The Role of Activating Protein 1 in the Transcriptional Regulation of the Human FCGR2B Promoter Mediated by the -343 G → C Polymorphism Associated with Systemic Lupus Erythematosus

Olferiev, Mikhail; Masuda, Eriko; Tanaka, Shizuko; Blank, Marissa C.; Pricop, Luminita

doi:10.1074/jbc.m605808200

Cited by 21 publications

(26 citation statements)

References 37 publications

(42 reference statements)

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“…22, 23) shows a particular strong association with human SLE. Recent studies suggest that this polymorphism leads to the displacement of activating transcription factors, such as AP1, by other transcriptional regulators; thus, offering a potential explanation for the lower expression level of Fc␥RIIB (22). Although we did not find homozygous CIDP patients for this SNP, one functionally impaired allele of Fc␥RIIB might be sufficient to result in a decreased expression level or functionally impaired regulation of expression during B cell development.…”

Section: Discussioncontrasting

confidence: 46%

“…In addition to our protein expression analysis, we could show that a certain Fc␥RIIB promoter haplotype, for which an association with the development and severity of SLE in humans has been previously reported (21)(22)(23), was significantly enriched in CIDP patients. The Ϫ386 GC haplotype (sometimes also referred to as the 343 haplotype; see refs.…”

Section: Discussionmentioning

confidence: 87%

“…2). Fc␥RIIB expression levels were also induced on monocytes in 9/12 patients (P Ͻ 0.03) To gain an insight into the possible mechanism of dysregulated Fc␥RIIB expression, we next investigated whether CIDP patients show increased frequencies of functionally relevant SNPs in the Fc␥RIIB promoter that have previously been associated with autoimmune phenotypes, i.e., SLE (9,(21)(22)(23). These polymorphisms are located at Ϫ386 or Ϫ120 base pairs upstream of the first exon of Fc␥RIIB and form 2 distinct haplotypes (Fig.…”

Section: Induction Of Fc␥riib Expression In Memory B Cells In Cidp Pamentioning

confidence: 99%

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Impaired inhibitory Fcγ receptor IIB expression on B cells in chronic inflammatory demyelinating polyneuropathy

Tackenberg

Jelčić

Baerenwaldt

et al. 2009

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

219

178

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The inhibitory Fc-γ receptor FcγRIIB, expressed on myeloid and B cells, has a critical role in the balance of tolerance and autoimmunity, and is required for the antiinflammatory activity of intravenous Ig (IVIG) in various murine disease models. However, the function of FcγRIIB and its regulation by IVIG in human autoimmune diseases are less well understood. Chronic inflammatory demyelinating polyneuropathy (CIDP) is the most common treatable acquired chronic polyneuropathy, and IVIG is widely used as a first-line initial and maintenance treatment. We found that untreated patients with CIDP, compared with demographically matched healthy controls, showed consistently lower FcγRIIB expression levels on naive B cells, and failed to up-regulate or to maintain up-regulation of FcγRIIB as B cells progressed from the naive to the memory compartment. Concomitantly, the rare −386C/−120A FcγRIIB promoter polymorphism resulting in reduced promoter activity previously associated with autoimmune phenotypes was overrepresented in CIDP. Also, FcγRIIB protein expression was up-regulated on monocytes and B cells after clinically effective IVIG therapy. Thus, our results suggest that the inhibitory FcγRIIB is impaired at a critical B cell differentiation checkpoint in CIDP, and that modulating FcγRIIB expression might be a promising approach to efficiently limit antibody-mediated immunopathology in CIDP.

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Section: Discussioncontrasting

confidence: 46%

Section: Discussionmentioning

confidence: 87%

Section: Induction Of Fc␥riib Expression In Memory B Cells In Cidp Pamentioning

confidence: 99%

See 1 more Smart Citation

Impaired inhibitory Fcγ receptor IIB expression on B cells in chronic inflammatory demyelinating polyneuropathy

Tackenberg

Jelčić

Baerenwaldt

et al. 2009

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

219

178

View full text Add to dashboard Cite

show abstract

“…Similarly, defucosylated IgG, which binds with a marked increased affinity to the activatory FcgRIIIA, shows ∼50-fold increase in Ab-dependent cellular cytotoxicity (ADCC) activity, which is expected to deliver significant improvement in clinical efficacy. In both mice and humans, polymorphisms that result in reduced expression or activity of the inhibitory FcgRIIB are associated with increased susceptibility to autoimmune disease (22)(23)(24)(25)(26)(27)(28).…”

mentioning

confidence: 99%

Immunotherapy Targeting Inhibitory Fcγ Receptor IIB (CD32b) in the Mouse Is Limited by Monoclonal Antibody Consumption and Receptor Internalization

