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PubMed1999

Complement and anti-alpha-galactosyl natural antibody-mediated inactivation of murine retrovirus occurs in adult serum but not in umbilical cord serum.

Many retroviral vectors for hematopoietic cell and other clinical gene therapy are derived from murine packaging cell lines. The exposure of these retroviruses and packaging cell lines to adult human serum (AS) inactivates them by complement and anti-alpha-galactosyl natural antibody-mediated mechanisms. We show that virus stability and infection efficiency of CRIP/BAG, a murine packaging cell line derived amphotropic retrovirus vector is reduced > 95% following a 30-min incubation in AS. This inactivation is prevented by replacing AS with umbilical cord serum (CS), wherein full retroviral transduction efficiency is maintained after 30 min of incubation. The loss of retrovirus transduction efficiency in AS was smaller upon blockage of anti-alpha-galactosyl antibodies with galactose alpha 1-3-galactose. Serum levels of CH 100, as well as C1q complement which inactivates retroviruses by an antibody-independent mechanism were similar in AS and CS. The high stability of CRIP/BAG retrovirus vector in CS is likely due to its lower levels of maternally derived anti-alpha-galactosyl antibodies. These results have implications for in vivo gene transfer in adults and also in newborns since neonates do not produce natural antibodies during the initial months of life.

Adult↗
PubMed1982

Serologic profile of alphamethyldopa-induced hemolytic anemia: correlation between cell-bound IgM and hemolysis.

Erythrocyte-bound immunoglobulins have been characterized by a PVP-potentiated antiglobulin test in 11 patients who had developed antibodies after treatment with alpha-methyldopa. Serologic profiles were recognized that could distinguish between the hemolyzing and nonhemolyzing patients: IgM antibodies together with the first component of complement (C1q) were demonstrated on erythrocytes of all eight hemolyzing patients. By contrast, these immunoproteins were absent from the cells of nonhemolyzing patients and became undetectable when the hemolyzing patients recovered. IgG and its subclasses were variably present on erythrocytes of all patients regardless of hemolytic activity. Eluates prepared from erythrocytes of the hemolyzing patients were shown to contain both IgG and IgM, and fixes C1q, C3, and C4. Eluates from the nonhemolyzing patients contained only IgG. The IgM antibodies differed from the commonly occurring cold agglutinins in that they were warm-reactive and were mainly concentrated on the patients' cells rather than being free in the serum. Because of their nonagglutinating property, it is suggested that they are monomeric IgM. It is concluded that the high affinity, warm-reactive IgM and not the IgG antibodies are primarily responsible for clinically manifest anemia in patients receiving alphamethyldopa and that the hemolytic activity is probably mediated by the classic pathway of complement activation.

Adult↗
PubMed1989

The biosynthesis of C1q, the collagen-like and Fc-recognizing molecule of the complement system.

C1q, the collagen-like and Fc-recognizing component of the complement system, is mainly synthesized in macrophages and epithelial cells. Inhibitors of collagen biosynthesis, known to inhibit the post-translational hydroxylation of proline and lysine residues, were as effective in macrophages as inhibitors of C1q synthesis and secretion as has been described for collagen. This indicates that post-translational processing of C1q is dependent upon its collagen portions and triple helical formation within the cells. The macrophage-derived C1q is immuno- and physicochemically identical with serum C1q indicating that macrophages have to be considered as a major source for serum C1q. This was recently confirmed by Northern blot analysis using a cDNA probe for the B-chain of murine C1q. In contrast, an extremely weak signal was found in kidney, lung, gut, muscle and liver RNA. Besides the 11 S C1q molecule macrophages also synthesize a low molecular weight (LMW) form of C1q. The biological function of this 4 S LMW-C1q is still unclear. Macrophage-derived and secreted C1q is reinserted into the macrophage membrane. It is unlikely that the membranous form of C1q is bound via C1q-receptors into the membrane of macrophages since the B-chain of membrane-associated C1q is structurally different to that of fluid-phase C1q. The demonstration of a distinct membrane form of C1q supports earlier functional studies which implicated C1q as a membrane-associated molecule with receptor functions for those molecules which also interact with fluid-phase C1q, such as polyanions, the Fc portions of immune complexes, and bacteria (LPS and outer membrane proteins, OMP).

