Association of the premature immunosenescence with the presence and severity of anemia among patients with systemic lupus erythematosus

Lupus ◽  
2021 ◽  
pp. 096120332110380
Author(s):  
Kusworini Handono ◽  
Cesarius Singgih Wahono ◽  
Mirza Zaka Pratama ◽  
Handono Kalim
Keyword(s):  
Systemic Lupus Erythematosus ◽  
T Cells ◽  
Lupus Erythematosus ◽  
Inflammatory Markers ◽  
Mononuclear Cells ◽  
Binding Capacity ◽  
Iron Status ◽  
Transferrin Saturation ◽  
Systemic Lupus ◽  
Peripheral Blood Mononuclear

Introduction One of the possible mechanisms that contribute to the development of anemia in systemic lupus erythematosus (SLE) is the presence of premature immunosenescence in SLE. This study aimed to observe the correlation between immunosenescence with anemia in SLE. Methods This research was a cross-sectional study with the subject was 60 women with SLE aged 16–45 years old. Subjects were recorded for the demographic and clinical data, complete blood counts, iron status (iron serum, total iron-binding capacity, and transferrin saturation), ferritin, inflammatory markers (erythrocyte sedimentation rate [ESR] and C-reactive protein [CRP]), and anti-dsDNA levels. Immunosenescence was observed by measuring the senescent T cells from peripheral blood mononuclear cells (PBMC) by flow cytometry, counted as CD4+CD57+ and CD8+CD57+ T cells. Serum IL-2 and IFNγ as the cytokines associated with immunosenescence were also measured from all subjects. Subjects were divided into anemic and non-anemic groups according to the classification of anemia from WHO (Hb < 12 gr/dl). Results Anemic SLE patients had higher CD4+CD57+, CD8+CD57+, and IFNγ, while IL-2 was lower in SLE patients with anemia. Multivariate linear regression revealed that the decreasing levels of Hb were associated with the increase of CD8+CD57+ percentages and IFNγ levels. Anti-dsDNA, ESR, CRP, ferritin, iron serum, and transferrin saturation were correlated with CD8+CD57+. IFNγ level also correlated with the anti-dsDNA, iron serum, and ferritin levels. No correlation was found between the iron status and inflammatory markers with CD4+CD57+ percentages and IL-2 levels. Multivariate regression analysis showed that IFNγ was positively associated with anti-dsDNA and negatively associated with iron serum and transferrin saturation, while CD8+CD57+ percentages were positively associated with the ferritin levels. Conclusion Immunosenescence is associated with anemia by modulating the inflammatory response and causing iron dysregulation in SLE.

scholarly journals Genomic sequencing and functional analyses identify MAP4K3/GLK germline and somatic variants associated with systemic lupus erythematosus

2021 ◽  
pp. annrheumdis-2021-221010
Author(s):  
Huai-Chia Chuang ◽  
Wei-Ting Hung ◽  
Yi-Ming Chen ◽  
Pu-Ming Hsu ◽  
Jeng-Hsien Yen ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
T Cells ◽  
Lupus Erythematosus ◽  
Mononuclear Cells ◽  
Site Directed Mutagenesis ◽  
Mrna Levels ◽  
Systemic Lupus ◽  
Peripheral Blood Mononuclear ◽  
Somatic Variant ◽  
Germline Variant

