scholarly journals Transcriptome reprogramming and myeloid skewing in haematopoietic stem and progenitor cells in systemic lupus erythematosus

2019 ◽  
Vol 79 (2) ◽  
pp. 242-253 ◽  
Author(s):  
Maria Grigoriou ◽  
Aggelos Banos ◽  
Anastasia Filia ◽  
Pavlos Pavlidis ◽  
Stavroula Giannouli ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Progenitor Cells ◽  
Immune Cells ◽  
Lupus Erythematosus ◽  
Transcriptional Activation ◽  
Severe Disease ◽  
Enrichment Analysis ◽  
Global Gene Expression ◽  
Systemic Lupus ◽  
Stem And Progenitor Cells

ObjectivesHaematopoietic stem and progenitor cells (HSPCs) are multipotent cells giving rise to both myeloid and lymphoid cell lineages. We reasoned that the aberrancies of immune cells in systemic lupus erythematosus (SLE) could be traced back to HSPCs.MethodsA global gene expression map of bone marrow (BM)-derived HSPCs was completed by RNA sequencing followed by pathway and enrichment analysis. The cell cycle status and apoptosis status of HSPCs were assessed by flow cytometry, while DNA damage was assessed via immunofluorescence.ResultsTranscriptomic analysis of Lin−Sca-1+c-Kit+ haematopoietic progenitors from diseased lupus mice demonstrated a strong myeloid signature with expanded frequencies of common myeloid progenitors (CMPs)—but not of common lymphoid progenitors—reminiscent of a ‘trained immunity’ signature. CMP profiling revealed an intense transcriptome reprogramming with suppression of granulocytic regulators indicative of a differentiation arrest with downregulation trend of major regulators such as Cebpe, Cebpd and Csf3r, and disturbed myelopoiesis. Despite the differentiation arrest, frequencies of BM neutrophils were markedly increased in diseased mice, suggesting an alternative granulopoiesis pathway. In patients with SLE with severe disease, haematopoietic progenitor cells (CD34+) demonstrated enhanced proliferation, cell differentiation and transcriptional activation of cytokines and chemokines that drive differentiation towards myelopoiesis, thus mirroring the murine data.ConclusionsAberrancies of immune cells in SLE can be traced back to the BM HSPCs. Priming of HSPCs and aberrant regulation of myelopoiesis may contribute to inflammation and risk of flare.Trial registration number4948/19-07-2016.

scholarly journals New Horizons in the Genetic Etiology of Systemic Lupus Erythematosus and Lupus-Like Disease: Monogenic Lupus and Beyond

2020 ◽  
Vol 9 (3) ◽  
pp. 712 ◽  
Author(s):  
Erkan Demirkaya ◽  
Sezgin Sahin ◽  
Micol Romano ◽  
Qing Zhou ◽  
Ivona Aksentijevich
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Current Knowledge ◽  
Association Studies ◽  
Severe Disease ◽  
Genetic Diagnosis ◽  
Genome Wide Association Studies ◽  
Systemic Lupus ◽  
Degree Relative ◽  
Adult Age

Systemic lupus erythematosus (SLE) is a clinically and genetically heterogeneous autoimmune disease. The etiology of lupus and the contribution of genetic, environmental, infectious and hormonal factors to this phenotype have yet to be elucidated. The most straightforward approach to unravel the molecular pathogenesis of lupus may rely on studies of patients who present with early-onset severe phenotypes. Typically, they have at least one of the following clinical features: childhood onset of severe disease (<5 years), parental consanguinity, and presence of family history for autoimmune diseases in a first-degree relative. These patients account for a small proportion of patients with lupus but they inform considerable knowledge about cellular pathways contributing to this inflammatory phenotype. In recent years with the aid of new sequencing technologies, novel or rare pathogenic variants have been reported in over 30 genes predisposing to SLE and SLE-like diseases. Future studies will likely discover many more genes with private variants associated to lupus-like phenotypes. In addition, genome-wide association studies (GWAS) have identified a number of common alleles (SNPs), which increase the risk of developing lupus in adult age. Discovery of a possible shared immune pathway in SLE patients, either with rare or common variants, can provide important clues to better understand this complex disorder, it’s prognosis and can help guide new therapeutic approaches. The aim of this review is to summarize the current knowledge of the clinical presentation, genetic diagnosis and mechanisms of disease in patents with lupus and lupus-related phenotypes.

Role of Inflammasome Activation in Systemic Lupus Erythematosus: Are Innate Immune Cells Activated?

