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PubMed1977

Gingival fluid and serum in periodontal diseases. II. Evidence for cleavage of complement components C3, C3 proactivator (factor B) and C4 in gingival fluid.

1. C3 activation products C3c and C3d can be demonstrated in gingival pocket fluid from patients with severe periodontitis. 2. Quantitatively, C3d levels in GF are comparable to levels attained consequent to immune-complex and tryptic activation of human serum. 3. The alternate pathway of complement activation occurs in the periodontal pocket, as demonstrated by conversion of C3 proactivator (Factor B) to C3-activator Bb. 4. C4 is present in an altered form in some, but not all, GF's. This form is electrophoretically similar to that generated from serum by C1s and several proteolytic enzymes.

Complement C3↗
PubMed1990

Studies of C3d,g in normal human epidermal basement membrane.

Recent studies in our laboratory have demonstrated that polyclonal as well as monoclonal antibodies directed against C3d,g, a specific 41,000-Da fragment of the third component of complement, bind normal human epidermal basement membrane in a continuous pattern. No such reactivity is present within dermal microvascular basement membranes. By direct immunofluorescence microscopy, anti-human C3d,g antibodies bind the base of the cleavage plane in 1 M NaCl split human skin. By immunoelectron microscopy, anti-human C3d,g reactivity is found along the base of the lamina densa and in the sublamina densa region. Control antibodies directed against human C3, C3c, C5, IgG, IgA, or IgM do not bind normal human epidermal basement membrane or identify in situ deposits of immune complexes in multiple samples of normal human skin that are all positive for C3d,g. Preabsorption of monoclonal or polyclonal anti-human C3d,g antibodies with purified human C3d completely blocks these reagents' epidermal basement membrane reactivity. Studies of skin samples from a patient with congenital C3 deficiency reveal that anti-human C3d,g antibodies do not bind this subject's epidermal basement membrane. Moreover, in vitro treatment of this patient's skin with normal serum, aged serum containing C3d,g, purified human C3, or zymosan-serum reaction mixtures does not restore epidermal basement membrane anti-human C3d,g binding. Studies of other primate tissues demonstrate that C3d,g is not restricted to basement membranes of stratified squamous epithelia as it is also present within renal tubule and glomerular basement membranes. While a recent study has demonstrated that C3d binds laminin in vitro, our investigations show a difference in both the regional and ultrastructural distribution of laminin and C3d,g in normal human skin. Furthermore, C3d,g is absent from laminin-rich basement membranes of papulonodular basal cell carcinomas. These findings suggest that C3d,g is not passively incorporated within selected epithelial basement membranes but rather is a previously unrecognized normal constituent. Basement membrane-associated C3d,g may play a role in adhesive interactions between leukocytes and matrix proteins. Moreover, a C3d,g binding site(s) in selected epithelial basement membranes may account for the accumulation of C3 containing immune complexes in such tissues.

Animals↗
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↗
PubMed1998

Disseminated intravascular coagulation in association with the delayed rejection of pig-to-baboon renal xenografts.

BACKGROUND: Intravascular fibrin deposition and platelet sequestration occur with porcine xenograft rejection by baboons. Disseminated intravascular coagulopathy may arise either as a direct consequence of the failure to fully deplete xenoreactive natural antibodies and block complement, or because of putative cross-species molecular incompatibilities in this discordant species combination. METHODS: Three baboons were conditioned with retrovirally transduced autologous bone marrow to induce tolerance to swine antigens. Xenoreactive natural antibodies and complement were depleted by plasmapheresis and the use of Gal alpha1-3Gal column adsorptions; baboons were then splenectomized and underwent renal xenografting from inbred, miniature pigs. Soluble complement receptor type-1 with protocol immunosuppression (mycophenolate mofetil, 15-deoxyspergualin, steroids, and cyclosporine) was administered. RESULTS: A bleeding diathesis was clinically evident from days 5 to 12 after transplantation in two baboons. Low levels of circulating C3a, C3d, and iC3b were measured despite the absence of functional circulating complement components. Profound thrombocytopenia with abnormalities in keeping with disseminated intravascular coagulopathy were observed. Prolongation of prothrombin and partial thromboplastin times was accompanied by evidence for tissue factor-mediated coagulation pathways, high levels of thrombin generation (prothrombin fragment F(1+2) production and thrombin-antithrombin complex formation), fibrinogen depletion, and production of high levels of the fibrin degradation product D-dimer. Importantly, these disturbances resolved rapidly after the excision of the rejected xenografts in two surviving animals. Histopathological examination of the rejected xenografts confirmed vascular injury, fibrin deposition, platelet deposition, and localized complement activation. CONCLUSIONS: Systemic coagulation disturbances are associated with delayed xenograft rejection.

