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At least 19 recordsLinked to original sources

PubMed1976

Thermal fragmentation of Escherichia coli beta-galactosidase. Isolation and characterization of an alpha-complementing and two non-complementing polypeptide fractions.

Carboxymethylated Escherichia coli beta-galactosidase EC 3.2.1.23 could be broken to polypeptides of fairly uniform size (average molecular weight about 22,000 daltons) by heating for less than or equal to 8 h at 100 degrees C and pH 7.5 IN 8 M-urea. Using phosphocellulose chromatography in NaCl-urea gradients, the resulting polypeptide mixture could be resolved in three fractions essentially homogeneous by disc gel electrophoresis in urea at several pH values, and by isoelectric focusing. One of these fractions was active as alpha-donor in in vitro complementation of beta-galactosidase activity with Escherichia coli mutant M15; this activity was largely retained after CNBr cleavage. All three fractions carried arginine as carboxyl-terminal amino acid. No significant amount of any specific amino could be detected in NH2-terminal position.

Amino Acids↗

PubMed2026

Complement expression profiles in human glomerular mesangial cells, endothelial cells, podocytes and proximal tubular epithelial cells.

BACKGROUND: Local expression of complement components in the kidney has been reported sporadically in both diseased and normal kidneys. This study aimed to comprehensively characterize the expression of complement components in human glomerular mesangial cells (GMCs), glomerular endothelial cells (GECs), podocytes, and proximal tubular epithelial cells (PTECs) in non-diseased renal tissue. METHODS: Complement expression in cultured human renal intrinsic cells was initially evaluated using reverse transcription polymerase chain reaction and immunofluorescence staining. These findings were further examined using publicly available single-cell RNA-sequencing datasets and 10×Genomics single-cell RNA sequencing of non-diseased human kidney tissue. The analyses focused on complement components involved in the initiation of the classical, lectin, and alternative pathways, as well as components shared among these activation pathways, terminal pathway components, complement regulators, and complement receptors. RESULTS: Complement components unique to the initial phase for classical pathway (C1S, C1R, C2, C4), lectin pathway (MBL2, FCN1, MASP1), alternative pathway (CFB, CFD), and the C3 component shared by the three activation pathways were detected in these cells. The components shared by the terminal pathways including C5, C6, C7, C8 and C9 exhibited lower expression, while complement regulators (CFH, CFI, CD55/DAF, CD46/MCP, CD59, C4BPB, PROS1/Protein S) or receptors (CD93/C1QR1, CR1), particularly membrane-bound proteins, such as DAF, MCP and CD59, which inhibit complement activation and the formation of the membrane attack complex, showed relatively high expression. CONCLUSION: These results showed that all four types of intrinsic renal cells expressed multiple complement components associated with the classical, lectin, and alternative pathways. In non-diseased kidney tissue, complement regulatory molecules involved in the control of complement activation showed relatively higher expression, whereas components of the terminal complement pathway were expressed at relatively lower levels, suggesting that renal intrinsic cells maintain a locally poised but tightly regulated complement system.

Humans↗

PubMed2026

The complement system in inflammatory bowel disease: from early observations to emerging frontiers.

PURPOSE OF REVIEW: The complement system is one of the most evolutionarily conserved arms of innate immunity and has re-emerged as an important regulator of intestinal inflammation in inflammatory bowel disease (IBD). Early observations from the mid-1970 s such as complement deposition in diseased bowel tissue and elevated serum complement levels in patients with ulcerative colitis and Crohn's disease have evolved into a nuanced understanding of how individual complement components can exert both protective and pathogenic effects in IBD. This review highlights recent advances in complement biology and examines how complement shapes intestinal immune responses, particularly in the setting of ongoing inflammation. RECENT FINDINGS: The complement system consists of more than 60 proteins that act as rapid first responders to infection. Although traditionally considered primarily liver-derived circulating effectors, recent work has demonstrated local synthesis and activation of key complement components at mucosal sites, including the colon. In parallel, genome-wide association studies have identified variants in complement genes associated with severe IBD complications. Collectively, these findings reveal a dichotomous role for complement in IBD, whereby excessive activation promotes inflammation, while impaired function compromises host defense and worsens disease outcomes. SUMMARY: Complement-targeted therapies have been effective in other diseases but have not yet translated to IBD. A deeper understanding of context-dependent protective versus pathogenic complement functions will be essential for developing future therapeutic strategies.

