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PubMed1993

Temporal sequence of changes in tear film composition during sleep.

Overnight eye closure induces a shift in the nature and composition of the tear film, from a dynamic reflex tear-rich to a stagnant secretory IgA-rich layer. This is accompanied by the induction of a state of sub-clinical inflammation, as evidenced by increases in albumin levels, plasminogen activation, conversion of complement C3 to C3c, and the recruitment of polymorphonuclear (PMN) cells into the tear film. To determine the time course and functional relationship between these potentially interdependent processes, tear samples were collected from ten non-contact lens wearers after 1, 2, 3 and 5 hours of sleep. A subgroup of 6 subjects also self-collected tear samples after 8 hours of sleep. Tear samples were analysed for albumin by quantitative immunofixation assay, secretory IgA (sIgA) by radial immunodiffusion assay, plasmin-like activity using a chromogenic substrate, and complement C3 to C3c conversion by immunoblot assay. Epithelial and PMN cells in the precorneal tear film were recovered from corneal washings from the same subjects after 1, 3, 5 and 8 hours of sleep, and quantified. Results revealed that, unlike epithelial cells which exhibited a slow progressive accumulation as a function of the period of sleep, PMN cell concentration exhibited a lag phase, with recruitment occurring after between 3 and 5 hours of eye closure. This was preceded by plasminogen activation, increases in albumin and sIgA levels, and complement C3 to C3c conversion, all of which occurred within 1 to 3 hours after eye closure. Plasmin-like activity appeared to plateau after 3 hours and then decreased.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1991

Analysis of corneal inflammation following the injection of heterologous serum into the rat cornea.

The immunopathologic response following the injection of various antigens into the rat cornea was evaluated. This reaction, known as Wessely's phenomenon, was believed to be primarily triggered by antibodies and complement activation. The keratitis model was originally described in rabbits, using heterologous serum or purified proteins. In rats only, heterologous serum induced corneal inflammation with the characteristics of Wessely's phenomenon, (ie, a quiescent period of several days between antigen injection and onset of clinical signs and corneal opacification). Using rats allowed us to characterize the cellular infiltrate with immunohistochemical methods. Marked infiltration of the cornea by macrophages was observed, as was infiltration by polymorphonuclear cells, although to a lesser extent. Furthermore, T lymphocytes of the helper phenotype were demonstrated. Antibodies to complement activation product C3c showed faint staining, whereas B lymphocytes and plasma cells were absent. In addition, inflammatory cells and ocular tissues, particularly the limbal and peripheral corneal epithelium, were found to express major histocompatibility complex class II antigens during the inflammatory response. After the inflammation had subsided, macrophages and T lymphocytes remained in the corneal stroma (at least until day 30). These findings suggest that antigen-induced keratitis in rats might be mediated, at least partially, by T helper lymphocytes.

Animals↗

PubMed1992

Diurnal tear cycle: evidence for a nocturnal inflammatory constitutive tear fluid.

To investigate the tear film in the closed eye, microliter tear samples were collected without overt reflex stimulation throughout the diurnal cycle, with closed eye samples recovered immediately upon eye opening. Samples were subjected to agarose, polyacrylamide, and two-dimensional electrophoresis, coupled with immunofixation, immunoblot, and lectin blot assays. Major protein constituents were densitometrically and immunologically quantified. Results revealed a distinct progression in composition from reflex to open to closed eye tear samples. Total protein increased from 6.0 to 9.0 to 18.0 mg/ml, secretory IgA increased from less than 0.23 to 0.85 to 8.40 mg/ml, and serum albumin increased from 0.02 to 0.06 to 1.10 mg/ml. In contrast, concentrations of the major reflex tear components (lysozyme, lactoferrin, and tear specific prealbumin) remained essentially static. Immunoblot assay for complement C3 and C3c revealed that eye closure was associated with C3 activation. Results indicate that: (1) the reflex and closed eye tear layers represent opposite extremes in composition and likely origins, with open eye tear film suggesting an intermediate origin; (2) reflex tears are derived from a neurologically inducible lacrimal or accessory gland secretion composed almost exclusively of lysozyme, lactoferrin, tear specific prealbumin, and a minor mixed alpha to beta globulin fraction; (3) upon eye closure, reflex secretion ceases or greatly diminishes, with ongoing slower flow maintained by a constitutive secretion composed almost exclusively of secretory IgA; (4) the closed eye environment induces a subclinical inflammation, accounting in part for the marked rise in albumin concentration. This increase, coupled with that of secretory IgA, may play a critical role in protecting the closed eye environment from pathogens. However, this may render the closed eye environment particularly vulnerable to inflammatory and immune-mediated pathological processes, such as those seen with extended wear soft contact lenses.

