Explore the vast range of titles available.

IgA nephropathy (IgAN) is still one of the leading causes of end-stage kidney disease (ESRD), and complement system activation is a key to the pathogenesis of IgAN. The role of complement C3a/C3aR and C5a/C5aR in late stage of IgAN remains unknown. Renal specimens of 75 IgAN patients at the stage 4 CKD were stained using immunofluorescence and immunohistochemistry. The primary outcome was a composite of end-stage renal disease (ESRD) and death. Associations of complement components with baseline clinicopathological characteristics and outcomes were assessed using multivariable Cox regression and Spearman analyses. During a median follow-up of 15.0 months, 27 patients progressed to ESRD and none died. Lower eGFR [hazards ratio (HR), 0.827, 95% confidence interval (CI), 0.732–0.935; P  = 0.002] and glomerular C3 deposition (HR, 3.179, 95% CI, 1.079–9.363; P  = 0.036) were predictive of time to ESRD in stage 4 CKD IgAN. Higher expression of C3a ( P  = 0.010), C3aR ( P  = 0.005), C5a ( P  = 0.015), and C5aR ( P  < 0.001) was identified in ESRD group than in non-ESRD group. Glomerular C3a/C3aR and C5a/C5aR deposits were both correlated with a lower baseline eGFR, higher baseline 24 h-urinary protein (24 h-UP) and faster decline of eGFR. Besides, C3a and C5a deposits were found in patients with high S (S1) and T (T1/2) scores, respectively. Complement C3a/C3aR and C5a/C5aR in IgAN patients with stage 4 CKD may portend a faster deterioration of kidney function.

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in industrialized nations, affecting 30-50 million people worldwide. The earliest clinical hallmark of AMD is the presence of drusen, extracellular deposits that accumulate beneath the retinal pigmented epithelium. Although drusen nearly always precede and increase the risk of choroidal neovascularization (CNV), the late vision-threatening stage of AMD, it is unknown whether drusen contribute to the development of CNV. Both in patients with AMD and in a recently described mouse model of AMD, early subretinal pigmented epithelium deposition of complement components C3 and C5 occurs, suggesting a contributing role for these inflammatory proteins in the development of AMD. Here we provide evidence that bioactive fragments of these complement components (C3a and C5a) are present in drusen of patients with AMD, and that C3a and C5a induce VEGF expression in vitro and in vivo. Further, we demonstrate that C3a and C5a are generated early in the course of laser-induced CNV, an accelerated model of neovascular AMD driven by VEGF and recruitment of leukocytes into the choroid. We also show that genetic ablation of receptors for C3a or C5a reduces VEGF expression, leukocyte recruitment, and CNV formation after laser injury, and that antibody-mediated neutralization of C3a or C5a or pharmacological blockade of their receptors also reduces CNV. Collectively, these findings establish a mechanistic basis for the clinical observation that drusen predispose to CNV, revealing a role for immunological phenomena in angiogenesis and providing therapeutic targets for AMD.

Background Emerging data suggest a complex pathophysiology of chronic subdural hematoma (CSDH) to which an inflammatory response might contribute. The complement system is activated in acute traumatic setting, although its role in CSDH is unknown. To investigate the complement system in CSDH pathophysiology, we analyzed blood and hematoma fluid biomarkers, as well as immunohistochemistry of the CSDH membrane and dura. Materials and Methods We simultaneously collected CSDH fluid and peripheral blood from 20 CSDH patients at the time of surgery. Biopsies of the dura mater and the CSDH capsule were obtained and analyzed by immunohistochemistry for C5b-C9 or C5a deposition. Biomarkers of inflammation and complement activation were analyzed by a 21-multiplex assay, including Adiponectin, Clusterin, Complement factor C9 and CRP. Complement factor C5a was analyzed separately by a commercial R-plex electrochemiluminescence assay. Results Ten biomarkers differed significantly between peripheral blood and paired CSDH of which two were significantly increased in CSDH fluid (Clusterin and Cystatin C). Eight of the significantly altered biomarkers were significantly decreased in CSDH fluid, including C5a, Complement 9 and Adiponectin. There was no immunoreactivity for C5a or the C5b-C9 membrane attack complex in the dura or CSDH membrane. Conclusions In CSDH levels of the complement inhibitor Clusterin were increased, whereas levels of C5a and C9 were decreased. Membrane attack complex C5b-C9 was not detected in the membrane or dura surrounding the CSDH. Inhibition of complement could lead to reduced clearance of debris in the CSDH as well as secondary inflammatory reactions.

