ABSTRACT
OBJECTIVES: To investigate the clinical value of complement-3a receptor 1 (C3aR1) and neutrophil extracellular traps (NETs) in predicting sepsis-induced coagulopathy (SIC). METHODS: A prospective study was conducted among 78 children with sepsis who attended Xuzhou Children's Hospital Affiliated to Xuzhou Medical University from June 2022 to June 2023. According to the presence or absence of SIC, they were divided into two groups: SIC (n=36) and non-SIC (n=42) . The two groups were compared in terms of clinical data and the levels of C3aR1 and NETs. The factors associated with the occurrence of SIC were analyzed. The receiver operating characteristic (ROC) curve was used to evaluate the performance of C3aR1 and NETs in predicting SIC. RESULTS: Compared with the non-SIC group, the SIC group had significantly higher levels of C-reactive protein, interleukin-6 (IL-6), interleukin-10, C3aR1, and NETs (P<0.05). The multivaiate logistic regression analysis showed that the increases in C3aR1, NETs, and IL-6 were closely associated with the occurrence of SIC (P<0.05). The ROC curve analysis showed that C3aR1 combined with NETs had an area under the curve (AUC) of 0.913 in predicting SIC (P<0.05), which was significantly higher than the AUC of C3aR1 or IL-6 (P<0.05), while there was no significant difference in AUC between C3aR1 combined with NETs and NETs alone (P>0.05). CONCLUSIONS: There are significant increases in the expression levels of C3aR1 and NETs in the peripheral blood of children with SIC, and the expression levels of C3aR1 and NETs have a high clinical value in predicting SIC.
Subject(s)
Blood Coagulation Disorders , Extracellular Traps , Receptors, Complement , Sepsis , Receptors, Complement/blood , Receptors, Complement/genetics , Extracellular Traps/metabolism , Sepsis/complications , Blood Coagulation Disorders/diagnosis , Blood Coagulation Disorders/etiology , Humans , Child , Biomarkers/blood , Gene Expression Profiling , Logistic Models , Multivariate AnalysisABSTRACT
BACKGROUND: Abnormal A Disintegrin and Metalloproteinase with Thrombospondin Motifs 2 (ADAMTS2) and V-set and immunoglobulin domain-containing 4 (VSIG4) were explored in serum of heart failure (HF) patients and its association with C-reactive protein (CRP), uric acid (UA), and homocysteine (HCY) indexes was manifested. METHODS: ADAMTS2 and VSIG4 expression in serum of HF patients was analyzed. Pearson's correlation coefficient analysis was employed to evaluate the correlation between the indexes. Receiver operating characteristic (ROC) curves to assess the recognition ability of ADAMTS2, VSIG4, and brain natriuretic peptide (BNP) for HF. Kaplan-Meier survival curve and multivariate Cox regression were applied to analyze the prognostic value of ADAMTS2 and VSIG4. RESULTS: ADAMTS2 and VSIG4 were upregulated in serum of HF patients. ROC curve affirmed that ADAMTS2 and VSIG4 in serum manifested diagnostic value for HF, and the combined diagnosis accuracy of ADAMTS2, VSIG4, and BNP was greatly improved. Kaplan-Meier and multivariate Cox regression analysis suggested that reduced ADAMTS2 and VSIG4 could forecast the overall survival of HF patients. CONCLUSIONS: This study assures that ADAMTS2 and VSIG4 are strengthening in HF patients, which makes them new non-invasive biomarkers for the diagnosis and prognosis of HF.
Subject(s)
C-Reactive Protein , Heart Failure , Receptors, Complement/blood , ADAMTS Proteins , Biomarkers , Homocysteine , Humans , Natriuretic Peptide, Brain , Prognosis , ROC Curve , Uric AcidABSTRACT
BACKGROUND: The relationship between C3a-C3aR, IL-1ß, and the acute exacerbation of chronic obstructive pulmonary disease is still unclear. This study aims to explore the expression levels of C3aR in peripheral blood WBCs and the concentrations of C3a, C3aR, and IL-1ß in plasma in healthy controls and patients with chronic obstructive pulmonary disease (COPD). METHODS: WBCs C3aR level in the peripheral blood, the concentrations of C3a, C3aR, and IL-1ß in plasma were measured in 60 patients with acute exacerbation of COPD (AECOPD), 30 patients with stable COPD (SCOPD), and 30 healthy controls. The baseline characteristics and clinical data collected from enrolled patients, including age, gender, laboratory indicators, and lung function. We analyzed the correlation between C3a, C3aR, IL-1ß, and lung function indicators (forced expiratory volume in the first second as a percentage of predicted value, FEV1%pred) in the AECOPD group. RESULTS: The white blood cell count (WBC), neutrophil/lymphocyte ratio (NLR), and C-reactive protein (CRP) of patients in COPD were higher than in healthy controls (P < 0.05). The peripheral blood WBCs C3aR mRNA and plasma C3a, C3aR, and IL-1ß in AECOPD were higher than in SCOPD and healthy controls (P < 0.05). The peripheral blood WBCs C3aR mRNA and plasma C3aR, and IL-1ß in AECOPD combined with respiratory failure were higher than in the non-respiratory failure group (P < 0.05). The peripheral blood WBCs C3aR mRNA and plasma C3a, C3aR, and IL-1ß in AECOPD with high-risk were higher than in the low-risk group (P < 0.05). The peripheral blood WBCs C3aR mRNA and plasma C3a, C3aR, and IL-1ß in AECOPD were negatively correlated with FEV1pred%. The peripheral blood WBCs C3aR mRNA, the plasma C3a and C3aR in AECOPD were positively correlated with IL-1ß. CONCLUSION: The peripheral blood WBCs C3aR mRNA and plasma C3a, C3aR, and IL-1ß in COPD patients were significantly related to the risk of disease deterioration. The C3a-C3aR axis may be involved in airway inflammation in patients with COPD.