ObjectivesMAP4K3 (GLK) overexpression in T cells induces interleukin (IL)-17A production and autoimmune responses. GLK overexpressing T-cell population is correlated with severity of human systemic lupus erythematosus (SLE); however, it is unclear how GLK is upregulated in patients with SLE.MethodsWe enrolled 181 patients with SLE and 250 individuals without SLE (93 healthy controls and 157 family members of patients with SLE) in two independent cohorts from different hospitals/cities. Genomic DNAs of peripheral blood mononuclear cells were subjected to next-generation sequencing to identify GLK gene variants. The functional consequences of the identified GLK germline or somatic variants were investigated using site-directed mutagenesis and cell transfection, followed by reporter assays, mass spectrometry, immunoblotting, coimmunoprecipitation, and in situ proximity ligation assays.ResultsWe identified 58 patients with SLE from Cohort #1 and #2 with higher frequencies of a somatic variant (chr2:39 477 124 A>G) in GLK 3′-untranslated region (UTR); these patients with SLE showed increased serum anti-double-stranded DNA levels and decreased serum C3/C4 levels. This somatic variant in 3′-UTR enhanced GLK mRNA levels in T cells. In addition, we identified five patients with SLE with GLK (A410T) germline variant in Cohort #1 and #2, as well as two other patients with SLE with GLK (K650R) germline variant in Cohort #1. Another GLK germline variant, A579T, was also detected in one patient with SLE from Cohort #2. Both GLK (A410T) and GLK (K650R) mutants inhibited GLK ubiquitination induced by the novel E3 ligase makorin ring-finger protein 4 (MKRN4), leading to GLK protein stabilisation.ConclusionsMultiple GLK germline and somatic variants cause GLK induction by increasing mRNA or protein stability in patients with SLE.

scholarly journals Increased interleukin-23 receptor+ T cells in peripheral blood mononuclear cells of patients with systemic lupus erythematosus

2010 ◽  
Vol 12 (6) ◽  
pp. R215 ◽  
Author(s):  
Hathaipat Puwipirom ◽  
Nattiya Hirankarn ◽  
Pimpayao Sodsai ◽  
Yingyos Avihingsanon ◽  
Jongkonnee Wongpiyabovorn ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
T Cells ◽  
Peripheral Blood Mononuclear Cells ◽  
Lupus Erythematosus ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Systemic Lupus ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells ◽  
Interleukin 23

mRNA expression analysis confirms CD44 splicing impairment in systemic lupus erythematosus patients

Lupus ◽  
2021 ◽  
pp. 096120332110047
Author(s):  
Andrea Latini ◽  
Lucia Novelli ◽  
Fulvia Ceccarelli ◽  
Cristiana Barbati ◽  
Carlo Perricone ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
T Cells ◽  
Mrna Expression ◽  
Lupus Erythematosus ◽  
Mononuclear Cells ◽  
Direct Sequencing ◽  
Healthy Controls ◽  
Systemic Lupus ◽  
Peripheral Tissues ◽  
Variant Isoforms

Background Systemic Lupus Erythematosus (SLE) is a complex chronic autoimmune disease characterized by several immunological alterations. T cells have a peculiar role in SLE pathogenesis, moving from the bloodstream to the peripheral tissues, causing organ damage. This process is possible for their increased adherence and migration capacity mediated by adhesion molecules, such as CD44. Ten different variant isoforms of this molecule have been described, and two of them, CD44v3 and CD44v6 have been found to be increased on SLE T cells compared to healthy controls, being proposed as biomarkers of disease and disease activity. The process of alternative splicing of CD44 transcripts is not fully understood. We investigated the mRNA expression of CD44v3 and CD44v6 and also analyzed possible CD44 splicing regulators (ESRP1 molecule and rs9666607 CD44 polymorphism) in a cohort of SLE patients compared to healthy controls. Methods This study involved 18 SLE patients and 18 healthy controls. Total RNA and DNA were extracted by peripheral blood mononuclear cells. The expression study was conducted by quantitative RT-polymerase chain reaction, using SYBR Green protocol. Genotyping of rs9666607 SNP was performed by direct sequencing. Results CD44v6 mRNA expression was higher in SLE patients compared to healthy controls (p = 0.028). CD44v3/v6 mRNA ratio in healthy controls was strongly unbalanced towards isoform v3 compared to SLE patients (p = 0.002) and decreased progressively from healthy controls to the SLE patients in remission and those with active disease (p = 0.015). The expression levels of CD44v3 and CD44v6 mRNA correlated with the disease duration (p = 0.038, Pearson r = 0.493 and p = 0.038, Pearson r = 0.495, respectively). Splicing regulator ESRP1 expression positively correlated with CD44v6 expression in healthy controls (p = 0.02, Pearson r = 0.532) but not in SLE patients. The variant A allele of rs9666607 of CD44 was associated with higher level of global CD44 mRNA (p = 0.04) but not with the variant isoforms. Conclusions In SLE patients, the increase in CD44v6 protein correlates with a higher transcript level of this isoform, confirming an impairment of CD44 splicing in the disease, whose regulatory mechanisms require further investigation.

