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PubMed1976

Mechanism of injury of virus-infected cells by antiviral antibody and complement: participation of IgG, F(ab')2, and the alternative complement pathway.

Antibody-mediated C-dependent lysis of cell lines infected with herpes simplex type 1 virus, influenza A degrees virus, measles virus, and mumps virus occurred by the alternative C pathway with the participation of IgG antibodies. Lysis occurred only with immune human sera, Mg++ EGTA immune sera, and immune sera depleted of C4 or treated with Fab anti-C4. Lysis did not occur with nonimmune sera, Mg++ EDTA immune sera, and immune sera heated 50 degrees C for 25 min, depleted of factor B or treated with Fab antifactor B. Lysis was restored to heated and factor B immunodepleted immune sera by addition of factor B, but not by addition of an excess of C2. Further studies showed that lysis of HeLa cells infected with measles virus was induced by both immune IgG and F(ab')2 but not Fab' in the presence of a nonantibody-containing human C source. Lysis of measles virus-infected cells was also indpendent of movement of viral antigens on the surface of the infected cells, as inhibition of viral antigen capping by cytochalasin B or sodium azide was not associated with abrogation of immune lysis.

Antibodies, Viral↗
PubMed1975

Interactions of the third component of complement (C3) with cross-linked dextran. III. Isolation and characterization of interacting components after enzymatic digestion of complement coated cross-linked dextran.

In previous investigations we could show that incubation of cross-linked dextran (Sephadex) with normal human and normal guinea pig serum results in the binding of C3 to Sephadex. This binding was found to be due to activation of C3 via an alternate pathway. In this paper data are presented which show that components bound to Sephadex can be recovered after enzymatic digestion of serum-reacted Sephadex beads. The digests were characterized with immuno-electrophoresis and double immunodiffusion techniques. It could be shown that the main component present in the digest was converted C3. Apart from C3 under our test conditions only minute amounts of C3A but no other serum proteins were detectable. The observation that almost exclusively C3 is bound to Sephadex is further supported by the finding that immunization of rabbits with serum-reacted Sephadex beads results in the exclusive formation of anti C3 antibodies. Implications from these findings and possible applications are discussed.

Antibody Formation↗
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↗
PubMed1979

Complement-enhanced immunity to infection with Neisseria gonorrhoeae in mice.

Subcutaneous chambers were implanted in mice, injected with Neisseria gonorrhoeae, and supplemented with complement as a model for studying the immunogenicity and strain diversity of N. gonorrhoeae. Immunotypic resistance to N. gonorrhoeae in immunized mice was significantly (P less than 0.01) increased by injection of exogenous guinea pig complement into the host before challenge with gonococci. By using this model to test gonococcal isolates from various geographical areas, two highly immunogenic but immunotypically different gonococcal strains were identified. The piliated cells of these strains induced both complement-enhanced immunity and a degree of exogenous complement-independent immunity. The immunity in mice not treated with complement developed more slowly, was less effective, and waned earlier than that which was complement-dependent. Pretreatment with complement, although highly effective in preventing infection in immunized mice, was much less beneficial in terminating already established infections, even though bactericidal antibodies were present at the time of complement treatment. The mouse chamber model in which both complement-mediated and complement-independent mechanisms of protection can be evaluated may provide an additional tool for elucidating the immunology of gonococcal or other microbial infections.

Animals↗
PubMed1979

Analysis of complement receptors on B-lymphocytes in human milk.

Experiments were performed on human B-lymphocytes in paired samples of milk and blood from the same patient to determine the numbers and percentages of lymphocytes with complement receptors, utilizing the erythrocyte-antibody-complement (EAC) rosette assay. Studies on nine paired samples show the numbers, as well as the percentages, of complement-reactive cells (CRCs) in milk are significantly lower than in blood. Milk lymphocytes were cultured in media containing serum for a 24 hour period to determine if the observed lower numbers of CRCs in milk were due to saturation of the lymphocyte receptors with free complement, as well as to determine if the culture of the cells in nutrient media might result in the reformation of shed complement receptors. Similarly, peripheral blood lymphocytes were incubated in milk supernatant to determine if free complement or other factors in milk might interfere with the EAC assay. These studies support previous findings from this laboratory that B-lymphocytes in milk represent a subpopulation of cells different from those in peripheral blood. The paucity of B-lymphocytes bearing complement receptors in milk may be due to the following: (1) B-lymphocytes in milk may be plasmablasts and/or antibody-producing plasma cells--both known to lack complement receptors; (2) selective processes operating at the mammary alveolar epithelium allowing transit of certain subclasses of maternal immunoglobulins may also allow transepithelial passage of B-lymphocytes with surface immunoglobulins, but no complement receptors. These possibilities are currently being studied.

Antibodies↗
PubMed1976

Interaction of human Waldenström's IgM proteins with guinea pig and human complement.

The activity of purified human Waldenström's IgM protein to fix complement of human and guinea pig origins was compared at different temperatures using the polystyrene latex particle-adsorption method. It was shown that the interaction of the IgM proteins with complement differed depending on the source of complement and that a pronounced heterogeneity in complement-fixing activity was observed among the IgM proteins when tested with guinea pig complement. Thus, by the use of guinea pig complement, six human IgM proteins examined were classified roughly into two groups, one having a high and the other a low activity at 3 C as well as at 37 degrees C. With human complement, five proteins showed a rather uniform activity at 37 degrees C. However, there was one protein with no detectable activity, suggesting the presence of non-complement-fixing protein in the IgM class. All the six proteins showed no significant activity with human complement at 3 C. No antigenic difference has been found as yet in the Fc or Cmu2 region among these IgM proteins examined.

