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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.

Hemodialysis reactions (HDRs) are a type of hypersensitivity reactions (HSRs), such as complement activation-related pseudoallergy (CARPA) observed during nanoparticle infusions. Our study aimed to elucidate the mechanisms of human HDRs by focusing on hemodynamic and clinical chemistry changes of HSR-related or biocompatibility issues during human hemodialysis (HD) and the reinfusion of blood. Based on our recent animal experiments, we hypothesize that increased pulmonary arterial pressure (PAP), and increases in thromboxane B2 (TXB2) and complement 3a (C3a) plasma concentrations will likely manifest in, or at least predict, human HDRs during HD and blood reinfusion. To verify our hypothesis, we measured these parameters during high-flux HD in patients. Since direct PAP measurement was not possible, the plasma concentration of the N-terminal fragment of the brain natriuretic peptide (NT-proBNP) was determined for the noninvasive estimation of PAP. Our results show an increase in NT-proBNP and TXB2 during the reinfusion of extracorporeal blood. The plasma concentration of C3a increased in early HD already and remained elevated up to blood reinfusion. In conclusion, the observed changes in HSR-related parameters or biocompatibility issues in otherwise asymptomatic patients may suggest that a greater activation of these mechanisms could explain the development of human hemodialysis reactions.

Introduction Many patients with polycystic ovary syndrome (PCOS) also experience thyroid disorders. There is a notable similarity in energy metabolism among PCOS, C1q/tumor necrosis factor (TNF)-related proteins (CTRP-5)deficiency, C3a/desArg (also known as acylation-stimulating protein (ASP)) deficiency, and hypothyroidism. This study aimed to investigate the relationship between serum levels of these factors and hypothyroidism in patients with PCOS. Improved clarity and vocabulary, corrected minor grammatical issues, and enhanced readability. Methods This case-control study involved three groups: healthy women (control group), women with PCOS and hypothyroidism, and women with PCOS without hypothyroidism. Serum levels of FBS, total cholesterol, triglycerides, and HDL-C were measured using enzymatic and colorimetric methods. TSH, T4, T3, and anti-thyroid peroxidase (Anti-TPO) levels were determined by ELISA to screen for hypothyroidism in women with PCOS. Additionally, serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), CTRP-5, ASP, and complement C3 were assessed using the ELISA method. Results The results indicated that reduced blood levels of CTRP-5, along with elevated levels of ASP (C3a/desArg) and complement C3 in patients with PCOS, may be linked to dysregulation of the thyroid gland. Furthermore, the study observed that changes in these parameters, in conjunction with thyroid dysfunction, are associated with pathological alterations in lipid profiles and blood glucose levels. Conclusion While changes in CTRP-5, ASP, and complement C3 can influence energy expenditure and storage in PCOS and thyroid function, the complex nature of PCOS requires further research to investigate the prevalence of hypothyroidism in individuals with PCOS. Clinical trial number Not applicable

Objective:To investigate the significance of complement activation in patients with primary antiphospholipid syndrome (APS).Methods:Thirty-six patients with primary APS, 42 control patients with non-systemic lupus erythematosus (SLE) connective tissue diseases, and 36 healthy volunteers were analysed retrospectively. Serum complement levels (C3, C4, CH50) and anaphylatoxins (C3a, C4a, C5a) were examined in all subjects, and serum complement regulatory factors (factor H and factor I) were measured in patients with primary APS. Plasma anticoagulant activity was determined in a mixing test using the activated partial thromboplastin time.Results:Serum complement levels were significantly lower in patients with primary APS than in patients with non-SLE connective tissue diseases (mean (SD) C3: 81.07 (17.86) vs 109.80 (22.76) mg/dl, p<0.001; C4: 13.04 (8.49) vs 21.70 (6.96) mg/dl, p<0.001; CH50: 31.32 (8.76) vs 41.40 (7.70) U/ml, p<0.001) or healthy volunteers. Only two healthy subjects with low serum C4 levels showed hypocomplementaemia, whereas most patients with primary APS showed raised serum C3a and C4a. No subjects showed raised C5a. Patients with primary APS with low serum C3 or C4 had significantly higher levels of C3a or C4a than healthy controls. No patients had low serum complement regulatory factors. Among patients with primary APS, hypocomplementaemia was significantly more common in those with high anticoagulant activity than in those with low or normal activity.Conclusion:Hypocomplementaemia is common in patients with primary APS, reflecting complement activation and consumption, and was correlated with anticoagulant activity, suggesting that antiphospholipid antibodies may activate monocytes and macrophages via anaphylatoxins produced in complement activation.

