Dysfunctional B cells in systemic lupus erythematosus

Renaudineau, Yves; Pers, Jacques‐Olivier; Bendaoud, Boutahar; Jamin, Christophe; Youinou, Pierre

doi:10.1016/j.autrev.2004.07.035

Cited by 65 publications

(48 citation statements)

References 32 publications

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“…B cells influence the pathogenesis of many autoimmune diseases, including lupus erythematosus and rheumatoid arthritis. [82][83][84][85][86] Recently, B-lymphocyte depletion therapy using anti-CD20 (rituximab) mAbs has shown great promise in rheumatoid arthritis. 87 At present, no orally available drugs that preferentially target the B-cell compartment are available.…”

Section: Discussionmentioning

confidence: 99%

Key role of the p110δ isoform of PI3K in B-cell antigen and IL-4 receptor signaling: comparative analysis of genetic and pharmacologic interference with p110δ function in B cells

Bilancio

Okkenhaug

Camps

et al. 2006

Blood

199

149

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Mouse gene-targeting studies have documented a central role of the p110␦ isoform of phosphoinositide 3-kinase (PI3K) in B-cell development and function. A defect in B-cell antigen receptor (BCR) signaling is key to this B-cell phenotype. Here we further characterize this signaling defect and report that a p110␦-selective small molecule inhibitor mirrors the effect of genetic inactivation of p110␦ in BCR signaling. p110␦ activity is indispensable for BCR-induced DNA synthesis and phosphorylation of Akt/protein kinase B (PKB), forkhead transcription factor/forkhead box O3a (FOXO3a), and p70 S6 kinase (p70 S6K), with modest effects on the phosphorylation of glycogen synthase kinase 3 ␣/␤ (GSK3␣/␤) and extracellular signal-regulated kinase (Erk). The PI3K-dependent component of intracellular calcium mobilization also completely relies on p110␦ catalytic activity. Resting B cells with inactive p110␦ fail to enter the cell cycle, correlating with an incapacity to up-regulate the expression of cyclins D2, A, and E, and to phosphorylate the retinoblastoma protein (Rb). p110␦ is also critical for interleukin 4 (IL-4)-induced phosphorylation of Akt/PKB and FOXO3a, and protection from apoptosis. Taken together, these data show that defects observed in p110␦ mutant mice are not merely a consequence of altered B-cell differentiation, and emphasize the potential utility of p110␦ as a drug target in autoimmune diseases in which B cells play a crucial role. IntroductionSignal transduction through the B-cell antigen receptor (BCR) and cytokine receptors regulates multiple biologic functions such as growth, proliferation, differentiation, and survival, depending on the maturation state of the B lymphocyte. [1][2][3][4] Intracellular signal transduction by the BCR and cytokine receptors is almost invariably dependent on the activity of the phosphoinositide 3-kinase (PI3K) signaling enzymes. 4,5 Mammals have 8 distinct isoforms of PI3K that have been divided in 3 classes on the basis of their lipid specificity and structure. 6,7 The class I subset of PI3K enzymes generate lipid second messengers that activate a plethora of downstream targets, including protein kinases (such as Akt/protein kinase B [PKB] and Bruton tyrosine kinase [Btk]), guanosine nucleotide exchange factors (such as P-Rex1 and cytohesins), GTPaseactivating proteins (such as members of the centaurin family), and adaptor molecules (such as Bam 32). [7][8][9] Class I PI3Ks are heterodimers consisting of a p110 catalytic subunit and a regulatory subunit. These PI3Ks have been further divided in the IA and IB subclasses, which signal in tyrosine kinase-driven and G protein-coupled receptor pathways, respectively.Genes for 3 class IA p110 isoforms (p110␣, p110␤, p110␦) and a single class IB PI3K isoform (p110␥) exist. p110␥ and p110␦ are mainly expressed in leukocytes, in contrast to p110␣ and p110␤, which have a broader tissue distribution. The class IA regulatory subunits have Src-homology region 2 (SH2) domains that recruit the class IA p110 catalytic subunits to p...