Detection and Functional Evaluation of −262A/T and −188A/G Polymorphisms of SLAM Gene in Patients with Systemic Lupus Erythematosus

2010 ◽  
Vol 37 (11) ◽  
pp. 2268-2272 ◽  
Author(s):  
YI YOU ◽  
ZHE WANG ◽  
GUO-HONG DENG ◽  
YI LIU ◽  
FEI HAO
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Mononuclear Cells ◽  
Gene Promoter ◽  
Chinese Patients ◽  
Luciferase Reporter ◽  
Functional Evaluation ◽  
Reporter System ◽  
Systemic Lupus ◽  
Peripheral Blood Mononuclear

Objective.Signaling lymphocytic activation molecule (SLAM) has been related to the pathology of systemic lupus erythematosus (SLE) through regulation of T cell-dependent humoral immune responses. We investigated the functional associations of the −262A/T and −188A/G polymorphisms of SLAM in Chinese patients with SLE.Methods.Genotyping of −262A/T (rs2295614) and −188A/G (rs2295613) in SLAM was carried out in 248 cases and 278 controls. Promoter activities of haplotypes on the SLAM gene were evaluated with the dual-luciferase reporter system. The mRNA expressions of SLAM on peripheral blood mononuclear cells (PBMC) of SLE patients with different genotypes were determined by real-time polymerase chain reaction.Results.Frequencies of −262A allele and −188G allele were significantly higher in SLE patients than in controls. Haplotype analysis and multifactorial logistic regression analysis showed that individuals with the AG/AG haplotype had increased susceptibility to SLE (p = 0.002, OR 1.478, 95% CI 1.152–1.897). In response to PHA stimulation, the SLAM mRNA expression on PBMC of SLE patients was significantly higher in −262A-188G haplotype homozygotes compared with −262A-188G heterozygotes and individuals with other genotypes.Conclusion.Our findings suggest that −262A-188G haplotype in the SLAM gene promoter contributes to the risk of SLE by increasing the expression of SLAM.

scholarly journals Association of the PINX1 Variant rs6984094, Which Lengthens Telomeres, with Systemic Lupus Erythematosus Susceptibility in Chinese Populations

2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
Yuan-yuan Qi ◽  
Xin-ran Liu ◽  
Ying-xin He ◽  
Min Zhou ◽  
Xiang-hui Ning ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Genetic Association ◽  
Lupus Erythematosus ◽  
Genome Wide Association Study ◽  
Mononuclear Cells ◽  
Critical Role ◽  
Systemic Lupus ◽  
Peripheral Blood Mononuclear ◽  
Chinese Populations ◽  
Genetic Heritability

A recent genome-wide association study (GWAS) of Asian ancestry reported that single nucleotide polymorphism (SNP) in TERT (telomerase reverse transcriptase) was associated with systemic lupus erythematosus (SLE). TERT has a critical role in maintaining the chromosomal stability and the length of telomere. Given that only a small portion of the genetic heritability of SLE has been explained so far, we aimed to identify novel loci in telomere-related genes responsible for SLE susceptibility in Chinese populations. We performed a comprehensive genetic association analysis of SLE with telomere-related genes. To identify functional significance, we analyzed the publicly available HaploReg v4.1 and RegulomeDB databases. Differential gene expression analysis was also performed using ArrayExpress. A novel signal of PINX1 rs6984094 was identified ( P discovery = 4.13 × 10 − 2 , OR = 0.58 , 95% CI 0.35-0.98) and successfully replicated ( P replication = 5.73 × 10 − 3 , OR = 0.45 , 95% CI 0.26-0.81). Multiple layers of functional analysis suggested that the PINX1 rs6984094 risk T allele exhibited increased nuclear protein binding. We also observed an increased expression of PINX1 mRNA in peripheral blood mononuclear cells from SLE patients compared with healthy controls. Overall, we observed a novel genetic association between PINX1 (encodes the PinX1 protein, an inhibitory telomerase enzyme that lengthens telomeres) and SLE susceptibility in Chinese populations.