Humans↗

PubMed2026

Complement Activation Linked to Type II Interferon Signaling in Still Disease.

OBJECTIVE: Still disease (SD) is an autoinflammatory syndrome characterized by innate immune dysregulation. Although complement can drive inflammation, its involvement in SD remains to be defined. Thus, we aimed to assess complement activation in SD. METHODS: Complement was assessed using transcriptomic, proteomic, and in vitro approaches. RNA sequencing of monocytes was performed in healthy donors (n = 15), those with nonsystemic juvenile idiopathic arthritis (JIA; n = 8), patients with SD at onset (n = 19) and remission (n = 18), and those with macrophage activation syndrome (n = 2). Whole-blood NanoString analysis of complement and interferon (IFN)-related gene expression was conducted in patients with SD (active n = 41, inactive n = 33) and JIA (n > 600). Complement products and inflammatory mediators were measured by Luminex and enzyme-linked immunosorbent assay. Functional complement activity was evaluated in SD (active n = 30, inactive n = 67) and JIA sera (n = 12). In vitro assays examined monocytic C1q induction and complement-mediated CD8+ T cell activation. RESULTS: Transcriptomic analysis of monocytes from patients with SD at onset revealed enrichment of the complement cascade compared with patients in remission (adjusted P = 3.7 × 10-36), ranking among the top 10 up-regulated pathways. Classical complement genes (C1QB/C1QC) were markedly up-regulated in onset SD compared with patients with remission SD and JIA. Patients with active SD showed increased C1q, C3a, C5a, and terminal complement complex protein levels, with enhanced functional classical complement activity. Whole-blood C1QB/C1QC expression correlated with IFN-related markers, including interleukin-18, CXCL9, and CXCL10. Recombinant IFN-γ induced monocytic C1q, whereas C1q enhanced IFN-γ production by CD8+ T cells, supporting a feed-forward loop. CONCLUSION: SD is characterized by complement activation with marked up-regulation of C1q, which is closely linked to IFN-γ/type II signaling.

Journal Article↗

PubMed2024

Proteomics identifies complement protein signatures in patients with alcohol-associated hepatitis.

Diagnostic challenges continue to impede development of effective therapies for successful management of alcohol-associated hepatitis (AH), creating an unmet need to identify noninvasive biomarkers for AH. In murine models, complement contributes to ethanol-induced liver injury. Therefore, we hypothesized that complement proteins could be rational diagnostic/prognostic biomarkers in AH. Here, we performed a comparative analysis of data derived from human hepatic and serum proteome to identify and characterize complement protein signatures in severe AH (sAH). The quantity of multiple complement proteins was perturbed in liver and serum proteome of patients with sAH. Multiple complement proteins differentiated patients with sAH from those with alcohol cirrhosis (AC) or alcohol use disorder (AUD) and healthy controls (HCs). Serum collectin 11 and C1q binding protein were strongly associated with sAH and exhibited good discriminatory performance among patients with sAH, AC, or AUD and HCs. Furthermore, complement component receptor 1-like protein was negatively associated with pro-inflammatory cytokines. Additionally, lower serum MBL associated serine protease 1 and coagulation factor II independently predicted 90-day mortality. In summary, meta-analysis of proteomic profiles from liver and circulation revealed complement protein signatures of sAH, highlighting a complex perturbation of complement and identifying potential diagnostic and prognostic biomarkers for patients with sAH.

Humans↗

PubMed1975

Pneumococcal type-associated variability in alternate complement pathway activation.