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Section: Discussionmentioning

confidence: 99%

Key role of the p110δ isoform of PI3K in B-cell antigen and IL-4 receptor signaling: comparative analysis of genetic and pharmacologic interference with p110δ function in B cells

Bilancio

Okkenhaug

Camps

et al. 2006

Blood

199

149

View full text Add to dashboard Cite

show abstract

“…Extensive immune system defects characterize this disease, including polyclonal B cell activation, production of pathological autoantibodies because of excessive T cell help provided to B cells, increased apoptosis and skewed cytokine production [1,2]. A characteristic gene expression profile comprising of type I interferon (IFN)-stimulated genes has been observed in SLE patients.…”

Section: Introductionmentioning

confidence: 99%

Enhanced expression of interferon-inducible protein-10 correlates with disease activity and clinical manifestations in systemic lupus erythematosus

Kong

Tan

Thong

et al. 2009

Clinical and Experimental Immunology

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SummaryOur objective was to investigate the serum levels of interferon-inducible protein-10 (IP-10) in systemic lupus erythematosus (SLE) and their correlation with disease activity and organ manifestations. Serum IP-10 levels were assessed in 464 SLE patients and 50 healthy donors. Disease activity was assessed by the revised SLE Activity Measure, and the concomitant active organ manifestations, anti-ds DNA antibody titres, complement levels and erythrocyte sedimentation rates recorded. Peripheral blood mononuclear cell (PBMC) synthesis of IP-10 in SLE patients and controls was determined by in vitro cultures stimulated with mitogen or lipopolysaccharide. Elevated serum IP-10 levels were observed in SLE patients, which were significantly higher in the presence of active haematological and mucocutaneous manifestations. SLE PBMCs exhibited enhanced spontaneous IP-10 production in vitro. Serial IP-10 levels correlated with longitudinal change in SLE activity, even at low levels where anti-dsDNA antibody and complement levels remain unchanged. These data demonstrate that IP-10 levels are increased in SLE and serum IP-10 may represent a more sensitive marker for monitoring disease activity than standard serological tests.

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“…Anti-histone antibodies are a hallmark of systemic lupus erythematosus (SLE), a chronic and potentially fatal autoimmune disease in humans whose etiology is unknown [32]. B cells play a key role in the pathogenesis of SLE [33][34][35], not only because they produce the autoantibodies, but because they play a role in regulation of T cells and other B cells during the disease course. In fact, SLE does not occur in SLE-susceptible mouse strains lacking B cells [36,37].…”

Section: Altered Lymphocyte Populations But No Leukemogenesis In Old mentioning

confidence: 99%

Expression of a non‐DNA‐binding Ikaros isoform exclusively in B cells leads to autoimmunity but not leukemogenesis

et al. 2007

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Ikaros is a transcriptional regulator whose function is essential for B cell development. It is expressed in the hematopoietic stem cell (HSC) through the mature B cell stage. Using genetically engineered mice in which the endogenous Ikaros gene is disrupted, it has been shown that a lack of Ikaros leads to a block in B cell development and that its severe diminution results in a hyperresponsive B cell compartment. Ikaros expression within the HSC has led to speculation as to whether the role of Ikaros in B cell biology is largely accomplished prior to B cell specification. In addition, widespread expression of Ikaros in hematopoietic cells leads to the possibility that some or all of the observed defects are not B cell autonomous. In this report, we demonstrate that over-expression of a dominant interfering Ikaros isoform exclusively in B cells has profound effects on mature B cell function. We provide evidence that continued high-level expression of Ikaros is essential for homeostasis of peripheral lymphocytes and maintenance of B cell tolerance. We also show that deregulation of Ikaros activity does not rapidly result in B cell leukemogenesis as it does with 100% penetrance within the T cell lineage.

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Dysfunctional B cells in systemic lupus erythematosus

Cited by 65 publications

References 32 publications

Key role of the p110δ isoform of PI3K in B-cell antigen and IL-4 receptor signaling: comparative analysis of genetic and pharmacologic interference with p110δ function in B cells

Key role of the p110δ isoform of PI3K in B-cell antigen and IL-4 receptor signaling: comparative analysis of genetic and pharmacologic interference with p110δ function in B cells

Enhanced expression of interferon-inducible protein-10 correlates with disease activity and clinical manifestations in systemic lupus erythematosus

Expression of a non‐DNA‐binding Ikaros isoform exclusively in B cells leads to autoimmunity but not leukemogenesis

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