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PubMedDate not supplied

Significance of glomerular deposition of C3c and C3d in IgA nephropathy.

BACKGROUND: Complement activation plays an important role in the pathogenesis of IgA nephropathy. The clinico-pathological significance of the glomerular deposition of complement breakdown products, C3c and C3d in IgA nephropathy remains to be clarified. METHODS: We examined the relationship between glomerular staining patterns of C3c and C3d and clinico-pathological findings with 163 patients with IgA nephropathy. Renal biopsy specimens were stained with C3c and C3d by immunofluorescence, and patients were divided into the following two groups: the intensity of C3c deposition stronger than C3d deposition, or equal to it (group A); the intensity of C3d deposition stronger than C3c deposition (group B). RESULTS: In group A, the incidence of severe hematuria (over 20 urinary red blood cells in high-power field microscope (x400)) or of higher urinary fibrinogen degenerated products (over 0.1 microg/ml) was significantly higher than that in group B. In addition, group A showed a significant decrease in the glomerular filtration rate. Group A also showed a significantly higher incidence of glomerular endocapillary proliferation than in group B. CONCLUSION: These findings suggest that the glomerular deposition of C3c is associated with the inflammatory active phase of glomeruli in IgA nephropathy.

Adolescent↗
PubMed1998

Linkages of innate and adaptive immunity.

The innate immune system is activated by pathogens or environmental antigens following their binding by recognition molecules such as mannan-binding lectin, C-reactive protein and the mannose receptor. Natural antibody, which represents a collection of germline-encoded antigen recognition molecules, is also important in recognition of pathogens and activation of the innate immune system via the classical pathway of complement activation. The major source of natural antibody is CD5+ B-1 cells which differ from conventional B cells (B-2 cells) firstly because they are thought to require contact with antigen for expansion and maintenance and secondly because in general they do not appear to undergo somatic hypermutation. We review results which support an important role for complement in maintenance of B-1 cells, the effect being mediated by B cell expression of complement receptors CD21 and CD35. We propose that complement and natural antibody are interdependent: clonal selection and expansion of CD5+ B-1 cells is dependent on contact with antigen coated by the complement component C3d, while efficient recognition of pathogens and activation of complement is dependent in a large part on natural antibody. This hypothesis is supported by the finding that mice deficient in CD21 and CD35 have a reduced number of CD5+ B-1 cells and are missing specificities for certain antigens commonly found in wild-type mice, such as lipopolysaccharide, Escherichia coli surface antigens and neoepitopes expressed on hypoxic intestinal endothelium.

Animals↗
PubMed1996

Immune attack on the Schwann cell surface in acute inflammatory demyelinating polyneuropathy.

The localization, mode of action, and roles of complement in the Guillain-Barre syndrome have been controversial. We used high-resolution immunocytochemistry to localize complement activation products in early stages of the acute inflammatory demyelinating polyneuropathy (AIDP) pattern of Guillain-Barre syndrome. Three AIDP subjects who were autopsied had had symptoms for 3 to 9 days at the time of death. Immunocytochemistry was performed on etched, epoxy resin-embedded sections, and the next thin section was compared by electron microscopy (thick/thin sections). Many fibers had a rim of the complement activation marker C3d and the terminal complement complex neoantigen C5b-9 along the outer surface of the Schwann cells. Ultrastructural analysis of these C3d-positive fibers showed mild vesicular changes of the outermost myelin lamellae. Vesicular degeneration was seen before the invasion of macrophages into the myelin, and was the predominant change in the subject with symptoms for 3 days. C3d staining was not found on myelin membranes. The results suggest that at least some forms of AIDP are complement mediated. We speculate that complement is activated by antibody bound to epitopes on the outer surface of the Schwann cell and that the resulting complement activation initiates the vesiculation of myelin.

Acute Disease↗
PubMed2003

Association between complement factor H and proteoglycans in early human coronary atherosclerotic lesions: implications for local regulation of complement activation.

