scholarly journals Systemic Inflammation and Complement Activation Parameters Predict Clinical Outcome of Severe SARS-CoV-2 Infections

Viruses ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2376
Author(s):  
Silke Huber ◽  
Mariam Massri ◽  
Marco Grasse ◽  
Verena Fleischer ◽  
Sára Kellnerová ◽  
...  
Keyword(s):  
Systemic Inflammation ◽  
Complement Activation ◽  
Activation Parameters ◽  
Kinetic Studies ◽  
Coagulation Cascade ◽  
Healthy Controls ◽  
Complement Components ◽  
X Ray ◽  
Chest X Ray ◽  
The Complement System

Overactivation of the complement system has been characterized in severe COVID-19 cases. Complement components are known to trigger NETosis via the coagulation cascade and have also been reported in human tracheobronchial epithelial cells. In this longitudinal study, we investigated systemic and local complement activation and NETosis in COVID-19 patients that underwent mechanical ventilation. Results confirmed significantly higher baseline levels of serum C5a (24.5 ± 39.0 ng/mL) and TCC (11.03 ± 8.52 µg/mL) in patients compared to healthy controls (p < 0.01 and p < 0.0001, respectively). Furthermore, systemic NETosis was significantly augmented in patients (5.87 (±3.71) × 106 neutrophils/mL) compared to healthy controls (0.82 (±0.74) × 106 neutrophils/mL) (p < 0.0001). In tracheal fluid, baseline TCC levels but not C5a and NETosis, were significantly higher in patients. Kinetic studies of systemic complement activation revealed markedly higher levels of TCC and CRP in nonsurvivors compared to survivors. In contrast, kinetic studies showed decreased local NETosis in tracheal fluid but comparable local complement activation in nonsurvivors compared to survivors. Systemic TCC and NETosis were significantly correlated with inflammation and coagulation markers. We propose that a ratio comprising systemic inflammation, complement activation, and chest X-ray score could be rendered as a predictive parameter of patient outcome in severe SARS-CoV-2 infections.

scholarly journals Dynamics of clinical, functional, and immune parameters in patients with myocardial infarction and early fluvastatin administration

2011 ◽  
Vol 10 (4) ◽  
pp. 52-58
Author(s):  
V. V. Belov ◽  
S. Yu. Bezdol’nova ◽  
I. I. Dolgushin
Keyword(s):  
Myocardial Infarction ◽  
Systemic Inflammation ◽  
Immunoglobulin A ◽  
Healthy Controls ◽  
C Reactive Protein ◽  
Complement Components ◽  
Reactive Protein ◽  
Immune Parameters ◽  
Factor Α ◽  
Necrosis Factor

Aim. To assess the interrelations in the dynamics of immune, clinical, and functional parameters among patients with myocardial infarction (MI) and early fluvastatin administration. Material and methods. The study included 129 men, aged from 42 to 67 years (mean age 57 years): 99 MI patients and 30 healthy controls. In all participants, clinical, biochemical, functional, and immune parameters were assessed, with comparisons between healthy individuals vs. MI patients, as well as between MI patients taking fluvastatin (80 mg/d) vs. MI patients not receiving this medication. Results. In men with MI, chronic systemic inflammation was manifested in elevated levels of C-reactive protein, interleukin (IL) 1β, IL8, tumor necrosis factor α, immunoglobulin A and G, and complement components, as well as in decreased levels of IL1 receptor antagonist, CD 3, CD 4, CD 16, and CD 4/CD 8, compared to healthy controls. Early fluvastatin administration (first post-MI hours) was associated with reduced severity of immune disturbances and systemic inflammation. Conclusion. In MI patients, early fluvastatin administration is associated with a significant reduction in systolic and diastolic blood pressure levels, compared to controls, as well as with a substantial increase in exercise capacity at 2 months.

