scholarly journals Patrolling human SLE haematopoietic progenitors demonstrate enhanced extramedullary colonisation; implications for peripheral tissue injury

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ioannis Kokkinopoulos ◽  
Aggelos Banos ◽  
Maria Grigoriou ◽  
Anastasia Filia ◽  
Theodora Manolakou ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Lupus Erythematosus ◽  
Tissue Injury ◽  
Human Peripheral Blood ◽  
Peripheral Tissue ◽  
Molecular Signatures ◽  
Healthy Individuals ◽  
Healthy Human ◽  
Haematopoietic Cells ◽  
Humanised Mice

AbstractSystemic lupus erythematosus (SLE) is an autoimmune disease where bone-marrow-derived haematopoietic cells have a key role in its pathogenesis with accumulating evidence suggesting an aberrant function of haematopoietic stem/progenitor cells (HSPCs). We examined whether patrolling HSPCs differ from bone-marrow HSPCs both in SLE and healthy individuals, and how they participate in peripheral tissue injury. By employing next-generation RNA sequencing, the transcriptomes of CD34+ HSPCs deriving from the bone marrow and those patrolling the bloodstream of both healthy and individuals with SLE were compared. Patrolling SLE and Healthy human HSPC kinetics were examined through their inoculation into humanised mice. Patrolling and bone-marrow HSPCs have distinct molecular signatures, while patrolling SLE HSPCs showed an enhanced extramedullary gene expression profile. Non-mobilised, SLE-derived circulating HSPCs demonstrated altered homing capacities. Xenotransplantation of circulating HSPCs in humanised mice showed that human peripheral blood HSPCs possess the ability for extramedullary organ colonisation to the kidneys. Circulating and bone marrow-derived HSPCs are distinct in steady and diseased states. Patrolling SLE CD34+ HSPCs are able to home at extramedullary sites such as the spleen and kidneys, potentially participating in peripheral tissue injury.

scholarly journals Patrolling human SLE haematopoietic progenitors demonstrate enhanced extramedullary colonisation; implications for peripheral tissue injury

2021 ◽  
Author(s):  
Ioannis Kokkinopoulos ◽  
Aggelos Banos ◽  
Maria Grigoriou ◽  
Anastasia Filia ◽  
Theodora Manolakou ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Lupus Erythematosus ◽  
Tissue Injury ◽  
Human Peripheral Blood ◽  
Peripheral Tissue ◽  
Systemic Lupus ◽  
Disease States ◽  
Haematopoietic Cells ◽  
Humanised Mice ◽  
Generation Sequencing

ABSTRACTSystemic Lupus erythematosus (SLE) is an autoimmune disease where bone-marrow-derived haematopoietic cells have a key role in its pathogenesis with accumulating evidence suggesting an aberrant function of haematopoietic stem/progenitor cells (HSPCs). By employing next-generation sequencing, we compared the gene transcription signatures of CD34+ HSPCs deriving from either the bone marrow or HSPCs patrolling the bloodstream of healthy and individuals with SLE, seeking common transcriptional pathways that may have been modified between steady and disease states. Our findings indicate that circulating and bone marrow-derived HSPCs are distinct in steady and diseased states. Non-mobilised, SLE-derived circulating HSPCs demonstrated enhanced engrafting and altered differentiation capacities. Importantly, xenotransplantation of circulating HSPCs in humanised mice showed that human peripheral blood HSPCs possess the ability for extramedullary organ colonisation to the kidneys. SLE CD34+ HSPCs homing and engraftment at extramedullary sites such as the spleen and kidneys may participate in peripheral tissue injury.

scholarly journals Ab initio Spillover Compensation in CyTOF Data

2020 ◽  
Author(s):  
Qi Miao ◽  
Fang Wang ◽  
Jinzhuang Dou ◽  
Ramiz Iqbal ◽  
Muharrem Muftuoglu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Large Scale ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Ground Truth ◽  
Spillover Effects ◽  
Lymphocytic Leukemia ◽  
Mouse Bone Marrow ◽  
Healthy Human ◽  
Human Cord Blood