Adult↗

PubMed1993

Glomerular C3c localization indicates ongoing immune deposit formation and complement activation in experimental glomerulonephritis.

In antibody-mediated glomerular disease, deposits of C3 (C3b) are common and are degraded by factor I to C3c and C3d. However, the kinetics of C3b degradation in glomerulonephritis have not been defined. To do this, we studied three models of complement-dependent glomerulonephritis with established C3 deposits (passive Heymann nephritis, cationized immunoglobulin G membranous nephropathy, and concanavalin A-anticoncanavalin A glomerulonephritis). C3b deposition was halted by administration of cobra venom factor, and the disappearance of C3c and C3d from glomeruli was measured with specific antibodies and quantitative fluorescence densitometry. Results showed that C3c deposits were reduced by over 85% within 24 hours in all three models. C3c clearance was unaffected by site or mechanism of deposit formation. C3d deposits persisted despite lack of ongoing complement activation. In passive Heymann nephritis when disease activity was monitored by urinary C5b-9 excretion, C3c was cleared in parallel with return of urine C5b-9 excretion to normal values. We conclude that glomerular deposits of C3c are cleared within 24 hours of cessation of complement activation. Positive staining for C3 utilizing antibody specific for the C3c portion documents recent complement activation usually reflecting new immune deposit formation.

Animals↗

PubMed1988

Effect of antigen site and complement receptor status on the rate of cleavage of C3c antigen from red cell bound C3b.

C3b was bound to human red cells when serum complement was activated by addition of antibodies directed against different red cell antigens, and the rate of cleavage to C3dg was determined by assay for loss of bound C3c antigens using radiolabeled monoclonal anti-C3c. When C3b was bound by antibodies to antigens on branched-chain glycoproteins, cleavage to C3dg occurred more rapidly than when C3b was bound by antibodies to antigens closer to the red cell lipid bilayer. The rate of cleavage to C3dg also correlated directly with the number of complement receptors (CR1) per red cell, reflecting their role as cofactors in the cleavage of iC3b by factor I. Thus, the life span of C3b/iC3b on human red cells, which may be important for determining the rate and mechanism of clearance of C3-coated red cells, appears to depend on the CR1 status of the red cells and the characteristics of the antigen sites around which complement is bound.

Antigens↗

PubMed1983

Acute complement activation during an anaphylactoid reaction to blood transfusion and the disappearance rate of C3c and C3d from the circulation.

A patient experienced an anaphylactoid shock after receiving a transfusion with 5-10 ml of leucocyte-depleted blood. Complement measurements revealed pronounced elevation of split products of the third complement factor (C3c and C3d), normal but fluctuating levels of native C3, significantly decreased levels of C4, normal factor B concentrations and low levels of factor B split products. The results indicate complement activation via the classical pathway as a causative mechanism of the anaphylactoid shock, and suggest an antigen-antibody reaction as the etiological factor. The nature of the antigen-antibody reaction initiating the complement activation could not be established. The disappearance rate (T/2) of C3d from the plasma after the acute C-activation was measured to approximately 4 hr, and the half life of C3c was significantly shorter.

Adult↗

PubMed1982

Demonstration of antigenic determinants specific for the split products of the third complement factor, C3.

Crossed anti-C3c immunoelectrophoresis of a plasma sample with in vivo complement activation revealed a pronounced 'spur' formation towards the cathodic region of immunochemical interaction between native C3 and C3c. In situ absorption of the antibody preparation against C determinants of the 3rd complement factor using fresh normal EDTA plasma as antigen demonstrated the presence of C3 split product specific determinants.

Antibody Formation↗

PubMed1995

Role of complement in renal tubular damage.

Deposition of immunoglobulins, complement proteins C1q, C3c, C3d, C4, C5, C6, C7, C8, C9, and terminal complement complex neoantigens in the renal tubulointerstitium was studied in serial sections by immunofluorescence microscopy. Renal tissue from 45 cases with various glomerular diseases, including 8 controls, was studied. The patients were divided into groups; one with tubulointerstitial lesions (24 cases) and the other without (13 cases). The immunoproteins were deposited mainly in the tubular basement membrane and blood vessels. Compared with controls there was a significantly increased staining score for C5 to C9 in the tubular basement membrane in both disease groups. However, the increase in terminal complement complex neoantigens score was significant only in the disease group with tubulo interstitial lesions. The changes in C3d score were not significant. Serial sections showed consistent and heavy ribbon-like deposits of complement proteins C3d, C5 to C9, and terminal complement complex neoantigens in corresponding locations of the segments of tubular basement membrane, mainly in the disease group with tubulointerstitial lesions and especially in the damaged tubules. These findings suggest that in situ activation of the complement cascade leads to the deposition of terminal complement complex neoantigens. Complement activation in the basal area of the tubules may, therefore, be an important pathogenetic mechanism in tubulointerstitial damage.