Animals↗
PubMed1997

Ex vivo lung model of pig-to-human hyperacute xenograft rejection.

OBJECTIVE: Our objective was to study lung hyperacute rejection in the pig-to-human xenotransplantation combination. METHODS: Pig lungs were harvested and continuously ventilated and perfused ex vivo, using a neonatal oxygenating system, with either xenogeneic unmodified human blood (n = 6) or autogeneic pig blood (n = 6). RESULTS: Autoperfused lungs displayed normal hemodynamics, oxygen extraction (arteriovenous oxygen difference), and histologic characteristics throughout the 3-hour study period. By contrast, xenoperfused lungs displayed, within 30 minutes, severe pulmonary hypertension and abolishment of arteriovenous oxygen difference culminating in massive pulmonary edema, hemorrhage, and lung failure after 115 +/- 44.2 minutes of reperfusion. Within 30 minutes, the human blood showed a significant drop of anti-alpha Gal immunoglobulin M and G xenoreactive antibodies (enzyme-linked immunosorbent assay) and complement activity, consumption of clotting factors, and hemolysis; total circulating human immunoglobulins remained substantially normal. Histologically, lungs perfused with human blood were congestive and showed alveolar edema and hemorrhage and multiple fibrin and platelet thrombi obstructing the small pulmonary vessels (arterioles, capillaries, and venules) but not large (segmental or lobar) pulmonary vessels. On immunohistologic examination, deposits of human immunoglobulin M and complement (C1q and C3) proteins were observed on the alveolar capillaries. CONCLUSIONS: This pig-to-human xenograft model suggests that the pig lung perfused with human blood has an early and violent hyperacute rejection that results in irreversible pulmonary dysfunction and failure within approximately 150 minutes of reperfusion.

Acute Disease↗
PubMed1976

Membranoproliferative glomerulonephritis. Localization of early components of complement in glomerular deposits.

A body of evidence suggests that in membranoproliferative glomerulonephritis (MPGN), complement is activated by the alternate pathway. Therefore, deposition of early components of complement should not be expected in glomeruli. The renal tissues of 16 patients--13 with classic MPGN and 3 with dense deposit disease, a variant of MPGN--were studied by light and electron microscopy and by means of elution and immunofluorescence for the localization of complement (C1q, C4, and C3), immunoglobulins (1gG, IgM, and 1gA), and other serum proteins. Variable amounts of C3, C4 and/or C1q, and IgM were detected in the glomeruli of all patients, whereas IgG and IgA were present, respectively, in 15 of 16 and 6 of 16 patients. Deposits were localized in mesangium and in peripheral capillary loops in a typical lobular distribution. The specificity of each antiserum was verified by immunodiffusion, immunoelectrophoresis, and blocking experiments utilizing unlabeled antibody. Glomerular-bound IgG was eluted with acid citrate buffer, suggesting that IgG might be complexed with antigen(s) in glomerular deposits. By light microscopy, lesions ranged from focal proliferation and lobulation to more severe involvement with typical splitting of glomerular basement membranes, sclerosis, and less frequently, crescent formation. Ultrastructurally, all patients with classic MPGN exhibited mesangial and subendothelial deposits, and in 5 of these patients, subepithelial deposits were demonstrated. With the exception of ultrastructural lesions, patients with the dense deposit variant lacked distinguishable features when compared with those with classic MPGN. The significance of these findings is discussed in relation to a) activation of complement and the possible role of an immune complex mechanism and b) the variability of the morphologic expression.

Adolescent↗
PubMed2000

Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages.

