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PubMed2005

Targeted complement inhibition by C3d recognition ameliorates tissue injury without apparent increase in susceptibility to infection.

Previous studies indicate a pivotal role for complement in mediating both local and remote injury following ischemia and reperfusion of the intestine. Here, we report on the use of a mouse model of intestinal ischemia/reperfusion injury to investigate the strategy of targeting complement inhibition to sites of complement activation by linking an iC3b/C3dg-binding fragment of mouse complement receptor 2 (CR2) to a mouse complement-inhibitory protein, Crry. We show that the novel CR2-Crry fusion protein targets sites of local and remote (lung) complement activation following intestinal ischemia and reperfusion injury and that CR2-Crry requires a 10-fold lower dose than its systemic counterpart, Crry-Ig, to provide equivalent protection from both local and remote injury. CR2-Crry has a significantly shorter serum half-life than Crry-Ig and, unlike Crry-Ig, had no significant effect on serum complement activity at minimum effective therapeutic doses. Furthermore, the minimum effective dose of Crry-Ig significantly enhanced susceptibility to infection in a mouse model of acute septic peritonitis, whereas the effect of CR2-Crry on susceptibility to infection was indistinguishable from that of PBS control. Thus, compared with systemic inhibition, CR2-mediated targeting of a complement inhibitor of activation improved bioavailability, significantly enhanced efficacy, and maintained host resistance to infection.

Animals↗

PubMed1978

Quantitative influence of antibody and complement coating of red cells on monocyte-mediated cell lysis.

Monocyte-mediated lysis in vitro of human red cells coated with measured amounts of immunoglobulin G (IgG) or complement were studied. 1,000-1,500 molecules of IgG anti-D are necessary to effect measurable lysis, and lysis increases linearly with increasing levels of antibody sensitization. 100 microgram/ml of IgG1 abolished lysis even at maximal levels of anti-D sensitization (15,000 molecules/cell). Two isoimmune IgG anti-A or anti-B antisera were 5 to 10-fold less efficient in promoting phagocytosis or lysis per molecule of IgG bound; however, because of the greater antigen density of A or B, more than 100,000 molecules IgG/cell could be bound, producing equivalent lysis to anti-D-coated cells. Although inhibition by IgG1 was similar at equivalent levels of sensitization with anti-A, anti-B, or anti-D at high levels of coating with anti-A or anti-B (not attainable with anti-D), lysis was not inhibited by IgG1. Cells coated with human complement components alone were not lysed by monocytes; however, complement coating augmented IgG-mediated lysis and reduced the quantity of anti-D necessary to produce lysis to less than 1,000 molecules/cell. After thorough degradation of C3b by serum to C3d, complement augmentation persisted.

ABO Blood-Group System↗

PubMed1986

Purification of the B lymphocyte receptor for the C3d fragment of complement and the Epstein-Barr virus by monoclonal antibody affinity chromatography, and assessment of its functional capacities.

The human C3d receptor (complement receptor type 2, CR2), that also serves as the B lymphocyte receptor for the Epstein-Barr virus, was purified from detergent lysates from the B lymphoblastoid cell lines, SB and Raji, by monoclonal antibody affinity chromatography using the anti-CR2 monoclonal antibody, HB-5. Relative to the concentration of cellular protein and receptor that was initially solubilized by detergent, the procedure provided a 37,000-fold purification with a 40-50% recovery of CR2. The purified receptor presented a single Coomassie blue-stained band when analyzed by SDS-PAGE, and it retained its function of binding to C3-Sepharose. The N-terminus of CR2 was blocked. The amino acid composition was significantly similar to that of the C3b/C4b receptor, factor H and C4 binding protein, suggesting that CR2 may be a member of this newly defined protein family. However, CR2 did not exhibit the regulatory functions of these proteins, namely, the decay dissociation of the classical or alternative pathway C3 convertases and serving as a cofactor for the cleavage of C3b.

Amino Acids↗

PubMed1992

Inhibition of the classical activation pathway of complement-mediated lysis by monoclonal antibodies to complement components C3c and C3d.