OBJECTIVE: Complement activation has been suggested to play a role in atherogenesis. To study the regulation of complement activation in human coronary atherosclerotic lesions, we examined the spatial relationships between the major complement inhibitor, factor H, and the complement activation products C3d and C5b-9. METHODS AND RESULTS: In early lesions (American Heart Association types II and III), factor H was immunohistochemically found in the superficial proteoglycan-rich layer in association with numerous macrophages and C3d, whereas C5b-9 was found deeper in the intima, where factor H was virtually absent. In vitro experiments involving surface plasmon resonance and affinity chromatography analyses demonstrated that isolated human arterial proteoglycans bind factor H, and functional complement assays showed that glycosaminoglycans inhibit the complement activation induced by modified low density lipoprotein or by a foreign surface. CONCLUSIONS: The present observations raise the possibility that proteoglycans, because of their ability to bind the major complement inhibitor factor H, may inhibit complement activation in the superficial layer of the arterial intima. In contrast, deeper in the intima, where factor H and proteoglycans are absent, complement may be activated and proceed to C5b-9. Thus, the superficial and the deep layers of the human coronary artery appear to differ in their ability to regulate complement activation.

Adult↗
PubMed2004

Impact of in vivo complement activation and cryoglobulins on graft outcome of HCV-infected renal allograft recipients.

BACKGROUND: Chronic hepatitis C virus (HCV) infection is closely associated with mixed cryoglobulinemia. Cryoglobulins can activate complement leading to vascular damage. We examined whether cryoglobulinemia and complement turnover is associated with HCV infection in renal transplant recipients and whether this has an adverse effect on graft outcome. METHODS: Sera and fresh plasma from 31 HCV-RNA-positive patients after renal transplantation (group I) were studied for cryoglobulins, complement hemolytic activity (CH50), and complement split product C3d. In total, 80 HCV-negative renal transplant recipients (group II) and 72 untreated patients with chronic hepatitis C (group III) without renal transplantation served as controls. RESULTS: Cryoglobulins were detected in 45, 28, and 26% of the patients in group I, II, and III, respectively. A high cryocrit ( > 5%) was present only in patients of group III (p < 0.01%). Mean CH50 values were lower and C3d levels higher in HCV-positive patients (group I and III) compared with HCV-negative patients (p < 0.0001). Cryoglobulins were not associated with extrahepatic manifestations or graft dysfunction, except in five patients of group III demonstrating cryoglobulinemic vasculitis. HCV-positive renal transplant recipients with signs of complement activation showed a significantly greater increase of serum creatinine (0.88 +/- 1.14 mg/dL) when compared with baseline than patients without complement activation (0.34 +/- 0.37 mg/dL; p = 0.035). There was also a tendency toward a higher extent of proteinuria in patients with complement activation (1.38 +/- 2.17 g/d vs. 0.50 +/- 0.77 g/d; p = 0.25, NS). CONCLUSIONS: Cryoglobulins are common in renal allograft recipients, but do not affect graft function. However, complement activation appears to be involved in chronic allograft dysfunction in HCV-infected recipients.

Adult↗
PubMed1999

Complement activation and expression of membrane regulators in the middle ear mucosa in otitis media with effusion.

The aetiopathogenesis of chronic otitis media with effusion (OME) in children is not yet fully understood. OME is characterized by metaplasia of the epithelium and accumulation of sticky, glue-like effusion in the middle ear containing different mediators of inflammation, including activation fragments of the complement system. Here we examined whether the fluid phase complement activation is reflected in the middle ear mucosa and how the mucosa is protected against the cytolytic activity of complement. Mucosal biopsies from 18 middle ears of children with a history of chronic OME were taken. The biopsies were analysed by immunofluorescence microscopy after staining for complement fragments iC3b/C3c, C3d and C9, and regulators membrane cofactor protein (MCP; CD46), decay-accelerating factor (DAF; CD55) and protectin (CD59). There was a strong staining for iC3b/C3c, and a weaker one for C3d and C9 on the surface of the middle ear epithelial cells of OME patients but not in controls without OME. MCP was expressed on the hyperplastic three to four outer cell layers of the epithelium, while CD59 was expressed throughout the middle ear mucosa. The results suggest a strong ongoing complement activation and consequent inflammation in the middle ear cavity. Unrestricted complement damage of the epithelial lining is prevented by the strong expression of MCP and CD59.

Antigens, CD↗
PubMed1994

Classical pathway complement activation in Kawasaki syndrome.

