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Results for “Complement Pathway, Classical”

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PubMed1994

Neuroimmune mechanisms in Alzheimer disease pathogenesis.

Lesions in Alzheimer disease are characterized by the assembly of a variety of cells and proteins associated with the immune system. Activated microglia express high levels of major histocompatibility complex glycoproteins and receptors for complement. Small numbers of T lymphocytes infiltrate tissue. Proteins of the classical complement pathway are closely connected with beta-amyloid deposits. beta-Amyloid protein binds C1q in vitro and activates the pathway. The membrane attack complex of complement, as well as proteins that defend against that complex, colocalize with dystrophic neurites. These data imply that an autodestructive process is occurring in Alzheimer disease, that overactive microglia might be responsible, and that antiinflammatory drugs might be an effective form of therapy.

Aged↗
PubMed2003

Rheumatic syndromes associated with complement deficiency.

Deficiency of an early component of the classical complement pathway, C1q, C1r/C1s, C4, or C2, regularly produces autoimmunity in man, especially systemic lupus erythematosus. It has long been suggested that disruption of this pathway would lead to the inappropriate handling of immune complexes. An intriguing hypothesis that builds on this idea relates to a defect in clearance of one's own cellular debris, namely apoptotic cells. An attractive feature of this emerging concept is that blebs on apoptotic cells are decorated with antigens to which much of the autoantibody specificity is directed in systemic lupus erythematosus. A second hypothesis, generated primarily from complement deficiencies, relates to an impairment in the humoral immune response or in the regulation of autoreactive B cells. This review begins by summarizing the recognized autoimmune manifestations of complement deficiency and then describes new data derived from targeted gene deletions of complement proteins.

Clinical Trials as Topic↗
PubMedDate not supplied

Reduction of blood activation in patients receiving aprotinin during cardiopulmonary bypass for coronary artery surgery.

Aprotinin reduces blood loss after cardiac surgery, particularly in patients taking aspirin. This study was performed to evaluate whether the reduction of contact phase activation by aprotinin is related to decreased complement activation during blood activation. Two hundred patients were prospectively operated on for coronary artery bypass. Aprotinin was used in the cardiopulmonary bypass (CPB) prime if aspirin was not discontinued 10 days before surgery and in patients undergoing second operation (n = 102). Blood loss was significantly reduced in patients receiving aprotinin (596 +/- 309 ml vs 754 +/- 329 ml without aprotinin; p = 0.0001), as was the need for transfusion (13% vs 34% without aprotinin; p = 0.0001) after surgery. Blood activation has been studied in 60 patients. Multivariate analysis showed that contact phase activation, as assessed by maximum values of C1 inhibitor/kallikrein complexes, was reduced by aprotinin treatment (p < 0.0001). Fibrinolytic activity decreased with aprotinin treatment, as reflected by lower values of D-dimers at the end of CPB (p < 0.0001). In addition, thrombin generation, as assessed by F1 + 2 scission peptide, was reduced by aprotinin (p = 0.01). However, the stepwise regression model emphasized that activation of the alternative and classic complement pathways, as reflected by C3b/c and C4b/c levels, was not affected by aprotinin; neither was leukocyte activation, as reflected by elastase release. These results suggest that aprotinin does not combine the reduction of complement activation with the reduced activation of the contact phase, fibrinolysis, or coagulation during CPB for coronary artery surgery.

Aged↗
PubMed1984

Significance of sequential changes in serum complement levels during acute anaphylactoid reactions.

Reduced levels of complement fractions C3 and C4 and total hemolytic complement (CH50) are usually attributed to classical complement pathway activation. However, studies in 26 patients undergoing severe anaphylactoid reactions during general anesthesia suggest that these changes may equally reflect plasma dilution and protein redistribution. Twelve patients showed a dramatic fall in complement complexes which tended to resolve after 24 h; however, this fall was not usually associated with the detection of C3 breakdown products or antigen-antibody complexes. Measurement of complement levels is not a reliable index of activation or cleavage when there are dynamic shifts in plasma volume.