Subject(s)
Pulmonary Disease, Chronic Obstructive , Case-Control Studies , Complement C3/chemistry , Forced Expiratory Volume , Humans , Interleukin-1beta/blood , Pulmonary Disease, Chronic Obstructive/diagnosis , RNA, Messenger/blood , Receptors, Complement/blood , Respiratory Function TestsABSTRACT
Inflammation is one of the fundamental processes in numerous diseases. Cluster of differentiation (CD) 93, a glycoprotein, has been reported to be associated with a number of these diseases. There are reports indicating that a high plasma level of CD93 is associated with adverse events in ischaemic heart disease. Additionally, there are reports indicating different cardiovascular risks between different single nucleotide polymorphisms (SNPs) of CD93. Therefore, the present study aimed to determine whether the plasma concentration of CD93 and polymorphism of rs2749812 in CD93 were associated with clinical conditions and mortality in an elderly population. In 470 healthy elderly communityliving individuals a novel clinical examination involving echocardiography and blood sampling was performed. The population was followed for 6.7 years. Plasma levels of CD93 and SNP analyses of rs2749812 of CD93 using PCR methodology were used. During the followup period, 106 (22.6%) allcause and 61 (13.0%) cardiovascular deaths were registered. Those with the highest plasma concentration had markedly higher allcause mortality. Evaluating the A/A, A/G and G/G genotypes, the G/G group exhibited significantly higher cardiovascular mortality (P=0.026), and an almost twofold increased risk in a multivariate Cox regression model compared with the A/G genotype. Evaluation of subgroups with respect to sex, diabetes and hypertension revealed markedly increased cardiovascular risk in the G/G genotype in all subgroups. All results persisted in the multiple models used. In the present study, the glycoprotein CD93 was demonstrated to have prognostic cardiovascular information, with increased risk for those with a high plasma concentration. Furthermore, the G/G genotype of rs2749812 of CD93 has a significantly higher cardiovascular risk, as demonstrated here, and could therefore be regarded as a possible cardiovascular risk biomarker that might in the future be used to offer optimised cardiovascular patient handling. However, this was a small study, and more research is required.
Subject(s)
Cardiovascular Diseases/genetics , Membrane Glycoproteins/genetics , Receptors, Complement/genetics , Aged , Biomarkers/blood , Cardiovascular Diseases/mortality , Cardiovascular System , Case-Control Studies , Coronary Artery Disease/genetics , Coronary Artery Disease/mortality , Female , Follow-Up Studies , Genetic Variation/genetics , Genotype , Humans , Inflammation/blood , Male , Membrane Glycoproteins/blood , Membrane Glycoproteins/metabolism , Plasma , Polymorphism, Single Nucleotide/genetics , Proportional Hazards Models , Receptors, Complement/blood , Receptors, Complement/metabolismABSTRACT
CR1 (CD35, Complement Receptor type 1 for C3b/C4b) is a high molecular weight membrane glycoprotein of about 200 kDa that controls complement activation, transports immune complexes, and participates in humoral and cellular immune responses. CR1 is present on the surface of many cell types, including erythrocytes, and exhibits polymorphisms in length, structure (Knops, or KN, blood group), and density. The average density of CR1 per erythrocyte (CR1/E) is 500 molecules per erythrocyte. This density varies from one individual to another (100-1,200 CR1/E) and from one erythrocyte to another in the same individual. We present here a robust flow cytometry method to measure the density of CR1/E, including in subjects expressing a low density, with the help of an amplifying immunostaining system. This method has enabled us to show the lowering of CR1 erythrocyte expression in diseases such as Alzheimer's disease (AD), systemic lupus erythematosus (SLE), AIDS, or malaria.
