SLE-associated risk factors affect DC function.
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ABSTRACT:
SUBMITTER: Son M
PROVIDER: S-EPMC4685736 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Over 30 years ago, receptors for the Fc region of IgG (FcgammaR) were implicated in the pathogenesis of systemic lupus erythematosus (SLE). Since those pioneering studies, our knowledge of the structure and function of these FcgammaRs has increased dramatically. We now know that FcgammaR contributes to the regulation of acquired immunity and to the regulation of innate immune responses where FcgammaRs act as specific receptors for innate opsonins (CRP and SAP). Our understanding of the genomic architecture of the genes encoding the FcgammaR has also witnessed remarkable advances. Numerous functionally relevant single-nucleotide polymorphism (SNP) variants and copy number (CN) variants have been characterized in the FcgammaR genes. Many of these variants have also been shown to associate with risk to development of SLE and some have been associated with disease progression. This review will provide an overview of the FcgammaR in relation to SLE, including consideration of the role of genetic variants in FcgammaR in SLE pathogenesis. The difficulties in assessing genetic variation in these genes will be discussed. To enhance our understanding of the functional roles of these receptors in SLE, future research will need to integrate our knowledge of SNP variants, CN variants and the functional diversity of these receptors.
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Project description:Evidence suggests that contemporaneous labor force participation affects cognitive function; however, it is unclear whether it is employment itself or endogenous factors related to individuals' likelihood of employment that protects against cognitive decline. We exploit innovations in counterfactual causal inference to disentangle the effect of postponing retirement on later-life cognitive function from the effects of other life-course factors. With the U.S. Health and Retirement Study (1996-2014, n = 20,469), we use the parametric g-formula to estimate the effect of postponing retirement to age 67. We also study whether the benefit of postponing retirement is affected by gender, education, and/or occupation, and whether retirement affects cognitive function through depressive symptoms or comorbidities. We find that postponing retirement is protective against cognitive decline, accounting for other life-course factors (population: 0.34, 95% confidence interval (CI): 0.20,0.47; individual: 0.43, 95% CI: 0.26,0.60). The extent of the protective effect depends on subgroup, with the highest educated experiencing the greatest mitigation of cognitive decline (individual: 50%, 95% CI: 32%,71%). By using innovative models that better reflect the empirical reality of interconnected life-course processes, this work makes progress in understanding how retirement affects cognitive function.
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Project description:Interferon regulatory factor 5 (IRF5) regulates innate immune responses to viral infection. IRF5 genetic variants have been shown to be strongly associated with risk for systemic lupus erythematosus (SLE). Functional roles of IRF5 exon 6 structural variants that occur as part of a SLE risk-associated haplotype, including a 30-bp in/del (in/del-10) and a 48-bp splice-site variant (SV-16), have not been established. In this study, we used IRF5-deficient cells overexpressing human IRF5 (hIRF5) variants to investigate the roles of exon 6 in/del-10 and SV-16 in regulation of the apoptosis response, nuclear translocation, and ability to transactivate IRF5 responsive cytokines. We found that expression of IRF5 isoforms including either SV-16 or in/del-10 confers ability of IRF5 to impair the apoptotic response and correlates with reduced capacity for IRF5 nuclear translocation in MEFs after a DNA-damaging stimulus treatment. Interestingly, the presence or absence of both SV-16 and in/del-10 results in abrogation of both the anti-apoptotic and enhanced nuclear translocation effects of IRF5 expression. Only cells expressing IRF5 bearing SV-16 show increased IL-6 production upon lipopolysaccharide stimulation. MEFs expressing hIRF5 variants containing in/del-10 showed no significant difference from the control; however, cells carrying hIRF5 lacking both SV-16 and in/del-10 showed reduced IL-6 production. Our overall findings suggest that exon 6 SV-16 is more potent than in/del-10 for IRF5-driven resistance to apoptosis and promotion of cytokine production; however, in/del-10 co-expression can neutralize these effects of SV-16.
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Project description:Transcriptional profiling of human monocyte-derived dendritic cells (MDDCs), comparing cells transfected with miR-29a mimic, or miR-29b mimic, or negative control. 3 condition experiment, control versus miR-29a, and control versus miR-29b. 3 biological replicates for each condition and control.
2013-06-01 | E-GEOD-44784 | biostudies-arrayexpress
Project description:Transcriptional profiling of human monocyte-derived dendritic cells (MDDCs), comparing cells transfected with miR-29a mimic, or miR-29b mimic, or negative control.
2013-06-01 | GSE44784 | GEO
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Project description:Avascular necrosis of bone (AVN) is increasingly being recognized as a complication of SLE and causes significant disability due to pain and mobility limitations. We studied the prevalence and factors associated with avascular necrosis (AVN) in a multiethnic SLE cohort. SLE patients who visited the outpatient clinic from October 2017 to April 2019 were considered eligible. Their medical records were reviewed to identify patients who developed symptomatic AVN, as confirmed by either magnetic resonance imaging or plain radiography. Subsequently, their SLE disease characteristics and treatment were compared with the characteristics of patients who did not have AVN. Multivariable logistic regression analyses were performed to determine the independent factors associated with AVN among the multiethnic SLE cohort. A total of 390 patients were recruited, and the majority of them were females (92.6%); the patients were predominantly of Malay ethnicity (59.5%), followed by Chinese (35.9%) and Indian (4.6%). The prevalence of symptomatic AVN was 14.1%, and the mean age of AVN diagnosis was 37.6 ± 14.4 years. Both univariate and multivariable logistic regression analyses revealed that a longer disease duration, high LDL-C (low density lipoprotein cholesterol), positive anti-cardiolipin (aCL) IgG and anti-dsDNA results, a history of an oral prednisolone dose of more than 30 mg daily for at least 4 weeks and osteoporotic fractures were significantly associated with AVN. On the other hand, hydroxychloroquin (HCQ), mycophenolate mofetil (MMF) and bisphosphonate use were associated with a lower risk of AVN. No associations with ethnicity were found. In conclusion, several modifiable risk factors were found to be associated with AVN, and these factors may be used to identify patients who are at high risk of developing such complications. The potential protective effects of HCQ, MMF and bisphosphonates warrant additional studies.
