Decreased expression of the C3b/C4b receptor (CR1) and the C3d receptor (CR2) on B lymphocytes and of CR1 on neutrophils of patients with systemic lupus erythematosus

Wilson, James G.; Ratnoff, William D.; Schur, Peter H.; Fearon, Douglas T.

doi:10.1002/art.1780290606

Cited by 167 publications

(106 citation statements)

References 52 publications

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“…The specific effects of dysregulated expression likely depend on the cell type affected and the time in ontogeny when expression is altered. Although CR2 levels are decreased by Ϸ50% on B cells of patients with SLE (31,32), this decrease may be the result of multiple factors, including alterations in B cell homeostasis, immune complex formation and deposition, and alterations in the cytokine milieu associated with active disease. The presence of low CR2 levels in individuals with established disease does not exclude the possibility that levels were increased before disease onset.…”

Section: Discussionmentioning

confidence: 99%

Association of a common complement receptor 2 haplotype with increased risk of systemic lupus erythematosus

Boackle

Hanvivadhanakul

et al. 2007

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

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A genomic region on distal mouse chromosome 1 and its syntenic human counterpart 1q23-42 show strong evidence of harboring lupus susceptibility genes. We found evidence of linkage at 1q32.2 in a targeted genome scan of 1q21-43 in 126 lupus multiplex families containing 151 affected sibpairs (nonparametric linkage score 2.52, P ‫؍‬ 0.006). A positional candidate gene at 1q32.2, complement receptor 2 (CR2), is also a candidate in the murine Sle1c lupus susceptibility locus. To explore its role in human disease, we analyzed 1,416 individuals from 258 Caucasian and 142 Chinese lupus simplex families and demonstrated that a common three-single-nucleotide polymorphism CR2 haplotype (rs3813946, rs1048971, rs17615) was associated with lupus susceptibility (P ‫؍‬ 0.00001) with a 1.54-fold increased risk for the development of disease. Single-nucleotide polymorphism 1 (rs3813946), located in the 5 untranslated region of the CR2 gene, altered transcriptional activity, suggesting a potential mechanism by which CR2 could contribute to the development of lupus. Our findings reveal that CR2 is a likely susceptibility gene for human lupus at 1q32.2, extending previous studies suggesting that CR2 participates in the pathogenesis of systemic lupus erythematosus.linkage ͉ disease susceptibility ͉ antoimmunity ͉ single-nucleotide polymorphisms ͉ syntenic conservation

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Section: Discussionmentioning

confidence: 99%

Association of a common complement receptor 2 haplotype with increased risk of systemic lupus erythematosus

Boackle

Hanvivadhanakul

et al. 2007

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

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“…CR2, which is located at the telomeric end of chromosome 1 (close to the D1 Mit17 marker locus) and plays a very important role in humoral immune response, is a possible candidate gene for Sle1c because Sle1c is associated with autoantibody production in the present study. The expression of CR2 was shown to be significantly decreased in human SLE patients (42) and in MRL/lpr mice (43).…”

Section: Discussionmentioning

confidence: 99%

A Novel Susceptibility Locus On Chromosome 2 in the (New Zealand Black × New Zealand White)F1 Hybrid Mouse Model of Systemic Lupus Erythematosus

Rahman

Tin

Buenaventura

et al. 2002

The Journal of Immunology

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Systemic lupus erythematosus (SLE) is inherited as a complex polygenic trait. (New Zealand Black (NZB) × New Zealand White (NZW)) F1 hybrid mice develop symptoms that remarkably resemble human SLE, but (NZB × PL/J)F1 hybrids do not develop lupus. Our study was conducted using (NZW × PL/J)F1 × NZB (BWP) mice to determine the effects of the PL/J and the NZW genome on disease. Forty-five percent of BWP female mice had significant proteinuria and 25% died before 12 mo of age compared with (NZB × NZW)F1 mice in which >90% developed severe renal disease and died before 12 mo. The analysis of BWP mice revealed a novel locus (χ2 = 25.0; p < 1 × 10−6; log of likelihood = 6.6 for mortality) designated Wbw1 on chromosome 2, which apparently plays an important role in the development of the disease. We also observed that both H-2 class II (the u haplotype) and TNF-α (TNFz allele) appear to contribute to the disease. A suggestive linkage to proteinuria and death was found for an NZW allele (designated Wbw2) telomeric to the H-2 locus. The NZW allele that overlaps with the previously described locus Sle1c at the telomeric part of chromosome 1 was associated with antinuclear autoantibody production in the present study. Furthermore, the previously identified Sle and Lbw susceptibility loci were associated with an increased incidence of disease. Thus, multiple NZW alleles including the Wbw1 allele discovered in this study contribute to disease induction, in conjunction with the NZB genome, and the PL/J genome appears to be protective.

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“…CD21 is a BCR coreceptor that is downregulated in activated B cells. Interestingly, decreased surface expression of CD21 and CD23 are observed in the lupus mice model and SLE patients in support of these cells being in an activated state (80)(81)(82)(83)(84). B220 identifies an isoform of the phosphatase CD45 present on naive B cells reduced in activation states and dysregulated in lymphoproliferative disorders (85).…”

Section: Alterations Of Circulating B Cell Subtypes and Overexpressiomentioning

confidence: 92%

Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity

Nakayama¹,

Kosek²,

Capone³

et al. 2017

The Journal of Immunology

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BAFF is a B cell survival and maturation factor implicated in the pathogenesis of systemic lupus erythematosus (SLE). In this in vitro study, we describe that soluble BAFF in combination with IL-2 and IL-21 is a T cell contact-independent inducer of human B cell proliferation, plasmablast differentiation, and IgG secretion from circulating CD27+ memory and memory-like CD27−IgD− double-negative (DN) B cells, but not CD27−IgD+ naive B cells. In contrast, soluble CD40L in combination with IL-2 and IL-21 induces these activities in both memory and naive B cells. Blood from healthy donors and SLE patients have similar circulating levels of IL-2, whereas SLE patients exhibit elevated BAFF and DN B cells and reduced IL-21. B cell differentiation transcription factors in memory, DN, and naive B cells in SLE show elevated levels of Aiolos, whereas Ikaros levels are unchanged. Treatment with CC-220, a modulator of the cullin ring ligase 4-cereblon E3 ubiquitin ligase complex, reduces Aiolos and Ikaros protein levels and BAFF- and CD40L-induced proliferation, plasmablast differentiation, and IgG secretion. The observation that the soluble factors BAFF, IL-2, and IL-21 induce memory and DN B cell activation and differentiation has implications for extrafollicular plasmablast development within inflamed tissue. Inhibition of B cell plasmablast differentiation by reduction of Aiolos and Ikaros may have utility in the treatment of SLE, where elevated levels of BAFF and Aiolos may prime CD27+ memory and DN memory-like B cells to become Ab-producing plasmablasts in the presence of BAFF and proinflammatory cytokines.

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Decreased expression of the C3b/C4b receptor (CR1) and the C3d receptor (CR2) on B lymphocytes and of CR1 on neutrophils of patients with systemic lupus erythematosus

Cited by 167 publications

References 52 publications

Association of a common complement receptor 2 haplotype with increased risk of systemic lupus erythematosus

Association of a common complement receptor 2 haplotype with increased risk of systemic lupus erythematosus

A Novel Susceptibility Locus On Chromosome 2 in the (New Zealand Black × New Zealand White)F1 Hybrid Mouse Model of Systemic Lupus Erythematosus

Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity

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