Subject(s)
Erythrocytes/metabolism , Flow Cytometry/methods , Receptors, Complement/blood , Calibration , Cell Count , Humans , Regression AnalysisABSTRACT
CD93 has been shown critical roles in inflammatory and immune diseases. However, in allergic asthma, the potential roles of soluble CD93 (sCD93) have not been well studied. We conducted house dust mite (HDM) stimulation with Der p 1 in BEAS-2B and U937 cells, followed by treatment with dexamethasone or small interfering RNA against CD93. A HDM-induced murine allergic asthma model was also established. We estimated the power of sCD93 to predict allergic asthma in a retrospective post-hoc analysis containing 96 human samples. HDM-stimulated BEAS-2B cells showed increased mRNA expression levels of IL-6, IL-8, IL-33, TSLP, and CD93. The CD93 level in culture supernatants steadily increased for 24 h after allergen stimulation, which was significantly suppressed by both dexamethasone and CD93 silencing. CD93 silencing increased IL-6 and TSLP, but not IL-33 levels in culture supernatants. HDM-induced asthma mice showed significant airway hyperresponsiveness and inflammation with Th2 cytokine activation, along with decreased CD93 expression in bronchial epithelial cells and lung homogenates but increased serum CD93 levels. The sCD93 level in asthma patients was significantly higher than that in healthy controls and could predict asthma diagnosis with moderate sensitivity (71.4%) and specificity (82.4%) (AUC = 0.787, P < 0.001). The level of sCD93 which has potential role to predict asthma significantly increased after HDM stimulation via IL-6 and TSLP in vitro and in vivo.
Subject(s)
Asthma/diagnosis , Membrane Glycoproteins/metabolism , Receptors, Complement/metabolism , Animals , Asthma/metabolism , Asthma/pathology , Biomarkers/blood , Bronchi/cytology , Cell Line , Disease Models, Animal , Epithelial Cells/cytology , Epithelial Cells/metabolism , Humans , Interleukin-33/genetics , Interleukin-33/metabolism , Interleukin-6/genetics , Interleukin-6/metabolism , Membrane Glycoproteins/antagonists & inhibitors , Membrane Glycoproteins/blood , Membrane Glycoproteins/genetics , Mice , Pyroglyphidae/immunology , RNA Interference , RNA, Small Interfering/metabolism , Receptors, Complement/antagonists & inhibitors , Receptors, Complement/blood , Receptors, Complement/genetics , Retrospective Studies , Sensitivity and Specificity , Th2 Cells/cytology , Th2 Cells/immunology , Th2 Cells/metabolismABSTRACT
Lymphoma-associated haemophagocytic lymphohistiocytosis (L-HLH) is characterized by excessively activated macrophages and cytotoxic T lymphocytes, but few reliable markers for activated macrophages are available clinically. This study, designed to discover novel biomarkers for the diagnosis of lymphoma patients with L-HLH, was initiated between 2016 and 2018. Fifty-seven adult lymphoma patients were enrolled - 39 without HLH and 18 with HLH. The differential serum protein expression profile was first screened between lymphoma patients with and without L-HLH by a quantitative mass spectrometric approach. Soluble V-set and immunoglobulin domain-containing 4 (sVSIG4), specifically expressed by macrophages, was significantly upregulated in the L-HLH group. Subsequently, sVSIG4 concentration was confirmed by enzyme-linked immunosorbent assay to be significantly increased in lymphoma patients with L-HLH. When it was exploited for the diagnosis of lymphoma patients with L-HLH, the area under a receiver operating characteristic curve was 0·98 with an optimal cut-off point of 2195 pg/ml and the corresponding sensitivity and specificity were 94·44% and 94·87% respectively. In addition, the one-year overall survival was significantly worse in patients with a sVSIG4 concentration above 2195 pg/ml compared with those below 2195 pg/ml (5·3% vs. 72·2%, P < 0·0001). sVSIG4 may be a surrogate marker of activated macrophages for the diagnosis of lymphoma patients with L-HLH.
Subject(s)
Biomarkers, Tumor/blood , Lymphohistiocytosis, Hemophagocytic , Lymphoma , Neoplasm Proteins/blood , Receptors, Complement/blood , Adult , Aged , Aged, 80 and over , Female , Follow-Up Studies , Humans , Lymphohistiocytosis, Hemophagocytic/blood , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/etiology , Lymphoma/blood , Lymphoma/complications , Lymphoma/diagnosis , Male , Middle Aged , Retrospective StudiesABSTRACT
Efferocytosis is essential for homeostasis and prevention of the inflammatory and autoimmune diseases resulting from apoptotic cell lysis. CD93 is a transmembrane glycoprotein previously implicated in efferocytosis, with mutations in CD93 predisposing patients to efferocytosis-associated diseases. CD93 is a cell surface protein, which is proteolytically shed under inflammatory conditions, but it is unknown how CD93 mediates efferocytosis or whether its efferocytic activity is mediated by the soluble or membrane-bound form. Herein, using cell lines and human monocytes and macrophages, we demonstrate that soluble CD93 (sCD93) potently opsonizes apoptotic cells but not a broad range of microorganisms, whereas membrane-bound CD93 has no phagocytic, efferocytic, or tethering activity. Using mass spectrometry, we identified αx ß2 as the receptor that recognizes sCD93, and via deletion mutagenesis determined that sCD93 binds to apoptotic cells via its C-type lectin-like domain and to αx ß2 by its EGF-like repeats. The bridging of apoptotic cells to αx ß2 markedly enhanced efferocytosis by macrophages and was abrogated by αx ß2 knockdown. Combined, these data elucidate the mechanism by which CD93 regulates efferocytosis and identifies a previously unreported opsonin-receptor system utilized by phagocytes for the efferocytic clearance of apoptotic cells.
