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PubMed1994

Immunohistological studies of complement activation after xenogeneic perfusion of a working heart model.

Transplantation of organs from one species to another leads to immediate hyperacute rejection. Activation of complement is one important factor involved in this process. Whether complement activation is induced by preformed natural antibodies (PNAbs) via the classical pathway or by an "activator surface" via the alternative pathway is unclear. In order to simulate the relevant clinical situation of animal donor/human recipient we perfused working porcine hearts ex vivo with human blood. This also offered the possibility to study the process of complement activation in a precisely defined system with human complement proteins. PNAb titer and complement lytic activity of the plasma were measured. Immunohistological stainings for IgG, IgM, C1q, C4, C3d, C5-9, factor B, and properdin were performed on tissue sections of the left ventricle. PNAb titer almost totally disappeared within the first 5 min of perfusion. Complement lytic activity of the classical pathway decreased similarly within the first 3 h of xenogeneic and autologous perfusion from 70% to 40%. More detailed immunohistological studies revealed positive staining for C3d on endothelium and myocardium of ex vivo perfused xenogeneic hearts. Complement-induced cytotoxicity was proven by the presence of C5-9 (membrane attack complex). However, hardly any C1q and C4 could be found in the ex vivo xenogeneic perfused hearts. Staining for factor B was positive and proved activation via the alternative pathway. Beyond that, the presence of properdin binding even indicated an upregulation of the alternative pathway C3 convertase.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1980

Quantitation of C3 subcomponents on red cells coated with complement in vitro.

In order further to characterise and evaluate the reproducibility of human red cells coated with complement in vitro, the number of molecules of C3 subcomponents/red cell were determined by Scatchard analysis of equilibrium concentrations of bound and free antibody using (125)I-labelled goat anti-rabbit IgG. A 1:1 combining ratio was assumed. Red cells coated via the classical pathway had twice as much bound C3b and C3d as alternative pathway-coated cells. Assays using different anti-C3d sera gave different amounts of bound antigen, but results with any one antiserum versus one cell type were reproducible. Anti-C3d sera raised to C3d-tryp and to C3d-KAF detected significantly different amounts of bound C3d on the same cells. Both trypsinisation and serum KAF treatment of classical pathway-coated cells resulted in marked reduction of C3b molecules/cell (over 90% in both cases). Similar reduction in bound C3b was seen after trypsinisation of alternative pathway-coated cells, but serum KAF treatment of such cells had no significant effect. K(0) values were lower with anti-C3c than with anti-C3d. Anti-C3d K(0) values with the various cells coated with complement in vitro were not statistically different (approximately 10(7) litres/mol), with the exception of trypsinised alternative pathway-coated cells (approximately 10(8) litres/mol, the same order of magnitude observed with cells coated with C3d in vivo). A non-linear relationship between antiglobulin titre and antigen strength was observed. The minimal number of C3d molecules/red cell detectable by agglutination with the various anti-C3d sera ranged from 200 to 670 molecules. The minimal number of C3b molecules detectable by agglutination was approximately 9000 molecules/cell.

Animals↗
PubMed1996

Neurofibrillary tangles of Guam parkinson-dementia are associated with reactive microglia and complement proteins.

Guamanian parkinsonism-dementia, locally described as bodig, is characterized by the widespread appearance of neurofibrillary tangles in cortical and subcortical areas. These tangles have similar regional distribution and immunohistochemical profile to those found in Alzheimer disease (AD). We studied the immunohistochemical staining of these tangles, as well as those of AD, using antibodies to complement proteins and related molecules. In bodig, as in AD, extracellular tangles were intensely decorated with antibodies to C1q, C4d and C3d, but not fraction Bb of factor B, properidin or immunoglobulins. This is evidence that the classical, but not the alternative complement pathway is activated on extracellular tangles and that the activation is independent of antibodies. Immunohistochemical staining for amyloid P, an in vitro activator of complement, was remarkably similar to that for the C1q, C4d and C3d in both bodig and AD. This was not the case for beta-amyloid protein (BAP), another in vitro complement activator. Positive staining was observed in only a minority of extracellular tangles in bodig and was only rarely observed in those of AD. BAP would therefore not appear to be a candidate for activating complement on extracellular neurofibrillary tangles. Reactive microglia and reactive astrocytes were closely associated with complement positive extracellular neurofibrillary tangles, indicating an inflammatory response similar to that seen in AD.

