Immunopathology and the gene therapy of lupus

Mageed, Rizgar A.; Prud’homme, Gérald J.

doi:10.1038/sj.gt.3302016

Cited by 45 publications

(46 citation statements)

References 139 publications

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“…For experiments involving activation of B lymphocytes, stimulatory beads were prepared by coating epoxy magnetic beads (Dynal) with 10 g/ml goat F(abЈ) 2 anti-IgG/IgA/IgM. For some experiments, B cells (1-2 ϫ 10 5 ) were rested for 1 hour at 37°C and then activated with the coated beads (cell: bead ratio 1:3) at 37°C.…”

Section: Methodsmentioning

confidence: 99%

Altered lipid raft–associated proximal signaling and translocation of CD45 tyrosine phosphatase in B lymphocytes from patients with systemic lupus erythematosus

Flores-Borja¹,

Kabouridis²,

Jury³

et al. 2007

Arthritis & Rheumatism

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Objective. B lymphocytes from patients with systemic lupus erythematosus (SLE) exhibit defective intracellular signaling, hyperactivity, and autoantibody production. Recent evidence indicates a reduced expression of Lyn kinase, a negative regulator of B cell signaling, and reduced translocation of Lyn into membrane signaling domains in SLE. The present study was undertaken to investigate the causes of this altered regulation of Lyn by assessing the expression levels of regulatory molecules and their translocation into the signaling domains of SLE B lymphocytes.Methods

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Section: Methodsmentioning

confidence: 99%

Altered lipid raft–associated proximal signaling and translocation of CD45 tyrosine phosphatase in B lymphocytes from patients with systemic lupus erythematosus

Flores-Borja¹,

Kabouridis²,

Jury³

et al. 2007

Arthritis & Rheumatism

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“…It has been suggested that a major factor responsible for sustained activation of lymphocytes and breakdown of self-tolerance is the persistence of antigens because of poor clearance and increased apoptosis. In human patients with lupus, decreased numbers of T, B, and NK cells are common [2]. In addition to decrease in the number of cells, there are known functional abnormalities [7,8].…”

Section: T Lymphocyte and Natural Killer (Nk)mentioning

confidence: 99%

“…One of the most consistent observations regarding cytokine production in lupus, which is widely targeted for gene therapy, is the general inability to make TGF-β [9]. Reduction in this cytokine might account for sustained T-and B-lymphocyte hyperactivity possibly owing reduced regulatory T-lymphocytes that require TGF-β to mediate their effects [2,10,11].…”

Section: T Lymphocyte and Natural Killer (Nk)mentioning

confidence: 99%

“…A wide range of immunological abnormalities have been described in SLE, and include the ability to produce pathogenic autoantibodies, lack of T-and B-lymphocyte regulation, and defective clearance of autoantigens and immune complexes. Majority of autoantibodies found in lupus are directed at intracellular nucleoprotein particles, with 98% of patients demonstrating antinuclear antibodies, while anti-double-stranded DNA (dsDNA) antibodies are found in 50-80% of patients [2]. These latter autoantibodies are exclusive to lupus.…”

Section: Introductionmentioning

confidence: 99%

“…Three important factors have been identified in the pathogenesis of SLE: endocrine-metabolic, environmental, and genetic [2].…”

Section: Pathogenic Mechanismsmentioning

confidence: 99%

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Systemic Lupus Erythematosus: Recent Concepts in Genomics, Pathogenetic Mechanisms, and Therapies

Krishnamurthy

Mahadevan

2011

ISRN Immunology

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Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disorder associated with multiple immunological abnormalities and a wide range of clinical manifestations. Recent progress in genetics has expanded the number of the genes associated with SLE to more than 20 in number and has contributed to improvement of understanding of the pathogenesis of the disease. This has enhanced the development of novel therapeutic targets and biomarkers for individualized and tailor-made clinical management of lupus patients. Despite this knowledge, however, it is a challenge to fully understand the genetic pathogenesis of the disease. The present paper describes the current concepts in the mechanisms, genomics, and pathogenesis of SLE and their implications for management of the disorder. The potential role of gene therapy, biological agents, intravenous immunoglobulin, anti-inflammatory cytokines, and cytokine inhibitors is discussed.

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Decreased Lyn expression and translocation to lipid raft signaling domains in B lymphocytes from patients with systemic lupus erythematosus

Flores-Borja¹,

Kabouridis²,

Jury³

et al. 2005

Arthritis & Rheumatism

112

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Objective. B lymphocytes from patients with systemic lupus erythematosus (SLE) are hyperactive and produce anti-double-stranded DNA (anti-dsDNA) autoantibodies. The cause or causes of B cell defects in SLE are unknown. In this study, we determined the level and subcellular distribution of Lyn protein, a key negative regulator of B cell receptor signaling, and assessed whether altered Lyn expression is characteristic of B cells in the setting of SLE.Methods. Negative selection was used to isolate B lymphocytes from blood. Lipid raft signaling domains were purified from B cells obtained from 62 patients with SLE, 15 patients with rheumatoid arthritis, and 31 healthy controls, by gradient ultracentrifugation. The total Lyn protein level was determined by Western blotting, confocal microscopy, and fluorescein-activated cell sorting (FACS). The distribution of Lyn into lipid raft and nonlipid raft domains was determined by Western blotting and confocal microscopy. Lyn content in B cell subpopulations was determined by FACS. In order to assess B lymphocyte activity, we used 3 Hthymidine incorporation and enzyme-linked immunosorbent assay to measure spontaneous proliferation and IgG and cytokine production by B cells.Results. This study revealed that B lymphocytes Patients with systemic lupus erythematosus (SLE) manifest immunologic abnormalities that include spontaneous B lymphocyte proliferation, hyperresponsiveness to physiologic stimuli, and altered pattern of production of and responses to cytokines (1-3). One consequence of these abnormalities is the production of pathogenic autoantibodies to nuclear antigens, including double-stranded DNA (dsDNA). Although anti-dsDNA autoantibodies have features indicating T lymphocytedriven responses, several studies suggest that the production of anti-dsDNA autoantibodies could also be attributable to intrinsic B cell defects (4). Furthermore, studies in gene-deficient mice have revealed that defects in negative regulators of B cell receptor (BCR) signaling, CD22, Fc␥ receptor II (Fc␥RII), or CD72, result in production of anti-dsDNA autoantibodies (5-7). In patients with SLE, there is evidence that a reduction in expression of Fc␥RIIA and CD22 relates to anti-dsDNA production (8,9). However, the molecular basis for the relationship between BCR signaling defects and SLE immunopathology remains unclear.

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Immunopathology and the gene therapy of lupus

Cited by 45 publications

References 139 publications

Altered lipid raft–associated proximal signaling and translocation of CD45 tyrosine phosphatase in B lymphocytes from patients with systemic lupus erythematosus

Altered lipid raft–associated proximal signaling and translocation of CD45 tyrosine phosphatase in B lymphocytes from patients with systemic lupus erythematosus

Systemic Lupus Erythematosus: Recent Concepts in Genomics, Pathogenetic Mechanisms, and Therapies

Decreased Lyn expression and translocation to lipid raft signaling domains in B lymphocytes from patients with systemic lupus erythematosus

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