Opsonization of Streptococcus pneumoniae may be mediated by the alternate complement pathway. To study the importance of this interaction to human disease, complement consumption by pneumococci of various serotypes was measured in humwn serum chelated with ethyleneglycoltraacetic acid, a substance that blocks the classic but not the alternate complement pathwway. Serotype I, in contrast to all other types studied, lacked ability to consume complement in this system. The ability for serotypes III, IV, and VIII to activate the alternate pathway could be eliminated by prior serum absorption at O C with they type in question, a condition that would remove antibody but not complement. Types VII, XII, XIV, and XXV readily activated the alternate pathway in unabsorbed and absorbed sera. Differences could not be related to properties of the capsules. It was concluded that types I, III, IV, and VIII lack intrinsic ability to activate and thus be opsonized by the alternate complement pathway, although types III, IV, and VIII can do so in concert with specific antibody. The fact that these same types are especially prominent in human disease suggests that the ability to evade opsonization by the alternate complement pathway in pre-antibody phases of infection may be a virulence factor in pneumococci.

Antigen-Antibody Complex↗

PubMed2025

Antibiotic-resistant Acinetobacter baumannii can be killed by a combination of bacteriophages and complement.

Infections caused by multidrug-resistant Acinetobacter baumannii are an emerging global health threat. Although phages have shown promising results in treating bacterial infections, the mechanisms of the combined effect of phages and innate immunity on clearing A. baumannii remain unclear. Here, we report a synergistic effect of the complement system and phages on clearing multidrug-resistant A. baumannii. We show that A. baumannii rapidly adapts and becomes resistant to phage or serum complement by modifying the expression of capsule and lipooligosaccharides, which can be regulated through reversible transposon mutagenesis in the K locus. Compared to the encapsulated phenotype, the non-encapsulated, phage-resistant A. baumannii showed a higher level of membrane attack complex deposition and were susceptible to killing by complement. In contrast, the encapsulated phenotype escaped the complement system by shedding the membrane attack complex to the environment. Thus, while the complement system targets the non-encapsulated phenotype, the phage infects and eliminates the encapsulated subpopulation. These results suggest means of combatting antibiotic-resistant A. baumannii by a simultaneous treatment with phages and complement, a combination which can be supplemented further with antibacterial antibodies.

Acinetobacter baumannii↗

PubMed1976

The binding of complement by complexes formed between a rabbit antibody and oligosaccharides of increasing size.

Immune complexes formed between a homogeneous rabbit antibody to type III pneumococcal polysaccharide and a series of oligosaccharides of varying size derived from it were prepared and tested for their ability to fix guinea pig hemolytic complement. Antibody and either tetra-, hexa-, or octasaccharide formed only monomeric antibody-hapten complexes and did not show any complement binding. A dodecasaccharide and a 16-sugar residues oligomer formed dimer and trimer immune complexes. These complexes were also unable to fix complement. However, as the size of the sugar oligomers was increased to about 21 sugar residues per oligosaccharide molecule or more, the resulting complexes exhibited substantial complement binding, concomitant with the formation of antigen-antibody aggregates higher than trimers. On the other hand, an independent study carried out with the same material suggested changes in the conformation of the Fc moiety in the antibody molecule upon addition of oligosaccharide ligands as small as a 16-residue unit. Since the resulting complexes hardly ehibited any complement binding, ligand-induced conformational changes in the Fc part of the antibody molecule appears to be an insufficient condition per se for triggering complement fixation.

Animals↗

PubMed1977

Complement-fixing antibody response in pneumococcal pneumonia.

Previous studies of complement-fixing antibodies to pneumococcal capsular polysaccharides in humans have yielded conflicting results. We studied 65 sera from 25 patients with pneumococcal pneumonia, using both fresh sera and heat-inactivated sera with added human complement. Only 4 of the 25 patients developed detectable levels of complement-fixing anticapsular antibody. Of the 25 patients, 22 developed detectable levels of hemagglutinating anticapsular antibody, indicating that they were able to develop an immunological response during the infection. Most of the antibody detected by hemagglutination was sensitive to 2-mercaptoethanol, but some 2-mercaptoethanol-resistant antibody was also detected. In studies with rabbit antiserum, the complement fixation test was found to be as sensitive as the hemagglutination test for detection of anticapsular antibody. It is not clear why detectable levels of complement-fixing antibody do not develop more often in patients with pneumococcal pneumonia. Studies of purified anticapsular antibody would be of interest to determine whether or not these antibodies are restricted to immunoglobulin subclasses having a limited capacity to fix complement.