Solution structures of complement components by X-ray and neutron scattering and analytical ultracentrifugation

2002 ◽  
Vol 30 (6) ◽  
pp. 996-1001 ◽  
Author(s):  
S. J. Perkins ◽  
H. E. Gilbert ◽  
M. Aslam ◽  
J. Hannan ◽  
V. M. Holers ◽  
...  
Keyword(s):  
Neutron Scattering ◽  
Complement System ◽  
Analytical Ultracentrifugation ◽  
Factor H ◽  
Protein Domain ◽  
Complement Receptor ◽  
Complement Components ◽  
X Ray ◽  
Solution Studies ◽  
The Complement System

The short consensus/complement repeat (SCR) domain (also known as the complement control protein domain) is the most abundant domain type in the complement system. Crystal and NMR structures for proteins that contain single and multiple SCR domains have now been published. These contain inter-SCR linkers of between three and eight residues, and the structures show much variability in inter-SCR orientations. X-ray and neutron scattering, combined with analytical ultracentrifugation and constrained modelling based on known subunit structures will yield a medium-resolution structure for the protein of interest. The fewer parameters that are associated with the structure of interest, the more defined the structure of interest becomes. These solution studies have been applied to several SCR-containing proteins in the complement system, most notably Factor H with 20 SCR domains, a complement receptor type 2 fragment with two SCR domains, and rat complement receptor-related protein (Crry) which contains five SCR domains. The results show great conformational variability in the inter-SCR orientation, and these will be reviewed. Even though the rotational orientation cannot be modelled, it is nonetheless possible to measure the degree of extension of the multi-SCR proteins and, from this, to obtain functionally useful results.

scholarly journals Activation of the Complement System in Patients with Cancer Cachexia

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5767
Author(s):  
Min Deng ◽  
Rianne D. W. Vaes ◽  
Annemarie A. J. H. M. van Bijnen ◽  
Steven W. M. Olde Damink ◽  
Sander S. Rensen
Keyword(s):  
Systemic Inflammation ◽  
Complement System ◽  
Complement Activation ◽  
Cancer Cachexia ◽  
Strongly Correlated ◽  
Metabolic Inflammation ◽  
Classical Complement Pathway ◽  
Patients With Cancer ◽  
Reactive Protein ◽  
The Complement System

Systemic inflammation is thought to underlie many of the metabolic manifestations of cachexia in cancer patients. The complement system is an important component of innate immunity that has been shown to contribute to metabolic inflammation. We hypothesized that systemic inflammation in patients with cancer cachexia was associated with complement activation. Systemic C3a levels were higher in cachectic patients with inflammation (n = 23, C-reactive protein (CRP) ≥ 10 mg/L) as compared to patients without inflammation (n = 26, CRP < 10 mg/L) or without cachexia (n = 13) (medians 102.4 (IQR 89.4–158.0) vs. 81.4 (IQR 47.9–124.0) vs. 61.6 (IQR 46.8–86.8) ng/mL, respectively, p = 0.0186). Accordingly, terminal complement complex (TCC) concentrations gradually increased in these patient groups (medians 2298 (IQR 2022–3058) vs. 1939 (IQR 1725–2311) vs. 1805 (IQR 1552–2569) mAU/mL, respectively, p = 0.0511). C3a and TCC concentrations were strongly correlated (rs = 0.468, p = 0.0005). Although concentrations of C1q and mannose-binding lectin did not differ between groups, C1q levels were correlated with both C3a and TCC concentrations (rs = 0.394, p = 0.0042 and rs = 0.300, p = 0.0188, respectively). In conclusion, systemic inflammation in patients with cancer cachexia is associated with the activation of key effector complement factors. The correlations between C1q and C3a/TCC suggest that the classical complement pathway could play a role in complement activation in patients with pancreatic cancer.

scholarly journals Immunological Basis of the Endometriosis: The Complement System as a Potential Therapeutic Target

2021 ◽  
Vol 11 ◽  
Author(s):  
Chiara Agostinis ◽  
Andrea Balduit ◽  
Alessandro Mangogna ◽  
Gabriella Zito ◽  
Federico Romano ◽  
...  
Keyword(s):  
Growth Factors ◽  
Complement System ◽  
Complement Activation ◽  
Uterine Cavity ◽  
Peritoneal Macrophages ◽  
Reproductive Age ◽  
Recurrent Bleeding ◽  
Complement Components ◽  
Uterine Anomalies ◽  
The Complement System