2020 ◽  
Author(s):  
Rodolfo Perez-Alamino ◽  
Raquel Cuchacovich ◽  
Luis R. Espinoza ◽  
Constance P. Porretta ◽  
Arnold H. Zea
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Immune Cells ◽  
Lupus Erythematosus ◽  
Innate Immune ◽  
Inflammasome Activation ◽  
Innate Immune Cells ◽  
Systemic Lupus

scholarly journals Serum vitamin D/25(OH)D associated with toll-like receptor (TLR) 2 expression of immune cells in the saliva of Systemic Lupus Erythematosus: a preliminary study

2021 ◽  
Vol 27 (2) ◽  
pp. 22
Author(s):  
Hendri Susanto ◽  
Bagus Soebadi ◽  
Diah Savitri Ernawati ◽  
Adiastuti Endah Pamardiati ◽  
Hening Tuti Hendarti ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Vitamin D ◽  
Immune Cells ◽  
Lupus Erythematosus ◽  
Serum Vitamin ◽  
Toll Like Receptor ◽  
Systemic Lupus ◽  
Tlr2 Expression ◽  
Cross Sectional ◽  
Serum Vitamin D

Objective: Vitamin D deficiency may contribute to Systemic Lupus Erythematosus (SLE) development. Vitamin D may involve in pathogen recognition through Toll-like receptor (TLR) 2 in immune cells in saliva. This study aimed to determine the correlation between serum vitamin D/25(OH)D and TLR2 expression of immune cells in the saliva of SLE. Materials and methods: This cross-sectional study conducted at the the SLE patients who met the inclusion and exclusion criteria. Those who had signed informed consent involved to underwent unstimulated saliva collection and blood samples for TLR2 and vitamin D/25(OH)D examination. The correlation between serum vitamin D/25(OH)D concentration and salivary TLR2 expression was analyzed using the correlation test, linear regression with 95% confidence level. Results: Thirty SLE patients had a mean serum vitamin D/25(OH)D concentration of 9.98 ± 4.64 ng/ml. The mean of TLR2 expression of CD11b+ cells in saliva was 26.03 ± 20.92%. There was a significant positive correlation between serum vitamin D/25(OH)D concentration and TLR 2 expression of CD11b+ cells in the saliva. (r = 0.434; P < 0.05). Vitamin D/25(OH)D was the only predictor for TLR 2 expression. Conclusion: Serum vitamin D/25(OH)D concentrations associated with TLR2 expression of CD11b+ cells in the saliva of SLE.

Systemic lupus erythematosus—management

2013 ◽  
pp. 938-947
Author(s):  
Ida Dzifa Dey ◽  
David Isenberg
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Immune Cells ◽  
Lupus Erythematosus ◽  
Immunosuppressive Drugs ◽  
Systemic Lupus ◽  
General Management ◽  
Autoimmune Rheumatic Disease ◽  
The Future

Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease with varied presentation and a disease course characterized by remission and flares. Over the last 50 years the prognosis of SLE has improved considerably. The introductions of corticosteroids and later of cytotoxic drugs, dialysis, and renal transplantation were the major contributors to this improvement. Nevertheless, the treatment and general management of lupus continues to present a challenge. While lupus may, for some patients, represent a relatively mild set of problems, many others require large doses of immunosuppressive drugs, which carry long-term concerns about side effects. New immunotherapeutic drugs, with actions more closely targeted to the immune cells and molecules involved in the pathogenesis of SLE, are being introduced and the future looks promising. The role of early atherosclerosis and cardiovascular disease as a cause of death in patients with SLE is increasingly recognized and will present further challenges in the future.

scholarly journals Deep sequencing reveals a DAP1 regulatory haplotype that potentiates autoimmunity in systemic lupus erythematosus

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Prithvi Raj ◽  
Ran Song ◽  
Honglin Zhu ◽  
Linley Riediger ◽  
Dong-Jae Jun ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Deep Sequencing ◽  
Immune Cells ◽  
Lupus Erythematosus ◽  
Risk Allele ◽  
Snp Array ◽  
Low Frequency ◽  
Risk Haplotype ◽  
Systemic Lupus ◽  
Altered Expression

Abstract Background Systemic lupus erythematosus (SLE) is a clinically heterogeneous autoimmune disease characterized by the development of anti-nuclear antibodies. Susceptibility to SLE is multifactorial, with a combination of genetic and environmental risk factors contributing to disease development. Like other polygenic diseases, a significant proportion of estimated SLE heritability is not accounted for by common disease alleles analyzed by SNP array-based GWASs. Death-associated protein 1 (DAP1) was implicated as a candidate gene in a previous familial linkage study of SLE and rheumatoid arthritis, but the association has not been explored further. Results We perform deep sequencing across the DAP1 genomic segment in 2032 SLE patients, and healthy controls, and discover a low-frequency functional haplotype strongly associated with SLE risk in multiple ethnicities. We find multiple cis-eQTLs embedded in a risk haplotype that progressively downregulates DAP1 transcription in immune cells. Decreased DAP1 transcription results in reduced DAP1 protein in peripheral blood mononuclear cells, monocytes, and lymphoblastoid cell lines, leading to enhanced autophagic flux in immune cells expressing the DAP1 risk haplotype. Patients with DAP1 risk allele exhibit significantly higher autoantibody titers and altered expression of the immune system, autophagy, and apoptosis pathway transcripts, indicating that the DAP1 risk allele mediates enhanced autophagy, leading to the survival of autoreactive lymphocytes and increased autoantibody. Conclusions We demonstrate how targeted sequencing captures low-frequency functional risk alleles that are missed by SNP array-based studies. SLE patients with the DAP1 genotype have distinct autoantibody and transcription profiles, supporting the dissection of SLE heterogeneity by genetic analysis.