Adult↗

PubMed1977

Effect of heparin on complement activation and lysis of paroxysmal nocturnal hemoglobinuria (PNH) red cells.

The effect of heparin upon the binding of the third component of complement (C3) to PNH red cells in vitro and their subsequent hemolysis is described. Heparin, in increasing concentrations, progressively inhibits membrane C3 fixation and hemolysis when the classic complement pathway is activated by anti-red cell antibodies. Heparin has a biphasic effect upon membrane C3 fixation and hemolysis when complement is activated in serum at decreased ionic strength (sucrose lysis) or in serum at decreased pH (Ham test). Heparin in concentrations above 2 U/ml inhibits C3 binding and hemolysis while lower concentrations of heparin enhance the consequences of complement activation by these two procedures. This enhanced complement activation may explain the increased hemolysis sometimes reported in PNH patients treated with heparin, and suggests that heparin may aggravate the consequences of pathologic alternative pathway complement activation in other diseases.

Binding Sites, Antibody↗

PubMed1977

Complement levels in pneumococcal pneumonia.

Levels of complement proteins and functional activity of the alternate complement pathway were assessed in 39 patients with pneumococcal pneumonia. Mean levels of C3 and properdin and the functional activity of the alternate pathway in acute sera were significantly (P less than 0.05) below normal, whereas levels of components of the early classical pathway were normal. Although levels of factor B were in the normal range, they correlated significantly with C3 levels; there was no significant relation between C3 levels and C4 or C1q levels. The 19 patients iwth pneumococcal pneumonia and bacteremia had significantly lower mean values of properdin and factor B than the 20 patients without bacteremia, suggesting a more severe depression of the alternate complement pathway with bacteremia. During convalescence, complement levels were normal or elevated in most of the patients, but mean levels of properdin remained significantly below normal in bacteremic patients. Functional activity of the alternate pathway also remained below normal. These results indicate that there is a selective depression of the alternate pathway in patients with pneumococcal pneumonia, and they are consistent with the concept that the alternate pathway has an important role in host defenses in pneumococcal infection.

Adult↗

PubMed1978

The effect of complement depletion on lung clearance of bacteria.

We have investigated the effect of hypocomplementemia on early pulmonary clearance of four species of bacteria. The experiments were performed in an inbred animal model to minimize immunologic variability. Complement was depleted by cobra venom factor, and activity in serum was monitored with a phagocytic assay. Bacterial specific antibodies were examined by an indirect radioimmunoassay, and animals with high levels of activity were excluded from anaysis. 4 h after aerosolization with Streptococcus pneumoniae, complement-depleted animals had cleared only 75% of the initial number of organisms, whereas saline-treated controls cleared 91% (P less than 0.01). Aerosolization with Pseudomonas aeruginosa was followed at 4 h by a twofold greater growth of organisms in the complement-depleted animals (446% of original deposition) as compared to the saline-treated controls (211% of original deposition) (P less than 0.02). Clearance of Klebsiella pneumoniae and Staphylococcus aureus were similar in complement-depleted animals and saline-treated controls. These experiments suggest that hypocomplementemia predisposes to bacterial pneumonia and may explain the high incidence of pulmonary infections in patients having impaired complement activity. Our results further indicate that varying defense mechanisms may be involved with clearing the lung of differing bacterial species.

Animals↗

PubMed2022

Heterogeneity of Acetylcholine Receptor Autoantibody-Mediated Complement Activity in Patients With Myasthenia Gravis.