Acute Disease↗
PubMed1982

Activation of the alternative complement pathway in ascitic fluid during spontaneous bacterial peritonitis.

We studied complement and immunoglobulin profiles on the serum and ascitic fluid of a patient before and during gram-negative spontaneous bacterial peritonitis (SBP). During the infection, activation of the alternative complement pathway in ascitic fluid was manifested by a 35% reduction in functional activity and depression of both properdin and factor B concentrations to nondetectable levels. Activation of the complement cascade was also demonstrated by a 50% reduction in the C3 concentration and depression of total hemolytic complement. There was no evidence of complement activation of a functionally intact complement system in the ascitic fluid of cirrhotic patients. Complement consumption in ascitic fluid may predispose the cirrhotic to SBP.

Ascitic Fluid↗
PubMed1979

Complement.

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Bacterial Infections↗
PubMed1980

Use of indium-111 in antibody-dependent complement-mediated cytotoxicity assay for detection of B locus alloantigens on chicken lymphocytes.

An antibody-dependent complement-mediated cytotoxicity assay has been devised to detect B locus alloantigens on the surface of peripheral blood lymphocytes. The assay utilizes unheated chicken antiserum and guinea pig complement, which cooperate to yield specific lysis of 111In-labeled target cells. Specific cell lysis appears to be mediated by the classical complement pathway and can be inhibited by heat inactivation of the guinea pig complement. Heat inactivation of the chicken antiserum results in partial inhibition of cell lysis which can be restored by the addition of a small amount of unheated normal chicken serum. The use of a 111In-oxine chelate was found to be a quick and efficient way to label chicken cells. It has a high labeling efficiency, localizes primarily in the cytoplasm, and is released specifically from dead cells in a form that cannot be reutilized. The highly sensitive detection of B locus alloantigens with this assay strongly suggest that it will be of equal value in the detection of other alloantigens, tumor-specific (transplantation) antigens, and differentiation antigens on the surface of chicken cells.

Animals↗
PubMed1994

Neutrophil adhesion and complement inhibition prolongs survival of cardiac xenografts in discordant species.

Hyperacute rejection results in rapid destruction of a discordant cardiac xenograft and is characterized by antibody deposition, complement activation, and platelet aggregation. The importance of neutrophils is unclear. Complement inhibition prolongs discordant cardiac xenograft survival. The purpose of this experiment was to determine the relative roles of complement and neutrophils. Selective inhibition of complement and neutrophil adhesion was used in a guinea pig-to-Lewis rat cardiac heterotopic xenotransplant model. NPC 15669 (N-[9H-(2,7-dimethylfluorenyl-9-methoxy)carbonyl]-L-leucine), a member of a new class of antiinflammatory agents termed leumedins, specifically prevents recruitment of neutrophils at inflammatory foci by inhibiting upregulation of the CD11b/CD18 adhesion molecule. Soluble complement receptor type 1 (sCR1, BRL 55730) is a potent inhibitor of the alternative and classical complement pathways. Group I (n = 13) received saline vehicle i.v. Group II (n = 15) was treated with NPC 15669 (10 mg/kg i.v. bolus) prior to reperfusion. Group III (n = 13) was treated with sCR1 (20 mg/kg i.v. bolus) prior to reperfusion. Group IV (n = 13) received both NPC 15669 and sCR1. Two xenografts were harvested at each interval time point (Groups I and II, 1, 2, 4, and 6 min; and Groups III and IV, 6, 15, 30, and 60 min). The remainder were followed to cessation of graft function. Graft survival was significantly increased in group IV and group III-375 +/- 13.4 min (mean +/- SD) and 112 +/- 29.4, respectively (P < .05), compared with 9.9 +/- 6.3 in group II and 8.7 +/- 4.9 in group I. Extreme interstitial hemorrhage and edema and contraction band injury were present in group I-III animals at end-stage, and neutrophil infiltration in group III. In group IV grafts, there was a decrease in these parameters despite the longer survival time, and at end-stage rejection the cellular infiltrate was primarily mononuclear. This study demonstrates that complement is an important mediator in early xenograft HYP injury. Combined treatment with NPC 15669 and sCR1 results in reduced histologic injury at all time points and longer graft survival than with sCR1 alone. These results suggest that neutrophil and complement activation play synergistic roles in the pathogenesis of xenograft hyperacute rejection. Neutrophil inhibition may prove to be an important component of multimodality therapy for hyperacute rejection, particularly in less-discordant transplants.