Animals↗
PubMed2004

Immunological analysis in paediatric HIV patients at different stages of the disease.

There are only few clinical studies on complement in well-defined (or characterized) paediatric HIV patients. Aim of this study was to evaluate the complement system and immunoglobulins in HIV-infected children and to correlate data to stage of disease. Blood samples of 127 HIV-infected children (11-134 months; 62 male : 65 female) were collected in order to evaluate humoral immunity. The patients were classified according to CDC clinical (N-asymptomatic; A-mild symptoms such as common recurrent infections; B-moderate symptoms such as Candidiasis and herpes infections, meningitis, sepsis and anaemia; C-severe symptoms such as opportunistic infections and neoplasia) and with respect to immunological criteria (T CD4(+) cell count). Analysis of complement system included the classical (CH50), alternative (APH50) pathway activities and plasma concentrations of mannan-binding lectin (MBL), of the C4 allotypic variants C4A and C4B. (ELISA), and of the C3 split product C3d (rocket immunoeletrophoresis). Immunodiagnosis also included CD4(+) and CD8(+) lymphocyte count and immunoglobulin concentrations. Complement activation and consumption was observed in all patients correlating with disease activity. Activated classical and alternative pathways and elevated C3d were significantly correlated with immunologic category 3. C3d levels were also significantly correlated with immunologic category 1. Undetectable CH50 and APH50 were found in two (group C) and 10 patients (n = 2, A = 2, B = 2, C = 4), respectively. Low MBL values were found in 13/127 but without correlation to disease severity. Undetectable C4B levels were observed in three patients, favouring the diagnosis of a complete deficiency. Although not related to clinical symptomatology, a strong ongoing complement activation can be observed in all stages of HIV infection. In contrast to earlier reports MBL could not be considered as a risk factor for HIV.

Antibodies↗
PubMedDate not supplied

Intermediate and long-acting insulin preparations without protamine sulphate are complement activators in vitro.

Recently, we have documented an abnormal in vivo complement metabolism in Type 1 diabetic children treated with monocomponent porcine insulin Monotard MC and its correction after switch-over to human insulin Protaphane HM. This prompted us to investigate the ability of different kinds of insulin preparations to induce complement activation in vitro. Freshly collected serum samples from healthy blood donors were incubated with commercial rapid and intermediate or long-acting (by protamine sulphate (PS) or zinc) insulin preparations for 2 hours at 37 degrees C. The C3d content of the supernatants was measured by turbidimetry as a marker of C3 complement fraction consumption. Only long-acting preparations of insulins without protamine sulphate were associated with highly significant increased levels of C3d, whatever the source of insulin, animal or human. Moreover, addition of exogenous protamine sulphate was able to inhibit the C3 conversion. This effect was dose-dependent and peaked at the concentration of commercial NPH insulin preparations. The mechanism by which protamine sulphate inhibits complement activation in vitro could be related to its ability to interfere with the physical nature of the solid surfaces presented by the insulin crystals. Indeed, insulin crystals were rapidly cleared (< 5 min) in the incubated serum when small doses of protamine sulphate were added. The complement activating capacity of long-acting insulin without protamine was dose dependent, equivalent to the known complement activator Zymosan, and abolished in the presence of EDTA. In conclusion, the present study has documented the ability of some protracted insulin preparations to activate the complement system in vitro if they are devoided of protamine sulphate. On the other hand, short-acting and NPH insulins are not complement activators.