Basement Membrane↗

PubMed1988

Characterization of a monoclonal antibody MoAb bH6 reacting with a neoepitope of human C3 expressed on C3b, iC3b, and C3c.

Activation products of the complement cascade contain neoepitopes that are not present in the individual native components. Monoclonal antibodies detecting neoepitopes have been used for direct quantification of activation at different steps in the cascade. These methods are suggested to be more sensitive and reliable than conventional complement activation tests, which are hampered by precipitation or fractionation procedures. The present study describes production screening and characterization of a monoclonal antibody (MoAb) bH6. MoAb bH6 exhibited a significantly higher binding capacity to ELISA plates coated with zymosan-activated human serum than to plates coated with EDTA plasma. When fixed to the enzyme-linked immunosorbent assay (ELISA) plates, MoAb bH6 retained material from zymosan-activated serum that only reacted with anti-C3 antibodies. Crossed immunoelectrophoresis performed on zymosan-activated serum demonstrated that MoAb bH6 co-precipitated with anti-C3c antibodies. In experiments using highly purified cell-bound fragments MoAb bH6 showed reactivity with C3b and iC3b, but not with C3d. MoAb bH6 reacted in ELISA with purified C3c, but not with C3dg, both as capture antibody and in tests with the fragments absorbed to the solid phase. Thus, MoAb bH6 is highly specific for a neoepitope of human C3 expressed on the cleavage fragments of C3b, iC3b, and C3c.

Antibodies, Monoclonal↗

PubMed1994

Reduced complement and granulocyte activation with heparin-coated cardiopulmonary bypass.

Plasma concentrations of the complement activation products C3b, iC3b, and C3c; the terminal C5b-9 complement complex; and the granulocyte proteins calprotectin, myeloperoxidase, and lactoferrin were assessed in two groups of patients undergoing aortocoronary bypass procedures. In 10 patients operated on, the bypass circuits were coated by the Carmeda Bio-Active Surface and systemic heparinization was reduced to 1.5 mg/kg; in another 10, the systems were uncoated and the dosage of systemic heparinization was 4 mg/kg. In both groups, significant complement activation was observed after the onset of cardiopulmonary bypass, but the maximum levels of C3b, iC3b, and C3c and the terminal C5b-9 complement complex were significantly lower in the heparin-coated group. In both groups, a significant increase in calprotectin, myeloperoxidase, and lactoferrin release was observed by the end of operation. The maximum myeloperoxidase levels were significantly lower in the heparin-coated group than those in the uncoated group (p = 0.03). There was a correlation of borderline significance between the formation of terminal C5b-9 complement complex and lactoferrin release, as well as between the formation of terminal C5b-9 complement complex and myeloperoxidase release (p = 0.05). The postoperative blood loss did not differ significantly between the two groups. We conclude that coating by end point-attached and functionally active heparin allows a significant reduction in the amount of systemic heparinization, and significantly reduces complement and granulocyte activation.

Aged↗

PubMed2006

The structure of complement C3b provides insights into complement activation and regulation.

The human complement system is an important component of innate immunity. Complement-derived products mediate functions contributing to pathogen killing and elimination. However, inappropriate activation of the system contributes to the pathogenesis of immunological and inflammatory diseases. Complement component 3 (C3) occupies a central position because of the manifold biological activities of its activation fragments, including the major fragment, C3b, which anchors the assembly of convertases effecting C3 and C5 activation. C3 is converted to C3b by proteolysis of its anaphylatoxin domain, by either of two C3 convertases. This activates a stable thioester bond, leading to the covalent attachment of C3b to cell-surface or protein-surface hydroxyl groups through transesterification. The cleavage and activation of C3 exposes binding sites for factors B, H and I, properdin, decay accelerating factor (DAF, CD55), membrane cofactor protein (MCP, CD46), complement receptor 1 (CR1, CD35) and viral molecules such as vaccinia virus complement-control protein. C3b associates with these molecules in different configurations and forms complexes mediating the activation, amplification and regulation of the complement response. Structures of C3 and C3c, a fragment derived from the proteolysis of C3b, have revealed a domain configuration, including six macroglobulin domains (MG1-MG6; nomenclature follows ref. 5) arranged in a ring, termed the beta-ring. However, because neither C3 nor C3c is active in complement activation and regulation, questions about function can be answered only through direct observations on C3b. Here we present a structure of C3b that reveals a marked loss of secondary structure in the CUB (for 'complement C1r/C1s, Uegf, Bmp1') domain, which together with the resulting translocation of the thioester domain provides a molecular basis for conformational changes accompanying the conversion of C3 to C3b. The total conformational changes make many proposed ligand-binding sites more accessible and create a cavity that shields target peptide bonds from access by factor I. A covalently bound N-acetyl-l-threonine residue demonstrates the geometry of C3b attachment to surface hydroxyl groups.