Animals↗
PubMed1996

Effect of anticomplement agent K76 COOH on hamster-to-rat and guinea pig-to-rat heart xenotransplantation.

In normal rats, the xenobiotic K76 inhibited the C5 and probably the C2 and C3 steps of complement and effectively depressed classical complement pathway activity, alternative complement pathway activity, and the C3 complement component during and well beyond the drug's 3-hr half-life. It was tested alone and with intramuscular tacrolimus (TAC) and/or intragastric cyclophosphamide (CP) in rat recipients of heterotopic hearts from guinea pig (discordant) and hamster (concordant) donors. Single prevascularization doses of 100 and 200 mg/kg increased the median survival time of guinea pig hearts from 0.17 hr in untreated controls to 1.7 hr and 10.2 hr, respectively; with repeated injections of the 200-mg dose every 9-12 hr, graft survival time was increased to 18.1 hr. Pretreatment of guinea pig heart recipients for 10 days with TAC and CP, with or without perioperative splenectomy or infusion of donor bone marrow, further increased median graft survival time to 24 hr. Among the guinea pig recipients, the majority of treated animals died with a beating heart from respiratory failure that was ascribed to anaphylatoxins. Hamster heart survival also was increased with monotherapy using 200 mg/kg b.i.d. i.v. K76 (limited by protocol to 6 days), but only from 3 to 4 days. Survival was prolonged to 7 days with the addition of K76 of intragastric CP at 5 mg/kg per day begun 1 day before operation (to a limit of 9 days); it was prolonged to 4.5 days with the addition of intramuscular TAC at 2 mg/kg per day beginning on the day of transplantation and continued indefinitely. In contrast to the limited efficacy of the single drugs, or any two drugs in combination, the three drugs together (K76, CP, and TAC) in the same dose schedules increased median graft survival time to 61 days. Antihamster antibodies rapidly increased during the first 5 days after transplantation, and plateaued at an abnormal level in animals with long graft survival times without immediate humoral rejection. However, rejection could not be reliably prevented, and was present even in most of the xenografts recovered from most of the animals dying (usually from infection) with a beating heart. Thus, although effective complement inhibition with K76 was achieved in both guinea pig- and hamster-to-rat heart transplant models, the results suggest that effective interruption of the complement cascade will have a limited role, if any, in the induction of xenograft acceptance.

Animals↗
PubMed2002

Humoral rejection in kidney transplantation: new concepts in diagnosis and treatment.

PURPOSE OF REVIEW: Evidence from several transplant centers indicates that a substantial proportion of acute and chronic renal allograft rejection is caused by antibodies to donor antigens. Antibody-mediated injury arises despite potent anti-T cell pharmacological agents, and probably requires different therapy. RECENT FINDINGS: Acute humoral rejection occurs in 20-30% of acute rejection cases, has a poorer prognosis than cellular rejection, and is refractory to conventional immunosuppressive therapy. C4d deposition in peritubular capillaries of renal allografts has been demonstrated to be a sensitive and diagnostic in-situ marker of acute humoral rejection that correlates strongly with the presence of circulating donor-specific antibodies. Biopsies with chronic allograft arteriopathy or glomerulopathy also have a high frequency of C4d deposition and donor-specific antibodies. The vessels of other organs, notably the heart, can also be targets of humoral rejection. New polyclonal C4d antibodies work in paraffin sections. Pitfalls in C4d staining have been identified and must be considered in the valid interpretation of results. SUMMARY: As the histology is variable, the current diagnosis of humoral rejection in biopsies relies on the demonstration of C4d, a component of the classical complement pathway, in peritubular capillaries. The new classification of renal allograft rejection incorporates humoral and cellular mechanisms of injury, with the diagnostic criteria of each. This should prove useful in guiding clinical treatment, and stratifying drug trials, replacing obsolete terms such as 'vascular rejection'. Specific therapeutic strategies for humoral rejection with controlled trials targeting the humoral limb of immunosuppression are needed.

