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PubMed1996

Complete heparin-coated cardiopulmonary bypass and low heparin dose reduce complement and granulocyte activation.

Complete heparin-coated extracorporeal circuits, including cardiotomy reservoir, have recently become available for routine cardiac surgery. The effects on complement and granulocyte activation using a heparin-coated circuit in combination with reduced systemic heparinization (activated clotting time (ACT) > 250 s) were studied in 33 patients undergoing elective first time myocardial revascularization. The patients were prospectively randomized either to a heparin-coated group (Group H, n = 17), or to a control group (Group C, n = 16) treated with an identical uncoated circuit and full heparin dose (ACT > 480 s). During cardiopulmonary bypass (CPB) the C3 activation products C3b, iC3b, and C3c (C3bc) and the terminal SC5b-9 complement complex (TCC) increased markedly in both groups compared to baseline, but to a much lesser extent in the heparin-coated group. The maximal increase of C3bc during the operation was a median of 28 arbitrary units (AU)/ml in the heparin-coated group, compared to 45 AU/ml in the control group (P = 0.01). Similarly, in Group H the maximal increase of TCC was significantly lower (median 0.8 AU/ml) than the levels recognized in Group C (median 1.9 AU/ml) (P < 0.0001). The release of the granulocyte activation enzymes lactoferrin and myeloperoxidase also increased during CPB in both groups compared to baseline level. The maximal increase of lactoferrin concentration was a median of 229 micrograms/l in Group H and significantly lower than 647 micrograms/l in the control group (P = 0.0002). As for myeloperoxidase, there were no significant intergroup differences. In conclusion, a complete heparin-coated circuit and low systemic heparinization for CPB in coronary artery surgery were associated with reduced activation of the complement system and less release of lactoferrin. The results indicate improved biocompatibility of this option for extracorporeal circulation.

Adult↗
PubMed1996

Expression of functional decay-accelerating factor (CD55) in transgenic mice protects against human complement-mediated attack.

Transgenic mice expressing human CD55 were generated by microinjection of a CD55-minigene under the control of the mouse H2K(b) (MHC class I) promoter. Offspring were tested for transgene integration by PCR analysis, and for CD55 expression on peripheral blood leukocytes (PBLs) by flow cytometry. Expression levels of 15 founders ranged from 30 to 80% of that on human neutrophils. Immunohistochemical analysis of kidney, heart, liver, and lung tissue demonstrated staining for CD55 on endothelial surfaces as well as general diffuse staining throughout the tissues. The capacity of the transgenically expressed CD55 to prevent human C3 deposition on the surface of mouse splenocytes was assessed by flow cytometry. Cells from hemizygous mice incubated with 10% fresh human serum as a source of natural antibody and complement bound approximately 65% less C3 than control littermates. No further protection was seen using cells from homozygous littermates, and the protective effect was abrogated by prior incubation with an OFFi-CD55 monoclonal antibody. Similarly, transgenic mice were afforded significant protection from human serum-mediated lysis, determined using an LDH release assay. Hearts perfused with human plasma showed no increase in survival time in a modified Langendorff perfusion system, however deposition of human C3c was greatly reduced in transgenic hearts.

Animals↗
PubMed1987

Immunohistochemical study of intrathyroidal lymph follicles.

Tissue samples from 76 cases of thyroid disease containing germinal centers (GCs) were selected from 396 cases of various thyroid diseases for immunohistochemical analysis of the GC and follicular dendritic cell (FDC). These 76 cases included 28 cases of thyroid cancer, 23 of chronic thyroiditis, 12 of nontoxic goiter, 8 of adenoma, and 5 of Graves' disease. In many lymphoid GCs IgG, IgM and kappa and lambda light chains were detected with a lacy dendritic pattern. Only thyroglobulin (Tg), among the various thyroid-associated antigens sought, was stained in GCs and was found in the same distribution as immunoglobulins. Tg was found in all of the disease categories studied. Moreover, early components in the classical complement (C) pathway, that is, C1q, C4, C3c, C3d, and C5, were detected in almost all GCs in the thyroid tissues in a lacy dendritic pattern. C3d was intensely positive and was seen also by immunoelectron microscopy on the cell surface of FDCs. It is concluded that not only immunoglobulins but also Tg and early C components are closely related to the GC and FDC in the intrathyroidal lymph follicle.