We investigated the functions of adiponectin, an adipocyte-specific secretory protein and a new member of the family of soluble defense collagens, in hematopoiesis and immune responses. Adiponectin suppressed colony formation from colony-forming units (CFU)-granulocyte-macrophage, CFU-macrophage, and CFU-granulocyte, whereas it had no effect on that of burst-forming units-erythroid or mixed erythroid-myeloid CFU. In addition, adiponectin inhibited proliferation of 4 of 9 myeloid cell lines but did not suppress proliferation of erythroid or lymphoid cell lines except for one cell line. These results suggest that adiponectin predominantly inhibits proliferation of myelomonocytic lineage cells. At least one mechanism of the growth inhibition is induction of apoptosis because treatment of acute myelomonocytic leukemia lines with adiponectin induced the appearance of subdiploid peaks and oligonucleosomal DNA fragmentation. Aside from inhibiting growth of myelomonocytic progenitors, adiponectin suppressed mature macrophage functions. Treatment of cultured macrophages with adiponectin significantly inhibited their phagocytic activity and their lipopolysaccharide-induced production of tumor necrosis factor alpha. Suppression of phagocytosis by adiponectin is mediated by one of the complement C1q receptors, C1qRp, because this function was completely abrogated by the addition of an anti-C1qRp monoclonal antibody. These observations suggest that adiponectin is an important negative regulator in hematopoiesis and immune systems and raise the possibility that it may be involved in ending inflammatory responses through its inhibitory functions. (Blood. 2000;96:1723-1732)

Adiponectin↗
PubMed1978

[The influence of intraoperative autotransfusion (IAT) on plasmaproteins in patients with posttraumatic intraabdominal bleeding or hemorrhage during vascular surgery (author's transl)].

In 29 patients (12 vascular and 17 trauma cases) the effect of intraabdominal bleeding and surgical management under intraoperative autotransfusion on several plasmaproteins was examined. The following parameters were monitored immediately before and after autotransfusion as well as 24, 48, 72 hours and one week later, in the thawed serum: 1. albumen and the carrier proteins prealbumen, transferrin, retinol-binding protein, 2. acute phase reactants: c-reactive protein coeruloplasmin, haptoglobin, 3. fractions of complement: C1q, C3c, C5 and C 3-activator, 4. serum-cholinesterase. With usual treatment by infusion of electrolyte solutions during operation and the following days, and further applicated blood transfusion, plasma and fresh frozen plasma by clinical needs, while the immediate blood loss during operation was replaced by autotransfusion, there was no change in preoperative dates. Only at the 3rd day the typical picture of catabolic situation of the postoperative period was observed in vascular cases and not at all in trauma cases. Thus the changes were closely related to the preexisting disease or state of shock, without further detoriation by intraoperative autotransfusion. 7 days later a sometimes overshooting normalization of the parameters was observed. Only cholinesterase remained extremely low, especially in vascular cases.

Abdominal Injuries↗
PubMed2001

Endothelial cells, megakaryoblasts, platelets and alveolar epithelial cells express abundant levels of the mouse AA4 antigen, a C-type lectin-like receptor involved in homing activities and innate immune host defense.

Phagocytic complement C1q receptor (C1qRp) and thrombomodulin (TM, CD141), are two key members of a novel family of lectin receptors involved in cell-cell interactions and innate immune host defense. We report here that the mouse homologue of human C1qRp (AA4) and TM are derived from a common ancestor on the basis that both genes co-localized to the same region of the chromosome 2 and also because they share similar domain composition and organization. Moreover, we found that mouse AA4 was localized to sites known to express TM. Mouse AA4 was identified by Western blot as a heavily glycosylated protein (110 kDa) expressed in all tissues tested. Brain and spleen expressed an additional 130-kDa band. Immunoperoxidase and double-immunofluorescence experiments showed that, surprisingly, the major site of AA4 expression in all tissue tested is on endothelial cells and that despite the apparent involvement of AA4 in the phagocytic response, it is not expressed by tissue macrophages. In contrast, megakaryoblasts (in bone marrow and spleen) and platelets expressed abundant levels of AA4 stored in cytoplasmic vesicles. Interestingly, alveolar epithelial cells (lung) but not other epithelia (e.g. uterus) were strongly stained for AA4. Although AA4 has been described on all hematopoietic progenitors, we found that only circulating immature B cells, monocytes and NK cells but not T cells and neutrophils expressed AA4.

Amino Acid Sequence↗
PubMed1990

Trimer and tetramer complexes containing C1 esterase inhibitor, C1r and C1s, in serum and synovial fluid of patients with rheumatic disease.