Antibody Formation↗
PubMed2001

Human antibodies to major histocompatibility complex alloantigens mediate lysis and neutralization of HIV-1 primary isolate virions in the presence of complement.

Cellular proteins, including major histocompatibility complex (MHC) class I and class II antigens, are incorporated into the membrane of HIV-1 when virions bud from infected cells. Experiments were performed to determine whether human sera that contained MHC class I and/or class II antibodies would lyse or neutralize a primary isolate of HIV. These results demonstrate that in the presence of complement, sera from some alloimmunized persons mediated significant anti-viral activity against an HIV primary isolate. Both lysis and neutralization of virus were observed. The antiviral effects were complement dependent because heat inactivation eliminated most anti-viral effects. Antiviral activity mediated by sera containing MHC alloantibodies in the presence of complement was > or = activity due to sera from HIV-infected persons as reported in this and a previous study. High levels of antibodies to both MHC class I and class II were present in sera that mediated the highest levels of anti-viral activity. Absorption of serum with platelets (which express class I but not class II antigens) substantially reduced their lytic activity. These studies suggest that MHC antibodies mediate potent anti-viral effects on primary isolates of HIV and support the possibility that deliberately alloimmunizing humans might protect against HIV infection.

Antibodies↗
PubMed2006

Anti-alphaGal-dependent complement-mediated cytotoxicity in metastatic melanoma.

Antibodies to the cell surface disaccharide galactose(alpha1,3)galactose (alphaGal) are the most prevalent natural antibodies in human serum. The anti-alphaGal immunoglobulin M-dependent activation of complement causes hyperacute rejection of organ transplants from discordant species by human recipients. It has been shown in vitro that human tumour cells transduced with the gene that synthesizes alphaGal become sensitive to human serum. A prerequisite for anti-alphaGal antibody-based therapeutic strategies is that patients with cancer have adequate serum levels of anti-alphaGal immunoglobulins and complement. The objective of this work was to measure the levels and function of anti-alphaGal immunoglobulins and complement in the serum of patients with metastatic melanoma and healthy volunteers. Serum complement levels were assayed by radial immunodiffusion. Anti-alphaGal immunoglobulin G and immunoglobulin M titres were measured by enzyme-linked immunosorbent assay. Disaccharide sugar blocking was used to investigate antibody specificity. The functional integrity of anti-alphaGal antibodies and complement was investigated in cell lysis assays. It was found that the levels of the complement components C1q, C3 and C4 and the function of the classical complement pathway were normal in metastatic melanoma patients. Anti-alphaGal antibody titres were as variable in metastatic melanoma patients as in healthy controls, and the lysis of alphaGal-expressing cells correlated with anti-alphaGal immunoglobulin M titre (P < 0.0001). Anti-alphaGal antibody titres, complement levels and overall cytolytic function in the serum of patients with metastatic melanoma were indistinguishable from those of healthy controls. There is thus nothing intrinsic to the disease that will limit anti-alphaGal-based therapeutic strategies for enhanced antigen presentation or induced cell lysis, including the mimicry of hyperacute rejection.

Adult↗
PubMed2003

Complement fragment C4d deposition in peritubular capillaries in acute humoral rejection after ABO blood group-incompatible human kidney transplantation.