Animals↗

PubMed1982

Circulating C3, C4, and C3 split products (C3c and C3d) during normal pregnancy.

The plasma concentrations of the complement components C3 and C4, as well as the split products C3c and C3d, were measured before, during, and after normal pregnancy. Significantly increased values were observed in the C3 and C3d levels in the second and third trimesters of pregnancy. The level of C4 was not significantly affected by pregnancy and C3c could not be detected using electroimmunoassays. These results suggest that the increased C3 split-product levels observed reflected an increased turnover of native C3 rather than activation of the complement cascade.

Complement C3↗

PubMed1998

Distribution of A beta-associated proteins in cerebrovascular amyloid of Alzheimer's disease.

Senile plaques and cerebrovascular amyloidosis (CA) are two of the major neuropathological lesions in brains of patients with dementia of the Alzheimer type. We studied the expression of a number of amyloid beta (A beta)-associated proteins in CA, which have previously been identified in senile plaques and which were suggested to play an important role in the pathogenesis of these lesions. Our findings show that involvement of inflammatory components in CA is restricted to activation of the complement system, resulting in deposition of the complement factors C1q, C3c, C4d and the membrane attack complex C5b-9 as well as of the complement inhibitor clusterin. Furthermore, we observed expression of apolipoprotein E, amyloid P component and heparan sulfate proteoglycans in CA, whereas expression of lactoferrin was almost absent. Other inflammatory proteins, known to be present in senile plaques, such as alpha1-antichymotrypsin, alpha2-macroglobulin and intercellular adhesion molecule-1, were absent or detectable only in small amounts. These data suggest that an incomplete inflammatory response occurs in CA as compared to senile plaques. This was confirmed by the finding that the number of cells of the monocyte/macrophage lineage around CA was not increased compared to unaffected vessels. Based on their expression patterns, complement factors, apolipoprotein E and heparan sulfate proteoglycans may be produced early in the process of CA formation and may play an important role in the formation of A beta fibrils in CA. The absence of a number of A beta-associated proteins in CA in comparison to senile plaques is in support of a different pathogenesis for these two lesions.

Aged↗

PubMed1993

Complement activation in septic baboons detected by neoepitope-specific assays for C3b/iC3b/C3c, C5a and the terminal C5b-9 complement complex (TCC).

We have investigated the cross-reactivity of various species in neoepitope-specific methods for quantification of human complement activation products. In contrast to most other species examined, baboon showed a substantial cross-reactivity supporting a high degree of homology between human and baboon complement. An assay for C3b, iC3b and C3c (MoAb bH6) showed moderately good reactivity, in contrast to a C3a assay which did not cross-react. Excellent reactivity was found for C5a using MoAbs C17/5 and G25/2. The reactivity of an established TCC assay (MoAb aE11 to a C9 neoepitope and polyclonal antibody to C5) was improved substantially by replacing the anti-C5 antibody with a new MoAb to C6 particularly selected on the basis of baboon cross-reactivity. Plasma samples from baboons receiving 2.5 x 10(9) and 1.0 x 10(10) live Escherichia coli bacteria/kg were examined with the assays described. In vivo complement activation with the lowest dose was moderate and kept under control, in contrast to the highest dose, where an uncontrolled increase in all activation products continued throughout the infusion period. These results support the hypothesis that sufficiently high amounts of endotoxin lead to uncontrolled activation of complement as seen in irreversible septic shock. The results are discussed with particular emphasis on activation of the terminal complement pathway.

Animals↗

PubMed2002

Complement components and terminal complement complex in oesophageal smooth muscle of patients with achalasia.

