scholarly journals Terminal complement activation is increased and associated with disease severity in CIDP

2016 ◽  
Vol 3 (9) ◽  
pp. 730-735 ◽  
Author(s):  
Isaak Quast ◽  
Christian W. Keller ◽  
Falk Hiepe ◽  
Björn Tackenberg ◽  
Jan D. Lünemann
Keyword(s):  
Disease Severity ◽  
Complement Activation ◽  
Terminal Complement

scholarly journals Increase in the Complement Activation Product C4d and the Terminal Complement Complex sC5b-9 Is Associated with Disease Severity and a Fatal Outcome in Necrotizing Soft-Tissue Infection

2021 ◽  
pp. 1-11
Author(s):  
Morten Hedetoft ◽  
Martin Bruun Madsen ◽  
Cecilie Bo Hansen ◽  
Ole Hyldegaard ◽  
Peter Garred
Keyword(s):  
Soft Tissue ◽  
Disease Severity ◽  
Soft Tissue Infection ◽  
Complement Activation ◽  
Sofa Score ◽  
Tissue Infection ◽  
Necrotizing Soft Tissue Infection ◽  
High Baseline ◽  
Terminal Complement Complex ◽  
Terminal Complement

The hyperinflammatory burden is immense in necrotizing soft-tissue infection (NSTI). The complement system is a key during the innate immune response and may be a promising target to reduce the inflammatory response, potentially improving the clinical outcome. However, complement activation and its association to disease severity and survival remain unknown in NSTI. Therefore, we prospectively enrolled patients with NSTI and sampled blood at admission and once daily for the following 3 days. Plasma C4c, C4d, C3bc, and C3dg and the terminal complement complex (TCC) were evaluated using ELISA techniques. In total, 242 patients were included with a median age of 62 years, with a 60% male predominance. All-cause 30-day mortality was 17% (95% confidence interval [CI] 13–23) with a follow-up of &#x3e;98%. C4c and C3dg were negatively correlated with Simplified Acute Physiology Score II (<i>Rho</i> −0.22, <i>p</i> &#x3c; 0.001 and <i>Rho</i> −0.17, <i>p</i> = 0.01). Patients with septic shock (<i>n</i> = 114, 47%) had higher levels of baseline TCC than those in non-shock patients (18 vs. 14, <i>p</i> &#x3c; 0.001). TCC correlated with the Sequential Organ Failure Assessment (SOFA) score (<i>Rho</i> 0.19, <i>p</i> = 0.004). In multivariate Cox regression analysis (adjusted for age, sex, comorbidity, and SOFA score), high baseline C4d (&#x3e;20 ng/mL) and the combination of high C4d and TCC (&#x3e;31 arbitrary units/mL) were associated with increased 30-day mortality (hazard ratio [HR] 3.26, 95% CI 1.56–6.81 and HR 5.12, 95% CI 2.15–12.23, respectively). High levels of both C4d and TCC demonstrated a negative predictive value of 0.87. In conclusion, we found that in patients with NSTI, complement activation correlated with the severity of the disease. High baseline C4d and combination of high C4d and TCC are associated with increased 30-day mortality. Low baseline C4d or TCC indicates a higher probability of survival.

scholarly journals Topical Application of Mesenchymal Stem Cell Exosomes Alleviates the Imiquimod Induced Psoriasis-Like Inflammation

2021 ◽  
Vol 22 (2) ◽  
pp. 720
Author(s):  
Bin Zhang ◽  
Ruenn Chai Lai ◽  
Wei Kian Sim ◽  
Andre Boon Hwa Choo ◽  
Ellen Birgit Lane ◽  
...  
Keyword(s):  
Stratum Corneum ◽  
Complement Activation ◽  
Alternative Therapy ◽  
Mouse Skin ◽  
Extracellular Traps ◽  
Cellular Source ◽  
Skin Explants ◽  
Therapy Strategies ◽  
Terminal Complement

Severe psoriasis, a chronic inflammatory skin disease is increasingly being effectively managed by targeted immunotherapy but long-term immunotherapy poses health risk and loss of response. Therefore, there is a need for alternative therapy strategies. Mesenchymal stem/stromal cell (MSC) exosomes are widely known for their potent immunomodulatory properties. Here we investigated if topically applied MSC exosomes could alleviate psoriasis-associated inflammation. Topically applied fluorescent exosomes on human skin explants were confined primarily to the stratum corneum with <1% input fluorescence exiting the explant over a 24-h period. Nevertheless, topically applied MSC exosomes in a mouse model of imiquimod (IMQ) psoriasis significantly reduced IL-17 and terminal complement activation complex C5b-9 in the mouse skin. MSC exosomes were previously shown to inhibit complement activation, specifically C5b-9 complex formation through CD59. Infiltration of neutrophils into the stratum corneum is characteristic of psoriasis and neutrophils are a major cellular source of IL-17 in psoriasis through the release of neutrophil extracellular traps (NETs). We propose that topically applied MSC exosomes inhibit complement activation in the stratum corneum and this alleviates IL-17 release by NETS from neutrophils that accumulate in and beneath the stratum corneum.