Endometriosis (EM) is a chronic disease characterized by the presence and proliferation of functional endometrial glands and stroma outside the uterine cavity. Ovaries and pelvic peritoneum are the most common locations for endometrial ectopic tissue, followed by deep infiltrating EM sites. The cyclic and recurrent bleeding, the progressive fibrosis and the peritoneal adhesions of ectopic endometrial glands, may cause different symptoms depending on the origin involved. EM is a frequent clinical condition affecting around 10% of women of mainly reproductive age, as well as in post-menopausal women and adolescents, especially with uterine anomalies. The risk of developing EM depends on a complex interaction between genetic, immunological, hormonal, and environmental factors. It is largely considered to arise due to a dysfunction of immunological surveillance. In fact, women with EM exhibit altered functions of peritoneal macrophages, lymphocytes and natural killer cells, as well as levels of inflammatory mediators and growth factors in the peritoneal fluid. In EM patients, peritoneal macrophages are preponderant and highly active compared to healthy women. Peritoneal macrophages are able to regulate the events that determine the production of cytokines, prostaglandins, growth factors and complement components. Several studies have shown alteration in the regulation of the complement activation, leading to chronic inflammation characteristic of EM. Aberrant regulation/activation of the complement system has been observed in the peritoneal cavity of women affected by EM. Thus, complement inhibition may represent a new approach for the treatment of EM, given that a number of complement inhibitors are under pre-clinical and clinical development. Such an intervention may provide a broader therapeutic control of complement-mediated inflammatory damage in EM patients. This review will focus on our current understanding of the role of complement activation in EM and possible modalities available for complement-based therapy.

Complement Activation in Transfusion Related Acute Lung Injury (TRALI).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 954-954
Author(s):  
Daniel R. Ambruso ◽  
Christopher C. Silliman ◽  
Marguerite Kelher ◽  
Gail Thurman ◽  
Patsy Giclas
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Complement Activation ◽  
Class Ii ◽  
Hla Class Ii ◽  
X Ray ◽  
Factor Xi Deficiency ◽  
Activation Products ◽  
Chest X Ray ◽  
Priming Activity

Abstract Background: TRALI is defined as acute lung injury occurring within six hours of a transfusion of blood products. Two major etiologies have been identified and include leukocyte antibodies activating complement. We report two patients with TRALI reactions who had documented activation of complement. Case Studies. Case 1: A 59 year old male with Factor XI deficiency and hematochezia was given 3 units of fresh frozen plasma (FFP). During infusion of the third unit, the patient developed dyspnea and cyanosis requiring ventilator support. A chest x-ray showed new diffuse infiltrates; CVP and an echocardiogram were normal. The symptoms resolved in 3 days. Case 2: An 87 year old female required surgical repair of a hip fracture. Four units were infused and with the last one, the patient developed chills, fever and tachypnea. On 6 l/min of O2, she had a saturation of 58%. Chest x-ray showed bilateral infiltrates; the echocardiogram was normal. The patient sustained a cardiac arrest and could not be resuscitated. Methods: Samples from donors or FFP units were screened for HLA and granulocyte antibodies. Priming of the fMLP stimulated neutrophil oxidase activity was performed by standard assay. Plasma from products implicated in TRALI and plasma samples from patients before and during the TRALI reaction were assayed for priming of the fMLP stimulated respiratory burst in neutrophils; C3a, C4a, C5a, C5–9, and Bb were measured by standard techniques. Results: In Case 1, HLA Class II, IgG reactivity by flow cytometry was documented with plasma from the implicated donor and recipient cells. Priming of neutrophils was detected in the implicated unit as well as the recipient’s plasma during the reaction in comparison to pre-transfusion specimen. Complement activation products were increased in samples during the reaction and the product being infused at the onset of TRALI. In the second case, HLA Class II antibodies with a specificity which would interact with the recipient’s antigens were detected in the product related to the TRALI reaction. Priming activity of the neutrophil oxidase was documented in the infused product and in post vs. pre reaction patient samples. Complement activation products were increased in the implicated FFP unit and C5a was increased in the patient’s post samples. Additional cases are being assessed for complement activation. Conclusions: In these cases of TRALI, the implicated products exhibited priming activity as well as antibodies which reacted with recipient antigens by flow crossmatch or by documentation of the cognate antigen. Complement activation was documented in patient samples during the reaction as opposed to those collected before the transfusion. Most importantly, complement was activated in the product transfused during the onset of TRALI symptoms. Thus, complement activation in the product is the most likely cause of the TRALI reaction. Infusion of products containing activated complement components may provide an alternative mechanism for TRALI reactions.