Antigens↗
PubMed1995

Complement and granulocyte activation in two different types of heparinized extracorporeal circuits.

Complement and granulocyte activation were studied in cardiopulmonary bypass circuits completely coated with either end-attached covalent-bonded heparin, the Carmeda BioActive Surface, or with the Duraflo II bonded heparin, in combination with reduced systemic heparinization (activated clotting time > 250 seconds). The control groups were perfused with uncoated circuits and full heparin dose (activated clotting time > 480 seconds). Altogether 67 patients undergoing elective first-time myocardial revascularization were investigated, having extracorporeal perfusion with a Duraflo II coated circuit (n = 17), an identical but uncoated circuit (n = 17), a Carmeda coated circuit (n = 17), or an equivalent uncoated circuit (n = 16). During cardiopulmonary bypass, the C3 activation products C3b, iC3b, and C3c (C3bc) and the terminal SC5b-9 complemented complex increased markedly in all four groups compared with baseline, but significantly less in the two coated groups than in their control groups. Additionally, a significantly lower concentration of C3bc was observed in the Carmeda coated group, with maximal increase of median 28 AU/ml compared with 50 AU/ml in the Duraflo II coated group (p = 0.003). Similarly, in the Carmeda coated group, the maximal increase of terminal complement complex was considerably lower (0.8 AU/ml) than the levels recognized in the Duraflo II coated group (2.4 AU/ml) (p < 0.001). The release of the granulocyte activation myeloperoxidase and lactoferrin increased from the beginning of the operation, with peak levels at the end of bypass. A significant reduction of lactoferrin release was recognized when comparing the coated groups with the control groups. The difference between the two coated groups (Carmeda 228 micrograms/L; Duraflo II 332 micrograms/L; p = 0.05) was marginally significant. For myeloperoxidase, no significant differences were observed between the coated and uncoated groups. In conclusion, both types of heparin-coated circuits reduced complement activation and release of lactoferrin, but the Carmeda circuit proved to be more effective than the Duraflo II equipment.

Aged↗
PubMed1986

Immunocytochemical study on the immune complex and germinal center of synovial tissue of rheumatoid arthritis with special regard to complement and follicular dendritic cells.

To analyze the immunological role of lymphoid germinal centers and follicular dendritic cells (FDC) in synovial tissue of rheumatoid arthritis (RA), we tried to detect the immune complex in germinal centers by light and electron microscopic immunocytochemistry with special emphasis on immunoglobulin, complement components, RA factor, and DRC-1 antigen. Immunoglobulins mainly distributed intercellularly in the germinal center in a lacy network pattern, and show partial intracytoplasmic localization in some germinal center lymphoid cells. Early complement components of classical pathway (C1q, C4, C3c, and C3d) and RA factor distributed lacily similarily to immunoglobulin, but intracytoplasmic positivity is never observed. These coexistent positive sites are identical to DRC-1 positive sites which are the surface of extended processes of FDC membrane. A similar finding is observed in primary follicles or lymphoid aggregates less often than germinal centers. These results indicate that some germinal centers trap the immune complex, including RA factor at least closely related with FDCs, and also RA factor is one of the triggers of antigen as well as developing germinal centers.

Antibodies, Monoclonal↗
PubMed2001

Composition of nephritic factor-generated glomerular deposits in membranoproliferative glomerulonephritis type 2.