AbstractSignal intensity measured in a mass cytometry (CyTOF) channel can often be affected by the neighboring channels due to technological limitations. Such signal artifacts are known as spillover effects and can substantially limit the accuracy of cell population clustering. Current approaches reduce these effects by using additional beads for normalization purposes known as single-stained controls. While effective in compensating for spillover effects, incorporating single-stained controls can be costly and require customized panel design. This is especially evident when executing large-scale immune profiling studies. We present a novel statistical method, named CytoSpill that independently quantifies and compensates the spillover effects in CyTOF data without requiring the use of single-stained controls. Our method utilizes knowledge-guided modeling and statistical techniques, such as finite mixture modeling and sequential quadratic programming, to achieve optimal error correction. We evaluated our method using five publicly available CyTOF datasets obtained from human peripheral blood mononuclear cells (PBMCs), C57BL/6J mouse bone marrow, healthy human bone marrow, chronic lymphocytic leukemia patient, and healthy human cord blood samples. In the PBMCs with known ground truth, our method achieved comparable results to experiments that incorporated single-stained controls. In datasets without ground-truth, our method not only reduced spillover on likely affected markers, but also led to the discovery of potentially novel subpopulations expressing functionally meaningful, cluster-specific markers. CytoSpill (developed in R) will greatly enhance the execution of large-scale cellular profiling of tumor immune microenvironment, development of novel immunotherapy, and the discovery of immune-specific biomarkers. The implementation of our method can be found at https://github.com/KChen-lab/CytoSpill.git.

scholarly journals Complement Consumption in Systemic Lupus Erythematosus Leads to Decreased OpsonophagocytosisIn Vitro

2018 ◽  
Vol 45 (11) ◽  
pp. 1557-1564 ◽  
Author(s):  
Amanda Mitander ◽  
Ying Fei ◽  
Estelle Trysberg ◽  
Majd Mohammad ◽  
Zhicheng Hu ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Infection Risk ◽  
Human Neutrophils ◽  
High Dose ◽  
Healthy Individuals ◽  
Systemic Lupus ◽  
Healthy Human ◽  
Infection Incidence ◽  
Host Immune Responses

Objective.Infections remain a major cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). The high prevalence of infections in SLE is attributed to both the disease and its treatments. The complement system plays an important role in host immune responses against invading microorganisms. We sought to provide the experimental and clinical evidence supporting the hypothesis that low levels of complement factors cause defective complement-mediated opsonization in patients with SLE.Methods.Staphylococcus aureuswas opsonized with sera from healthy individuals (n = 16), SLE patients with normal (n = 5) or low complement (n = 8) levels. Phagocytosis ofS. aureusby healthy human neutrophils was analyzed by an imaging flow cytometry-based method. We retrospectively examined the infection incidence in relation to complement levels in a cohort of 165 patients with SLE during a 1.5-year period. The association was analyzed for infection incidence and disease-related variables.Results.Uptake ofS. aureusby neutrophils was decreased whenS. aureuswas opsonized with sera from SLE patients with low complement levels compared to sera from healthy individuals and SLE patients with normal complement. In our SLE cohort, 44% of patients had at least 1 infection during the 1.5 years. No significant association was observed between complement levels and infection risk. Importantly, high-dose glucocorticoids (GC; prednisone ≥ 10 mg/day) were the most important predictive factor for infections in patients with SLE.Conclusion.Low complement levels affect bacterial opsonization in SLE blood and lead to downregulated phagocytosis by neutrophils. High-dose GC increase the infection risk in patients with SLE.