In this study the complement breakdown products C3d, C4d, Bb and membrane attack complex were measured in plasma of patients with Kawasaki syndrome. The results suggested strong activation of the classical activation pathway. However, there was no significant decrease in hemolytic titer or in the concentrations of the intact proteins C3, C4, and B. The relationship between the serum concentrations of cytokines and complement components was examined; increased interleukin-6 concentration on the fifth day after the onset of fever was found to correlate well with the C3 and B concentrations in serum obtained 5 days later. We conclude that complement activation occurred in Kawasaki syndrome via the classical pathway but that the inflammatory reaction was accompanied by increased production of complement components. As a result, there was increased formation of activation products without changes in the serum complement levels.

Child, Preschool↗
PubMed1998

X-ray crystal structure of C3d: a C3 fragment and ligand for complement receptor 2.

Activation and covalent attachment of complement component C3 to pathogens is the key step in complement-mediated host defense. Additionally, the antigen-bound C3d fragment interacts with complement receptor 2 (CR2; also known as CD21) on B cells and thereby contributes to the initiation of an acquired humoral response. The x-ray crystal structure of human C3d solved at 2.0 angstroms resolution reveals an alpha-alpha barrel with the residues responsible for thioester formation and covalent attachment at one end and an acidic pocket at the other. The structure supports a model whereby the transition of native C3 to its functionally active state involves the disruption of a complementary domain interface and provides insight into the basis for the interaction between C3d and CR2.

Amino Acid Sequence↗
PubMed1992

Expression of the C3d-binding protein (CR2) from Candida albicans during experimental candidiasis as measured by lymphoblastogenesis.

The complement C3d-binding protein (CR2) of Candida albicans has been purified by immunoaffinity chromatography, and its specificity has been characterized by immunoblotting with monoclonal antibodies to the C. albicans CR2 and the mammalian CR2. Recent studies with immunoelectron microscopy indicated that the CR2 was expressed during a systemic infection in a murine model of candidiasis. As a continuation of these observations, the immunogenicity of the C. albicans CR2 was investigated in a lymphoblastogenesis assay. Lymph node cells as well as splenic lymphocytes from mice infected subcutaneously with viable blastoconidia of C. albicans reacted to the C. albicans CR2 to a significantly greater extent than did lymphocytes from uninfected mice (P less than 0.01). The maximum stimulation of splenic lymphocytes by the purified receptor occurred at a concentration of 0.54 micrograms of protein per ml after 72 h of incubation of lymphocytes and receptor. Also, splenocytes from infected or CR2-immunized mice exhibited significantly reduced responses to the T-cell-dependent mitogen phytohemagglutinin (P less than 0.01). These data indicate that lymphocytes from infected mice respond to the C. albicans CR2 in a lymphoproliferation assay to a greater extent than do lymphocytes from uninfected mice, indicating that the CR2 is expressed in vivo.

Animals↗
PubMed1984

A simple method for quantitative measurement of C3d in human plasma.

We describe a simple and reliable method for quantitating C3d in human plasma. The method rests on the finding that native C3 and its activation/inactivation product C3c bind to Concanavalin A, whereas C3d does not. Rocket affinoimmunoelectrophoresis with Con-A Sepharose incorporated into an intermediate gel permits quantitation of free C3d in 2-20 microliters aliquots of EDTA-plasma without any manipulation prior to sample application. Using this method, we found that the level of circulating C3d in plasma of 30 healthy donors was usually well below 3% of maximally convertable C3d.

Complement C3↗
PubMed2001

Complement activation in patients with rheumatoid arthritis mediated in part by C-reactive protein.

