Defective activity of ERK-1 and ERK-2 mitogen-activated protein kinases in peripheral blood T lymphocytes from patients with systemic lupus erythematosus: potential role of altered coupling of Ras guanine nucleotide exchange factor hSos to adapter protein Grb2 in lupus T cells☆☆Supported by Grant S1-200000440 from Fondo Nacional de Ciencia, Innovación y Tecnologia (FONACIT), Ministerio de Ciencia y Tecnologia.

Cedeño, Samandhy; Cifarelli, Domenico F; Blasini, Ana M.; Paris, Magdalena; Pláceres, Fabiola; Alonso, Guillermina; Rodríguez, M.

doi:10.1016/s1521-6616(02)00052-9

Cited by 64 publications

(57 citation statements)

References 36 publications

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“…Consistently, human lupus B cells that suffer from defective tolerance exhibit abnormal BcR signaling (34,35). Several observations also indicate that the ras-MAPK pathway is defective in lupus patients (36)(37)(38) and aberrantly activated in B cells from lupus mice bearing the Sle1 gene cluster (39). 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).…”

Section: Discussionsupporting

confidence: 76%

“…Remarkably, hydralazine also decreases Erk phosphorylation in T cells in response to in vitro stimulation, and T cells treated with an Erk pathway inhibitor trigger anti-dsDNA Abs in vivo (42). Because the lymphocyte Erk signaling pathway is impaired in patients with active lupus (37,38), in hydralazine-treated T cells (42), and in experimental lupus (39), it is possible that this T cell signaling defect contributes to disease pathogenesis. Our current observations suggest that the Erk signaling pathway is also impaired in B cells, providing a novel potential unifying T and B cell-mediated mechanism for the development of autoimmunity in both idiopathic and hydralazine-induced lupus.…”

Section: Discussionmentioning

confidence: 99%

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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: 76%

Section: Discussionmentioning

confidence: 99%

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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“…Lupus T cells analyzed immediately ex vivo have an anergic phenotype due to repeated autoantigenic stimulation and rounds of activation in vivo (31). This is consistent with the diminished ERK phosphorylation, despite an activated phenotype found in lupus T cells (24,25). It is possible to reverse some abnormalities in lupus T cells by resting T cells away from sources of activation (31).…”

Section: Discussionsupporting

confidence: 67%

“…In lupus T cells however, TCR-driven phosphorylation of ERK1 and ERK2 is diminished in contrast to an increase in global protein tyrosine phosphorylation (24,25). SLE T cells failed to display significant ERK1/2 phosphorylation following TCR-mediated activation (Fig.…”

Section: Normalization Of Intracellular Signaling Pathways In Sle T Cmentioning

confidence: 91%

Atorvastatin Restores Lck Expression and Lipid Raft-Associated Signaling in T Cells from Patients with Systemic Lupus Erythematosus

Jury

Isenberg

Mauri

et al. 2006

The Journal of Immunology

123

104

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Loss of tolerance to self-Ags in patients with systemic lupus erythematosus (SLE), a prototypic autoimmune disease, is associated with dysregulation of T cell signaling, including the depletion of total levels of lymphocyte-specific protein kinase (Lck) from sphingolipid-cholesterol-enriched membrane microdomains (lipid rafts). Inhibitors of 3-hyroxy-3-methylgluteryl CoA reductase (statins) can modify the composition of lipid rafts, resulting in alteration of T cell signaling. In this study, we show that atorvastatin targets the distribution of signaling molecules in T cells from SLE patients, by disrupting the colocalization of total Lck and CD45 within lipid rafts, leading to a reduction in the active form of Lck. Upon T cell activation using anti-CD3/anti-CD28 in vitro, the rapid recruitment of total Lck to the immunological synapse was inhibited by atorvastatin, whereas ERK phosphorylation, which is decreased in SLE T cells, was reconstituted. Furthermore, atorvastatin reduced the production of IL-10 and IL-6 by T cells, implicated in the pathogenesis of SLE. Thus, atorvastatin reversed many of the signaling defects characteristic of SLE T cells. These findings demonstrate the potential for atorvastatin to target lipid raft–associated signaling abnormalities in autoreactive T cells and provide a rationale for its use in therapy of autoimmune disease.

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“…Kinases modulate the activity of CREM and CREB by altering their transcriptional and translational regulation, as well as by implementing posttranslational modifications. Kinases known to regulate the activity of CREB and CREM include PKA, PKC, ERK1, and Ca 2+ /calmodulin-dependent kinase II (CaMKII) and CaMKIV (10,11). The facts that PKA, ERK1, and PKC expression and/or activity have been reported to be decreased in SLE T cells (10)(11)(12) and that SLE T cells display increased TCR-mediated free intracytoplasmic Ca 2+ responses (13) have provided a rationale for the exploration of the role of CaMKs in the increased expression of CREM in SLE T cells.…”

Section: Introductionmentioning

confidence: 99%

Systemic lupus erythematosus serum IgG increases CREM binding to the IL-2 promoter and suppresses IL-2 production through CaMKIV

Juang

Wang²,

Solomou³

et al. 2005

J. Clin. Invest.

208

113

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Systemic lupus erythematosus (SLE) T cells express high levels of cAMP response element modulator (CREM)that binds to the IL-2 promoter and represses the transcription of the IL-2 gene. This study was designed to identify pathways that lead to increased binding of CREM to the IL-2 promoter in SLE T cells. Ca 2+ /calmodulin-dependent kinase IV (CaMKIV) was found to be increased in the nucleus of SLE T cells and to be involved in the overexpression of CREM and its binding to the IL-2 promoter. Treatment of normal T cells with SLE serum resulted in increased expression of CREM protein, increased binding of CREM to the IL-2 promoter, and decreased IL-2 promoter activity and IL-2 production. This process was abolished when a dominant inactive form of CaMKIV was expressed in normal T cells. The effect of SLE serum resided within the IgG fraction and was specifically attributed to anti-TCR/CD3 autoantibodies. This study identifies CaMKIV as being responsible for the increased expression of CREM and the decreased production of IL-2 in SLE T cells and demonstrates that anti-TCR/CD3 antibodies present in SLE sera can account for the increased expression of CREM and the suppression of IL-2 production.

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Cited by 64 publications

References 36 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

Atorvastatin Restores Lck Expression and Lipid Raft-Associated Signaling in T Cells from Patients with Systemic Lupus Erythematosus

Systemic lupus erythematosus serum IgG increases CREM binding to the IL-2 promoter and suppresses IL-2 production through CaMKIV

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