EBV load is associated with cfDNA fragmentation and renal damage in SLE patients

Lupus ◽  
2021 ◽  
pp. 096120332110103
Author(s):  
Anna Truszewska ◽  
Agnieszka Wirkowska ◽  
Kamila Gala ◽  
Piotr Truszewski ◽  
Łucja Krzemień-Ojak ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Lupus Erythematosus ◽  
Epstein Barr Virus ◽  
Renal Damage ◽  
Healthy Individuals ◽  
Pcr Assay ◽  
Barr Virus ◽  
Fragmentation Index ◽  
Epstein Barr

Background For long Epstein–Barr virus (EBV) has been suspected to be involved in the pathogenesis of systemic lupus erythematosus (SLE). The aim of this study was to verify the association between EBV, cell-free DNA (cfDNA) and kidney disease in SLE. Methods Blood samples were obtained from 43 SLE patients and 50 healthy individuals. EBV load was measured via real-time PCR assay. Sizing and quantification of plasma cfDNA was performed on Bioanalyzer. We proposed that the uniformity of cfDNA fragmentation can be described using cfDNA fragmentation index. Results SLE patients with chronic kidney disease (CKD +) had higher EBV load compared to CKD(–) patients (P = 0.042). Patients with high cfDNA level had higher EBV load (P = 0.041) and higher cfDNA fragmentation index (P < 0.001) compared to patients with low cfDNA level. Among patients with high cfDNA level, EBV load was higher in CKD(+) group compared to CKD(–) group (P = 0.035). EBV load was positively correlated with the fragmentation index in all SLE patients (P = 0.028, R2 = 0.13), and the correlation was even more pronounced in CKD (+) patients (P < 0.001, R2 = 0.20). Conclusions We showed that EBV load was associated with non-uniform cfDNA fragmentation, higher cfDNA levels, and kidney disease in SLE patients. Although the causality of this relationship could not be determined with the current study, it brings rationale for further investigations on the role of EBV and cfDNA interplay in SLE pathogenesis.

scholarly journals Serum levels and gene polymorphisms of angiopoietin 2 in systemic lupus erythematosus patients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jia-Min Wang ◽  
Wang-Dong Xu ◽  
Zhi-Chao Yuan ◽  
Qian Wu ◽  
Jie Zhou ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Autoimmune Diseases ◽  
Lupus Erythematosus ◽  
Gene Polymorphisms ◽  
Serum Levels ◽  
Healthy Individuals ◽  
Systemic Lupus ◽  
Potential Biomarker ◽  
Angiopoietin 2 ◽  
Inflammatory Autoimmune Diseases

AbstractThis study aimed to discuss association between serum Angiopoietin2 (Ang2) levels, Ang2 gene polymorphisms and systemic lupus erythematosus (SLE) susceptibility. It was carried out by 235 SLE, 342 other inflammatory autoimmune diseases patients and 380 healthy individuals. Serum Ang2 levels was examinated by ELISA, and Ang2 rs12674822, rs1823375, rs1868554, rs2442598, rs3739390 and rs734701 polymorphisms were genotyped using KASP. Increased Ang2 concentrations in SLE patients were observed compared with healthy controls and patients with other inflammatory autoimmune diseases. For allelic contrast, except for rs1823375 (P = 0.058) and rs2442598 (P = 0.523), frequencies of alleles for other polymorphisms were significantly different between SLE patients and controls. Genotypes for rs12674822 (TT), rs1868554 (TT, TA and TT+TA), rs734701 (TT) were negatively correlated with SLE susceptibility (OR = 0.564 for rs12674822; OR = 0.572, OR = 0.625, OR = 0.607 for rs1868554; OR = 0.580 for rs734701). Patients carrying rs1868554 T allele and rs3739390 G allele were more likely to develop hematuria (P = 0.039; P = 0.003). The G allele frequencies of rs12674822 and rs2442598 were higher in SLE patients with proteinuria (P = 0.043; P = 0.043). GC genotype frequency of rs3739390 was higher in patients with ds-DNA (+) (P = 0.024). In summary, SLE had increased serum Ang2, which may be a potential biomarker, and the polymorphisms correlated with SLE.