OBJECTIVE: Complement activation in patients with rheumatoid arthritis (RA) is considered to be triggered by immune complexes. Recently, it was shown that C-reactive protein (CRP) can activate the complement system in vivo. We therefore hypothesized that part of the complement activation in RA is due to CRP. The aim of this study was to investigate CRP-mediated complement activation in RA, and to assess its correlation with disease activity. METHODS: Complexes between CRP and the activated complement components C3d (C3d-CRP) and C4d (C4d-CRP), which reflect CRP-mediated complement activation, as well as the overall levels of activated C3 and C4 were measured in the plasma of 107 patients with active RA and 177 patients with inactive RA. Inactive RA was defined according to the American College of Rheumatology criteria for clinical remission. Disease activity was assessed by the modified Disease Activity Score (DAS28). RESULTS: Plasma levels of C3d-CRP and C4d-CRP were increased in the majority of the patients, and were significantly higher in patients with active disease versus those with inactive RA (P < 0.001). In patients with active RA, the plasma concentrations of C3d-CRP and C4d-CRP correlated significantly with the DAS28 (Spearman's rho 0.61 and 0.55, respectively; P < 0.001), whereas these correlations were less pronounced in patients with inactive RA (Spearman's rho 0.28 [P < 0.001] and 0.25 [P = 0.001], respectively). Levels of activated C3 and C4 were also increased in the majority of the patients, particularly in patients with active RA. CONCLUSION: Part of the activation of complement in RA is mediated by CRP and is correlated with disease activity. We suggest that this activation is involved in the pathogenesis of RA.

Adolescent↗
PubMed1996

Antineutrophil cytoplasmic antibodies (ANCA) in rheumatoid arthritis: a prospective study.

To investigate a possible relationship between the presence of antineutrophil cytoplasmic antibodies (ANCA), rheumatoid factor (RF), antinuclear antibodies (ANA), complement, disease activity and disease severity, 111 clinically well-documented RA patients were studied prospectively for ANCA, RF, ANA, C-reactive protein (CRP), total haemolytic complement (CH50) and complement split product C3d. Disease activity and severity were also assessed clinically, as well as anamnestically, using the Hannover Activity of Daily Living Questionnaire, the functional Steinbrocker grades, and numeric and verbal rating scales. At a serum dilution of 1:50, 20% of the 111 sera showed predominantly an atypical perinuclear staining pattern. There was no correlation between ANCA positivity and serological markers, disease activity and disease severity. Regarding previous therapies with disease-modifying antirheumatic drugs, ANCA+ patients took sulphasalazine significantly more often than ANCA- patients.

Activities of Daily Living↗
PubMed1975

Immunologic cell features in lymphocytic leukemias: a review.

Since four years, it has been possible to classify most cases of Chronic Lymphocytic Leukemia (CLL) as given to the expansion of abnormal B-lymphocytes. On the contrary, the T-cell class is apparently normal and the T cell extent in CLL-peripheral blood can be even greater than normal when taken as absolute value. The clonal nature theory of B-lymphocytes in CLL is substantiated by the fact that, in general, in every patient only one Ig light chain determinant is present. Again, when serum Ig monoclonality is present in CLL, it appears idiotypically identical to the Ig shown by the lymphocytes of the same patient. Among the most important B-lymphocyte abnormalities in CLL, there are: (a) fluorescence of surface Ig is usually less intense than that in normal subjects, and fluorescence intensity may vary not only from patient to patient, but also from cell to cell in the same patient; (b) the Fc-receptor can be lacking; (c) the C3b-receptor is not always present, or it is from 2 to 20 folds less frequent than the C3d-receptor, whereas normal human lymphocytes do not show any outstanding differences between the number of EAC rosette-forming cells either when tested with mouse complement (C3d-receptor) or with human complement (C3b-receptor); (d) the traffic capacity of peripheral-blood B-lymphocytes in CLL is quite defective. All the above-mentioned data, taken as a whole, suggest that CLL is in general given by the expansion of an abnormal clone of cells of B origin, arrested in their maturative development, non-responsive to the mitogen stimulation, accumulating in the peripheral-blood for a traffic deficiency.

Animals↗
PubMed1975

Lymphocyte immunological patterns in leukaemia: a review.