Animals↗
PubMed1992

Lewy bodies in Parkinson's disease are recognized by antibodies to complement proteins.

The substantia nigra (SN) in 11 Parkinson's disease (PD) patients and 5 neurologically normal controls was examined immunohistochemically using antibodies to various proteins of the complement system. In PD, but not in control SN, intra- and extraneuronal Lewy bodies and dendritic spheroid bodies were stained with anti-human C3d, C4d, C7 and C9 antibodies, but not with antibodies to C1q, fraction Bb of factor B or properdin. Axonal spheroid bodies in the nigrostriatal tract were not stained by any of the complement antibodies. However, complement-activated oligodendroglia were revealed by anti-C3d and anti-C4d antibodies in the PD substantia nigral area. These data indicate that some pathological structures in PD activate the classical complement pathway.

Aged↗
PubMed1984

Serum IgG levels and complement activity in hypogammaglobulinaemic patients under substitution therapy.

Haemolytic activity of the classical and alternative pathways of complement as well as serum levels of C1q, Factor B, Factor H, C3, C4, C3d,g and IgG were determined in 15 hypogammaglobulinaemic patients on immunoglobulin replacement therapy. Alternative pathway activity (AP) and C1q were defective in the presence of low IgG levels and normalized on achievement of normal IgG levels; for both variables the correlation with serum IgG was highly significant. Classical pathway activity (CP), C3, C4 and Factor H serum levels were normal independently of IgG levels; Factor B and C3d, g serum levels were elevated in hypogammaglobulinaemic patients regardless of IgG levels. The present report supports the hypothesis that IgG serum levels influence complement function.

Adolescent↗
PubMed2004

Activation of mitogen activated protein kinases via complement receptor type 2.

BACKGROUND: Complement receptor type 2 (CR2) is the receptor for C3d and C3dg and for Epstein-Barr virus. The aim of our study was to explore whether CR2 can independently mediate the activation of mitogen-activated protein kinases (MAPKs, including ERK, JNK, and p38MAPK), and to highlight the molecular mechanism of CD4+ cell deletion in AIDS. METHODS: HOS cells (HOS-CR2) and HOS-CD4 cells (HOS-CD4CR2) stably expressing CR2 were established and then identified by FACS and Western blotting. Activation and blocking tests of MAPKs were assessed by Western blot. Cell proliferation was determined using Cell Titer 96((R)) Aqueous One Solution Reagent. RESULTS: FACS results showed that the positive rates of HOS-CR2 and HOS-CD4CR2 cells were greater than 96%, and Western blot showed that the CR2 expression levels on HOS-CR2 and HOS-CD4CR2 cells were high. Activation and blocking tests of MAPKs (ERK, JNK, and p38MAPK) were carried out in HOS-CR2, HOS-CD4, and HOS-CD4CR2 cells. The activation of MAPKs in HOS-CR2 cells stimulated with PMA (100 ng/ml) and NHS (10%) was identical. The activation of MAPKs increased at 5 minutes, reached a peak at 10 minutes, and decreased to baseline within 30 minutes, all in a time-dependent manner; the activation of MAPKs was blocked by anti-CR2 McAb, PD98059 (inhibitor of ERK), and Wortmanin (inhibitor of PI-3K), respectively. In HOS-CD4 cells, MAPKs were activated by HIV-gp160. In HOS-CD4CR2 cells, MAPK activation was induced by HIV-gp160, 10% NHS, and HIV-gp160 + 10% NHS; phosphorylation of p38MAPK was dramatically induced by HIV-gp160 + NHS, and lasted for 1 hour. The cell proliferation results showed that HIV-gp160 inhibited the proliferation of HOS-CD4 and HOS-CD4CR2 cells (P < 0.01) and that NHS enhanced the effect of HIV-gp160 (P < 0.01). CONCLUSIONS: The activation of MAPKs is independently mediated by CR2 and that anti-CR2 McAb, PD98059, and Wortmanin block the activation of MAPKs, respectively. The results of the signal transduction and cell proliferation assays of HOS-CD4CR2 cells show that CR2 plays a role in the pathogenesis of HIV infection, especially in the inhibition of CD4+ cell proliferation.