Subject(s)
Apoptosis , Integrins/metabolism , Membrane Glycoproteins/metabolism , Opsonin Proteins/metabolism , Receptors, Complement/metabolism , Animals , Biomarkers , CHO Cells , Cell Line , Cricetulus , HEK293 Cells , Humans , Macrophages/immunology , Macrophages/metabolism , Membrane Glycoproteins/blood , Membrane Glycoproteins/genetics , Protein Binding , Receptors, Complement/blood , Receptors, Complement/genetics , Recombinant ProteinsABSTRACT
Objectives: The aim was to describe the clinical characteristics and epidemiology of hypocomplementaemic urticarial vasculitis (HUV; anti-C1q vasculitis) in two geographically defined areas of Sweden. Methods: In the health-care districts surrounding Skåne University Hospital (mean population 950 560) and Linköping University Hospital (mean population 428 503), all incident cases of HUV residing within the study areas at the onset of disease were identified during the years 2000-15. The diagnosis of HUV was confirmed by review of medical records. Only patients meeting the proposed diagnostic HUV criteria and/or the 2012 Chapel Hill consensus definitions in combination with an ever-positive anti-C1q antibody test were included. Results: Sixteen patients (14 females) were identified during the study period. The median (interquartile range) age at diagnosis was 51 (40.7-56.7) years. Median (interquartile range) time of follow-up from diagnosis to 31 December 2015, or death, was 94 (46.5-136.2) months. The most frequent manifestations at diagnosis were urticaria (100%), arthritis (88%), followed by biopsy-proven glomerulonephritis (19%), episcleritis/scleritis (19%) and recurrent abdominal pain (13%). The annual incidence rate per million inhabitants was estimated as 0.7 (95% CI: 0.4, 1.1). Sixty-three per cent suffered from pulmonary disease at the last follow-up. Two patients died during the follow-up period. One patient underwent lung transplantation, and two patients proceeded to end-stage renal disease. The point prevalence on 31 December 2015 was 9.5/million (95% CI: 4.5, 14.5). Conclusion: Hypocomplementaemic urticarial vasculitis constitutes a rare, but not always benign condition. Renal and lung manifestations were severe in some cases, highlighting the need for careful screening and monitoring of this potentially serious condition.
Subject(s)
Membrane Glycoproteins/deficiency , Population Surveillance , Receptors, Complement/deficiency , Urticaria/epidemiology , Vasculitis/epidemiology , Adult , Aged , Female , Follow-Up Studies , Humans , Incidence , Male , Membrane Glycoproteins/blood , Middle Aged , Receptors, Complement/blood , Retrospective Studies , Sweden/epidemiology , Urticaria/blood , Urticaria/complications , Vasculitis/blood , Vasculitis/etiologyABSTRACT
BACKGROUND: Platelets have distinct roles in the vascular system in that they are the major mediator of thrombosis, critical for restoration of tissue integrity, and players in vascular inflammatory conditions. In close spatiotemporal proximity, the complement system acts as the first line of defense against invading microorganisms and is a key mediator of inflammation. Whereas the fluid phase cross-talk between the complement and coagulation systems is well appreciated, the understanding of the pathophysiological implications of such interactions is still scant. METHODS: We analyzed coexpression of the anaphylatoxin receptor C3aR with activated glycoprotein IIb/IIIa on platelets of 501 patients with coronary artery disease using flow cytometry; detected C3aR expression in human or murine specimen by polymerase chain reaction, immunofluorescence, Western blotting, or flow cytometry; and examined the importance of platelet C3aR by various in vitro platelet function tests, in vivo bleeding time, and intravital microscopy. The pathophysiological relevance of C3aR was scrutinized with the use of disease models of myocardial infarction and stroke. To approach underlying molecular mechanisms, we identified the platelet small GTPase Rap1b using nanoscale liquid chromatography coupled to tandem mass spectrometry. RESULTS: We found a strong positive correlation of platelet complement C3aR expression with activated glycoprotein IIb/IIIa in patients with coronary artery disease and coexpression of C3aR with glycoprotein IIb/IIIa in thrombi obtained from patients with myocardial infarction. Our results demonstrate that the C3a/C3aR axis on platelets regulates distinct steps of thrombus formation such as platelet adhesion, spreading, and Ca2+ influx. Using C3aR-/- mice or C3-/- mice with reinjection of C3a, we uncovered that the complement activation fragment C3a regulates bleeding time after tail injury and thrombosis. Notably, C3aR-/- mice were less prone to experimental stroke and myocardial infarction. Furthermore, reconstitution of C3aR-/- mice with C3aR+/+ platelets and platelet depletion experiments demonstrated that the observed effects on thrombosis, myocardial infarction, and stroke were specifically caused by platelet C3aR. Mechanistically, C3aR-mediated signaling regulates the activation of Rap1b and thereby bleeding arrest after injury and in vivo thrombus formation. CONCLUSIONS: Overall, our findings uncover a novel function of the anaphylatoxin C3a for platelet function and thrombus formation, highlighting a detrimental role of imbalanced complement activation in cardiovascular diseases.