This study investigates whether patients with achalasia exhibit autoimmune reactions with subsequent complement activation within oesophageal smooth muscle, vessels and neurones. Oesophageal muscular biopsies from 8 patients undergoing surgery for achalasia and from 6 patients operated for oesophageal cancer were investigated by immunofluorescence for the presence of the complement components C1q, C4, C3c, C3d, C9 and the C9 neoantigen of the terminal C5b-C9 complement complex. Tissues were also investigated for the expression of immunoglobulins (G,A,M) and of the antigens of rubella and varicella zoster viruses. In addition, sera of both patient groups were tested for the presence of autoantibodies against Auerbach's plexus. The terminal complement complex C5b-C9 was found within muscle cells from all patients with achalasia but in only one specimen from a patient with cancer. Two patients with achalasia also exhibited the terminal complement complex as well as IgM within ganglion cells. Muscle cells stained positive for the complement component C9 in all five patients with achalasia in whom this test was performed but in none of the control tissues. In addition, sera from four patients with achalasia contained antibodies against Auerbach's plexus. Studies for the complement components C1q, C4, C3c and for antigens of rubella and varicella zoster viruses revealed negative results in all patients and controls. The results of this study suggest that a complement activation is involved in the autoimmune pathogenesis of achalasia. However, the triggering mechanism of this phenomenon remains to be determined.

Adolescent↗

PubMed1985

Platelet associated complement components (PAC3c and PAC3d) in patients with autoimmune thrombocytopenia.

Platelet associated C3c and C3d (PAC3c and PAC3d) were quantitated by enzyme linked assay in 105 patients with idiopathic autoimmune thrombocytopenia (AITP) in whom elevated platelet associated immunoglobulins (IgG and IgM) had previously been documented. Increased levels of complement components were demonstrated in 46 of 105 patients (43.8%). In 11 of these patients, PAC3d alone was abnormal implying that C3b had been inactivated after cleavage by C3 inactivator in vivo. Complement binding was seen in two of 16 patients (12.5%) with raised PAIgG alone, four of 19 patients (21.0%) with raised PAIgM alone and in 40 of 70 patients (57.1%) in whom PAIgG and PAIgM were raised together. This difference was highly significant (P = 0.01). The clinical implication of these findings are discussed.

Autoimmune Diseases↗

PubMed1992

Complement activation by polyclonal immunoglobulin G1 and G2 antibodies against Staphylococcus aureus, Haemophilus influenzae type b, and tetanus toxoid.

To obtain information on effector functions of human immunoglobulin G2 (IgG2), we have measured the complement-activating properties of polyclonal IgG subclass antibodies against bacterial antigens. IgG1 and IgG2 were purified from serum samples from five healthy individuals, and complement activation was measured with different bacterial antigens. We used Staphylococcus aureus Wood 46 (STAW), which is a common antigen, Haemophilus influenzae type b (Hib), which is a common pathogenic microorganism in children, and formaldehyde-inactivated tetanus toxin (TT). Bacteria were incubated with antibodies and then incubated with sera from agammaglobulinemic patients as a complement source, and C3c deposition was measured by enzyme-linked immunosorbent assay. We found that anti-STAW IgG2 activated complement to a level similar to that of anti-STAW IgG1. Anti-Hib IgG1 complement activation was as much as seven times higher than that of anti-Hib IgG2 in four individuals. In one individual, anti-Hib IgG2 was more effective in complement activation than anti-Hib IgG1. Anti-TT antibodies showed patterns similar to those of anti-Hib. Our results indicate that IgG2 antibodies may contribute significantly to antibacterial defense. Also, individual differences in antibody effector functions should be taken into account when evaluating the immune status of patients and during early phase 1 studies of new vaccines.

Antibodies, Bacterial↗

PubMed1990

[Platelet immunoglobulins and complement in idiopathic thrombocytopenic purpura. Specificity to the IIb/IIIa membrane complex].

Platelet-associated IgG, IgM and C3c was studied by an enzyme-linked immunosorbent assay (ELISA) procedure using polystyrene microter plates and solubilize platelets. At the time of investigation patients fell into the following disease categories: 24 chronic ITP, 10 acute ITP and 11 ITP in remission (normal platelet counts). A significant elevation of platelet IgG was found in acute and chronic ITP. The C3c was increased in acute categories and normal in the others. There was not significant difference in the immunoglobulins and complement values between ITP in remission and normal donors. The platelet specificity of IgG and IgM antibodies to IIb/IIIa membrane complex was positive in 20% from chronic ITP and in none from acute. It is concluded that an elevated platelet immunoglobulins or complement is usefull for ITP diagnosis but the difference between acute and chronic categories only is possible in some cases by the antibodies specificity.

Blood Platelets↗