scholarly journals Autoantibodies against the fibrinolytic receptor, annexin 2, in antiphospholipid syndrome

Blood ◽  
2006 ◽  
Vol 107 (11) ◽  
pp. 4375-4382 ◽  
Author(s):  
Gabriela Cesarman-Maus ◽  
Nina P. Ríos-Luna ◽  
Arunkumar B. Deora ◽  
Bihui Huang ◽  
Rosario Villa ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Surface ◽  
Antiphospholipid Syndrome ◽  
Lupus Erythematosus ◽  
Antiphospholipid Antibodies ◽  
Cell Surface Receptor ◽  
Enzyme Linked Immunosorbent Assay ◽  
Target Antigen ◽  
Healthy Individuals ◽  
Annexin 2

AbstractThe association of thrombosis and gestational morbidity with antiphospholipid antibodies is termed antiphospholipid syndrome (APS). Annexin 2 (A2) is a profibrinolytic endothelial cell surface receptor that binds plasminogen, its tissue activator (tPA), and β2-glycoprotein I (β2GPI), the main antigen for antiphospholipid antibodies. Here, we evaluate A2 as a target antigen in APS. Serum samples from 434 individuals (206 patients with systemic lupus erythematosus without thrombosis, 62 with APS, 21 with nonautoimmune thrombosis, and 145 healthy individuals) were analyzed by enzyme-linked immunosorbent assay (ELISA) and immunoblot for antiphospholipid and A2 antibodies. Anti-A2 antibodies (titer > 3 SDs) were significantly more prevalent in patients with APS (22.6%; venous, 17.5%; arterial, 34.3%; and mixed thrombosis, 40.4%) than in healthy individuals (2.1%, P < .001), patients with nonautoimmune thrombosis (0%, P = .017), or patients with lupus without thrombosis (6.3%, P < .001). Anti–A2 IgG enhanced the expression of tissue factor on endothelial cells (6.4-fold ± 0.13-fold SE), blocked A2-supported plasmin generation in a tPAdependent generation assay (19%-71%) independently of β2GPI, and inhibited cell surface plasmin generation on human umbilical vein endothelial cells (HUVECs) by 34% to 83%. We propose that anti-A2 antibodies contribute to the prothrombotic diathesis in antiphospholipid syndrome.

2. Peripheral injury in the rat: behavioural and neuronal correlates

1985 ◽  
Vol 308 (1136) ◽  
pp. 408-408
Keyword(s):  
Tissue Injury ◽  
Primary Afferents ◽  
Peripheral Tissue ◽  
Peripheral Injury ◽  
Induced Changes

Peripheral tissue injury alters dramatically the relation between a cutaneous stimulus and the sensation experienced by producing both a decrease in the threshold necessary to elicit pain and an increase in the pain resulting from suprathreshold stimuli (hyperalgesia). We have now investigated whether these injury-induced changes result from alterations in the properties of primary afferents (sensitization) (Lynn 1977) or whether the injury triggers a change within the c.n.s. (Woolf 1983).

Increased Serum Soluble OX40 in Patients with Systemic Sclerosis

2008 ◽  
Vol 35 (12) ◽  
pp. 2359-2362 ◽  
Author(s):  
KAZUHIRO KOMURA ◽  
AYUMI YOSHIZAKI ◽  
MASANARI KODERA ◽  
YOHEI IWATA ◽  
FUMIHIDE OGAWA ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Systemic Sclerosis ◽  
Lupus Erythematosus ◽  
Tumor Necrosis ◽  
Disease Duration ◽  
Tumor Necrosis Factor Receptor ◽  
Healthy Individuals ◽  
Systemic Lupus ◽  
Clinical Associations ◽  
Necrosis Factor