Subject(s)
Blood Coagulation , Blood Platelets/metabolism , Immunity, Innate , Myocardial Infarction/blood , Receptors, Complement/blood , Stroke/blood , Thrombosis/blood , Animals , Blood Platelets/immunology , Calcium Signaling , Complement Activation , Complement C3/genetics , Complement C3/immunology , Complement C3/metabolism , Disease Models, Animal , Humans , Mice, Inbred C57BL , Mice, Knockout , Myocardial Infarction/immunology , Platelet Activation , Platelet Glycoprotein GPIIb-IIIa Complex/metabolism , Platelet Glycoprotein GPIb-IX Complex/genetics , Platelet Glycoprotein GPIb-IX Complex/metabolism , Receptors, Complement/deficiency , Receptors, Complement/genetics , Receptors, Complement/immunology , Stroke/immunology , Thrombosis/immunologyABSTRACT
BACKGROUND: CD93 is a membrane-associated glycoprotein, which can be released in a soluble form (sCD93) into the serum. CD93 has received renewed attention as a candidate biomarker of inflammation in various inflammatory and immune-mediated diseases, including asthma. OBJECTIVE: We aimed to evaluate the effects of airway inflammation on CD93 levels in murine models. METHODS: We established an ovalbumin (OVA)-induced acute asthma murine model (OVA model) and a lipopolysaccharide (LPS)-induced airway inflammation murine model (LPS model). Dexamethasone was administered by gavage to attenuate the airway inflammation. RESULTS: The OVA model demonstrated typical allergic asthma features with increased airway hyper-responsiveness, inflammatory cell infiltration, increased Th2 cytokine levels, compared to the control group. CD93 levels were decreased in lung homogenates and, respiratory epithelial cells, whereas serum sCD93 levels were increased in the OVA model, as compared to the control group. Dexamethasone reversed these effects of OVA. In contrast, in the LPS model, CD93 levels were not affected in neither respiratory epithelial cells nor serum. CONCLUSIONS: Our findings demonstrate the potential of using sCD93 as a biomarker for allergic asthma.
Subject(s)
Asthma/diagnosis , Membrane Glycoproteins/blood , Receptors, Complement/blood , Animals , Asthma/blood , Asthma/chemically induced , Asthma/pathology , Biomarkers/blood , Inflammation/blood , Mice , Ovalbumin/adverse effectsABSTRACT
Iron oxide nanoparticles (IONPs) are promising nanomaterials for biomedical applications. However, their inflammatory potential has not been fully established. Here, we used a lepirudin anti-coagulated human whole blood model to evaluate the potential of 10 nm IONPs to activate the complement system and induce cytokine production. Reactive oxygen species and cell death were also assessed. The IONPs activated complement, as measured by C3a, C5a and sC5b-9, and induced the production of pro-inflammatory cytokines in a particle-dose dependent manner, with the strongest response at 10 µg/mL IONPs. Complement inhibitors at C3 (compstatin analog Cp40) and C5 (eculizumab) levels completely inhibited complement activation and secretion of inflammatory mediators induced by the IONPs. Additionally, blockade of complement receptors C3aR and C5aR1 significantly reduced the levels of various cytokines, indicating that the particle-induced secretion of inflammatory mediators is mainly C5a and C3a mediated. The IONPs did not induce cell death or reactive oxygen species, which further suggests that complement activation alone was responsible for most of the particle-induced cytokines. These data suggest that the lepirudin anti-coagulated human whole blood model is a valuable ex vivo system to study the inflammatory potential of IONPs. We conclude that IONPs induce complement-mediated cytokine secretion in human whole blood.