Antiphospholipid syndrome (APS) in patients with systemic lupus erythematosus (SLE) implies a more severe disease with more damage accrual and higher mortality

Lupus ◽  
2020 ◽  
Vol 29 (12) ◽  
pp. 1556-1565
Author(s):  
Leyre Riancho-Zarrabeitia ◽  
Victor Martínez-Taboada ◽  
Iñigo Rúa-Figueroa ◽  
Fernando Alonso ◽  
María Galindo-Izquierdo ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Antiphospholipid Syndrome ◽  
Lupus Erythematosus ◽  
Severe Disease ◽  
Organ Damage ◽  
Systemic Lupus ◽  
Katz Index ◽  
Damage Accrual ◽  
Major Organ ◽  
Clinical Profiles

Introduction Antiphospholipid antibodies (aPL) have been associated with organ damage and certain features in systemic lupus erythematosus(SLE) patients. Our aim was to investigate the differences between SLE patients according to the presence of aPL and/or clinical antiphospholipid syndrome (APS). Materials and methods Patients from the RELESSER-T registry were included. RELESSER-T is a Spanish multicenter, hospital-based, retrospective, SLE registry. Results We included 2398 SLE patients, 1372 of whom were positive for aPL. Overall 1026 patients were classified as SLE, 555 as SLE-APS and817 as SLE-aPL. Regarding cardiovascular risk factors, SLE-APS patients had higher rates of hypertension, dyslipidemia and diabetes than those with SLE-aPL and SLE ( p < 0.001). SLE-APS patients showed higher rates of neuropsychiatric, cardiac, pulmonary, renal and ophthalmological manifestations than the other groups ( p < 0.001). SLE-APS patients presented greater damage accrual with higher SLICC values (1.9 ± 2.2 in SLE-APS, 0.9 ± 1.4 in SLE-aPL and 1.1 ± 1.6 in SLE, p < 0.001) and more severe disease as defined by the Katz index (3 ± 1.8 in SLE-APS, 2.7 ± 1.7 in SLE-aPL and 2.6 ± 1.6 in SLE, p  < 0.001). SLE-APS patients showed higher mortality rates ( p < 0.001). Conclusions SLE-APS patients exhibited more severe clinical profiles with higher frequencies of major organ involvement, greater damage accrual and higher mortality than SLE-aPL and SLE patients.

scholarly journals Genetic variations in A20 DUB domain provide a genetic link to citrullination and neutrophil extracellular traps in systemic lupus erythematosus

2019 ◽  
Vol 78 (10) ◽  
pp. 1363-1370 ◽  
Author(s):  
Lina Odqvist ◽  
Zala Jevnikar ◽  
Rebecca Riise ◽  
Lisa Öberg ◽  
Magdalena Rhedin ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Immune Cells ◽  
Lupus Erythematosus ◽  
Genetic Alterations ◽  
Genetic Variations ◽  
Negative Regulator ◽  
Systemic Lupus ◽  
Trap Formation ◽  
Autoimmune Pathology ◽  
Extracellular Trap

ObjectivesGenetic variations in TNFAIP3 (A20) de-ubiquitinase (DUB) domain increase the risk of systemic lupus erythematosus (SLE) and rheumatoid arthritis. A20 is a negative regulator of NF-κB but the role of its DUB domain and related genetic variants remain unclear. We aimed to study the functional effects of A20 DUB-domain alterations in immune cells and understand its link to SLE pathogenesis.MethodsCRISPR/Cas9 was used to generate human U937 monocytes with A20 DUB-inactivating C103A knock-in (KI) mutation. Whole genome RNA-sequencing was used to identify differentially expressed genes between WT and C103A KI cells. Functional studies were performed in A20 C103A U937 cells and in immune cells from A20 C103A mice and genotyped healthy individuals with A20 DUB polymorphism rs2230926. Neutrophil extracellular trap (NET) formation was addressed ex vivo in neutrophils from A20 C103A mice and SLE-patients with rs2230926.ResultsGenetic disruption of A20 DUB domain in human and murine myeloid cells did not give rise to enhanced NF-κB signalling. Instead, cells with C103A mutation or rs2230926 polymorphism presented an upregulated expression of PADI4, an enzyme regulating protein citrullination and NET formation, two key mechanisms in autoimmune pathology. A20 C103A cells exhibited enhanced protein citrullination and extracellular trap formation, which could be suppressed by selective PAD4 inhibition. Moreover, SLE-patients with rs2230926 showed increased NETs and increased frequency of autoantibodies to citrullinated epitopes.ConclusionsWe propose that genetic alterations disrupting the A20 DUB domain mediate increased susceptibility to SLE through the upregulation of PADI4 with resultant protein citrullination and extracellular trap formation.

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