Two observations suggest that nephritic factors (NFs) may be nephritogenic. First, glomerulonephritis is present in unusual frequency in three conditions in which the function of factor H is blocked, a dysfunction also produced by NFS: Second, in membranoproliferative glomerulonephritis (MPGN) type 2, subepithelial deposits on the paramesangial portion of the glomerular basement membrane are found only in renal biopsy specimens obtained during hypocomplementemia when NF is presumably present. In the present study, the composition of these deposits with respect to C3 derivatives was assessed by immunohistological evaluation using anti-C3c and anti-C3d. The assessment used routinely obtained photomicrographs, as well as immunohistologic examination of freshly cut tissue using the double-antibody method. Deposits in patients with typical hypocomplementemic MPGN type 2 reacted only with anti-C3c, whereas those in two patients with rapidly progressive MPGN type 2, six patients with poststreptococcal acute glomerulonephritis, and five patients with juvenile acute nonproliferative glomerulitis reacted with anti-C3d, as well as anti-C3c. Because all products derived from the breakdown of C3 except C3c react with anti-C3d, the deposits in typical MPGN type 2 must be composed only of C3c. With complete breakdown of bound C3b, C3c is released into the fluid phase. Therefore, the C3c in the deposits cannot be a product of a glomerular complement reaction, but instead must be formed in the circulation by the reaction of NF with native C3. Supporting C3c as the only constituent of these deposits is the observation that they are devoid of properdin and C5 is present in only small amounts.

Antibodies, Monoclonal↗
PubMed1989

Persistent complement activation in submucosal blood vessels of active inflammatory bowel disease: immunohistochemical evidence.

Extensively washed and ethanol-fixed colonic specimens from 10 patients with ulcerative colitis, 3 patients with Crohn's disease of the colon, and 8 histologically normal controls were examined by two-color immunohistochemistry with monoclonal antibody to a neoepitope in the terminal complement complex combined with antiserum to factor VIII-related antigen (von Willebrand's factor), C3c, C3d, or C5. An alternative combination was monoclonal antibody to S-protein and antiserum to C9. Submucosal vessel walls in both normal and diseased colon showed parallel positivity for C3d, C5, C9, terminal complement complex, and S-protein, but the staining intensity and the proportion of positive vessels were significantly higher in inflammatory bowel disease than in controls. In addition, there was significantly more C3c reactivity associated with the terminal complement complex-positive submucosal vessels of active inflammatory bowel disease lesions than in histologically normal colon. Vascular C activation may therefore be a continuous process in active inflammatory bowel disease lesions, presumably related to the degree of inflammation and immune complex formation.

Adolescent↗
PubMed1978

Immunofluorescence studies in granuloma eosinophilicum faciale.

Direct immunofluorescence investigations were performed on skin biopsies from five patients with granuloma eosinophilicum faciale (GEF; facial granuloma). An extensive and brilliant granular picture was observed along the basement membrane (BM) of the epidermis and the hair follicles, in the walls of the vessels, in the cellular infiltrates and on the connective tissue fibers. These granules were positively stained by antisera directed against IgG, complement (C3/4) and, although less consistently, against IgA and IgM. IgE was found in one case along the BM, but anti- IgD was negative. Concomitantly heavy fibrillar deposits of fibrin were present in the walls of the vessels and in the cellular infiltrates, together with granular depositions along the BM. The analysis of the complement factors showed that C1q, C4, C3, C3c, C3d and C5 were present in the same pattern as C3/4. These results indicate that GEF can be considered as a chronic form of leukoclastic vasculitis mediated by an Arthus-like mechanism, maintained by an unidentified, persistent antigen or by locally produced Ig aggregates.

Basement Membrane↗
PubMed1993

Soluble interleukin-2 receptors, antineutrophil cytoplasmic antibodies, and other autoantibodies in patients with ulcerative colitis.