Complement C5 inhibition protects against hemolytic anemia and acute kidney injury in anthrax peptidoglycan-induced sepsis in baboons

2021 ◽  
Vol 118 (37) ◽  
pp. e2104347118
Author(s):  
Ravi Shankar Keshari ◽  
Narcis Ioan Popescu ◽  
Robert Silasi ◽  
Girija Regmi ◽  
Cristina Lupu ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Hemolytic Anemia ◽  
Complement Activation ◽  
Inflammatory Responses ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Kidney Injury ◽  
Multiple Organ ◽  
Immune Recognition ◽  
Gram Positive ◽  
Terminal Complement

Late-stage anthrax infections are characterized by dysregulated immune responses and hematogenous spread of Bacillus anthracis, leading to extreme bacteremia, sepsis, multiple organ failure, and, ultimately, death. Despite the bacterium being nonhemolytic, some fulminant anthrax patients develop a secondary atypical hemolytic uremic syndrome (aHUS) through unknown mechanisms. We recapitulated the pathology in baboons challenged with cell wall peptidoglycan (PGN), a polymeric, pathogen-associated molecular pattern responsible for the hemostatic dysregulation in anthrax sepsis. Similar to aHUS anthrax patients, PGN induces an initial hematocrit elevation followed by progressive hemolytic anemia and associated renal failure. Etiologically, PGN induces erythrolysis through direct excessive activation of all three complement pathways. Blunting terminal complement activation with a C5 neutralizing peptide prevented the progressive deposition of membrane attack complexes on red blood cells (RBC) and subsequent intravascular hemolysis, heme cytotoxicity, and acute kidney injury. Importantly, C5 neutralization did not prevent immune recognition of PGN and shifted the systemic inflammatory responses, consistent with improved survival in sepsis. Whereas PGN-induced hemostatic dysregulation was unchanged, C5 inhibition augmented fibrinolysis and improved the thromboischemic resolution. Overall, our study identifies PGN-driven complement activation as the pathologic mechanism underlying hemolytic anemia in anthrax and likely other gram-positive infections in which PGN is abundantly represented. Neutralization of terminal complement reactions reduces the hemolytic uremic pathology induced by PGN and could alleviate heme cytotoxicity and its associated kidney failure in gram-positive infections.

Morphofunctional Effects of C5 Convertase Blockade in Immune Complex-Mediated Membranoproliferative Glomerulonephritis: Report of Two Cases with Evidence of Terminal Complement Activation

Nephron ◽  
2020 ◽  
Vol 144 (4) ◽  
pp. 195-203
Author(s):  
Camillo Carrara ◽  
Manuel Alfredo Podestà ◽  
Mauro Abbate ◽  
Paola Rizzo ◽  
Rossella Piras ◽  
...  
Keyword(s):  
Immune Complex ◽  
Complement Activation ◽  
Membranoproliferative Glomerulonephritis ◽  
Terminal Complement

scholarly journals Systemic complement activation levels in Stargardt disease

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0253716
Author(s):  
Patty P. A. Dhooge ◽  
Esmee H. Runhart ◽  
Catherina H. Z. Li ◽  
Corrie M. de Kat Angelino ◽  
Carel B. Hoyng ◽  
...  
Keyword(s):  
Disease Severity ◽  
Complement System ◽  
Complement Activation ◽  
T Test ◽  
Mean Difference ◽  
Age Related Macular Degeneration ◽  
Stargardt Disease ◽  
Blood Draw ◽  
The Complement System ◽  
Age And Sex