Preeclampsia is characterized by reduced placental perfusion with placental ischemia and hypertension during pregnancy. Preeclamptic women also exhibit a heightened inflammatory state and greater number of neutrophils in the vasculature compared to normal pregnancy. Since neutrophils are associated with tissue injury and inflammation, we hypothesized that neutrophils are critical to placental ischemia-induced hypertension and fetal demise. Using the reduced uteroplacental perfusion pressure (RUPP) model of placental ischemia-induced hypertension in the rat, we determined the effect of neutrophil depletion on blood pressure and fetal resorptions. Neutrophils were depleted with repeated injections of polyclonal rabbit anti-rat polymorphonuclear leukocyte (PMN) antibody (antiPMN). Rats received either antiPMN or normal rabbit serum (Control) on 13.5, 15.5, 17.5, and 18.5 days post conception (dpc). On 14.5 dpc, rats underwent either Sham surgery or clip placement on ovarian arteries and abdominal aorta to reduce uterine perfusion pressure (RUPP). On 18.5 dpc, carotid arterial catheters were placed and mean arterial pressure (MAP) was measured on 19.5 dpc. Neutrophil-depleted rats had reduced circulating neutrophils from 14.5 to 19.5 dpc compared to Control, as well as decreased neutrophils in lung and placenta on 19.5 dpc. MAP increased in RUPP Control vs Sham Control rats, and neutrophil depletion attenuated this increase in MAP in RUPP rats without any effect on Sham rats. The RUPP-induced increase in fetal resorptions and complement activation product C3a were not affected by neutrophil depletion. Thus, these data are the first to indicate that neutrophils play an important role in RUPP hypertension and that cells of the innate immune system may significantly contribute to pregnancy-induced hypertension.

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.

Background We investigated whether various inflammatory and immune proteins in plasma predict intra-amniotic infection and imminent preterm delivery in women with preterm labor and compared their predictive ability with that of amniotic fluid (AF) interleukin (IL)-6 and serum C-reactive protein (CRP). Methods This retrospective cohort study included 173 consecutive women with preterm labor who underwent amniocentesis for diagnosis of infection and/or inflammation in the AF. The AF was cultured, and assayed for IL-6. CRP levels and cervical length by transvaginal ultrasound were measured at the time of amniocentesis. The stored maternal plasma was assayed for IL-6, matrix metalloproteinase (MMP)-9, and complements C3a and C5a using ELISA kits. The primary and secondary outcome criteria were positive AF cultures and spontaneous preterm delivery (SPTD) within 48 h, respectively. Univariate, multivariate, and receiver operating characteristic analysis were used for the statistical analysis. Results In bivariate analyses, elevated plasma IL-6 level was significantly associated with intra-amniotic infection and imminent preterm delivery, whereas elevated plasma levels of MMP-9, C3a, and C5a were not associated with these two outcomes. On multivariate analyses, an elevated plasma IL-6 level was significantly associated with intra-amniotic infection and imminent preterm delivery after adjusting for confounders, including high serum CRP levels and short cervical length. In predicting intra-amniotic infection, the area under the curve (AUC) was significantly lower for plasma IL-6 than for AF IL-6 but was similar to that for serum CRP. Differences in the AUCs between plasma IL-6, AF IL-6, and serum CRP were not statistically significant in predicting imminent preterm delivery. Conclusions Maternal plasma IL-6 independently predicts intra-amniotic infection in women with preterm labor; however, it has worse diagnostic performance than that of AF IL-6 and similar performance to that of serum CRP. To predict imminent preterm delivery, plasma IL-6 had an overall diagnostic performance similar to that of AF IL-6 and serum CRP. Plasma MMP-9, C3a, and C5a levels could not predict intra-amniotic infection or imminent preterm delivery.

Background: Therapeutic hypothermia (HT) is the only intervention that improves outcomes in neonatal hypoxic-ischemic encephalopathy (HIE). However, the multifactorial mechanisms by which HT impacts HIE are incompletely understood. The complement system plays a major role in the pathogenesis of ischemia-reperfusion injuries such as HIE. We have previously demonstrated that HT modulates complement activity in vitro . Methods: Term equivalent rat pups were subjected to unilateral carotid ligation followed by hypoxia (8% O2) for 45 min to simulate HIE. A subset of animals was subjected to HT (31–32°C for 6 h). Plasma and brain levels of C3a and C5a were measured. Receptors for C3a (C3aR) and C5a (C5aR) along with C1q, C3, and C9 were characterized in neurons, astrocytes, and microglia. Results: We found that HT increased systemic expression of C3a and decreased expression of C5a after HIE. In the brain, C3aR and C5aR are predominantly expressed on microglia after HIE. HT increased local expression of C3aR and decreased expression on C5aR after HIE. Furthermore, HT decreased local expression of C1q, C3-products, and C9 in the brain. Conclusion: HT is associated with significant alteration of complement effectors and their cognate receptors. Complement modulation may improve outcomes in neonatal HIE.

Background Complement (C) can be activated during malaria, C components consumed and inflammatory mediators produced. This has potential to impair host innate defence. Methods In a case-control study, C activation was assessed by measuring serum haemolytic activity (CH50), functional activity of each pathway and levels of C3a, C4a and C5a in children presenting at Kisumu District Hospital, western Kenya, with severe malarial anaemia (SMA) or uncomplicated malaria (UM). Results CH50 median titers for lysis of sensitized sheep erythrocytes in SMA (8.6 U/mL) were below normal (34–70 U/mL) and were one-fourth the level in UM (34.6 U/mL ( P < 0.001). Plasma C3a median levels were 10 times higher than in normals for SMA (3,200 ng/ml) and for UM (3,500 ng/ml), indicating substantial C activation in both groups. Similar trends were obtained for C4a and C5a. The activities of all three C pathways were greatly reduced in SMA compared to UM (9.9% vs 83.4% for CP, 0.09% vs 30.7% for MBL and 36.8% vs 87.7% for AP respectively, P < 0.001). Conclusion These results indicate that, while C activation occurs in both SMA and UM, C consumption is excessive in SMA. It is speculated that in SMA, consumption of C exceeds its regeneration.