Ulcerative colitis (UC) is an inflammatory bowel disease of unknown aetiology. In this study, serum samples from 80 patients with UC were studied for the presence of various autoantibodies and soluble interleukin-2 receptor molecules (sIL-2Rs) in an attempt to determine the degree of activation of the immune system in this disease process. Autoantibodies detected included rheumatoid factors (in 5% of patients), antinuclear antibodies (in 51.3%), anti-Ro(SSA) (in 1.3%), anticardiolipin antibodies (IgG and/or IgM classes in 26.3%), anti-double stranded DNA (IgG or IgM classes in 45%), and antineutrophil cytoplasmic antibodies (ANCAs, in 30%). The ANCAs had a perinuclear pattern (p-ANCA) in 95.8%, without anti-myeloperoxidase activity, at least in an enzyme linked immunosorbent assay (ELISA) system. Raised concentrations of sIL-2R were found in 32.5% of patients (26/80, 18 with active and eight with inactive UC). The mean (SD) sIL-2R concentrations were significantly higher in patients with active UC (595 (219) u/ml v 406 (162) u/ml, p = 0.0001) and in patients with ANCAs (584 (177) u/ml in ANCA positive v 447 (212) u/ml in ANCA negative patients, p < 0.01). The sIL-2R concentrations were correlated with increased serum concentrations of C3c (r = 0.23, p < 0.05) or C4 (r = 0.4, p < 0.001) components of the complement system and erythrocyte sedimentation rate (ESR, r = 0.44, p = 0.0001). Platelets, ESR, and C3c were not associated with disease activity (p = 0.06, 0.33 and 0.86) whereas mean (SD) serum concentrations of C4 were higher in active disease (37.4 (11.9) mg/dl v 32.3 (10.3) mg/dl, p < 0.05). The sIL-2Rs had 53% sensitivity and 82.6% specificity for disease activity whereas platelet counts had 53% sensitivity and 58.7% specificity. To conclude, UC is accompanied by an autoimmune response that results in the production of several autoantibodies and cellular immune activation, as shown by the high sIL-2R concentration, is also present. The identification of the target antigen(s) of p-ANCA would possibly act as an indicator of disease activity if this distinct subset of ANCAs can be attributed to the pathogenesis of UC. The sIL-2R concentrations seem to be a useful laboratory marker for assessing activity of the disease.

Adolescent↗
PubMedDate not supplied

[Effect of a 49-day space flight on immunological reactivity indices and on the blood protein makeup in the crew of Saliut-5].

The prolonged 49-day space flight resulted in a significant inhibition of immunological reactivity of the Salyut-5 crewmembers which involved a decline in bactericidal activity of the serum and lysozyme activity of the saliva, and a decrease in the content of immunoglobulins in the saliva and tonsillary lacunae. After the flight recovery of reduced immunoreactivity took a longer time than after shorter-term flights. The prolonged space mission led to an increase of most globulin fractions and a decrease of albumin in blood. With respect to globulin fractions, a predominant increase in the content of C3c and C4-factors of the complement and immunoglobulins G, A, M was noted. Blood proteins returned to normal within a long period of time.

Antigen-Antibody Reactions↗
PubMedDate not supplied

[Effect of flights of varying duration on the blood protein makeup of cosmonauts].

After space flights of varying duration different adaptive changes in the protein composition of cosmonaut's blood were detected. A short-term 2-day flight induced a decline of gamma-globulin (immunoglobulins G and A) and beta 2-glycoprotein fractions. Longer-term 16- and 18-day flights caused an increase in albumin and most globulin fractions. A long-duration 49-day flight brought about an increase in the content of C3c- and C4-factors of the complement and immunoglobulins G, A and M. Return of the blood protein composition to the normal after prolonged space flights takes a long period of time.

Blood Proteins↗
PubMed1986

Immunohistochemical detection of the terminal C5b-9 complement complex in children with glomerular diseases.

Kidney biopsies were obtained in 28 children with glomerular diseases and studied using indirect immunofluorescence and immunoperoxidase for IgG, IgA, IgM, C1q, C3c, C4, fibrinogen and the neoantigens of the terminal C5b-9 complement complex. C5b-9 deposits were detected in glomeruli of 14, in tubules of eight and in vessels of 12 cases. Patients with C5b-9 deposits fared worse than those without such deposits, even with the same histopathological type of glomerulonephritis. The C5b-9 complex suggests an in situ complement activation.

Adolescent↗
PubMed1993

C3d,g deposits in inflammatory skin diseases: use of psoriatic skin as a model of cutaneous inflammation.