Adult↗
PubMed1980

Morphological and immunological definition of a malignant lymphoma derived from germinal-centre cells with cleaved nuclei (centrocytes).

Thirteen lymphomas consisting of one particular cell type were selected from 135 cases of non-Hodgkin's lymphoma. The lymphoma cells were mainly characterized by irregularly shaped nuclei and faintly stained cytoplasm. The growth pattern of the tumour was diffuse. Immunological phenotyping of suspended cells showed that the tumour cells, irrespective of whether they were isolated from lymphoma tissue or from lymphoma tissue or from peripheral blood of leukaemic cases, bore a dense layer of surface immunoglobulin, lacked cytoplasmic immunoglobulin and receptors for mouse erythrocytes, and expressed both complement-receptor subtypes (i.e., receptors for C3b and C3d) in all but one case. The exceptional case was C3b receptor-positive and C3d receptor-negative. The number of IgG-Fc receptor-bearing cells was usually small. There was a consistently small proportion of non-malignant T cells in the tumour tissue. A comparison of the properties of these lymphomas with those of other types of non-Hodgkin's lymphoma and of non-malignant lymphoid cells, shows that the cells of this type of lymphoma (a) differ morphologically and/or immunologically from the cells of all other known types of non-Hodgkin's lymphoma and (b) resemble centrocytes (cleaved follicular-centre cells) of reactive germinal centres. Thus, this type of lymphoma appears to be an entity that is closely related to, or even derived from, centrocytes.

Cytoplasm↗
PubMed1985

Comparison of peripheral blood lymphocyte C3 receptor capping properties in patients with chronic lymphocytic leukemia and lymphoma.

Bacteria-antibody complexes were used to study capping of receptors for the activated third component of complement on peripheral blood lymphocytes. The impairment of C3d receptor capping improves in patients with chronic lymphocytic leukemia responding to therapy, but this does not necessarily correspond to the fall in peripheral lymphocytosis. Following lymphapheresis, increased capping appears to be due to selective removal of noncapping cells, but the mechanisms of improvement remain unexplained following other therapeutic measures. Lymphoma capping at 37 degrees C was normal in untreated patients but impaired after treatment, suggesting that this is related to the therapy itself. A high proportion of lymphocytes had receptors in the capped configuration in the basal state before incubation. In non-Hodgkin's lymphoma this was unrelated to treatment status, but it occurred only in untreated patients with Hodgkin's lymphoma with no further increment in capping after incubation. These receptors may exist in the aggregated state without the addition of exogenous ligand.

Complement C3↗
PubMed1979

Decreased heat-labile opsonic activity and complement levels associated with evidence of C3 breakdown products in infected pleural effusions.

Heat-labile opsonic activity was measured simultaneously in serum and pleural fluid of patients with transudates, infectious exudates (with positive or negative bacterial culture) and neoplastic exudates, using two different complement-dependent phagocytic tests: the killing of Staphylococcus aureus Wood 46 variant strain (K50 opsonic titers) and the assessment of ingestion rate of endotoxin-coated paraffin particles (Oil Red 0 uptake test). K50 opsonic titers were lower in culture-positive pleural effusions as compared to culture-negative (P < 0.002) or neoplastic effusions (P < 0.002). These results were corroborated by the Oil Red 0 uptake test. The data obtained with the two assays showed a significant correlation (P < 0.001). The hemolytic activity of complement (CH50) as well as the levels of C3 breakdown product, C3d, were measured in the same sera and pleural fluid samples and in an additional group of patients with pleural effusions of the same etiology. Effusions with positive cultures showed lower CH50 values (P < 0.01) and higher C3d values (P < 0.05) when compared to culture-negative pleural fluids. Finally, evidence for immune complexes in pleural effusions and sera was looked for by determination of Clq binding activity. Levels were higher in culture-positive effusions when compared to culture-negative fluids (P = 0.005).K50 opsonic titers showed a positive correlation with CH50 values (P < 0.001) for all fluids tested. Similarly Clq binding activity correlated with C3d levels in effusions of infectious origin (P = 0.05). Recovery experiments using the various bacterial species isolated from culture-positive pleural effusions showed evidence of complement inactivation upon incubation with pooled sera at concentrations of 10(7)-10(8) microorganisms/ml. These results indicate that one important reason for bacterial persistence in empyema may be decreased opsonization secondary to local consumption of complement.