Subject(s)
Complement Activation , Cytokines/blood , Ferric Compounds/chemistry , Metal Nanoparticles/chemistry , Anti-Inflammatory Agents/pharmacology , Anticoagulants/pharmacology , Cell Survival , Complement C3a/metabolism , Complement C5a/metabolism , Complement C5b/metabolism , Complement Inactivating Agents/pharmacology , Hirudins/pharmacology , Humans , Particle Size , Reactive Oxygen Species/blood , Receptors, Complement/blood , Recombinant Proteins/pharmacologyABSTRACT
BACKGROUND AND AIMS: Atherogenesis is dependent upon monocyte influx into the vessel wall. In humans, three monocyte subsets exist, the number and function of which are significantly altered in cardiovascular disease (CVD). Whether such alterations arise in individuals with a perturbed lipid profile remains largely unanswered, but is important to delineate, as adoption of a pro-inflammatory state may promote plaque formation. Here, we compared the inflammatory status of monocyte subsets and determined whether monocyte inflammatory changes are evident in individuals with a perturbed lipid profile. METHODS: Monocyte subset cytokine production, inflammatory and anti-inflammatory marker expression were determined by whole blood flow cytometry and related to participants' lipid levels. RESULTS: The intermediate and non-classical monocytes were more inflammatory than classicals as seen by their higher cytokine production (TNF-α, IL-1ß, IL-6) and M1 marker (CD86) expression, but lower levels of M2 markers (CD93, CD163). More importantly, a considerable variation was seen between participants, with all monocytes of one individual being more inflammatory than those of another. Many inter-individual differences were related to participants' lipid levels. IL-1ß production correlated negatively with Apo A1 and HDL-C. CD86 and TLR2 correlated positively with Chol:HDL-C but negatively with HDL-C and Apo A1:Apo B. Interestingly, CD163 expression correlated positively with Chol:HDL-C but negatively with Apo A1:Apo B. CONCLUSIONS: Our data indicates that priming of all monocytes to an inflammatory state occurs in individuals with a perturbed lipid profile, overriding the normal functional distinction attributed to the different monocyte subsets. As such, all monocytes may be important in CVD.
Subject(s)
Cholesterol, HDL/blood , Inflammation/blood , Lipids/blood , Monocytes/cytology , Adult , Aged , Antigens, CD/blood , Antigens, Differentiation, Myelomonocytic/blood , Apolipoprotein A-I/blood , Apolipoprotein B-100/blood , Atherosclerosis/metabolism , B7-2 Antigen/blood , C-Reactive Protein/metabolism , Cardiovascular Diseases/blood , Cardiovascular Diseases/immunology , Chronic Disease , Female , Flow Cytometry , Humans , Interleukin-1beta/blood , Interleukin-6/blood , Macrophages/metabolism , Male , Membrane Glycoproteins/blood , Middle Aged , Receptors, Cell Surface/blood , Receptors, Complement/blood , Toll-Like Receptor 2/blood , Tumor Necrosis Factor-alpha/bloodABSTRACT
OBJECTIVES: The protein V-set and Ig domain-containing 4 (VSIG4), a novel B7 family-related macrophage protein with the capacity to inhibit T-cell activation, has a potential role in cancer. Here we suggest its possibility as a therapeutic target and prognostic biomarker of ovarian cancer. METHODS: Between January 2011 and June 2015, tumor tissues and peripheral blood samples were obtained during surgery from 10 patients with benign ovarian tumors and 22 patients with ovarian cancers. Messenger RNA and protein expression levels of VSIG4 in benign tumor and cancer tissues were examined by the reverse transcription polymerase chain reaction and Western blot, respectively. Soluble VSIG4 concentrations were measured by an enzyme-linked immunosorbent assay. The correlation between VSIG4 expression and the prognosis of ovarian cancer was analyzed according to the patients' clinicopathologic characteristics. RESULTS: VSIG4 messenger RNA and protein expression levels in ovarian cancer tissues were higher than those in benign ovarian tumors (P = 0.0013 and 0.0001, respectively). Soluble VSIG4 concentrations were increased in patients with ovarian cancer compared with that in patients with benign ovarian tumors (P = 0.0452). Moreover, soluble VSIG4 levels were significantly increased in advanced-stage and recurrent ovarian cancer (P = 0.0244 and 0.0288, respectively). High VSIG4 expression of cancer tissue and low VSIG4 expression of plasma (soluble VSIG4) were associated with a longer disease-free interval (P = 0.0246 and 0.0398, respectively). CONCLUSIONS: VSIG4 is overexpressed in ovarian cancers compared with that in benign tumors. This finding supports VSIG4 being used as a potential therapeutic target for ovarian cancer. Furthermore, soluble VSIG4 levels are associated with the progression and recurrence of ovarian cancer, indicating that soluble VSIG4 may be used as a potential biomarker for predicting tumor prognosis.