Recent studies in our laboratories have shown that human keratinocytes synthesize and secrete complement components including C3. Moreover, human keratinocyte-derived C3 is regarded as a potential source of C3d,g, a recently described constituent of the sublamina densa region of normal epidermal basement membrane. Additionally, human keratinocyte-derived C3 may also contribute to epidermal basement membrane deposits of C3 in autoimmune or inflammatory skin disorders. To further our understanding of the specificity and origin of epidermal basement membrane C3 deposits in normal and diseased skin, we have characterized in situ deposits of C3 and C3 cleavage fragments in various inflammatory skin diseases and utilized a skin equivalent model to assess the deposition of C3 cleavage fragments in neo-basement membrane of epidermal outgrowths from normal or diseased human skin. C3d,g reactivity was found to be greater in all samples of inflamed skin, and typically associated with C3c reactivity at these sites. No immunoglobulins or other complement components were detected. When lesional psoriatic skin rich in epidermal basement membrane C3c was used in our organ culture system, C3 incorporation within neo-basement membrane was observed. These results show that human keratinocyte-derived C3 may contribute to inflammatory reactions in skin as well as account for deposits of C3d,g in normal epidermal basement membrane.

Basement Membrane↗
PubMed1992

The apolipoprotein(a) moiety of lipoprotein(a) interacts with the complement activation fragment iC3b but does not functionally affect C3 activation or degradation.

A previous study has shown that complement component C3 binds to recombinant apolipoprotein(a) (r-apo(a)). In the present report we have investigated the interactions between lipoprotein(a) (Lp(a)), r-apo(a) and C3 in relation to complement activation and degradation. Neither Lp(a) nor r-apo(a) affected complement activation as indicated by sheep and rabbit red blood cell hemolytic assays, and by assessment of the amount of C3a generated in zymosan-activated human serum in the presence or absence of Lp(a). Crossed immunoelectrophoretic analyses indicated that Lp(a) retarded the migration of iC3b in complement-activated serum but had no effects on C3, C3b, C3c or C3dg. Recombinant apo(a) exhibited the same properties as intact Lp(a) indicating that it is the apo(a) portion of Lp(a) that mediates this effect and not the lipid moiety. Low density lipoprotein had no effect on the migration of C3 cleavage fragments. Treatment of Lp(a) or apo(a) with neuraminidase abolished their capacity to alter iC3b migration. SDS-PAGE immunoblotting analysis of C3 activation fragments generated in the presence of Lp(a) demonstrated the usual physiologic C3 cleavage fragments. Rocket intermediate gel immunoelectrophoresis of complement-activated serum demonstrated that Lp(a) did not hinder or accelerate the generation of C3c and C3dg breakdown fragments of iC3b. The results indicate that the apo(a) moiety of Lp(a) alters the migration of iC3b in an electric field but does not affect complement activation or degradation of activated C3. The sialic acid residues on apo(a) are necessary for the apo(a)-iC3b interaction.

Apolipoproteins↗
PubMed1989

Immunohistochemical demonstration of complement components in formalin-fixed and paraffin-embedded renal tissues.

Although there are many articles describing the detection of complement components in formalin-fixed and paraffin-embedded renal tissues, it is still difficult to obtain reproducible results. The authors determined the optimal conditions for detecting complement components in routine paraffin sections by the avidin-biotin-peroxidase complex method and concluded that proteolytic digestion of the deparaffinized sections was crucial to detect complement and to preserve tissue structures. The optimal proteolytic digestion was a 15-minute incubation at 37 degrees C in trypsin solution, 0.5 mg/ml, pH 7.6. Under these conditions, all of the complement components so far studied (C1q, C1s, C4, C3c, C3b, C5, C6, C9, and properdin) were detected without significant destruction of tissue structures in 52 renal biopsy specimens from patients with various forms of glomerulonephritis. Immunohistochemistry using the avidin-biotin-peroxidase complex method was equivalent to indirect immunofluorescence and superior to direct immunofluorescence in utility and was useful in the diagnosis of glomerular diseases.