SAT0268 COMPLEMENT ACTIVATION VIA ALTERNATIVE PATHWAY IN ANCA-ASSOCIATED VASCULITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1077-1078
Author(s):  
A. Zykova ◽  
P. Novikov ◽  
N. Bulanov ◽  
A. Kronbichler ◽  
E. Gitel ◽  
...  
Keyword(s):  
Complement Activation ◽  
Alternative Pathway ◽  
Immunosuppressive Treatment ◽  
Control Group ◽  
Healthy Controls ◽  
Research Support ◽  
Complement Components ◽  
C5a Receptor ◽  
Factor B ◽  
Anca Associated Vasculitis

Background:There is increasing evidence that the complement system, in particular the alternative pathway, plays a crucial role in the pathogenesis of ANCA-associated vasculitis (AAV) [1]. Efficacy of C5a receptor antagonists indicates that chemoattraction mediated by C5a plays a key role in the inflammatory process observed in AAV [2]. Another promising research object are regulatory proteins such as factor B [3].Objectives:To study complement activation via the alternative pathway in patients with active ANCA-associated vasculitis.Methods:59 patients with newly diagnosed (n=35) or relapsing GPA or MPA (n=24) were enrolled in this prospective study. Median BVAS v.3 at the time of AAV onset was 16.5 (9.5; 20). In 28 patients activation of complement was reassessed during sustained remission (BVAS v.3 = 0) after a median of 16 months. Thirty six age-and gender-matched healthy volunteers comprised the control group. Levels of complement components (C3, C5, C3a, C5a, vitronectin, factor B and factor P) were measured by ELISA (Cloud Inc.). Data were not normally distributed, therefore, values are given as medians and IQRs and nonparametric statistical tests were used.Results:The concentrations of C5, C3, vitronectin and CFB were significantly higher in patients with active AAV than control group. There were no significant differences in the levels of factor P in patients with active AAV and control group (388000 (371960; 417150)) vs 416000 (400200; 437000), ng/ml, p >0.05) (Fig. 1).Fig 1.Concentration of complement components in patients with active AAV and healthy controls (*p<0.05)Serum level of C5a and C3a were higher in patients with active AAV than in healthy controls (22.9 (14.4; 33.0) vs 3.0 (0.35; 6.73), ng/ml, p<0.001; 21436 (11395; 21436) vs 1224.5 (798.5; 1947.7), ng/ml, p<0.001). Patients with active AAV had significantly higher MAC levels than healthy controls (24646 (15342; 46681) vs 3305.5 (2780.2; 3777.5), mAU/ml, p<0.001).The levels of complement components were similar in PR3-ANCA and MPO-ANCA disease, and severe and non-severe AAV. C5a/C5 and C3a/C3 ratios were not influenced by disease activity, severity or ANCA type.After immunosuppressive treatment concentrations of C5, C3, and their activated products, C5a, C3a significantly decreased (Fig. 2). However, concentrations of regulatory proteins such as factor B, factor P and vitronectin were unaffected. Interestingly, that there was no significant difference in MAC levels before and after immunosuppressive treatment (24646 (15342; 46681) vs 20057.4 (19709.3; 41477.6), mAU/ml, p=0.925).Fig 2.Concentration of complement components in patients with active disease and remission (*p<0.001)Conclusion:The complement system plays an important role in AAV. While treatment affects some component, some remain unchanged and are not dependent on AAV severity or ANCA serotype.References:[1]Jennette JC, Xiao H, Hu P. Complement in ANCA-Associated Vasculitis. Seminars in Nephrology 2013; 33 (6): 557 – 564[2]Schreiber A, Xiao H, Jennette JC et al. C5a receptor mediates neutrophil activation and ANCA-induced glomerulonephritis. J Am Soc Nephrol 2009; 20(2): 289-298.[3]Gou SJ, Yuan J, Chen M et al. Circulating complement activation in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis. Kidney Int 2013; 83(1): 129-137.Disclosure of Interests:Anastasiia Zykova Grant/research support from: This work was supported by the 5-100 Project, Sechenov University, Moscow, Pavel Novikov Grant/research support from: This work was supported by the 5-100 Project, Sechenov University, Moscow, Nikolai Bulanov Grant/research support from: This work was supported by the 5-100 Project, Sechenov University, Moscow, Andreas Kronbichler Grant/research support from: This work was supported by unrestricted grant from the Austrian Society of Rheumatology., Evgeny Gitel: None declared, Oxana Novikova: None declared, Mayra Bulanova: None declared, Elizaveta Safonova: None declared, Sergey Moiseev Grant/research support from: This work was supported by the 5-100 Project, Sechenov University, Moscow

