C1q is the initiator of the classical complement pathway and opsonizes apoptotic cells to facilitate phagocytosis. Deficiency of C1q is the strongest known risk factor for development of systemic ...lupus erythematosus (SLE), which appears to be related to ensuing impaired clearance of apoptotic material. The objective of the current study was to investigate new ligands for C1q on the surface of apoptotic cells. We revealed that the two phospholipid-binding proteins annexin A2 and A5 are, beside DNA, significant C1q ligands. We furthermore, demonstrated that C1q binds directly to histones exposed on the surface of dying cells but we did not detect significant interaction with phosphatidylserine. The complement inhibitors C4b-binding protein and factor H also interact with dying cells, most likely to decrease complement activation beyond the level of C3 to allow noninflammatory clearance. Despite the fact that C4b-binding protein, factor H, and C1q share some ligands on dying cells, we showed that these three proteins did not compete with one another for binding to apoptotic cells. We additionally demonstrated that the way in which apoptosis is induced influenced both the degree of apoptosis and the binding of C1q. The knowledge, that annexin A2 and A5 act as ligands for C1q on apoptotic cells, sheds new light on the pathophysiology of autoimmune diseases.
Background: C1q opsonizes apoptotic cells to facilitate clearance.
Results: Annexin A2 and A5 as well as DNA and histones serve as ligands for C1q on apoptotic cells.
Conclusion: Disturbances in the interaction between C1q and these ligands might exacerbate autoimmune diseases.
Significance: The knowledge of new C1q ligands helps to further the understanding of autoimmune diseases.
COVID‐19 disease is the manifestation of syndrome coronavirus 2 (SARS‐CoV‐2) infection, which is causing a worldwide pandemic. This disease can lead to multiple and different symptoms, being ...lymphopenia associated with severity one of the most persistent. Natural killer cells (NK cells) are part of the innate immune system, being fighting against virus‐infected cells one of their key roles. In this study, we determined the phenotype of NK cells after COVID‐19 and the main characteristic of SARS‐CoV‐2‐specific‐like NK population in the blood of convalescent donors. CD57+ NKG2C+ phenotype in SARS‐CoV‐2 convalescent donors indicates the presence of ‘memory’/activated NK cells as it has been shown for cytomegalovirus infections. Although the existence of this population is donor dependent, its expression may be crucial for the specific response against SARS‐CoV‐2, so that, it gives us a tool for selecting the best donors to produce off‐the‐shelf living drug for cell therapy to treat COVID‐19 patients under the RELEASE clinical trial (NCT04578210).
SARS‐CoV‐2 infection induce a pro‐inflammatory environment that could lead to NK cells secreting IFN‐γ, increasing HLA‐E expression and being activated through NKG2C‐HLA‐E recognition. The NK cells become adaptive or “memory” cells that can recognize SARS‐CoV‐2 soluble peptides via NKG2C, triggering a specific inflammatory response to fight this virus.
This study tested an actor-partner interdependence mediation model (APIMeM) in which dyadic relational maintenance behaviors (RMBs) mediate the relationship between romantic attachment (i.e., anxious ...and avoidant) and multiple indicators of relationship quality among couples in long-distance relationships (LDRs). Data were collected from 137 couples (women’s mean age = 20.37 years; men’s mean age = 21.93) who were in a serious romantic LDR and who completed an attachment measure, a measure of dyadic RMBs, and four measures of relationship quality (i.e., relationship satisfaction, relational commitment, closeness with the partner, and connection with others). Path analyses revealed significant actor and partner effects. Moreover, a total mediation between women’s anxious attachment and both partners’ relationship quality, and a partial mediation between men’s and women’s avoidant attachment and their own relationship quality were uncovered. Overall, the results suggest that, for couples in LDRs, one partner’s behaviors, cognitions, or emotions influence each member of the dyad as well as the quality of the relationship.
Flow cytometric platelet activation has emerged as an alternative diagnostic test for inherited platelet disorders. It is, however, labor intensive and few studies have directly compared the ...performance of flow cytometric platelet activation (PACT) to light transmission aggregometry (LTA). The aims of this study were 1/ to develop a simplified flow cytometric platelet activation assay using microtiter plates and 2/ to correlate the outcome to gold standard method LTA, and to clinical bleeding assessment tool scores (BAT score).
The PACT method was developed in microtiter plates using adenosine diphosphate (ADP), collagen-derived peptide (CRP-XL) and thrombin receptor activator for peptide 6 (TRAP-6) as agonists. Antibodies against GPIIb-IIIa activation epitope (PAC1), P-selectin (CD62P) and lysosome-associated membrane glycoprotein 3 (LAMP3; CD63) were used as platelet activation markers. Sixty-six patients referred to the coagulation unit for bleeding symptoms were included in this single-center observational study. Platelet activation was determined by PACT and LTA. The results of both methods were correlated to BAT score.