BACKGROUND: Acute humoral rejection (AHR) is the most important risk factor for early graft loss in ABO-incompatible (ABO-i) kidney transplantation (RTx). The pathogenesis and diagnostic criteria for AHR after ABO-i RTx remain unclear. Complement fragment C4d deposition in peritubular capillaries (PTC), which is a sensitive indicator for activation of the classical complement pathway, was studied to establish the pathologic diagnostic indicator of AHR. METHODS: Forty-four graft biopsy specimens from 19 patients with ABO-i living donors were analyzed within 90 days after RTx. Nineteen biopsy specimens with acute rejection after ABO-compatible (ABO-c) living-related RTx were used as controls. Diffuse and bright C4d deposition in PTC was considered significantly positive. RESULTS: All of 8 recipients with AHR showed significantly positive C4d in PTC in the ABO-i group, but 9 of 11 recipients without AHR were negative. In the ABO-c RTx group, 16 of 19 recipients were negative for C4d in PTC. The prevalence of C4d in PTC was significantly higher in ABO-i RTx (P<0.05). CONCLUSIONS: C4d deposition is valuable as a specific and sensitive indicator for AHR, even of mild severity, in ABO-i RTx.

ABO Blood-Group System↗
PubMed1984

Structure and activity of C1r and C1s.

During activation of the first component of the classical complement pathway the two zymogen subcomponents, C1r and C1s are converted to active proteolytic enzymes. Activated C1r cleaves C1s which then becomes the activator of C4 and C2. Amino acid sequence studies of the proteolytic chains of C1r and C1s, carried out in Oxford and Aberdeen respectively, have shown that they belong to the serine proteinase family. Modelling of these sequences to the three-dimensional coordinates of chymotrypsin (Birktoft & Blow 1972) reveals that both molecules have a conserved structural core, and that most of the differences lie in the external loops. Catalytically functional residues (Ile-16, His-57, Asp-102, Ser-195) are conserved, and residue 189 is aspartic acid, consistent with the known trypsin-like specificity of cleavage. Examination of the amino acid sequences of C4a, and comparison with those of the homologous molecules C3a and C5a, shows that there is a marked difference in the distribution of basic residues near the C-terminal arginine residue which is the site of action of C1s. When these amino acid sequences are modelled to the coordinates of C3a (Huber et al. 1980) and docked to the active site of C1s, the basic residues of C4a appear to interact with two glutamate residues peculiar to C1s, suggesting that this interaction may contribute to the ability of C1s to discriminate C4 from C3 and C5.

Amino Acid Sequence↗
PubMed1982

Bactericidal activity of serum for Klebsiella rhinoscleromatis: studies on serum from a patient with rhinoscleroma and sera deficient in antibody or complement.

The in-vitro bactericidal effect of serum for Klebsiella rhinoscleromatis was tested. Experiments with C2-deficient and hypogammaglobulinaemic human sera suggested that killing depended on activation of the classical complement pathway, although the alternative pathway probably amplified the effect. Serum from a patient with active rhinoscleroma, and another cured of the disease, showed normal killing.

Agammaglobulinemia↗
PubMed1982

Impairment by Bacteroides species of opsonisation and phagocytosis of enterobacteria.

The ability of human polymorphonuclear leucocytes to phagocytose and kill Proteus mirabilis was impaired in vitro when the human serum, used to opsonise the target bacteria, was pretreated with cultures of various Bacteroides species. Live and dead, either heat-killed or clindamycin-treated, bacteroides cells elicited the same phenomenon. When bacteroides-treated serum was used to opsonise different Proteus species, the subsequent uptake of all strains by polymorphonuclear leucocytes was inhibited, whereas bacteroides-treated serum inhibited the uptake of some but not all of the test strains of Escherichia coli. The opsonic activity of untreated human serum was reduced when the classical complement pathway was inhibited by ethyleneglycol-bis-(beta-aminoethyl ether)N,N'-tetra-acetic acid (EGTA); subsequent treatment with bacteroides did not further reduce the opsonic activity of the serum for P. mirabilis.

Bacteroides↗
PubMed1987

Interaction of Campylobacter pyloridis with human immune defence mechanisms.

The in-vitro susceptibility to host immune defence mechanisms of Campylobacter pyloridis was investigated. C. pyloridis was sensitive to antibody-dependent complement-mediated bactericidal activity of serum. The bacteria were phagocytosed and efficiently killed by polymorphonuclear neutrophils in the presence of serum opsonins. Serum opsonin depletion studies indicated that an intact classical complement pathway was required for optimal phagocytic killing.

Blood Bactericidal Activity↗