Adult↗
PubMed1981

Induction of complement receptor expression in cell lines derived from human undifferentiated lymphomas. II. Characterization of the induced complement receptors and demonstration of the simultaneous induction of EBV receptor.

We have studied the specificity of complement receptors induced by theophylline in 2 cell lines derived from undifferentiated lymphomas, one of Burkitt's type, and compared it to that of complement receptors in other cell types. Both C3b and C3d receptors were induced. The induced C3b receptor differed from the C3b receptor of mature normal lymphocytes, polymorphonuclear leukocytes and the cells of a nodular lymphoma in 2 respects. Firstly, it bound C3b much less avidly (by a factor of several hundred-fold) and secondly, we were unable to demonstrate C4b binding. EBV receptors were induced at the same time as complement receptors, and permitted the conversion of a greater fraction of cells to EBNA positivity after experimental infection with EBV. The induction of receptors was not associated with a change in the fluidity of the plasma membranes and our data do not favor a different orientation of induced receptors within the membrane as compared to receptors of other cell types--a potential explanation for the different specificities. Our findings are consistent with the possibility that the complement receptors of lymphocyte precursors differ from these of mature lymphocytes.

Binding, Competitive↗
PubMed1975

Specificity of human lymphocyte complement receptors.

Erythrocytes, bone marrow-derived lymphocytes, monocytes, and granulocytes were shown to have a receptor activity for C4. Theis C4 receptor activity was studied in relation to the previously identified C3b and C3d receptors. By assay for inhibition of rosette formation by fluid-phase complement (C), only two different lymphocyte C receptors were demonstrated. The immune adherence receptor, the only one of the two shared in common with erythrocytes, was specific for C4 or the C3c region of C3b, but was unreactive with C3d. The other lymphocyte receptor, the C3d receptor, was specific for C3d fragments, but would also react to a lesser extent with the C3d region of uncleaved C3b. ThC3d receptor did not react with either C3c or C4. This specificity of the C3d receptor allowed certain cells which contained only C3d receptors to form rosettes with EAC1-3b and EAC1-3d, but not with EAC14. However, because C3d receptors bound EAC1-3d or C3d fragments more firmly than they did EAC1-3b or C3b fragments, many other types of cells containing only C3d receptors, formed rosettes with EAC1-3d but not with EAC1-3b. Erythrocytes and those lymphocytes which contained only immune adherence receptors, formed rosettes with EAC14 and EAC1-3D but not with EAC1-3d. A double-label assay was devised for the simultaneous detection of both types of C receptors on individual lymphocytes. This assay involved fluorescence labeling of one of the two C receptors with soluble C fragments in combination with the usual rosette method for labeling the other type of C receptor. With this double-label assay, it was observed that the two different lymphocyte C receptors capped independently and thus were located on different molecules which could each move through the fluid membrane matrix independently of the other.

Animals↗
PubMed1996

Human immune response to pneumococcal polysaccharides: complement-mediated localization preferentially on CD21-positive splenic marginal zone B cells and follicular dendritic cells.