A two-by-two analysis using Cohen's kappa analysis gave moderate agreement between LTA and PACT (82%, kappa = 0.57), when PACT analysis with ADP and CRP-XL was compared to LTA. Using LTA as reference method, positive predictive value was 70% and negative predictive value was 87%. A substantial number of patients had high BAT score and normal LTA and PACT results. Patients with abnormal LTA or PACT results had higher BAT score than patients with normal results, but the difference was not significant.
The performance in microtiter plates simplified the PACT method and enabled analysis of more patients at the same time. Our results indicate that with modification of the current PACT assay, a higher negative predictive value can be obtained. Furthermore, with comparable result to LTA the PACT could be used as a screening assay for inherited platelet disorders.
Aberrant expression of miR-96 in prostate cancer has previously been reported. However, the role and mechanism of action of miR-96 in prostate cancer has not been determined. In this study, the ...diagnostic and prognostic properties of miR-96 expression levels were investigated by qRT-PCR in two well documented prostate cancer cohorts. The miR-96 expression was found to be significantly higher in prostate cancer patients and correlate with WHO grade, and decreased overall survival time; patients with low levels of miR-96 lived 1.5 years longer than patients with high miR-96 levels. The therapeutic potential was further investigated in vitro, showing that ectopic levels of miR-96 enhances growth and cellular proliferation in prostate cancer cells, implying that miR-96 has oncogenic properties in this setting. We demonstrate that miR-96 expression decreases the transcript and protein levels of FOXO1 by binding to one of two predicted binding sites in the FOXO1 3'UTR sequence. Blocking this binding site completely inhibited the growth enhancement conveyed by miR-96. This finding was corroborated in a large external prostate cancer patient cohort where miR-96 expression inversely correlated to FOXO1 expression. Taken together these findings indicate that miR-96 plays a key role in prostate cancer cellular proliferation and can enhance prostate cancer progression. This knowledge might be utilized for the development of novel therapeutic tools for prostate cancer.
Increased platelet destruction is central in the pathogenesis of immune thrombocytopenia. However, impaired platelet production is also relevant and its significance underlies the rationale for ...treatment with thrombopoietin receptor agonists (TPO-RAs). Previous studies have associated enhanced complement activation with increased disease severity. Additionally, treatment refractoriness has been demonstrated to resolve by the administration of complement-targeted therapeutics in a subset of patients. The association between complement activation and the platelet response to TPO-RA therapy has previously not been investigated. In this study, blood samples from patients with immune thrombocytopenia (n = 15) were prospectively collected before and two, six and 12 weeks after the initiation of TPO-RA therapy. Plasma levels of complement degradation product C4d and soluble terminal complement complexes were assessed. Patients with significantly elevated baseline levels of terminal complement complexes exhibited more often an inadequate platelet response (p = .04), were exclusively subjected to rescue therapy with intravenous immunoglobulin (p = .02), and did not respond with a significant platelet count increase during the study period. C4d showed a significant (p = .01) ability to distinguish samples with significant terminal complement activation, implying engagement of the classical complement pathway. In conclusion, elevated levels of complement biomarkers were associated with a worse TPO-RA treatment response. Larger studies are needed to confirm these results. Biomarkers of complement activation may prove valuable as a prognostic tool to predict which patients that potentially could benefit from complement-inhibiting therapy in the future.
What is the context?
What is new?
The potential association between complement activation and a poor platelet response to TPO-RA therapy in primary ITP has not been previously studied.
In fifteen patients with primary ITP starting TPO-RA therapy, we prospectively followed the platelet response and levels of complement biomarkers for 12 weeks.
We showed that patients with high levels of complement biomarkers exhibited a worse treatment response during the study period.
What is the impact?
Abstract
Rheumatoid arthritis (RA) involves several classes of pathogenic autoantibodies, some of which react with type-II collagen (COL2) in articular cartilage. We previously described a subset of ...COL2 antibodies targeting the F4 epitope (ERGLKGHRGFT) that could be regulatory. Here, using phage display, we developed recombinant antibodies against this epitope and examined the underlying mechanism of action. One of these antibodies, R69-4, protected against cartilage antibody- and collagen-induced arthritis in mice, but not autoimmune disease models independent of arthritogenic autoantibodies. R69-4 was further shown to cross-react with a large range of proteins within the inflamed synovial fluid, such as the complement protein C1q. Complexed R69-4 inhibited neutrophil FCGR3 signaling, thereby impairing downstream IL-1β secretion and neutrophil self-orchestrated recruitment. Likewise, human isotypes of R69-4 protected against arthritis with comparable efficiency. We conclude that R69-4 abrogates autoantibody-mediated arthritis mainly by hindering FCGR3 signaling, highlighting its potential clinical utility in acute RA.