Subject(s)
Neoplasms, Glandular and Epithelial/metabolism , Ovarian Neoplasms/metabolism , Receptors, Complement/biosynthesis , Biomarkers, Tumor/biosynthesis , Biomarkers, Tumor/blood , Carcinoma, Ovarian Epithelial , Female , Humans , Middle Aged , Neoplasms, Glandular and Epithelial/blood , Neoplasms, Glandular and Epithelial/pathology , Ovarian Diseases/blood , Ovarian Diseases/metabolism , Ovarian Diseases/pathology , Ovarian Neoplasms/blood , Ovarian Neoplasms/pathology , Prognosis , Receptors, Complement/bloodABSTRACT
PURPOSE: CD93 is receiving renewed attention as a biomarker of inflammation. We aimed to evaluate the potential for serum sCD93 to serve as a novel biomarker for allergic inflammation. MATERIALS AND METHODS: We enrolled 348 subjects with an allergic disease [allergic rhinitis (AR), chronic spontaneous urticaria (CSU), or bronchial asthma (BA)], including 14 steroid-naïve BA patients who were serially followed-up. RESULTS: The serum sCD93 levels (ng/mL) in patients with exacerbated AR (mean±standard deviation, 153.1±58.4) were significantly higher than in patients without AR (132.2±49.0) or with stable AR (122.3±42.1). Serum sCD93 levels in exacerbated CSU (169.5±42.8) were also significantly higher than those in non-CSU (132.4±51.6) and stable CSU (122.8±36.2). This trend was also seen in BA. Serum levels in patients with ICS-naïve BA (161.4±53.1) were significantly higher than those in healthy controls without BA (112.2±30.8), low- and medium-dose ICS users. Serum sCD93 levels in high-dose ICS users (72.2±20.6) were significantly lower than those in low- and medium-dose users. The serum sCD93 levels in steroid-naïve patients with BA (195.1±72.7) decreased after ICS use for 4 weeks (134.4±42.8) and 8 weeks (100.7±13.4), serially. CONCLUSION: Elevated serum sCD93 levels reflected exacerbated status of allergic diseases, including CSU, AR, and asthma. ICS use significantly diminished serum sCD93 levels in steroid-naïve patients with BA. This result may suggest sCD93 in serum as a therapeutic marker for allergic inflammation.
Subject(s)
Asthma/blood , Membrane Glycoproteins/blood , Receptors, Complement/blood , Rhinitis, Allergic/blood , Urticaria/blood , Adult , Asthma/diagnosis , Asthma/immunology , Biomarkers/blood , Case-Control Studies , Chronic Disease , Cross-Sectional Studies , Female , Humans , Inflammation/blood , Inflammation/diagnosis , Membrane Glycoproteins/metabolism , Middle Aged , Receptors, Complement/metabolism , Rhinitis, Allergic/immunology , Urticaria/diagnosis , Urticaria/immunology , Young AdultABSTRACT
Remarkable progress has been made in recent years on the research of body fluid identification through messenger RNA(mRNA) profiling. In order to examine the viability of mRNA profiling as a method to identify aged bloodstains, this study tested two groups of bloodstain samples, dated 30 years and 50 years back respectively, on seven blood specific markers, i.e. HBB, HBA, GYPA, CD93, ALAS2, SPTB (91bp and 247bp primers), and PBGD. Test results indicate that HBA and HBB are the most stable markers in aged bloodstains, returning positive results in over 80% of the 50-year-old samples and over 90% of the 30-year-old samples. This finding proves mRNA profiling an effective way of identifying aged bloodstains.
Subject(s)
Blood Stains , DNA Fingerprinting/methods , RNA, Messenger/blood , 5-Aminolevulinate Synthetase/blood , Biomarkers/blood , DNA/isolation & purification , Glycophorins/blood , Hemoglobins/analysis , Humans , Hydroxymethylbilane Synthase/blood , Membrane Glycoproteins/blood , Polymerase Chain Reaction , RNA, Messenger/genetics , Receptors, Complement/blood , Spectrin/blood , Time Factors , beta 2-Microglobulin/bloodABSTRACT
Plasma biomarkers to aid the early diagnosis of Alzheimer's disease (AD) or to monitor disease progression have long been sought and continue to be widely studied. Biomarkers that correlate with AD polygenic risk score, a measure of the polygenic architecture of the disease and highly predictive of AD status, would be excellent candidates. Therefore, we undertook a preliminary study to assess the association of plasma inflammatory biomarkers with an overall AD polygenic risk score as well as with an inflammation-specific AD polygenic risk score in a sample set of 93 AD cases. We measured five complement biomarkers [complement receptor 1 (CR1), clusterin, complement component 9 (C9), C1 inhibitor (C1inh), terminal complement complex (TCC)] and the benchmark inflammatory marker C-reactive protein (CRP). Plasma clusterin level showed an association with overall AD polygenic risk score, while clusterin, C1inh, and CRP levels each displayed some association with the inflammatory-specific AD polygenic risk score. The results suggest that elevated plasma levels of inflammatory biomarkers, including complement proteins, associate with polygenic risk scores in AD, further strengthening the link between genetic and biomarker disease predictors and indicating a potential role for these markers in disease prediction and patient stratification in AD.