Eight epitope-mapped monoclonal antibodies (MoAbs) to complement component C3d and five to complement component C3c were investigated to determine whether they could inhibit the classical activation pathway of complement-mediated lysis (CML) by using blood group AB red cells sensitized by A or B MoAbs. Three IgM C3d MoAbs and one IgG1 C3c MoAb were able to inhibit CML in a dose-dependent manner. In the presence of excess complement, no inhibition was observed. The greatest inhibition was observed with two high-affinity IgM antibodies that were specific for epitope 1 on the C3d component. Some inhibition was observed with a high-affinity IgM antibody specific for epitope 3 of the C3d component and also with a lower-affinity IgG antibody specific for epitope 1 of the C3c component. The results indicate that some complement MoAbs have the capacity to distinguish between conformationally and/or functionally different forms of red cell-bound C3.

Antibodies, Monoclonal↗

PubMed1976

Surface markers on human B and T lymphocytes. VIII. Association between complement and Epstein-Barr virus receptors on human lymphoid cells.

An association has been found between the Epstein-Barr virus (EBV) and complement (C3d) receptors on human lymphoid cells. The evidence was four-fold: there was a correlation between the expression of these two receptors; inhibition experiments showed that the binding sites probably are close to each other in the cell membrane, although not identical; EBV and complement receptors have been found to co-cap in either order; and lymphoid cell lines lacking complement receptors could not be superinfected with EBV.

Antigens, Viral↗

PubMedDate not supplied

[Laboratory diagnosis of auto-immune hemolytic anemia: characteristics of the manual direct test of Polybrene].

UNLABELLED: The direct manual Polybrene test (DPT) and the direct antiglobulin tests (DAT) were employed to detect antibody sensitizing red blood cell (RCB) in patients with clinical and laboratorial findings of autoimmune hemolytic anemia (AIHA). PURPOSE: To compare the sensitivity and specificity of DPT and DAT in the diagnosis of AIHA. METHODS: Eighteen consecutive patients with diagnosis of AIHA were evaluated. The control group consisted of 20 normal volunteers blood donors and 20 patients with sickle cell anemia. All patients and controls were submitted to DPT and DAT. All DAT positive samples were further tested using monospecific reagents (anti-IgG heavy chain and anti-C3d). Positive samples for either DPT or DAT were evaluated by eluate technique using. The dichloromethane (DCM). RESULTS: The DAT was positive in 14 patients and negative in 4 subjects, while the DPT was positive in 17 patients and negative in 1 individual who had a positive DAT owing to complement (C3d). All positive eluates performed with DCM showed RBC autoantibodies with presumed "anti-Rh" specificity. The sensitivity rate of the DPT (94%) was significantly (p < 0.05) higher than the sensitivity rate of DAT (78%) to determine whether IgG was bound in vivo, but no difference was found regarding the specificity of the two tests. CONCLUSION: 1) The DPT is more sensitive than the DAT in detecting IgG autoantibody on the RBCs of patients with AIHA; 2) because of its simplicity and rapidity, the DPT is a useful additional screening test for the investigation of Coombs-negative AIHA.

Adult↗

PubMed1978

Traffic of T and B lymphocytes in the normal spleen.

The occurrence of C3b and C3d complement receptors and of Fc and E receptors in normal splenic tissue was studied in cryostat sections incubated with specific marker cells. Thereby the topographic distribution of T and B lymphocytes in the splenic tissue was mapped: Te lymphocytes are found especially in the periateriolar sheaths, B lymphocytes in eccentric zones around the arterioles. The cells in the splenic pulp carry especially Fc, but also C3b receptors, whereas C3d receptors appear to be specific of lymphocytes. The basic lymphocyte traffic behind the mapped distribution of the lymphocyte subpopulations in the spleen was elucidated by lymphocyte kinetic studies using autologous 51Cr-labelled reinfused lymphocytes. These studies were performed partly on normal persons and partly on splenectomized persons without immune defects. The results indicate the presence of an exchangeable pool of T as well as of B lymphocytes in the spleen, the T cell pool being larger and making up in normals about 30% of the total exchangeable T lymphocyte mass. The matrix for the T lymphocyte pool in the spleen is the periateriolar sheaths. The difference in structure between the lymph nodes and the lymphoid tissue of the spleen, including differences in the distribution of lymphocyte subpopulations, are explained by the special vascular arrangement in the spleen.

Adult↗

PubMed2005

Regulation of B lymphocyte activation by complement C3 and the B cell coreceptor complex.

