we show that the in vivo production of natural Abs requires p110δ and that p110δ inhibitors can reduce in vivo autoantibody responses. Thus, targeting p110δ may be a novel approach for regulating innate-like B cells and for treating Ab-mediated autoimmune diseases.

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Rap1 Signal Controls B Cell Receptor Repertoire and Generation of Self-Reactive B1a Cells

Cited by 58 publications

References 62 publications

Subversion of B lymphocyte tolerance by hydralazine, a potential mechanism for drug-induced lupus

Subversion of B lymphocyte tolerance by hydralazine, a potential mechanism for drug-induced lupus

Dermatan Sulfate Interacts with Dead Cells and Regulates CD5+ B-Cell Fate

Phosphoinositide 3-Kinase p110δ Regulates Natural Antibody Production, Marginal Zone and B-1 B Cell Function, and Autoantibody Responses

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