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Project description:Immunoregulatory cytokine interleukin-10 (IL-10) is elevated in sera from patients with systemic lupus erythematosus (SLE) correlating with disease activity. The established association of IL10 with SLE and other autoimmune diseases led us to fine map causal variant(s) and to explore underlying mechanisms. We assessed 19 tag SNPs, covering the IL10 gene cluster including IL19, IL20 and IL24, for association with SLE in 15,533 case and control subjects from four ancestries. The previously reported IL10 variant, rs3024505 located at 1 kb downstream of IL10, exhibited the strongest association signal and was confirmed for association with SLE in European American (EA) (P?=?2.7×10??, OR?=?1.30), but not in non-EA ancestries. SNP imputation conducted in EA dataset identified three additional SLE-associated SNPs tagged by rs3024505 (rs3122605, rs3024493 and rs3024495 located at 9.2 kb upstream, intron 3 and 4 of IL10, respectively), and SLE-risk alleles of these SNPs were dose-dependently associated with elevated levels of IL10 mRNA in PBMCs and circulating IL-10 protein in SLE patients and controls. Using nuclear extracts of peripheral blood cells from SLE patients for electrophoretic mobility shift assays, we identified specific binding of transcription factor Elk-1 to oligodeoxynucleotides containing the risk (G) allele of rs3122605, suggesting rs3122605 as the most likely causal variant regulating IL10 expression. Elk-1 is known to be activated by phosphorylation and nuclear localization to induce transcription. Of interest, phosphorylated Elk-1 (p-Elk-1) detected only in nuclear extracts of SLE PBMCs appeared to increase with disease activity. Co-expression levels of p-Elk-1 and IL-10 were elevated in SLE T, B cells and monocytes, associated with increased disease activity in SLE B cells, and were best downregulated by ERK inhibitor. Taken together, our data suggest that preferential binding of activated Elk-1 to the IL10 rs3122605-G allele upregulates IL10 expression and confers increased risk for SLE in European Americans.
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Project description:OBJECTIVES:Genetic variants in the transcription factor STAT4 are associated with increased susceptibility to systemic lupus erythematosus (SLE) and a more severe disease phenotype. This study aimed to clarify how the SLE-associated intronic STAT4 risk allele rs7574865[T] affects the function of immune cells in SLE. METHODS:Peripheral blood mononuclear cells (PBMCs) were isolated from 52 genotyped patients with SLE. Phosphorylation of STAT4 (pSTAT4) and STAT1 (pSTAT1) in response to interferon (IFN)-α, IFN-γ or interleukin (IL)-12, total levels of STAT4, STAT1 and T-bet, and frequency of IFN-γ+ cells on IL-12 stimulation were determined by flow cytometry in subsets of immune cells before and after preactivation of cells with phytohaemagglutinin (PHA) and IL-2. Cellular responses and phenotypes were correlated to STAT4 risk allele carriership. Janus kinase inhibitors (JAKi) selective for TYK2 (TYK2i) or JAK2 (JAK2i) were evaluated for inhibition of IL-12 or IFN-γ-induced activation of SLE PBMCs. RESULTS:In resting PBMCs, the STAT4 risk allele was neither associated with total levels of STAT4 or STAT1, nor cytokine-induced pSTAT4 or pSTAT1. Following PHA/IL-2 activation, CD8+ T cells from STAT4 risk allele carriers displayed increased levels of STAT4 resulting in increased pSTAT4 in response to IL-12 and IFN-α, and an augmented IL-12-induced IFN-γ production in CD8+ and CD4+ T cells. The TYK2i and the JAK2i efficiently blocked IL-12 and IFN-γ-induced activation of PBMCs from STAT4 risk patients, respectively. CONCLUSIONS:T cells from patients with SLE carrying the STAT4 risk allele rs7574865[T] display an augmented response to IL-12 and IFN-α. This subset of patients may benefit from JAKi treatment.
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Project description:Elite rugby league and union have some of the highest reported rates of concussion (mild traumatic brain injury) in professional sport due in part to their full-contact high-velocity collision-based nature. Currently, concussions are the most commonly reported match injury during the tackle for both the ball carrier and the tackler (8-28 concussions per 1000 player match hours) and reports exist of reduced cognitive function and long-term health consequences that can end a playing career and produce continued ill health. Concussion is a complex phenotype, influenced by environmental factors and an individual's genetic predisposition. This article reviews concussion incidence within elite rugby and addresses the biomechanics and pathophysiology of concussion and how genetic predisposition may influence incidence, severity and outcome. Associations have been reported between a variety of genetic variants and traumatic brain injury. However, little effort has been devoted to the study of genetic associations with concussion within elite rugby players. Due to a growing understanding of the molecular characteristics underpinning the pathophysiology of concussion, investigating genetic variation within elite rugby is a viable and worthy proposition. Therefore, we propose from this review that several genetic variants within or near candidate genes of interest, namely APOE, MAPT, IL6R, COMT, SLC6A4, 5-HTTLPR, DRD2, DRD4, ANKK1, BDNF and GRIN2A, warrant further study within elite rugby and other sports involving high-velocity collisions.
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