Complement is an essential innate immune mechanism that recognizes and eradicates microbes and associated toxins. In addition, complement receptors (CD21 and CD35) on B cells cooperate with the B-cell antigen receptor (BCR) to efficiently recognize and respond to antigens bearing complement C3d(g). Fixation of C3d(g) to antigen confers adjuvant properties and therefore its deposition may need to be carefully regulated to avoid autoreactivity. CD21 and/or CD35 engagement is nonmitogenic, and B-cell activation via BCR-CD21 coligation is enhanced through the recruitment of CD19. Recent efforts have sought a better understanding of the topological and biochemical properties of BCR and coreceptor (CD19-CD21-CD81) signaling, as well as the context for complement activation in the response to foreign and self antigens.

Animals↗

PubMed2001

Tissue injury and the inflammatory response to pediatric cardiac surgery with cardiopulmonary bypass: a descriptive study.

BACKGROUND: There are few detailed descriptions of the inflammatory response to cardiac surgery with cardiopulmonary bypass (CPB) in children beyond 24 h postoperatively. This is especially true for the antiinflammatory cytokines and the extent of tissue injury. The aim of the current study was to describe the inflammatory and injury responses in uncomplicated pediatric cardiac surgery with CPB, where methylprednisolone and modified ultrafiltration (MUF) were used. METHODS: Blood samples were collected up to 48 h postoperatively. Cytokines (tumor necrosis factor-alpha and interleukin-6, -1beta, -10, and -1ra), complement (C3d and C4d) and coagulation system (prothrombin activation fragments 1 and 2 and antithrombin III) activation, neutrophil elastase, and the resulting tissue injury (creatine kinase, lactate dehydrogenase, alanine transaminase, amylase, and gamma-glutamyl transferase) were measured. RESULTS: The proinflammatory cytokine release varied widely, in contrast to a clear-cut antiinflammatory response. Cytokine concentrations did not decrease immediately after MUF, and no rebound increases later in the postoperative period were observed. The coagulation system, but not complement, was activated. There was a late release of C-reactive protein. Tissue injury could be quantified biochemically without evidence of hepatic or pancreatic dysfunction. CONCLUSION: In this group of uncomplicated subjects, the antiinflammatory cytokine and tissue injury responses were well defined, in contrast to a variable proinflammatory cytokine release. This was accompanied by activation of the coagulation system but not of complement. Concentrations of inflammatory mediators did not decrease immediately after MUF, and there was no evidence for rebound release later in the postoperative period.

Blood Coagulation↗

PubMed2002

CD19-CD21 complex regulates an intrinsic Src family kinase amplification loop that links innate immunity with B-lymphocyte intracellular calcium responses.

CD19 is a B-lymphocyte cell surface molecule that functions as a general response regulator or rheostat, which defines intrinsic and B-cell antigen receptor-induced signalling thresholds that are critical for humoral immunity and expansion of the peripheral B-cell pool. In addition, B-cell responses are influenced by signals transduced through a CD19-CD21 cell surface receptor complex, where the binding of complement C3d to CD21 links humoral immune responses with the innate immune system. This review outlines recent biochemical and genetic studies that characterize the signal transduction pathways utilized by this receptor complex to regulate B-cell intracellular calcium responses.

Antigens, CD19↗

PubMed1986

Plasma concentrations of complement split product C3d and immune complexes after procainamide induced production of antinuclear antibodies.

Seventeen patients treated with procainamide for cardiac ventricular arrhythmias were followed for up to 40 weeks. Immunological data as a clue to developing the systemic lupus erythematosus (SLE)-like syndrome was emphasized. Ten patients developed antinuclear antibodies (IgG or IgM), but no increase in the plasma concentration of the complement split product C3d or immune complexes, measured by two different methods, was demonstrated. This finding is in contrast to the high levels of both C3d and immune complexes in SLE. The discrepancy may be caused by a lack of immune complex mediated complement activation by the procainamide induced antibodies, or may be due to a difference in severity of disease. The acetylator phenotype of the patients was determined but due to the low frequency of fast acetylators no comparison of the immunological response of the two phenotypes could be done.

Aged↗

PubMed2001

Structural studies in solution of the recombinant N-terminal pair of short consensus/complement repeat domains of complement receptor type 2 (CR2/CD21) and interactions with its ligand C3dg.