Although evidence from basic studies indicates that C5a induces hyperalgesia, knowledge from studies of humans is limited. This comparative analysis of the peripheral blood C5a concentration of women diagnosed with fibromyalgia (FM) who exhibited widespread pain and that of female healthy controls (HCs) was done to assess possible correlations of C5a concentration with pain threshold. The data of 30 patients with FM and 29 HCs were included in the analysis. C5a concentration in the peripheral blood was quantified by ELISA, and the cold pain threshold (CPT) was assessed. The correlation between C5a concentration and CPT was analyzed using the Spearman correlation coefficient, and the peripheral blood C5a concentrations of FM and HC were compared by t-test. The mean (standard deviation) peripheral blood C5a concentrations of FM and HC were 12.7 (6.48) ng/ml and 8.82 (4.79) ng/ml, respectively ( p  = 0.0114). Although no significant relation was observed between CPT and C5a concentration in FM (R = − 0.12, p  = 0.52), a significant correlation was found for HC (R = 0.41, p = 0.03). The results suggest that C5a would be a potential biomarker for the pain sensitivity of women and give new insights into the pathophysiology of FM.

Background Alzheimer’s disease (AD) is a common cause of dementia. Serum complement factor 5a (C5a) is exceedingly implicated in AD. We explored the role of C5a levels in AD patients of different severity. Methods Mild, moderate, and severe AD patients, and healthy controls were included. C5a and pro-inflammatory factor (TNF-α, IL-1β, IL-6, CRP) levels were assessed by ELISA, and cognitive function was evaluated by Mini-Mental state examination (MMSE) score. The correlations between C5a, inflammatory factor levels, MMSE score, and plasma Aβ42/Aβ40 ratio were analyzed by Pearson tests. Independent risk factors for AD aggravation were assessed by logistic multivariate regression analysis. According to the cut-off value of receiver operating characteristic (ROC) curve analysis of C5a level, AD patients were assigned into low/high expression groups, and severe AD incidence was compared. Severe AD cumulative incidence was analyzed by Kaplan-Meier curve. Results Serum C5a, TNF-α, IL-1β, IL-6 and CRP levels were raised, and MMSE score was lowered in AD. Serum C5a, TNF-α, IL-1β, IL-6 and CRP levels in severe AD patients were higher than those in mild/moderate AD patients, but there were no significant differences in these cytokines between moderate and mild AD groups. The MMSE score of severe AD patients was lower than that of mild/moderate AD patients. Serum C5a level was positively correlated with serum TNF-α, IL-1β, IL-6, and CRP levels, and negatively correlated with MMSE score, with no obvious correlation with plasma Aβ42/Aβ40 ratio. Serum C5a level was one of the independent risk factors for AD aggravation. The occurrence of severe AD might be related to an increase in serum C5a level. Conclusion Serum C5a level increased with AD severity, and its expression was positively correlated with serum pro-inflammatory factor levels, and negatively correlated with cognitive function.

Coronavirus disease-2019 (COVID-19) was declared as a pandemic by WHO in March 2020. SARS-CoV-2 causes a wide range of illness from asymptomatic to life-threatening. There is an essential need to identify biomarkers to predict disease severity and mortality during the earlier stages of the disease, aiding treatment and allocation of resources to improve survival. The aim of this study was to identify at the time of SARS-COV-2 infection patients at high risk of developing severe disease associated with low survival using blood parameters, including inflammation and coagulation mediators, vital signs, and pre-existing comorbidities. This cohort included 89 multi-ethnic COVID-19 patients recruited between July 14 th and October 20 th 2020 in Doha, Qatar. According to clinical severity, patients were grouped into severe (n=33), mild (n=33) and asymptomatic (n=23). Common routine tests such as complete blood count (CBC), glucose, electrolytes, liver and kidney function parameters and markers of inflammation, thrombosis and endothelial dysfunction including complement component split product C5a, Interleukin-6, ferritin and C-reactive protein were measured at the time COVID-19 infection was confirmed. Correlation tests suggest that C5a is a predictive marker of disease severity and mortality, in addition to 40 biological and physiological parameters that were found statistically significant between survivors and non-survivors. Survival analysis showed that high C5a levels, hypoalbuminemia, lymphopenia, elevated procalcitonin, neutrophilic leukocytosis, acute anemia along with increased acute kidney and hepatocellular injury markers were associated with a higher risk of death in COVID-19 patients. Altogether, we created a prognostic classification model, the CAL model (C5a, Albumin, and Lymphocyte count) to predict severity with significant accuracy. Stratification of patients using the CAL model could help in the identification of patients likely to develop severe symptoms in advance so that treatments can be targeted accordingly.