ObjectiveTo determine levels of serum soluble OX40 (also termed CD134, a member of the tumor necrosis factor receptor superfamily) and their clinical associations in patients with systemic sclerosis (SSc).MethodsSerum soluble OX40 levels were examined by ELISA in 53 patients with SSc, 15 patients with systemic lupus erythematosus (SLE), and 32 healthy individuals.ResultsOX40 levels were significantly elevated in SSc patients (125.7 ± 5.7 pg/ml) compared to patients with SLE (80.7 ± 1.7 pg/ml; p < 0.005) and controls (88.2 ± 3.0 pg/ml; p < 0.0001). Elevated OX40 levels were found to be associated with disease duration of less than 2 years (p < 0.05).ConclusionOur results suggest that serum soluble OX40 levels correlate with the early-onset of SSc disease.

Abstract 3153: Endoglin Deficiency in Bone Marrow is Sufficient to Cause Vascular Dysplasia in the Adult Mouse Brain After VEGF Stimulation

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Eun-Jung Choi ◽  
Espen J. Walker ◽  
Kristine Jun ◽  
Robert Kuo ◽  
Hua Su ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mouse Brain ◽  
Adult Mouse ◽  
Viral Vector ◽  
Vascular Density ◽  
Index Number ◽  
Adult Mouse Brain ◽  
Healthy Human ◽  
Angiogenic Response ◽  
The Mean

Background and Objective: We have previously demonstrated that VEGF overexpression in the brain of adult Eng+/- mice causes vascular abnormalities. We also found that bone marrow-derived cells (BMDCs) home to vascular endothelial growth factor (VEGF)-induced angiogenic foci in the adult mouse brain and contribute to angiogenesis. Impaired angiogenesis in infarcted myocardium of Eng+/- mice was rescued using treatment with healthy human BMDCs but not with BMDCs from Hereditary Hemorrhagic Telangiectasia (HHT1) patients carrying ENG mutations. We hypothesized that ENG-haploinsufficiency in BMDCs can cause cerebrovascular dysplasia in the adult mouse after VEGF stimulation. Methods: WT or Eng+/- BM (2×106 cells) were transplanted to lethally irradiated C57BL/6 recipient mice (8-10 weeks old) via tail vein injection. After 4 weeks of BM transplantation, adeno-associated viral vector expressing VEGF (AAV-VEGF, 2×109 genome copies) was stereotactically injected into the basal ganglia. Brain sections were collected at 4 weeks after virus injection. The vascular density (vessels per 20× objective field) and dysplasia index (number of vessels >15µm in diameter per 200 vessels) were quantified on lectin-stained brain sections. Results: To examine the angiogenic response to VEGF, the vascular density around the AAV-VEGF injection site was analyzed. The mean vascular density increased in all mice with VEGF stimulation. Mice transplanted with Eng+/- BM showed less vascular density compared to mice transplanted with WT BM. The mean vascular densities were167 ± 21 (Eng+/-BM, n=4) and 202 ± 15 (WT BM, n=5) (P<0.01). Further, mice with WT BM had angiogenesis with normal vascular morphology. In contrast, mice with Eng+/- BM had markedly enlarged and dysmorphic vessels. To assess the degree of the dysplastic response, dysplasia index was analyzed. Mice with Eng+/- BM had several fold-higher dysplasia index than mice with WT BM: 2.6 ± 1.4 (Eng+/- BM) versus 0.7 ± 0.4 (WT BM) (P<0.01). Conclusions: In the adult mouse after VEGF stimulation, ENG-deficiency in BM (1) caused a 17% reduction in brain angiogenic response, and (2) increased cerebrovascular dysplasia, compared to control animals. These data support the possibility that cerebrovascular malformations resulting from VEGF stimulation with ENG-haploinsufficiency is attributable to impaired cell-autonomous monocyte/macrophage function, in contrast to the view that ENG dysfunction is primarily an endothelial phenomenon.

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