During activation, the first component of complement C1q (C1r-C1s)2 is dissociated in conjunction with the formation of complexes containing C1 esterase inhibitor (C1-INH). Trimer complexes, with zymogen C1s associated with a firm C1-INH-C1r complex (C1-INH-C1r-C1s) can be distinguished from tetramer complexes C1-INH-C1r-C1s-C1-INH) in which C1-INH is firmly bound to both proteases. In the present study a two-stage electroimmunoassay was developed for the specific measurement of C1-INH-C1r-C1s. In the first step, C1-INH and its complexes were immunoprecipitated with anti-C1-INH during electrophoresis in the presence of Ca2+. In the second step, C1s contained in C1-INH-C1r-C1s was dissociated in the presence of EDTA and was measured by immunoprecipitation with anti-C1s. C1-INH-C1r-C1s were consistently found in normal sera. Normal sera did not contain C1-INH-C1r-C1s-C1-INH as assessed with a previously described ELISA procedure. Sera and synovial fluids from two groups of patients with inflammatory arthritis were investigated. In rheumatoid arthritis patients (n = 15) C1-INH-C1r-C1s complexes were usually found at high concentration both in serum and synovial fluid. C1-INH-C1r-C1s-C1-INH complexes were also present with values that were higher in synovial fluid than in serum, in accord with previous findings of classical pathway activation in the inflamed joints of the patients. Patients with spondylarthritic syndromes (n = 7) had serum and synovial fluid C1-INH-C1r-C1s concentrations that were comparable to those of the rheumatoid arthritis patients. If at all present, C1-INH-C1r-C1s-C1-INH were detected in trace amounts. Thus, C1 activation in patients with spondylarthritic syndromes appeared to be efficiently controlled at the C1r level. Distinguishing between C1-INH-C1r-C1s and C1-INH-C1r-C1s-C1-INH may prove of value in further studies of the activation and control of C1 in disease.

Animals↗
PubMed1986

Circulating immune complexes in Meniere's disease.

Sixty-six patients with Meniere's disease were studied for possible general immunologic abnormalities. The disease was bilateral in 20 cases, causing active symptoms in 49. Thirty-six healthy control subjects were also studied. Immune activity was assessed by quantitative measurement of the circulating immune complexes, serum immunoglobulin assay, and acetate electrophoresis, and by an autoantibody screen to a battery of ten general tissue antigens. Thirty-six (54.5%) of the 66 patients with Meniere's disease were found to have significantly raised circulating immune complex levels compared with one (2.9%) of the 36 controls. A statistically significant increased incidence of autoantibodies was also found in the Meniere's group.

Adolescent↗
PubMed2002

The role of complement receptors type 1 (CR1, CD35) and 2 (CR2, CD21) in promoting C3 fragment deposition and membrane attack complex formation on normal peripheral human B cells.

Normal human B lymphocytes are known to activate the alternative pathway (AP) of complement, leading to C3-fragment deposition and membrane attack complex (MAC) formation. The process is mediated via complement receptor type 2 (CR2, CD21), with complement receptor type 1 (CR1, CD35) playing a subsidiary role. In this study, we examine the relative contributions of CR1 and CR2 to the deposition of C3 fragments and MAC on B lymphocytes under circumstances where all complement pathways are operational. C3-fragment deposition and MAC formation were assessed on human peripheral B lymphocytes in the presence of 30% autologous serum. Blocking the CR2 ligand-binding site with monoclonal antibody (mAb) FE8 resulted in significant reduction (37.9+/-11.9%) in C3-fragment deposition, whereas MAC formation was only marginally affected (12.1+/-22.2% reduction). Blocking the CR1 binding-site resulted in significant reduction of both C3-fragment deposition (22.0+/-14.5%) and MAC formation (47.4+/-13.8%). Both the lack of CR2 influence on MAC formation and the promotion of C3-fragment deposition by CR1 are in striking contrast to the situation where only the AP is operational. The presence of erythrocytes (E) bearing CR1, however, markedly reduced both C3-fragment deposition and MAC formation. Our data suggest that C3-fragment deposition and MAC formation on B lymphocytes in vivo may involve both AP and classical pathway activation, with CR1 contributing significantly to the latter. On the other hand, the presence of extrinsic CR1, on E, may serve to limit spontaneous MAC formation and thereby ensure cell survival in the circulation.

B-Lymphocytes↗
PubMed1989

Solitary plasmacytoma of the skull revealed by a mononeuritis multiplex associated with immune complex vasculitis.