Animals↗
PubMed1975

Interaction of complex polysaccharides with the complement system: effect of calcium depletion on terminal component consumption.

Complex polysaccharides and lipopolysaccharides can activate the terminal components of complement by either the classical (antibody, C1, C4, and C2) or alternative complement pathways, but the relative importance of either pathway for terminal component consumption in normal serum is poorly understood. Since classical complement pathway function requires both calcium and magnesium ions, whereas the alternative pathway requires only magnesium ions, selective chelation of calcium ions in serum can be used to block the classical complement pathway while leaving the alternative pathway intact. In these studies, ethyleneglycol-bis-(beta-aminoethyl ether)N, N-tetraacetic acid, a potent chelator or calcium, was used to block the classical complement pathway in normal guinea pig serum. Consumption of the terminal complement components by endotoxin, inulin, and zymosan in such serum was strikingly depressed when compared to serum containing an intact classical complement pathway. These studies demonstrate that in normal serum, both the classical and alternative complement pathways participate in the consumption of the terminal complement components by complex polysaccharides and lipopolysaccharides.

Animals↗
PubMed1975

Diagnosis of bovine respiratory syncytial virus infection by complement fixation test.

The complement fixation test by the microtiter method was applied to the serological diagnosis of bovine respiratory syncytial (RS) virus infection. When used as complement fixing antigens, untreated infected cell culture fluid, fluorocarbon-treated, and ether-treated materials showed no differences in antigenicity among them. The complement fixing antigenicity of bovine RS virus appeared in bovine kidney and Vero cell cultures for the first time 4 days after inoculation. Both the infectivity and complement fixing antigenicity reached a maximum 6 days after inoculation. In detecting complement fixing antibody from infected cattle, the most outstanding specific reaction was obtained when 5% fresh normal calf serum had been added to the diluent of complement. Neutralizing and complement fixing antibodies were examined in serum samples from two cattle in the course of experimental infection. It was found that both antibodies turned to be positive 2 weeks after inoculation. There was a linear correlation between neutralizing and complement fixing antibody titers, when serum samples from 40 natural cases were tested in the acute and convalescent stages. In addition, common antigenicity was demonstrated between the virus of bovine origin and the Long strain of human RS virus by complement fixation test.

Animals↗
PubMed1978

Haemolytic complement in peripheral lymph of normal men.

The haemolytic activity of nine individual components of complement and the concentrations of C1q, C1s, C4, C3, C3PA and C9 proteins were measured in the leg lymph and serum of four normal men. The mean lymph/serum ratio for total haemolytic complement was 0.257, for C1H50 it was 0.138, for C4H50 0.105, for C2H50 0.279, for C3H50 0.063, for C5H50 0.266, for C6H50 0.145, for C7H50 0.25, for C8H50 0.244 and for C9H50 0.253. The mean lymph/serum ratio for complement proteins was: for C1q 0.048, for C1s 0.06, for C4 0.199, for C3 0.225, for C9 0.244 and for C3PA 0.263. The low haemolytic activity of total complement and of all components in lymph seems to be dependent on the low complement protein concentration. The remarkably low lymph C1q protein concentration may play a physiological role in controlling total complement activity in lymph and interstitial fluid. The total complement haemolytic activity in lymph exceeded the haemolytic activity of C1 and C3, which may indicate the possibility of independent activation of C5-7 and C8-9. The considerably low C3H50 level, with high C3 protein concentration, at present lacks a proper explanation.

Adolescent↗
PubMed1978

Profiles of serum complement in patients with hepatobiliary diseases.

CH50 and the concentrations of C3, C4, C1 INH and factor B have been measured in sera from 34 control subjects and 178 patients with various hepatobiliary diseases, including primary biliary cirrhosis (PBC), chronic active hepatitis (CAH), cryptogenic cirrhosis (CC), alcoholic liver disease (ALD), Wilson's disease (WD), large duct biliary obstruction (LDBO) and viral hepatitis (VH). CH50 was decreased in CAH and CC. C3 was increased in PBC, LDBO and VH and decreased in CAH and CC. C4 was decreased in PBC, CAH, ALD and WD. C1 INH was increased in PBC, CAH, ALD, LDBO and VH. Factor B was increased in LDBO and VH and decreased in CC. In none of the patient groups was the mean C4 level increased or the mean C1 INH level decreased. All 5 indices of serum complement were lower in ascitic than nonascitic patients. Data on serum complement were similar in HBsAg positive and negative VH. Discriminant analysis facilitated separation of all the patient groups on the basis of complement data, except PBC and VA. Analysis of data using a within-group correlation matrix revealed a significant negative correlation between C4, the most discriminating variable of serum complement in CAH, and gamma-globulin concentration in CAH. The possible contribution of factors such as activation of complement, impaired hepatic synthesis of complement components, an acute phase response and cholestasis to altered serum complement profiles in different hepatobiliary diseases is discussed.

Adolescent↗
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↗