Purpose Preclinical research provides evidence for the complement system as a potential common pathway in Stargardt disease (STGD1) and age-related macular degeneration (AMD) leading to retinal pigment epithelium (RPE) loss. However, systemic complement activation has not yet been assessed in STGD1 patients. We conducted a cross-sectional case-control study to assess systemic complement activation in STGD1 patients and its association with disease severity. Methods Systemic concentrations of complement component C3 and its degradation product C3d were compared between 80 STGD1 patients and 80 controls that were frequency matched for age and sex. The C3d/C3 ratio was used as parameter of systemic complement activation. Within the STGD1 cohort, we additionally examined the association between the C3d/C3 ratio, demographic and behavioural factors (age, sex, smoking and BMI), and measures of disease severity (age at onset, visual acuity, and area of atrophy). Results The C3d/C3 ratio did not significantly differ between patients (mean C3d/C3 ratio 3.5±1.4) and controls (mean C3d/C3 ratio 3.6±1.0), mean difference -0.156 (p = 0.804, independent samples t-test). The overall effect size was 8% (95% confidence interval, 3–15%). Elevated C3d/C3 ratios (>8.1) were found in three patients who all had a concomitant inflammatory condition at the time of blood draw. Within the patient cohort, C3 levels were associated with sex (mean difference -134, p = 0.001, independent samples t-test) and BMI (correlation coefficient 0.463, p<0.001, Spearman’s Correlation). Conclusions Systemic complement levels were not elevated in STGD1 patients compared to age and sex matched controls and was not associated with STGD1 severity. Considering the continued absent proof of a systemic contribution of the complement system to RPE loss in STGD1 patients, we hypothesize that complement activation in STGD1 is more likely a local process. In light of upcoming complement-targeted therapies, further studies are needed that measure complement levels in the eye of STGD1 patients.

scholarly journals Opsonization of Early Apoptotic Cells by IgG from Lupus Nephritis Amplifies Activation of Early Complement Components and Promotes Inflammatory Phagocytosis

2020 ◽  
Author(s):  
Chenghua Wang ◽  
Bing Zhao ◽  
Xiang Liu ◽  
Xiaowei Yang
Keyword(s):  
Lupus Nephritis ◽  
Proinflammatory Cytokines ◽  
Complement Activation ◽  
Apoptotic Cell ◽  
Apoptotic Cells ◽  
Complement Components ◽  
Early Apoptotic Cell ◽  
Apoptotic Cell Clearance ◽  
Cell Clearance ◽  
Terminal Complement

Abstract Background SSA/Ro 60 has been reported to be exposed on the surface of early apoptotic cells and recognized by autoantibodies from lupus. The aim of this study was to explore the subsequent effects of the binding of IgG from anti-SSA positive LN patients on the fate of early apoptotic cells. Results IgG which have been confirmed with extensive binding to early apoptotic cells were purified from three anti-SSA positive LN patients. Opsonization of early apoptotic cells by IgG from LN augmented C3c deposition without influence on the assembly of the terminal complement components or cell lysis. IgG from LN enhanced opsonization and phagocytosis of early apoptotic cells by macrophages directly or dependent on complement activation, with massive TNF-a and IL-1β secretions. Conclusions IgG from anti-SSA positive LN facilitates early apoptotic cell clearance by macrophages and triggers proinflammatory cytokines release, possibly exacerbating underlying pathogenic mechanisms in lupus nephritis.

scholarly journals Involvement of Antilipoarabinomannan Antibodies in Classical Complement Activation in Tuberculosis

1998 ◽  
Vol 5 (2) ◽  
pp. 211-218 ◽  
Author(s):  
Geir Hetland ◽  
Harald G. Wiker ◽  
Kolbjørn Høgåsen ◽  
Beston Hamasur ◽  
Stefan B. Svenson ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Complement Activation ◽  
Mononuclear Phagocytes ◽  
Factor B ◽  
Tuberculosis Patients ◽  
Terminal Complement Complex ◽  
Classical Activation ◽  
Normal Human ◽  
Terminal Complement ◽  
Classical Complement

ABSTRACT We examined alternative and classical complement activation induced by whole bacilli of Mycobacterium bovis BCG andMycobacterium tuberculosis products. After exposure to BCG, there were higher levels of the terminal complement complex in sera from Indian tuberculosis patients than in sera from healthy controls. The addition of BCG with or without EGTA to these sera indicated that approximately 70 to 85% of the total levels of the terminal complement complex was formed by classical activation. Sera from Indian tuberculosis patients contained more antibody to lipoarabinomannan (LAM) than sera from healthy Indians. Levels of anti-LAM immunoglobulin G2 (IgG2), but not anti-LAM IgM, correlated positively with classical activation induced by BCG in the sera. By flow cytometry, deposition of C3 and terminal complement complex on bacilli incubated with normal human serum was demonstrated. The anticomplement staining was significantly reduced in the presence of EGTA and EDTA. Flow cytometry also revealed the binding of complement to BCG incubated with rabbit anti-LAM and then with factor B-depleted serum. This indicates that classical activation plays a major role in complement activation induced by mycobacteria and that anti-LAM IgG on the bacilli can mediate this response. Classical complement activation may be important for the extent of phagocytosis of M. tuberculosis by mononuclear phagocytes, which may influence the course after infection.

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