We describe a patient with solitary plasmacytoma of the skull, in whom mononeuritis multiplex was the presenting manifestation. Some features of the POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal [M] protein, skin changes), including thrombocytosis, were found. Muscle and nerve biopsies disclosed a small vessel hypersensitivity-type vasculitis and complement-fixing immune complex deposits in vessel walls. Removal of the plasmacytoma resulted in clinical improvement and clearance of the vasculitis and immune complex deposits.

Adult↗
PubMed1992

Selective inhibition of immune complex trapping by follicular dendritic cells with monoclonal antibodies against rat C3.

The role of complement component C3 in the trapping of immune complexes by follicular dendritic cells (FDC) was studied in the rat, by means of the C3-specific monoclonal antibody ED11. Immunocytochemistry revealed the presence of C3 on FDC, where it co-localized with trapped peroxidase anti-peroxidase complexes. Furthermore, C3 was detected on reticular cells occupying the T cell areas of peripheral lymphoid organs, which are not involved in the handling of immune complexes. The in vivo administration of anti-C3 abolished the trapping of immune complexes in splenic follicles, but was unable to release preexisting complexes from the FDC. Trapping of immune complexes was also prevented by treatment of rats with cobra venom factor (CoVF). While CoVF caused massive depletion of C3 from serum, ED11 treatment had no such effect. The effect of anti-C3 appeared at least in part to be due to an inhibition of complement activation by immune complexes. We also analyzed earlier stages of the trapping process, with respect to their C3 dependence. Upon systemic injection immune complexes are initially observed in the marginal zone. Administration of anti-C3 reduced this localization, indicating a role for C3 in the entry of immune complexes into the spleen. Our results confirm experiments in CoVF-treated animals and extend the evidence for a role of C3 in the follicular trapping process using anti-C3 in vivo. The mechanism of immune complex trapping and the role of complement therein is discussed.

Animals↗
PubMed1982

Complement components in kidney allograft recipients: relationship to cytomegalovirus infection.

Serum complement profiles of 19 renal transplant recipients were studied serially before and after renal transplantation to determine if there is any relationship between cytomegalovirus (CMV) infection and alteration in the serum complement (C) levels. Most patients had low serum C3 and C4 levels before transplantation, but afterwards these levels increased in some patients. Clq was elevated before and after transplantation. Factor B was low before transplantation, but after surgery, its level approached normal in patients without cytomegalovirus viremia, whereas in those with viremia, Factor B level became even more depressed. Circulating Factor B fragments were found in the sera of five out of seven patients with active cytomegalovirus infection, which suggests activation of the alternative pathway possibly related to active CMV infection.

Adult↗
PubMed1996

Perforant path transection induces complement C9 deposition in hippocampus.

The presence of complement system proteins in amyloid plaques and the up-regulation of several complement mRNAs in neurons and glial cells in affected brain regions during Alzheimer disease (AD) provided a basis for further examination of complement protein expression in a rodent lesion model of AD. Perforant path transection in rats was used as a model for the degeneration of entorhinal cortex (EC) layer II neurons and the consequent deafferentation of the hippocampus that occurs during AD. Immunostaining for C9, a key terminal component of the complement cascade membrane attack complex (MAC), showed extracellular C9 deposition in parenchyma around the EC wound and in hippocampus as early as 1 day, and disappeared by 14 days postlesion. Apoptosis of EC layer II neurons was seen and was presumably due to severing of their axonal projections to the hippocampus by the transection lesion. However, apoptotic EC layer II neurons were not immunostained by anti-rat C9 antibody, suggesting complement was not involved in inducing apoptosis. In the deafferented hippocampus, extracellular C9 immunostaining was localized to the dentate gyrus middle molecular layer, a region of synaptic loss, dendritic degeneration, and early synaptogenesis. In addition, intracellular C9 immunostaining was seen only in select hippocampal interneurons. Dentate gyrus granule neurons and pyramidal neurons were not C9 immunostained. Clusterin (SGP-2), a soluble inhibitor of the MAC that is up-regulated in AD, was also detected in the wound area (extracellular), the dentate gyrus middle molecular layer (extracellular), and intracellularly in scattered hippocampal interneurons. The data support the hypothesis that the complement system generally participates in responses to brain injury, as well as in AD.

Afferent Pathways↗