Williams

Tutt²,

Beers

et al. 2013

The Journal of Immunology

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Genetic deficiency of the inhibitory Fc receptor, FcγRIIB (CD32b), has been shown to augment the activity of activatory FcγR and promote mAb immunotherapy. To investigate whether mAbs capable of blocking FcγRIIB have similar capacity, we recently generated a panel of specific anti-mouse FcγRIIB mAbs that do not cross-react with other FcRs, allowing us to study the potential of FcγRIIB as a therapeutic target. Previous work revealed a number of these mAbs capable of eliciting programmed cell death of targets, and in the present study we demonstrated their ability to promote target cell phagocytosis. However, in a variety of murine tumor models, anti-FcγRIIB mAbs demonstrated limited therapeutic activity despite optimized treatment regimens. Unexpectedly, we observed that the anti-FcγRIIB mAbs are rapidly and extensively consumed in vivo, both by the tumor and host cells, including B cells, leading to a precipitous loss from the circulation. Closer analysis revealed that the anti-FcγRIIB mAbs become extensively internalized from the cell surface within 24 h in vivo, likely explaining their suboptimal efficacy. Subsequent studies revealed that anti-FcγRIIB mAb immunotherapy was effective when used against FcγRIIB+ tumors in FcγRIIB−/− recipients, indicating that consumption of the mAb by nontumor cells is the primary limitation of these reagents. Importantly, similar rates of internalization were not seen on human target cells, at least in vitro. These studies further highlight the need to determine the propensity of mAb therapeutics to internalize target receptors and also identify potential key differences between human and mouse cells in this respect.

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“…43 Likewise, common functional polymorphisms within the promoter of genes associated with lupus or CAD in patients with diabetes mellitus influence AP-1 DNAbinding activity and gene expression. 44,45 Allele-specific SP1 activity may also explain the association between several SNPs and susceptibility to mild fasting hyperglycemia, atherothrombotic stroke, and lung, breast, and ovarian cancer. 44,[46][47][48][49] Regulation of human gene promoters by polymorphic NF-Y, AP-1, or SP1 sites thus seems to contribute to genetically determined interindividual variability in diverse pathophysiological scenarios.…”

Section: In This Study We Show That the Snps Rs350099 (−957[t/c]) Rmentioning

confidence: 99%

Genetic Variants in CCNB1 Associated With Differential Gene Transcription and Risk of Coronary In-Stent Restenosis

Silvestre-Roig¹,

Fernández²,

Mansego³

et al. 2014

Circ Cardiovasc Genet

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Background-The development of diagnostic tools to assess restenosis risk after stent deployment may enable the intervention to be tailored to the individual patient, for example, by targeting the use of drug-eluting stent to highrisk patients, with the goal of improving safety and reducing costs. The CCNB1 gene (encoding cyclin B1) positively regulates cell proliferation, a key component of in-stent restenosis. Therefore, we hypothesized that single-nucleotide polymorphisms in CCNB1 may serve as useful tools in risk stratification for in-stent restenosis. The incidence of restenosis is highly influenced by clinical, biological, and procedural and lesion-related risk factors. 4 However, information on restenosis biomarkers is scarce. Single-nucleotide polymorphisms (SNPs) are recognized as suitable markers of disease predisposition. Methods and Results-We5 SNPs in the human genome occur on average once every 300 nucleotides (≈10 million SNPs), making them the most common type of genetic variation. SNPs reported to influence restenosis risk affect platelet activation, leukocyte recruitment, the inflammatory response, metalloproteinases, lipid metabolism, oxidative stress, nitric oxide, the renin-angiotensin system, and cell proliferation. 4,6,7 Interestingly, the 838C>A SNP in CDKN1B (encoding the tumor suppressor p27 Kip1 ) has been associated with restenosis risk after coronary stenting, which might be because of augmented vascular smooth muscle cell proliferation caused by reduced CDKN1B promoter activity in patients carrying the risk allele.8 However, other SNPs in CDKN1B or TP53 (encoding the tumor suppressor p53) showed lack of association with restenosis risk. 8,9 In the present study, we investigated a potential association of restenosis risk with SNPs in the CCNB1 gene (encoding cyclin B1). Cyclin B1 is essential for cell proliferation, and its ablation in the mouse is embryonically lethal.10 Several regulatory mechanisms are necessary to ensure that cyclin B1 protein accumulates appreciably only during the G2/M cell cycle transition, and deregulated CCNB1 transcription leading to aberrantly high levels of cyclin B1 throughout the cell cycle is associated with excessive hyperplasia in several human cancers.11 Several lines of evidence indicate that cyclin B1 is also important in the context of cardiovascular disease: its expression has been reported in human restenotic tissue obtained by directional coronary atherectomy, 12 it is induced in balloon-injured rat carotid artery, 13,14 and its inhibition reduces neointimal thickening in this animal model. 15 Herein, we present evidence from 2 independent cohorts of patients undergoing coronary stent deployment (Clinica Mediterranea and Genetic risk factors for In-Stent Hyperplasia study Amsterdam [GEISHA]) 8 cohorts showing that alleles of the SNPs rs350099, rs350104, and rs164390, located in regulatory regions of CCNB1, are associated with higher CCNB1 mRNA expression and increased risk of in-stent restenosis (ISR) after PCI. Furthermore, we identify mole...

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The Role of Activating Protein 1 in the Transcriptional Regulation of the Human FCGR2B Promoter Mediated by the -343 G → C Polymorphism Associated with Systemic Lupus Erythematosus

Cited by 21 publications

References 37 publications

Impaired inhibitory Fcγ receptor IIB expression on B cells in chronic inflammatory demyelinating polyneuropathy

Impaired inhibitory Fcγ receptor IIB expression on B cells in chronic inflammatory demyelinating polyneuropathy

Immunotherapy Targeting Inhibitory Fcγ Receptor IIB (CD32b) in the Mouse Is Limited by Monoclonal Antibody Consumption and Receptor Internalization

Genetic Variants in CCNB1 Associated With Differential Gene Transcription and Risk of Coronary In-Stent Restenosis

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