Investigation of the cell S--Ig in acute lymphocytic leukaemia (ALL), at the onset of relapse of the disease, shows quite marked differences from patient to patient according to the extent of the immunofluorescent-positive cells. They may vary from 0.5 to 25% or more. When these Ig-positive cells are treated with trypsin and then incubated "in vitro" for six hours, many of them are no longer Ig-positive, i.e. they do not synthesize Ig. It might be possible, that the membrane-Ig observed before trypsinization does not represent true Ig-determinants of mature B-cells (antibodies attached to leukaemia-specific determinants?). The extent of these features decrease in remission until their disappearance. Relationship between the cell immunological patterns and the treatment response in ALL could exist. In a group of ALL-patients under the same treatment, that is, vincristine and prednisone, the correlation between the course of the disease after the above-mentioned therapy showed quick and complete remission in patients with low percentage of Ig-positive cells (below 10%) and poor improvement (often without complete remission) in patients with higher percentage of Ig-positive cells. Among the most important B-lymphocyte abnormalities in chronic lymphocytic leukaemia (CLL) are the following: (a) fluorescence intensity may vary not only from patient to patient, but also from cell to cell in the same patient; (b) the Fc-receptor can be lacking; (c) the C3b-receptor is not always present, or it is from 2 to 20-folds less frequent than the C3d-receptor, whereas normal human lymphocytes do not show any outstanding differences between the number of EAC rosette-forming cells either when tested with mouse complement (C3d-receptor) or with human complement C3b-receptor); (d) the traffic capacity of peripheral-blood B-lymphocytes in CLL is quite defective. Results of the observations on lymphocytes in CLL, taken as a whole, suggest that CLL is in general given by the expansion of an abnormal clone of cells of B origin, arrested in their maturative development, non-responsive to the mitogen stimulation, accumulating in the peripheral-blood for a traffic deficiency. On the contrary, the T-cells class is apparently normal, and the T-cell extent in CLL-peripheral blood can be even greater than normal when taken as absolute value.

B-Lymphocytes↗
PubMed1983

Platelet-associated complement C3 in thrombocytopenic states.

Platelet-associated complement components C3, C3d and C4 (PAC3, PAC3d, PAC4) were quantitated by a modification of the platelet radioactive anti-IgG test using highly purified C3 antibodies in 74 patients with immune thrombocytopenia (ITP), 26 patients with presumed nonimmune thrombocytopenia (NTP), and 114 normal individuals. Elevated PAC3 levels were found in 26 out of 74 patients with ITP (35%) and in 10 out of 26 patients with NTP. Although the percentage of elevated PAC3 values was higher in thrombocytopenic patients than in nonthrombocytopenic patients, no statistically significant correlation existed between platelet counts and PAC3 levels, neither for ITP nor for NTP. However, such a relationship was demonstrable between PAC3 and platelet-associated IgG, both for ITP (P less than 0.05) as well as NTP patients (P less than 0.001). We conclude that elevated PAC3 values are not restricted to immune thrombocytopenias. Quantitative differences of PAC3 between ITP and NTP patients suggest that part of the PAC3 is immunologically mediated and has a role in the pathogenesis of autoimmune thrombocytopenias.

Adult↗
PubMedDate not supplied

Biochemical pathways of acute lung injury.

Complement fragments (C3, C3d, C5a), thromboxane B2 (TxB2), 6-keto-PGF1 alpha and immunoreactive trypsin (IRT) were measured in 98 patients at risk of developing the adult respiratory distress syndrome (ARDS): 53 multiple trauma, 28 abdominal surgery and 17 acute pancreatitis. Sixty-five of these patients developed ARDS: 30 multiple trauma, 19 abdominal surgery and 16 acute pancreatitis patients. Forty of the 65 ARDS patients and 9 out of the 33 non-ARDS patients died. Mean value of the C3d to C3 ratio was abnormal in both ARDS and non-ARDS patients. C5a-like activity was detected in 70 out of the 98 patients (49 ARDS and 22 non-ARDS patients). TxB2 abnormal values (greater than 100 pg . ml-1) were found in 70% of the patients, especially when sepsis occurred. No correlation could be made between abnormal 6-keto PGF1 alpha values and ARDS or sepsis. The mean peak IRT value was 675 micrograms . 1(-1) for ARDS patients and 274 micrograms . 1(-1) for non-ARDS patients (p less than 0.05). A firm correlation was also measured between IRT and sepsis (p less than 0.01). C5a-like activity was regularly detected soon after injury, while TxB2 and IRT tend to appear later in patients developing ARDS. Neither C3d/C3, nor C5a-like activity, nor TxB2, nor IRT are specific markers of ARDS, since they also appeared in severely ill patients who did not develop ARDS.

6-Ketoprostaglandin F1 alpha↗