Genomewide analysis of 6-methyladenine DNA in peripheral blood mononuclear cells of systemic lupus erythematosus

Lupus ◽  
2019 ◽  
Vol 28 (3) ◽  
pp. 359-364 ◽  
Author(s):  
F Zheng ◽  
D Tang ◽  
H Xu ◽  
Y Xu ◽  
W Dai ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Peripheral Blood Mononuclear Cells ◽  
Lupus Erythematosus ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Systemic Lupus ◽  
Peripheral Blood Mononuclear ◽  
Initial Development ◽  
Blood Mononuclear Cells ◽  
High Level

Aim The aim of this paper is to explore the expression of 6-methyladenine (6mA) DNA and to elucidate its gene regulation role in systemic lupus erythematosus (SLE). Methods Twenty SLE patients and 20 normal control healthy individuals (HCs) were included in this study. Genomic DNA was isolated from peripheral blood mononuclear cells and subsequently underwent 6mA-immunoprecipitation-sequencing (6mA-IP-Seq) after DNA quality control and 6mA precipitation. Bioinformation analysis was applied to the raw data comparing 6mA levels between SLE patients and HCs. Results We identified 5462 hypermethylation and 431 hypomethylation genes in PBMCs of individuals with SLE, which indicated that a high level of 6mA participates in the pathogenesis of SLE. Gene ontology analysis revealed that hypermethylation genes might regulate the inflammatory process, which has been well documented in the pathogenesis of SLE. Conclusion 6mA may be involved in the initial development of SLE, which may lead to its potential use as an early diagnostic marker and therapeutic target.

scholarly journals Belimumab alters transitional B-cell subset proportions in patients with stable systemic lupus erythematosus

Lupus ◽  
2019 ◽  
Vol 28 (11) ◽  
pp. 1337-1343 ◽  
Author(s):  
A Benitez ◽  
K Torralba ◽  
M Ngo ◽  
L M Salto ◽  
K S Choi ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
B Cells ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Mononuclear Cells ◽  
Cell Subset ◽  
Systemic Lupus ◽  
Peripheral Blood Mononuclear ◽  
Healthy Donors ◽  
Immature B Cells

Objective We evaluated the effects of the B-cell activating factor (BAFF)-targeting antibody Belimumab on human nonmemory B-cell pools. Human B-cell pools were identified using surface markers adapted from mouse studies that specifically assessed reductions in immature B cells due to BAFF depletion. Patients with systemic lupus erythematosus (SLE) have high levels of both BAFF and immature B cells. Mechanistic mouse studies provide a framework for understanding human responses to therapies that target B cells. Methods Peripheral blood mononuclear cells were isolated from healthy donors and SLE patients on Belimumab or standard-of-care therapy (SCT). Cells were stained for flow cytometry to identify B-cell subsets based on CD21/CD24. Differences in subset proportions were determined by one-way ANOVA and Tukey’s post hoc test. Results Patients treated with Belimumab show alterations in the nonmemory B-cell pool characterized by a decrease in the Transitional 2 (T2) subset ( p = 0.002), and an increase in the proportion of Transitional 1 (T1) cells ( p = 0.005) as compared with healthy donors and SCT patients. The naïve B-cell compartment showed no significant differences between the groups ( p = 0.293). Conclusion Using a translational approach, we show that Belimumab-mediated BAFF depletion reduces the T2 subset in patients, similar to observations in mouse models with BAFF depletion.

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