BACKGROUND AND OBJECTIVES: Autoantibodies targeting the acetylcholine receptor (AChR), found in patients with myasthenia gravis (MG), mediate pathology through 3 mechanisms: complement-directed tissue damage, blocking of the acetylcholine binding site, and internalization of the AChR. Clinical assays, used to diagnose and monitor patients, measure only autoantibody binding. Consequently, they are limited in providing association with disease burden, understanding of mechanistic heterogeneity, and monitoring therapeutic response. The objective of this study was to develop a cell-based assay that measures AChR autoantibody-mediated complement membrane attack complex (MAC) formation. METHODS: An HEK293T cell line-modified using CRISPR/Cas9 genome editing to disrupt expression of the complement regulator genes (CD46, CD55, and CD59)-was used to measure AChR autoantibody-mediated MAC formation through flow cytometry. RESULTS: Serum samples (n = 155) from 96 clinically confirmed AChR MG patients, representing a wide range of disease burden and autoantibody titer, were tested along with 32 healthy donor (HD) samples. AChR autoantibodies were detected in 139 of the 155 (89.7%) MG samples through a cell-based assay. Of the 139 AChR-positive samples, autoantibody-mediated MAC formation was detected in 83 (59.7%), whereas MAC formation was undetectable in the HD group or AChR-positive samples with low autoantibody levels. MAC formation was positively associated with autoantibody binding in most patient samples; ratios (mean fluorescence intensity) of MAC formation to AChR autoantibody binding ranged between 0.27 and 48, with a median of 0.79 and an interquartile range of 0.43 (0.58-1.1). However, the distribution of ratios was asymmetric and included extreme values; 16 samples were beyond the 10-90 percentile, with high MAC to low AChR autoantibody binding ratio or the reverse. Correlation between MAC formation and clinical disease scores suggested a modest positive association (rho = 0.34, p = 0.0023), which included a subset of outliers that did not follow this pattern. MAC formation did not associate with exposure to immunotherapy, thymectomy, or MG subtypes defined by age-of-onset. DISCUSSION: A novel assay for evaluating AChR autoantibody-mediated complement activity was developed. A subset of patients that lacks association between MAC formation and autoantibody binding or disease burden was identified. The assay may provide a better understanding of the heterogeneous autoantibody molecular pathology and identify patients expected to benefit from complement inhibitor therapy.

Autoantibodies↗

PubMed1976

Principles of complementation interaction of ts mutants of orthomyxoviruses.

The possibility of complementation between ts mutants of fowl plague virus (FPV) belonging to 5 different complementation groups was studied using various time intervals between inoculation of the cells with two complementation partners. The structural proteins of virions formed on complementation of individual ts mutants with wild virus were analysed by polyacrylamide gel electrophoresis after amino acid pulse label followed by pulse chase. The features of complementation interactions between the mutants are discussed.

Genetic Complementation Test↗

PubMed1978

Complement activating factor(s) of Trypanosoma lewisi: some physiochemical characteristics of the active components.

Of the complement activating factors present in Trypanosoma lewisi, the major component, a carbohydrate containing substance was further investigated. This component was found to have a lag time of complete activation of 2 CH50 units of bovine complement of approximately 15 minutes while 1% trypsin (a known activator of complement, used as a control system) was capable of instant consumption of a similar quantity of complement. In addition, the complement activating factor of trypanosomes was observed to be stable at 100 degrees C for 15 minutes and over a pH range of 3.0 to 11.0. Thin layer chromatography studies suggested that at least part of the active component contained lipid, perhaps indicating that it may be glycolipid in nature.

Animals↗

PubMed2026

Qingfei Dayuan granules alleviate the inflammatory response in lipopolysaccharide-induced acute lung injury mice by inhibiting the Nf-κB signaling pathway and regulating the complement pathway.