Cell Division↗
PubMedDate not supplied

Life-threatening, antiglobulin test-negative, acute autoimmune hemolytic anemia due to a non-complement-activating IgG1 kappa cold antibody with Pra specificity.

A 21-year-old man with fulminant cold autoantibody hemolytic anemia (CAHA) was hospitalized with hemoglobinemia, hemoglobinuria, hemoglobin concentration of 3.3 gm per dL, a negative direct antiglobulin test (DAT) with polyspecific and anti-C3d reagents, a negative Donath-Landsteiner test, and a cold agglutinin titer of 80. He failed to respond to corticosteroids, multiple plasma exchanges, and cyclophosphamide; he required 54 transfusions in 10 days to maintain a hemoglobin concentration of 6.0 to 10.0 g per dL. He improved dramatically after a splenectomy was performed. The wide-thermal-amplitude cold agglutinin proved to be an IgG1 kappa antibody with Pra specificity. The patient's serum exhibited normal complement activation. When the DAT was carried out at 0 to 4 degrees C, the result was strongly positive for IgG; the indirect antiglobulin test at 0 to 4 degrees C was positive with the patient's serum diluted 1 in 640. Within 6 months, he was in complete remission and receiving no therapy. As compared with eight patients with CAHA that was exclusively IgG-mediated, this patient is remarkable for his requirement for many transfusions and for DATs that were consistently negative for C3d.

Adult↗
PubMed1989

Immunohistological demonstration of lymph node reticulum cells in the acquired immunodeficiency syndrome related complex. A study in Bouin-fixed tissues.

The results of an immunohistochemical study on paraffin sections of the lymph nodes from 5 patients with the acquired immunodeficiency syndrome (AIDS) related complex (ARC) are presented. The distribution and frequency of follicular dendritic cells (FDC) and of interdigitating cells (IDC) were examined with the monoclonal antibodies J3D3 (directed against the C3b complement receptor, CD 35) and IOB1a (specific for the C3D, CD21) as well as with the polyclonal anti-S-100 protein antiserum in Bouin-fixed, paraffin-embedded sections using a Streptavidin-biotin-peroxidase technique. Disruption of the follicular FDC network was demonstrated. No major alteration of the IDC was noted. The immunomorphological patterns observed in this study were comparable with the previously reported lymph node alterations studied in frozen section.

AIDS-Related Complex↗
PubMed1980

Circulating antigens, immune complexes and C3d levels in human schistosomiasis: relationship with Schistosoma mansoni egg output.

Circulating schistosome antigens (CSA), circulating immune complexes (CIC) and C3 breakdown product - C3d - were investigated in human schistosomiasis in comparison to the S. mansoni egg count. A close relationship was observed between the mean number of eggs/g of stool and the detection of CSA (evaluated by the radioimmunoprecipitation-PEG assay - Ripega), CIC (Clq-binding test) and C3d levels (quantitated by radial immunodiffusion). All the patients with more than 500 S. mansoni eggs/g of stool also presented antigen '4', specific of the genus Schistosoma, in the serum. A significant correlation was noticed between levels of CSA and CIC. This suggests the involvement of several schistosome antigens in the detected CIC. No relationship was noted between CIC and C3d levels. In contrast, there was a highly significant correlation between levels of CSA and C3d. The interaction between certain schistosome antigens and the complement system is discussed.

Adolescent↗
PubMed1992

Immunologic reactions in amyotrophic lateral sclerosis brain and spinal cord tissue.