scholarly journals Secreted Aspergillus fumigatus Protease Alp1 Degrades Human Complement Proteins C3, C4, and C5

2010 ◽  
Vol 78 (8) ◽  
pp. 3585-3594 ◽  
Author(s):  
Judith Behnsen ◽  
Franziska Lessing ◽  
Susann Schindler ◽  
Dirk Wartenberg ◽  
Ilse D. Jacobsen ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Complement Activation ◽  
Culture Supernatant ◽  
Fungal Infections ◽  
Pathogenic Fungus ◽  
Factor H ◽  
Complement Components ◽  
Human Pathogenic Fungus ◽  
Endogenous Activity ◽  
The Complement System

ABSTRACT The opportunistic human pathogenic fungus Aspergillus fumigatus is a major cause of fungal infections in immunocompromised patients. Innate immunity plays an important role in the defense against infections. The complement system represents an essential part of the innate immune system. This cascade system is activated on the surface of A. fumigatus conidia and hyphae and enhances phagocytosis of conidia. A. fumigatus conidia but not hyphae bind to their surface host complement regulators factor H, FHL-1, and CFHR1, which control complement activation. Here, we show that A. fumigatus hyphae possess an additional endogenous activity to control complement activation. A. fumigatus culture supernatant efficiently cleaved complement components C3, C4, C5, and C1q as well as immunoglobulin G. Secretome analysis and protease inhibitor studies identified the secreted alkaline protease Alp1, which is present in large amounts in the culture supernatant, as the central molecule responsible for this cleavage. An alp1 deletion strain was generated, and the culture supernatant possessed minimal complement-degrading activity. Moreover, protein extract derived from an Escherichia coli strain overproducing Alp1 cleaved C3b, C4b, and C5. Thus, the protease Alp1 is responsible for the observed cleavage and degrades a broad range of different substrates. In summary, we identified a novel mechanism in A. fumigatus that contributes to evasion from the host complement attack.

Tuberculosis: Diagnostic Challenges in Rural Africa

Praxis ◽  
2019 ◽  
Vol 108 (15) ◽  
pp. 991-996
Author(s):  
Ngisi Masawa ◽  
Farida Bani ◽  
Robert Ndege
Keyword(s):  
Extrapulmonary Tuberculosis ◽  
X Ray ◽  
Molecular Tests ◽  
Rural Settings ◽  
Chest X Ray ◽  
Screening Questions ◽  
Rural Africa ◽  
Tb Diagnostics ◽  
Strip Test ◽  
Urine Strip

Abstract. Tuberculosis (TB) remains among the top 10 infectious diseases with highest mortality globally since the 1990s despite effective chemotherapy. Among 10 million patients that fell ill with tuberculosis in the year 2017, 36 % were undiagnosed or detected and not reported; the number goes as high as 55 % in Tanzania, showing that the diagnosis of TB is a big challenge in the developing countries. There have been great advancements in TB diagnostics with introduction of the molecular tests such as Xpert MTB/RIF, loop-mediated isothermal amplification, lipoarabinomannan urine strip test, and molecular line-probe assays. However, most of the hospitals in Tanzania still rely on the TB score chart in children, the WHO screening questions in adults, acid-fast bacilli and chest x-ray for the diagnosis of TB. Xpert MTB/RIF has been rolled-out but remains a challenge in settings where the samples for testing must be transported over many kilometers. Imaging by sonography – nowadays widely available even in rural settings of Tanzania – has been shown to be a useful tool in the diagnosis of extrapulmonary tuberculosis. Despite all the efforts and new diagnostics, 30–50 % of patients in high-burden TB countries are still empirically treated for tuberculosis. More efforts need to be placed if we are to reduce the death toll by 90 % until 2030.

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