In the present study, we sought to evaluate the complement activation product C4d as a marker for lupus nephritis in systemic lupus erythematosus (SLE).
C4d levels were determined by enzyme-linked ...immunosorbent assay in plasma samples of patients with established SLE using a novel approach based on detection of a short linear cleavage neoepitope. Cross-sectional associations were studied in 98 patients with SLE with samples taken at lower or higher respective disease activity. Temporal associations were investigated in 69 patients with SLE who were followed longitudinally for up to 5 years. Plasma samples from 77 healthy donors were included as controls.
C4d levels were negligible in healthy control subjects and significantly increased in patients with SLE in the cross-sectional study (p < 0.0001). C4d levels discriminated between higher and lower disease activity according to ROC curve analysis (p < 0.001), exhibiting a positive predictive value of 68%. At higher disease activity, C4d levels correlated with the modified Systemic Lupus Erythematosus Disease Activity Index (p = 0.011) and predominantly with lupus nephritis (p = 0.003), exhibiting a sensitivity of 79% to identify patients with nephritis. High C4d levels together with the presence of anti-dsDNA autoantibodies preceded and thus predicted future lupus nephritis in the longitudinal study (OR 5.4, 95% CI 1.4-21.3). When we considered only patients with renal involvement (19 of 69) during the longitudinal study, we found that high C4d levels alone could forecast recurrence of future lupus nephritis (OR 3.3, 95% CI 1.2-9.6).
C4d appears to be a valuable marker for use in monitoring of patients with SLE, particularly for lupus nephritis. Importantly, C4d levels can predict impending flares of lupus nephritis and may thus be useful for informing treatment.
Virtual games in social science education Lopez, Jose M. Cuenca; Caceres, Myriam J. Martin
Computers and education,
11/2010, Letnik:
55, Številka:
3
Journal Article
Recenzirano
Odprti dostop
The new technologies make the appearance of highly motivating and dynamic games with different levels of interaction possible, in which large amounts of data, information, procedures and values are ...included which are intimately bound with the social sciences.
We set out from the hypothesis that videogames may become interesting resources for their inclusion in the education processes in formal contexts. Videogames become laboratories for social experimentation where the scenarios, conditions and situations affecting a given human phenomenon are reproduced.
In this article, 35 videogames are analysed to find out which contents can be approached through them for the teaching of Social Sciences using problem-solving strategies. To this end, instruments for information gathering (data collection grid) and analysis (category system) were designed. The different contents of a social nature are analysed according to the study categories and in turn from the areas of social issues detected in them.
We present a working proposal for the use of videogames in the classroom on the basis of resolution of relevant problems, determining which are the issues that we consider relevant, what questions the pupils can be asked to approach through videogames and what the characteristics, benefits and obstacles are in the use of these resources in the teaching of Social Sciences.
To examine whether C4d plasma levels correlate with treatment response and C4d kidney deposition in systemic lupus erythematosus (SLE) with lupus nephritis (LN).
C4d plasma levels were analyzed by a ...unique assay specifically detecting C4d arising from complement activation and C4 plasma levels were quantified with competitive ELISA. SLE patients with LN (71) and active SLE patients without LN (22) plus 145 controls were included. For 52 LN patients samples were available both at baseline and after immunosuppressive treatment. C4d kidney deposition was detected using immunohistochemistry in two matching kidney biopsies of 12 LN patients.
In comparison to population-based controls, plasma C4d levels were significantly increased in SLE patients (0.33 mg/L versus 0.94 mg/ml,
< 0.0001) with significantly higher levels in LN patients (1.02 mg/L) than in non-renal SLE patients (0.57 mg/L,
= 0.004). The C4d/C4 ratio was also significantly higher in LN (11.2) than in non-renal SLE patients (2.5,
= 0.0002). According to ROC curve analysis, C4d was found to be an accurate marker to discriminate LN from non-renal SLE patients (
= 0.004). The C4d/C4 ratio displayed even higher specificity, sensitivity and overall accuracy as marker for LN than C4d and C4 alone. At baseline, C4d levels correlated significantly with urine-albumin to creatinine ratio (
= 0.43,
= 0.011) and with renal activity index (
= 0.37,
= 0.002). Immunohistochemical staining showed glomerular deposits of C4d in kidney biopsies, which strikingly correlated with plasma C4d levels (
= 0.7,
= 0.0002). Plasma C4d declined significantly after treatment in patients that experienced favorable clinical and histopathological response (
< 0.0001), while levels remained mainly unchanged in non-responders.
Plasma C4d discriminates LN from active non-renal SLE, correlates with C4d kidney deposits and appears valuable in monitoring responsiveness to various treatments. The C4d/C4 ratio might be superior to C4d alone.
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