Expression of proteins associated with immune function was investigated immunohistochemically in postmortem brain and spinal cord of patients with amyotrophic lateral sclerosis (ALS). Reactive microglia/macrophages displaying high levels of leukocyte common antigen (LCA), the immunoglobulin receptor Fc gamma R1, lymphocyte function associated molecule-1 (LFA-1), the complement receptors CR3 and CR4, the class II major histocompatibility complex molecules HLA-DR, HLA-DP and HLA-DQ and common determinants of the class I HLA-A,B,C complex were abundant in affected areas in ALS. These areas included the primary motor cortex, motor nuclei of the brain stem, the anterior horn of the spinal cord, and the full extent of the corticospinal tract. A significant number of T lymphocytes of the helper/inducer (CD4+) and cytotoxic/suppressor (CD8+) subtypes were observed marginating along the walls of capillaries and venules and extending into the parenchyma of affected areas. Clusters of complement activated oligodendroglia as well as degenerating neurites positive for C3d and C4d were frequently detected in ALS-affected areas. These data provide evidence of immune-effector changes in ALS. They are consistent with an autoimmune or slow virus theory of the disorder, but may reflect only secondary changes.

Amyotrophic Lateral Sclerosis↗
PubMed2005

Successful plasma therapy for atypical hemolytic uremic syndrome caused by factor H deficiency owing to a novel mutation in the complement cofactor protein domain 15.

Quantitative or functional deficiency of complement factor H results in uncontrolled complement activation. This leads to thrombotic microangiopathy and finally causes renal failure (atypical hemolytic uremic syndrome [aHUS]). By regular analysis of factor H in patients with aHUS, the authors found a complete factor H deficiency in an infant in whom aHUS developed at 8 months of age. Factor H was quantified by enzyme-linked immunosorbent assay and further analyzed by Western blot using a factor H-specific antibody. Complement activation was determined by measuring total hemolytic activity of the classical (CH50) and alternative (APH50) pathways, C3 and C3d. The sequence of factor H gene was determined. Serial factor H measurements after fresh frozen plasma infusion allowed calculation of a factor H half-life. Factor H was absent in plasma (<1 mug/mL), and the complement system was highly activated (CH50, APH50, C3 decreased; C3d increased). Genetic analysis identified a novel homozygous factor H mutation (T2770A; Y899Stop) in CCP domain 15, most likely causing defective protein secretion. Time course measurements of factor H after plasma infusion established a factor H half-life of about 6 days. By repetitive plasma infusions (20 mL/kg over about 2 to 3 hours) the authors were able to interrupt the vicious circle of thrombotic microangiopathy in a factor H-deficient patient with aHUS. Based on the measured factor H half-life of about 6 days, regular plasma infusions in 2-week intervals were given, which prevented further aHUS episodes and stopped the decline of kidney function.

Complement Factor H↗
PubMed1989

[Activation of complement by hemodialysis membrane].

Incubation of normal human serum with hemodialysis membranes in vitro resulted in conversion of C3 which was detected by crossed immunoelectrophoresis. In addition, formation of C3d was also observed, as was detected by double-decker rocket immunoelectrophoresis. Furthermore, breakdown products of complement (iC3b, C4d & Bb) in plasma samples were measured by ELISA. The microassay plates were coated with monoclonal antibodies which bind specifically to human iC3b, C4d and Bb, respectively, while the plasma samples were drawn from five polycystic kidney patients during initial hemodialysis. As a result, the iC3b and Bb levels in plasma were seen to increase during hemodialysis but the C4d levels revealed no significant changes. It was also observed that the Bb levels in patients undergoing hemodialysis were significantly higher than those in various renal and collagen diseases. Terminal complement complex (TCC) was not present in detectable amounts in normal human serum when measured by ELISA. However, incubation of normal human serum with hemodialysis membranes in vitro resulted in detection of TCC. TCC was present in the same plasma samples drawned from the five polycystic kidney patients during initial hemodialysis. It is suggestive that activation of complement by hemodialysis membrane is predominantly mediated through the alternative pathway and products such as TCC and anaphylatoxin are formed by this activation.

Complement Activation↗
PubMed1994

Bovine conglutinin binds to an oligosaccharide determinant presented by iC3b, but not by C3, C3b or C3c.