Subject(s)
Alzheimer Disease/blood , Alzheimer Disease/complications , Biomarkers/blood , Cytokines/blood , Inflammation/etiology , Alzheimer Disease/genetics , C-Reactive Protein/metabolism , Clusterin/blood , Complement C1 Inhibitor Protein/metabolism , Disease Progression , Female , Humans , Inflammation/blood , Male , Multifactorial Inheritance/genetics , Neuropsychological Tests , Receptors, Complement/blood , Risk Factors , Statistics as Topic , Statistics, NonparametricABSTRACT
Both the invasion of red blood cells (RBCs) by Plasmodium falciparum parasites and the sequestration of parasite-infected RBCs in the microvasculature are mediated in part by complement receptor one (CR1). RBC surface CR1 level can vary between individuals by more than 20-fold and may be associated with the risk of severe malaria. The factors that influence RBC CR1 level variation are poorly understood, particularly in African populations. We studied 3535 child residents of a malaria-endemic region of coastal Kenya and report, for the first time, that the CR1 Knops blood group alleles Sl2 and McC(b), and homozygous HbSS are positively associated with RBC CR1 level. Sickle cell trait and ABO blood group did not influence RBC CR1 level. We also confirm the previous observation that α(+)thalassaemia is associated with reduced RBC CR1 level, possibly due to small RBC volume, and that age-related changes in RBC CR1 expression occur throughout childhood. RBC CR1 level in malaria-endemic African populations is a complex phenotype influenced by multiple factors that should be taken into account in the design and interpretation of future studies on CR1 and malaria susceptibility.
Subject(s)
Erythrocytes/immunology , Receptors, Complement/blood , Blood Group Antigens/genetics , Child , Humans , Kenya , Malaria, Falciparum/genetics , Plasmodium falciparum/immunology , Thalassemia/metabolismABSTRACT
BACKGROUND: This study measured the serum levels of complement component (C)3a and C5a and the placental expressions of C3a receptor (R) and C5aR to determine a potential correlation with circulating angiotensin II type 1 (AT1) receptor agonistic autoantibody (AT1-AA) in severe pre-eclampsia. METHODS: A total of 118 women were recruited and divided into 2 groups: the control group (normotensive preterm pregnancies, n = 66) and severe pre-eclampsia group (n = 52). Levels of C3a, C5a and AT1-AA in serum were measured by enzyme-linked immunosorbent assay and C3aR and C5aR in placenta by Western blotting. RESULTS: Levels of C3a, C5a and AT1-AA in serum from the severe pre-eclampsia group were significantly higher than in controls (p < 0.05). Placental expression of C3aR and C5aR in the pre-eclampsia group was lower than that in controls (p < 0.05). There were significant positive correlations between levels of C3a, C5a and AT1-AA in serum from the pre-eclampsia group (p < 0.05). In contrast, there was no correlation between C3aR and C5aR in the placenta and AT1-AA in serum in the pre-eclampsia group (p > 0.05). CONCLUSION: Increased C3a, C5a and AT1-AA in the serum provide indirect evidence that AT1-AA-mediated activation contributes to activate complement, which is a key mechanism underlying the pathogenesis of severe pre-eclampsia.
Subject(s)
Autoantibodies/blood , Placenta/metabolism , Pre-Eclampsia/immunology , Pre-Eclampsia/metabolism , Receptor, Anaphylatoxin C5a/metabolism , Receptor, Angiotensin, Type 1/immunology , Receptors, Complement/metabolism , Adult , Case-Control Studies , Female , Humans , Pre-Eclampsia/blood , Pregnancy , Receptor, Anaphylatoxin C5a/blood , Receptors, Complement/bloodABSTRACT
OBJECTIVE: Fever in systemic lupus erythematosus (SLE) can be caused by infection or flare-up of the disease. This study aimed to determine whether the ratio of the level of erythrocyte-bound C4d to that of complement receptor 1 (C4d/CR1) can serve as a useful biomarker in the differentiation between infection and flare-up in febrile SLE patients. METHODS: We enrolled febrile SLE patients and determined the ratio on the day of admission. The patients were divided into 2 groups according to the subsequent clinical course. RESULTS: Among the febrile SLE patients, those with flare-up had higher ratios and lower C-reactive protein (CRP) levels than those with infection. Cut-off values of <1.2447 and >4.67 for C4d/CR1 ratio and CRP, respectively, were 40.91% sensitive and 100.0% specific for the presence of infection in febrile SLE patients; similarly, cut-off values of >1.2447 and <2.2, respectively, were 80% sensitive and 100% specific for the absence of infection in febrile SLE patients. CONCLUSION: The C4d/CR1 ratio is a simple and quickly determinable biomarker that enables the differentiation between infection and flare-up in febrile SLE patients at initial evaluation. Further, when combined with the CRP level, it is useful to evaluate disease activity in SLE patients with infection.