OBJECTIVES: The study aimed to explore the effects and mechanisms by which Qingfei Dayuan granules (QFDY) mitigate pulmonary inflammation in lipopolysaccharide (LPS)-induced acute lung injury (ALI). METHODS: We established an ALI mouse model by intraperitoneal injection of LPS. HE, Transmission electron microscopy, ELISA assay of inflammatory cytokines, and immunohistochemistry (IHC) were used to assess the degree of lung injury and inflammation. Utilizing network analysis and proteomics analysis, the potential targets and pathways of QFDY were identified. Western blot, IHC, and qRT-PCR analysis were used to evaluate the potential mechanism of QFDY. Additionally, the chemical composition of QFDY were performed using UPLC-MS/MS. KEY FINDINGS: QFDY reduced the pathologic changes and inflammatory cell infiltration in lung tissue inflammation. Network and proteomic analysis showed that the mechanism of QFDY protection against ALI is closely related to the Nuclear factor-kappa B (NF-κB) signaling pathway and complement pathway. Animal experiments showed that Qingfei Dayuan granules (QFDY) significantly reduced the levels of IL-1β, IL-6, TNF-α, and lung tissue F4/80-positive alveolar macrophages. Additionally, western blot and qRT-PCR analyses showed the inhibition of the NF-κB pathway. Notably, the levels of mannose-binding lectin (MBL2) were significantly increased, while complement C3a and complement C5a proteins were reduced in the QFDY group compared to the LPS group. CONCLUSIONS: QFDY suppressed the inflammation in LPS-induced ALI by inhibiting the NF-κB and complement pathway.

Animals↗

PubMed2026

IL-33 Drives Inflammatory Changes and Extracellular Trap Formation in Eosinophils Involving Oxidised LDL and Complement Pathways.

BACKGROUND: IL-33 levels are elevated in the airways of patients with eosinophilic diseases, and IL-33 receptor expression on eosinophils is upregulated in type 2-high environments. However, the role of IL-33 in the regulation of human eosinophils remains unclear. OBJECTIVE: To elucidate the inflammatory effects of IL-33 on the cellular function of human eosinophils. METHODS: Blood eosinophils were stimulated with IL-33, TNF-α, oxidised low-density lipoprotein (oxLDL) and complement fragments (C3a and C5a). Multi-omics analyses, including transcriptomics and proteomics, were performed. Extracellular trap formation (ETosis) was assessed by SYTOX nucleic acid staining and was visualised by immunofluorescence and transmission electron microscopy. RESULTS: Multi-omics analyses revealed an IL-33- and TNF-α-induced inflammatory gene signature characterised by the upregulation of cell surface markers (oxLDL receptor 1, CD22, CD4 and ICAM-1) and inflammatory mediators (C3, CCL3/4 and IL1A/B). CD22 upregulation was specific to IL-33 stimulation. Eosinophils derived from nasal polyps exhibited a gene expression profile similar to that of IL-33-stimulated eosinophils. Functional assays demonstrated that oxLDL and complement fragments differentially prolonged eosinophil survival and altered the expression of adhesion molecules. OxLDL- and complement fragment-induced gene signatures were partly detected in eosinophils derived from nasal polyps. Furthermore, IL-33 triggered ETosis via NADPH oxidase, mitogen-activated protein kinase and phosphoinositide 3-kinase pathways. CONCLUSIONS: IL-33, in conjunction with oxLDL and the complement cascade, induces inflammatory changes in eosinophils, promoting an ETosis-prone phenotype. These pathways represent potential therapeutic targets in refractory eosinophilic diseases.

Humans↗

PubMed1978

Hemolytic assay of complement and its components from Syrian hamster (Mesocricetus auratus) and Mongolian gerbil (Mariones unguiculatus).

Syrian hamster sera may be assayed for hemolytic complement (C) activity by standard procedures with sensitized sheep erythrocytes as used for human sera, but mongolian gerbil sera had higher complement titers when tested with sensitized guinea pig erythrocytes as target cells. The optimal conditions for in vitro testing of hamster C were pH 7.3, ionic strength 0.15, and presence of 1 micrometer of Mg2+ and 0.3 micrometer Ca2+. For gerbil C the optimum pH was 8, ionic strength 0.074, and the same concentration of Mg2+ and Ca2+ as for hamster. Incubation at 37 degrees C for 60 minutes yielded optimal results. Complement components in the serum of both species could be tested with commercially prepared intermediates of sheep erythrocytes pretreated with guinea pig C1 and human C4 respectively, using purified human C2 through 9 and standard methods applied for testing human C components. Both species have all nine components of the complement system.

Animals↗