Complement System Proteins↗
PubMed2000

Novel mechanism of antibody-independent complement neutralization of herpes simplex virus type 1.

The envelope surface glycoprotein C (gC) of HSV-1 interferes with the complement cascade by binding C3 and activation products C3b, iC3b, and C3c, and by blocking the interaction of C5 and properdin with C3b. Wild-type HSV-1 is resistant to Ab-independent complement neutralization; however, HSV-1 mutant virus lacking gC is highly susceptible to complement resulting in > or =100-fold reduction in virus titer. We evaluated the mechanisms by which complement inhibits HSV-1 gC null virus to better understand how gC protects against complement-mediated neutralization. C8-depleted serum prepared from an HSV-1 and -2 Ab-negative donor neutralized gC null virus comparable to complement-intact serum, indicating that C8 and terminal lytic activity are not required. In contrast, C5-depleted serum from the same donor failed to neutralize gC null virus, supporting a requirement for C5. EDTA-treated serum did not neutralize gC null virus, indicating that complement activation is required. Factor D-depleted and C6-depleted sera neutralized virus, suggesting that the alternative complement pathway and complement components beyond C5 are not required. Complement did not aggregate virus or block attachment to cells. However, complement inhibited infection before early viral gene expression, indicating that complement affects one or more of the following steps in virus replication: virus entry, uncoating, DNA transport to the nucleus, or immediate early gene expression. Therefore, in the absence of gC, HSV-1 is readily inhibited by complement by a C5-dependent mechanism that does not require viral lysis, aggregation, or blocking virus attachment.

Adult↗
PubMed1997

Vitronectin-binding staphylococci enhance surface-associated complement activation.

Coagulase-negative staphylococci are well recognized in medical device-associated infections. Complement activation is known to occur at the biomaterial surface, resulting in unspecific inflammation around the biomaterial. The human serum protein vitronectin (Vn), a potent inhibitor of complement activation by formation of an inactive terminal complement complex, adsorbs to biomaterial surfaces in contact with blood. In this report, we discuss the possibility that surface-immobilized Vn inhibits complement activation and the effect of Vn-binding staphylococci on complement activation on surfaces precoated with Vn. The extent of complement activation was measured with a rabbit anti-human C3c antibody and a mouse anti-human C9 antibody, raised against the neoepitope of C9. Our data show that Vn immobilized on a biomaterial surface retains its ability to inhibit complement activation. The additive complement activation-inhibitory effect of Vn on a heparinized surface is very small. In the presence of Vn-binding strain, Staphylococcus hemolyticus SM131, complement activation on a surface precoated with Vn occurred as it did in the absence of Vn precoating. For S. epidermidis 3380, which does not express binding of Vn, complement activation on a Vn-precoated surface was significantly decreased. The results could be repeated on heparinized surfaces. These data suggest that Vn adsorbed to a biomaterial surface may serve to protect against surface-associated complement activation. Furthermore, Vn-binding staphylococcal cells may enhance surface-associated complement activation by blocking the inhibitory effect of preadsorbed Vn.

Animals↗
PubMed1985

Humoral immunity induced by a live Francisella tularensis vaccine. Complement fixing antibodies determined by an enzyme-linked immunosorbent assay (CF-ELISA).

A complement-fixing enzyme-linked immunosorbent assay (CF-ELISA) with bacterial sonicate as the antigen, human AB serum as the source of complement and alkaline-phosphatase-labelled anti-(human C3c) as the conjugate was developed for detecting antibodies to Francisella tularensis. Humoral responses after inoculation with a live attenuated tularemia vaccine were studied in 13 subjects by this method. Twelve responded with CF antibodies, which in most cases appeared 4 weeks after vaccination, the response time varying from 1 week to 2 months. The highest individual CF titres, of 140-9990, were reached 1-4 months after vaccination (average 2.4 months). The CF titres tended to decrease with time, and at 10 months two of the 12 subjects with an earlier CF positive response were negative again. CF antibodies were nevertheless still detectable in all three subjects studied 1.5 years after vaccination.

Antibodies↗