Human complement receptor type 2 (CR2, CD21) is a cell surface receptor that binds three distinct ligands (complement C3d, Epstein-Barr virus gp350/220, and the low-affinity IgE receptor CD23) via the N-terminal two of fifteen or sixteen short consensus/complement repeat (SCR) domains. Here, we report biophysical studies of the CR2 SCR 1-2 domain binding to its ligand C3dg. Two recombinant forms of CR2 containing the SCR 1-2 and SCR 1-15 domains were expressed in high yield in Pichia pastoris and baculovirus, respectively. Circular dichroism spectroscopy showed that CR2 SCR 1-2 receptor possessed a beta-sheet secondary structure with a melting temperature of 59 degrees C. Using surface plasmon resonance, kinetic parameters for the binding of either CR2 SCR 1-2 or the full-length SCR 1-15 form of CR2 showed that the affinity of binding to immobilized C3d is comparable for the SCR 1-15 compared to the SCR 1-2 form of CR2. Unexpectedly, both the association and dissociation rates for the SCR 1-15 form were slower than for the SCR 1-2 form. These data show that the SCR 1-2 domains account for the primary C3dg binding site of CR2 and that the additional SCR domains of full-length CR2 influence the ability of CR2 SCR 1-2 to interact with its ligand. Studies of the pH and ionic strength dependence of the interaction between SCR 1-2 and C3d by surface plasmon resonance showed that this is influenced by charged interactions, possibly involving the sole His residue in CR2 SCR 1-2. Sedimentation equilibrium studies of CR2 SCR 1-2 gave molecular weights of 17 000, in good agreement with its sequence-derived molecular weight to show that this was monomeric. Its sedimentation coefficient was determined to be 1.36 S. The complex with C3d gave molecular weights in 50 mM and 200 mM NaCl buffer that agreed closely with its sequence-derived molecular weight of 50 600 and showed that a 1:1 complex had been formed. Molecular graphics views of homology models for the separate CR2 SCR 1 and SCR 2 domains showed that both SCR domains exhibited a distribution of charged groups throughout its surface. The single His residue is located near a long eight-residue linker between the two SCR domains and may influence the linker conformation and the association of C3d and CR2 SCR 1-2 into their complex. Sedimentation modeling showed that the arrangement of the two SCR domains in CR2 SCR 1-2 is highly extended in solution.

Amino Acid Sequence↗

PubMed1993

Amyloid P component and other acute-phase proteins associated with cerebellar A beta-deposits in Alzheimer's disease.

It is established that amyloid P (AP) component and complement proteins are associated with amyloid beta (A beta)-protein deposits in the cerebral cortex of Alzheimer's disease (AD) subjects. Here, we used immunocytochemical methods to examine the association of these acute-phase proteins with the characteristic diffuse plaques of cerebellum in AD. We observed AP and complement C3d, C1q, C5 and C4bp immunoreactivities in most A beta-protein-reactive plaques of the cerebellum. Further, a1-antichymotrypsin immunoreactivity was apparent in at least 60% of all the cerebellar diffuse plaques examined. Cerebellar tissue bearing the A beta-protein deposits also often exhibited marked angiopathy in the pial vessels. We suggest that diffuse plaques of the cerebellum also acquire components of the chronic inflammatory response evident in neocortical plaques.

Acute-Phase Proteins↗

PubMed1986

Circadian and diurnal variation of circulating immune complexes, complement-mediated solubilization, and the complement split product C3d in rheumatoid arthritis.

Nine patients with active classical rheumatoid arthritis (ARA criteria) were studied with reference to circadian variation of immunological and clinical parameters. Complement-mediated solubilization (CMS) of immune complexes (IC) and the level of circulating IC were found to be inversely related with low CMS and increased IC levels in the morning, and vice versa in the afternoon. Bed rest and exercise did not influence these fluctuations. The C3d concentration in plasma was increased but showed no diurnal or circadian periodic fluctuations when the levels were corrected for fluctuations in plasma albumin concentration. Clinical assessment by means of pain score exhibited marked variations, with high scores in the morning, and lower in the daytime, whereas measurements of Ritchie's joint index showed no consistent pattern. The circadian variations in CMS, serum IC and clinical parameters indicate the need to collect blood specimens and perform clinical examinations of patients at a fixed time of day.