BackgroundVascular leakage and shock are the major causes of death in patients with dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Thirty years ago, complement activation was proposed to be a key underlying event, but the cause of complement activation has remained unknown MethodsThe major nonstructural dengue virus (DV) protein NS1 was tested for its capacity to activate human complement in its membrane-associated and soluble forms. Plasma samples from 163 patients with DV infection and from 19 patients with other febrile illnesses were prospectively analyzed for viral load and for levels of NS1 and complement-activation products. Blood and pleural fluids from 9 patients with DSS were also analyzed ResultsSoluble NS1 activated complement to completion, and activation was enhanced by polyclonal and monoclonal antibodies against NS1. Complement was also activated by cell-associated NS1 in the presence of specific antibodies. Plasma levels of NS1 and terminal SC5b-9 complexes correlated with disease severity. Large amounts of NS1, complement anaphylatoxin C5a, and the terminal complement complex SC5b-9 were present in pleural fluids from patients with DSS ConclusionsComplement activation mediated by NS1 leads to local and systemic generation of anaphylatoxins and SC5b-9, which may contribute to the pathogenesis of the vascular leakage that occurs in patients with DHF/DSS

Critically ill patients are highly susceptible to hospital-acquired infection. Neutrophil function in critical illness remains poorly understood. To characterize and define mechanisms of peripheral blood neutrophil (PBN) dysfunction in critically ill patients. To determine whether the inflamed lung contributes additional phagocytic impairment. Prospective collection of blood and bronchoalveolar lavage fluid from patients with suspected ventilator-associated pneumonia and from age- and sex-matched volunteers; laboratory analysis of neutrophil functions. Seventy-two patients and 21 volunteers were included. Phagocytic capacity of PBNs was 36% lower in patients than in volunteers (P < 0.0001). From several biologically plausible candidates only activated complement was significantly associated with impaired PBN phagocytosis (P < 0.0001). Phagocytosis was negatively correlated with serum C3a and positively correlated with expression of C5a receptor type 1 (CD88) on PBNs. C5a recapitulated impaired PBN phagocytosis and significantly down-regulated CD88 expression in vitro. C5a-mediated phagocytic impairment was prevented by blocking either CD88 or phosphoinositide 3-kinase, and completely reversed by granulocyte-macrophage colony-stimulating factor. C5a also impaired killing of Pseudomonas aeruginosa by, and migration of, PBNs, indicating that effects were not restricted to phagocytosis. Bronchoalveolar lavage fluid leukocytes from patients also demonstrated significantly impaired function, and lavage supernatant reduced phagocytosis in healthy neutrophils by 43% (P = 0.0001). However, lavage fluid did not affect CD88 expression and lavage-mediated impairment of phagocytosis was not blocked by anti-CD88 antibody. Critically ill patients have significant dysfunction of PBNs, which is mediated predominantly by activated complement. Further, profound complement-independent neutrophil dysfunction occurs in the inflamed lung.

Purpose Invasive candidiasis poses a life-threatening risk, and early prognosis assessment is vital for timely interventions to reduce mortality. Serum C5a levels have recently been linked to prognosis, but confirmation in cancer patients is pending. Methods We detected the concentrations of serum C5a in hospitalized cancer patients with invasive candidiasis from 2020 to 2023, and retrospectively analyzed the clinical data. Results 372 cases were included in this study, with a 90-day mortality rate of 21.8%. Candida albicans (48.7%) remained the predominant pathogen, followed by Candida glabrata (25.5%), Candida tropicalis (12.4%), and Candida parapsilosis (8.3%). Gastrointestinal cancer was the most diagnosed pathology type (37.6%). Serum C5a demonstrated a noteworthy correlation with 90-day mortality, and employing a cutoff value of 36.7 ng/ml revealed significantly higher 90-day mortality in low-C5a patients (41.2%) compared to high-C5a patients (6.3%) ( p  < 0.001). We also identified no source control, no surgery, metastasis, or chronic renal failure independently correlated with the 90-day mortality. Based on this, a prognostic model combining C5a and clinical parameters was constructed, which performed better than models built solely on C5a or clinical parameters. Furthermore, we weighted scores to each parameter in the model and presented diagnostic sensitivity and specificity corresponding to different score points calculated by the model. Conclusion We constructed a prognostic scoring model including serum C5a and clinical parameters, which would contribute to precise prognosis assessment and benefit the outcome among cancer patients.

The complement system may be crucial during dengue virus infection and progression to severe dengue. This study investigates the role of MBL2 genetic variants and levels of MBL in serum and complement proteins in Vietnamese dengue patients. MBL2 genotypes (− 550 L/H, MBL2 codon 54 ), MBL2 diplotypes ( XA/XO , YA/XO ) and MBL2 haplotypes ( LXPB , HXPA , XO ) were associated with dengue in the study population. The levels of complement factors C2, C5, and C5a were higher in dengue and dengue with warning signs (DWS) patients compared to those in healthy controls, while factor D levels were decreased in dengue and DWS patients compared to the levels determined in healthy controls. C2 and C5a levels were associated with the levels of AST and ALT and with WBC counts. C9 levels were negatively correlated with ALT levels and WBC counts, and factor D levels were associated with AST and ALT levels and with platelet counts. In conclusions, MBL2 polymorphisms are associated with dengue in the Vietnamese study population. The levels of the complement proteins C2, C4b, C5, C5a, C9, factor D and factor I are modulated in dengue patients during the clinical course of dengue.