A functionally intact spleen with a marginal zone, containing B cells with high density of surface C3d-receptors (CD21), is essential for the ability to induce a primary immune response to thymus-independent type 2 (TI-2) antigens. Main representatives of natural TI-2 antigens are capsular pneumococcal polysaccharides (PPSs). In this study the localization of different types of PPS antigen is determined in human spleen tissue. Our findings indicate that a main type of TI-2 antigen, PPS, localizes preferentially in the marginal zone. PPSs show co-localization with C3, presumably C3d, at the surface of strongly CD21+ B cells equipped for rapid activation. This enables a rapid primary humoral response. The other main PPS localization at follicular dendritic cells in germinal centers, relevant for isotype switching of anti-PPS antibodies, does not seem to be dependent on the presence of specific immunoglobulin. This may explain the finding of specific IgG in an early stage after antigenic challenge. It seems likely that complement C3 fragments (likely C3d), bound to PPSs, enable PPS localization at B-cell and follicular dendritic cell surfaces by binding to CD21, the C3d receptor.

Adolescent↗
PubMed1987

Complement component deposition in uteroplacental (spiral) arteries in normal human pregnancy.

There is conflicting evidence for the deposition of complement in spiral arteries in normal and abnormal human pregnancies. The immunogold silver staining (IGSS) technique was used to investigate the distribution of C1q, C3d, C4, C6 and C9 within the spiral arteries of formalin-fixed normal pregnancy hysterectomy specimens ranging in gestational age from 4 to 40 weeks. Deposition of complement components studied was observed in all cases suggesting classical pathway activation. Reactivity was not confined to vessels showing endovascular trophoblast though the latter showed a characteristic linear deposition subjacent to the trophoblast. Reactivity was most intense for C3d and C9. An appreciation of complement deposition as a feature of normal pregnancy is essential before significant immunopathology can be recognised in placental bed vessels in abnormal pregnancy.

Antigen-Antibody Reactions↗
PubMed1983

Complement studies in splenectomized patients.

Total haemolytic complement activity, C2, C5, total alternative pathway activity, factor B, and C3d were measured in 85 splenectomized patients from 1 month to 32 years after splenectomy. Furthermore the patients were investigated for circulating immune complexes. No major deficiencies of the complement factors were detected. In a few patients a reduced C2 level was caused by genetically determined defects or was due to complement consumption in conjunction with circulating immune complexes. The complement levels were normal in 2 patients who had survived overwhelming infections after splenectomy. C5 was elevated in a major proportion of the patients, and it is suggested that this might be caused by post-splenectomy monocytosis. Circulating immune complexes were found in 20% of all cases, irrespective of the presence of residual splenic tissue. Thus the commonly cited impairment of the complement system after splenectomy does not seem to be substantiated, and the deficient resistance against bacterial infections in splenectomized patients does not seem to include abnormalities of the complement system.

Adolescent↗
PubMed2000

Degeneration process of Lewy bodies in the brains of patients with dementia with Lewy bodies using alpha-synuclein-immunohistochemistry.

We investigated the degeneration process of Lewy bodies (LB) in the brains of dementia with Lewy bodies, using alpha-synuclein-immunohistochemistry. Intracellular LB, LB-related neurites and some extracellular LB were positively immunostained with anti-alpha-synuclein antibodies. Concentric LB-bearing neurons had no microglial involvement, while degenerated neurons with ill-defined LB displayed intense microglial involvement. The late stage of extracellular LB were immunoelectron-microscopically composed of loose aggregates of filamentous components with lost alpha-synuclein-immunoreactivity and penetrated astroglial processes. These findings suggest that microglias are involved during the stages from degenerated LB-bearing neurons to extracellular LB, while astroglias are involved during the stage of extracellular LB. Some intracellular LB were positive for anti-C3d and -C4d antibodies, suggesting that the classical complement pathway is activated in degenerated LB-bearing neurons, inducing microglial activation and neuronal death.

Aged↗
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↗
PubMed1973

Human lymphocytes bear membrane receptors for C3b and C3d.

Human peripheral blood lymphocytes have membrane receptors for EAC43b (sheep erythrocytes sensitized with antibody and complement) and also for EAC43d, obtained by treating EAC43b with C3b inactivator. Human granulocytes bind only EAC43b, C3 fragments obtained by limited trypsin digestion of purified human C3 display both C3b and C3d sites, since they inhibit rosette formation of lymphocytes with EAC43b and EAC43d. These findings raise the possibility that C3b and C3d receptor sites may be selectively distributed among normal subpopulations of B lymphocytes as well as among leukemic leukocytes.