Adult↗

PubMed1997

The affinity threshold for human B cell activation via the antigen receptor complex is reduced upon co-ligation of the antigen receptor with CD21 (CR2).

The present studies have examined whether the potential of an Ag to co-ligate the complement (C3d)-binding CD21 receptor complex with the membrane IgM (mIgM) receptor complex can reduce the mIgM:Ag affinity threshold for triggering human B cell S phase entry. A series of Ab:dextran conjugates consisting of affinity-diverse anti-IgM mAb, with and without anti-CD21 mAb, were synthesized as polyclonally reactive, moderately multivalent ligands that mimic C3d-bearing and non-C3d-bearing Ag. Co-ligation of mIgM and CD21 significantly diminished both the ligand concentration threshold and the IgM:ligand affinity threshold for eliciting S phase entry in the presence of IL-4. Furthermore, such co-engagement ablated the triggering bonus associated with high mlgM:ligand affinity, suggesting that B cells with a high affinity for Ag are not preferentially activated over B cells of intermediate affinity upon encountering a multivalent Ag with bound C3d. The enhancing effects of mIgM:CD21 co-ligation were restricted to low concentrations of ligand; at high concentrations, a decrease in B cell DNA synthesis was often observed. The findings suggest that the ability a moderately multivalent Ag substrate to engage B cells through both mIgM and CD21 is critical for B cell activation at limiting Ag concentrations, and furthermore, that mIgM:CD21 co-engagement may be particularly important in eliciting an immune response to such Ags in unprimed individuals in whom the majority of specific B cells are of low affinity.

Adolescent↗

PubMed2005

The CD19-CD21 signal transduction complex of B lymphocytes regulates the balance between health and autoimmune disease: systemic sclerosis as a model system.

Cell-surface CD19 functions as a general rheostat for defining intrinsic and antigen receptor-induced signaling thresholds critical for clonal expansion of the B cell pool and humoral immunity. CD19 also governs B cell responses initiated through the CD21 receptor, where complement C3d binding to CD21 links humoral immune responses with the innate immune system. Alterations in this signaling pathway can predispose mice and humans to autoantibody production and systemic autoimmunity. Transgenic mice that overexpress CD19 by 20-170% lose tolerance and generate autoantibodies. Likewise, B cells from CD21-deficient mice overexpress CD19 by approximately 50%, which leads to autoantibody production. Autoimmune patients with systemic sclerosis also overexpress CD19 by approximately 20%, which may contribute to their intrinsic B cell abnormalities and autoantibody production. Thus, chronic B cell activation resulting from augmented CD19 expression or signaling through the CD19 pathway may reveal a prototype autoimmune disease susceptibility pathway in mice and humans.

Animals↗

PubMed1984

Complement in chronic secretory otitis media. C3 breakdown and C3 splitting activity.

Occurrence of in vivo C3 breakdown and in vitro C3 splitting activity was studied in serum and middle-ear effusion (MEE) samples from 30 children with chronic secretory otitis media (SOM). The MEE showed strongly elevated levels of both low- and high-molecular-weight C3 breakdown products, along with decreased factor B, C4, and C3 levels. Total hemolytic complement component activity was virtually absent from MEE. The MEE fluids were found to contain C3 splitting factors as demonstrated by their high capacity to convert C3 in vitro from fresh normal human serum. This activity was not inhibited by the classic complement pathway inhibitor, 0.01M ethylene glycol tetra-acetic acid with 0.005M magnesium chloride. The results suggest that a strong local complement activation has taken place and that the factors responsible are present in the MEE of patients with SOM.

Antigen-Antibody Complex↗

PubMed1994

Widenings of the myelin lamellae in a typical Guillain-Barré syndrome.

The so-called "widening of the myelin lamellae" are thought to be specific ultrastructural features of peripheral nerve myelin in patients with peripheral neuropathy associated with a monoclonal dysglobulinemia of IgM type and antiglycolipid activity. We report here a case of Guillain-Barré syndrome with no evidence of serum monoclonal dysglobulinemia, presenting the typical widenings of the myelin lamellae in small-diameter myelinated fibers from a sural nerve biopsy. In view of the positive reaction with anti-C3d complement on direct immunofluorescence, an immunological mechanism may be involved in the widenings of the myelin lamellae.

Axons↗