Bovine conglutinin is a serum lectin that agglutinates erythrocytes preincubated with antibodies and complement. This agglutination occurs through the binding of conglutinin to iC3b, a fragment of the complement component C3. It was reported that conglutinin binds fluid-phase C3b and C3c as well as iC3b. We re-investigated the reactivity of conglutinin towards fluid-phase C3 degradation products. ELISA wells were coated with conglutinin and reacted with C3 split products generated in normal human serum, in factor I-deficient serum, or in factor I-depleted serum. Conglutinin-bound C3 fragments were detected with anti-C3c and anti-C3d antibodies. An increased signal was observed during the activation of complement in normal human serum with the peak response after 1-2 hr, following which the signal decreased, reaching background level after 72 hr. The oligosaccharides on C3c, generated in serum, are thus not recognized by conglutinin. No signal was observed when factor I-deficient serum or factor I-depleted serum was used instead of normal serum. Reconstitution with purified factor I re-established the normal pattern. Examination of the conglutinin-bound C3 molecules by SDS-PAGE and Western blotting with anti-C3c and anti-C3d antibodies revealed bands characteristic for iC3b, and no bands corresponding to C3b or C3c. Reduction of the disulphide bonds prior to the incubation of the activated serum with the conglutinin-coated wells revealed a band of 63,000 MW, characteristic of the N-terminal fragment of the alpha-chain of iC3b. We also investigated the binding to the solid-phase conglutinin of purified C3 and degradation products generated with enzymes. In this case, C3 as well as C3b and C3c were bound, suggesting conformational changes in C3 during purification. In conclusion, when C3 conversion takes place at near physiological conditions, conglutinin interacts specifically with the oligosaccharide on the alpha-chain of iC3b.

Animals↗
PubMed2000

Local activation of the complement system in endoneurial microvessels of diabetic neuropathy.

Quantitative immunocytochemical analysis of complement proteins (CP) was performed on sural nerve biopsies from 15 patients with diabetic neuropathy (DN) and 18 nondiabetic patients with other forms of chronic neuropathy (ON). The mean age of the patients and the pathological severity of the neuropathy were similar in both groups. The percentage of patients that expressed strongly immunoreactive CP in the walls of endoneurial microvessels was significantly greater in DN than in ON for all proteins tested. C3d neoantigen was expressed in 100% of DN cases compared with 17% of ON; and membrane attack complex (MAC), C5b-9 neoantigen, in 93% of DN and 17% of ON. In the cases with DN, 81% of endoneurial microvessels, as identified by the endothelial marker, Ulex europaeus, contained C5b-9 neoantigen deposits, compared with 22% in those of ON, and the staining in DN was significantly more intense. Expression of the neoantigens of C3d and C5b-9 in nerve implies local activation of the complement system. In DN, activation of the complement pathway and formation of the MAC could injure blood vessels and adversely affect the circulation in the endoneurium.

Adult↗
PubMed2003

B cell activation leads to shedding of complement receptor type II (CR2/CD21).

Complement receptor type II (CR2/CD21) is the major receptor for C3d fragments on immune complexes. CD21 also serves as the receptor for Epstein-Barr virus in humans. On mature B cells, CD21 reduces the threshold of BCR signaling together with CD81, Leu13 and CD19, but it also occurs on other cells of the immune system where it performs unknown functions. A soluble form of CD21 (sCD21) is shed from the cell surface and is found in human blood plasma. An as-yet-unknown protease is thought to be responsible for this shedding. Altered levels of sCD21 occur in plasma in certain clinical conditions. We show here by mass spectrometry that sCD21 in human plasma of healthy donors is predominantly a short form of CD21 without the exon-11-encoded sequences. Whereas the N terminus of sCD21 was found unmodified, the C terminus is truncated, implying that only the extracellular portion of CD21 is shed. Peripheral blood B cells, but not T cells, contribute to the plasma CD21-pool. CD21 shedding is induced by stimulation with PMA plus Ca(2+) ionophore, or by stimulation of the BCR with anti-IgM+anti-CD40.

B-Lymphocytes↗