Animals↗
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↗
PubMed1988

Activation of complement in IgA nephropathy.

Considerable evidence supports a role for the complement system in the pathogenesis of IgA nephropathy (IgAN). The alternative pathway components C3 and properdin (P) and the membrane attack complex (C5b-9) are generally found in the mesangial deposits in IgAN, while the classical pathway components C1q and C4 are usually absent. This pattern of immunofluorescence staining for complement components suggests activation of the alternative and terminal pathways in most patients. Despite normal serum concentrations of C3 and other complement proteins, fragments generated by activation of C3, including iC3b, C3d, and iC3b-C3d neoantigen, and sometimes C4, are often detected in plasma. We found that the severity of the histologic changes in the renal biopsy specimens correlated with plasma iC3b-C3d neoantigen concentrations as measured by an enzyme-linked immunosorbent assay. However, no other clinical feature correlated with the plasma concentrations of this neoantigen.

Complement Activation↗
PubMed1989

Defective expression of basement membrane-associated C3d,g in papulonodular basal cell carcinomas.

Recent studies in our laboratory have shown that C3d,g, a 41,000-Da fragment of the third component of complement, is present along the base of the lamina densa and in the sublamina densa region of normal human epidermal basement membrane, but absent from the skin of a patient with congenital C3 deficiency. In studies of human skin, papulonodular basal cell carcinomas have served as a useful model for the investigation of various basement membrane antigens and matrix proteins. To further investigate the presence of C3d,g within epidermal basement membrane as well as examine its relationship with other known basement membrane constituents, we have analyzed serial sections of ten papulonodular basal cell carcinomas by light and immunofluorescence microscopy. In these studies, C3d,g was either absent (N = 9) or minimumly detectable (N = 1) in tumor nest basement membranes. While bullous pemphigoid and KF-1 antigens were absent (N = 6 and N = 3, respectively) or significantly decreased (N = 4 and N = 7, respectively), epidermolysis bullosa acquisita antigen was routinely present though somewhat (N = 3) or moderately decreased (N = 3). Laminin and type IV collagen were expressed normally in all tumor nest basement membranes. All constituents, including C3d,g, were present in adjacent normal epidermal basement membrane of these tumor samples. This study has demonstrated antigenic alterations within each ultrastructural subregion of papulonodular basal cell carcinoma tumor nest basement membranes by identifying the virtual absence of C3d,g (sublamina densa) as well as a significant reduction in KF-1 (lamina densa) and bullous pemphigoid (lamina lucida) antigens. Moreover, the presence of laminin, type IV collagen, and epidermolysis bullosa acquisita antigen in tumor nest basement membranes suggests that these particular constituents neither cleave C3 nor act as essential binding sites for passive incorporation of this complement component in epidermal basement membrane. These studies give additional support to the hypothesis that C3d,g is a previously unrecognized constituent of normal epidermal basement membrane and does not represent passive incorporation of circulating C3 at this site in human skin.

Adult↗
PubMed1980

Assessment of complement binding by anti-D and anti-M antibodies employing labelled antiglobulin antibodies.

The presence of small amounts of C3d on freshly obtained normal red blood cells (RBC) was demonstrated by a radio-labelled antiglobulin technique; this increased 1.5-fold after incubation in fresh normal serum. No significant further increase in bound C3d was demonstrated for cDE/cDE, CDe/CDe, -D-/-D- RBC maximally sensitized with any of three potent anti-D antibodies. When anti-c, anti-D and anti-E antibodies were used in combination to sensitize cDE/cDE RBC, bound C3d increased by approximately 22%; however, a similar increase occurred with cde/cde RBC and was therefore considered non-Rh specific. Umbilical cord RBC from four infants severely affected by anti-D haemolytic disease of the newborn did not exhibit more bound C3d than cord RBC from normal controls. One serum containing IgM anti-M bound a small amount of complement in vitro; two IgG anti-M sera did not.

Antibodies, Anti-Idiotypic↗