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PubMed2001

Regulation of CD21 expression by DNA methylation and histone deacetylation.

The complement receptor II (CD21) serves as a receptor for the complement component C3d of immune complexes on B lymphocytes. Expression of the CD21 gene is tightly regulated during B lymphocyte differentiation. Only mature B lymphocytes, but not pro-, pre- or plasma B lymphocytes, express CD21. There is evidence that cell type-specific expression is mediated by a silencer element located in the first intron. The CD21 promoter region contains a CpG island adjacent to the ATG start codon. We have analyzed the methylation status of this CpG island in B lymphoid cell lines representing the various differentiation stages of B lymphocyte development and primary lymphocytes. We found that the pro-, pre- and intermediate B lymphocytes contain a methylated CpG island and do not express CD21, whereas CD21-expressing mature B lymphocytes, plasma B lymphocytes and non-lymphoid cells carry a demethylated CD21 CpG island. To analyze whether the lack of CD21 expression in early B lymphocytes is due to inhibition by CpG methylation we have used 5-aza-2'-deoxycytidine to inhibit DNA methyltransferase activity. Treatment of pro-B lymphocytes with the drug resulted in expression of CD21. We have also applied Trichostatin A (TSA), an inhibitor of histone deacetylation, to determine whether the state of histone deacetylation affects the expression of CD21. We found that TSA induces expression of CD21 in early B lymphocytes. Thus CD21 expression is controlled by both methylation of the CD21 CpG island and chromatin modification through histone deacetylation in early B lymphocyte development.

Acetylation↗
PubMed1988

Ligand-loaded but not free complement receptors for C3b/C4b and C3d co-cap with cross-linked B cell surface IgM and IgD.

We have performed experiments to investigate possible physical interactions between C receptors (CR) and surface Ig (sIg) on the B cell plasma membrane. These molecules were found to be independent, non-linked, B cell surface structures, because capping CR1, CR2, sIgM, or sIgD with a specific antibody did not affect the distribution of the remainder of these molecules. Both CR1 and CR2, if bound by antibodies that did not independently cap CR, however, became associated with cross-linked sIg because CR that have been bound by intact anti-CR antibodies or their Fab fragments co-capped with sIgM or sIgD that had been bound by divalent anti-IgM or anti-IgD antibody. CR1 that had bound C3b similarly co-capped with sIg when sIg was cross-linked. Ligand-bound or even cross-linked CR did not associate with non-cross-linked sIg because sIgD, bound by a univalent Fab fragment of anti-IgD antibody, did not co-cap with CR that had been cross-linked by a sandwich of mouse anti-CR antibody and goat anti-mouse Ig. Other surface molecules, such as B1 and HLA-DR Ag, when bound by specific antibodies, did not cap with cross-linked sIg, and sIgD, when bound by a univalent Fab fragment of anti-IgD antibody, did not co-cap with cross-linked sIgM. Interactions between CR and sIg were not mediated by an association with IgG FcR because co-capping of CR and sIg was observed when F(ab')2 fragments of both anti-CR and anti-Ig antibodies were used. These results demonstrate that B cell surface CR can become associated with sIg, but only if sIg is cross-linked and CR is bound by anti-CR antibody or has bound its natural ligand.

Animals↗
PubMed1983

Generation of low m.w., C3-bearing immunoglobulin in human serum.

The generation of low m.w. C3-bearing immunoglobulin (lg) in normal human serum by an immune complex (IC) model was investigated in vitro by using discontinuous sucrose density gradient centrifugation (DGC) and an assay that measures C3-bearing Ig. In this method developed to measure circulating IC, all C3 and C3-bearing material is precipitated from serum by using anti-C3 sera in C3d antibody excess, and immune precipitated, C3-bearing Ig is quantitated by the uptake of 125I-5S-anti-IgG. When plasma from patients with clinically active systemic lupus erythematosus was assayed after DGC, most of the reactive material was low m.w. (7S), rather than greater than or equal to 19S as expected for IC, in agreement with a previous report. Low m.w., C3-bearing Ig was found in normal EDTA plasma after extended storage at -29 degrees C but not after storage at -70 degrees C. Such material was also generated in normal human serum during incubation at 37 degrees C and its generation was stimulated by the addition of an IC model, high m.w., heat-aggregated IgG (HMW-HAIgG). In experiments in which the participation of serum IgG was monitored by the addition of 125I-7S-IgG and 131I-HMW-HAIgG was used as an IC model, low m.w., C3-bearing Ig was generated exclusively from serum IgG and the amount generated was proportional to the concentration of 131I-HMW-HAIgG. No significant decrease in sedimentation of 131I-HMW-HAIgG was observed, but the ability of anti-C3 sera to precipitate 131I-HMW-HAIgG decreased 66% 4 hr after initial C activation. These results indicate that generation of nascent C3b in serum results in its interaction with monomeric serum IgG, producing low m.w., C3-bearing IgG. In addition, the data indicate that circulating IC that activate C have a brief time span during which they can be detected by methods that depend upon the binding of C3.

Animals↗
PubMed1985

Failure of local immunity. A potential cause of burn wound sepsis.

Destruction of the skin barrier by thermal injury removes the major local defense barrier to bacteria. To determine whether a local defect in immunity also existed, the opsonic activity of blister fluid against Staphylococcus aureus and Pseudomonas aeruginosa as well as neutrophil chemotaxis were measured. The results of these studies indicated that blister fluid could not opsonize Pseudomonas. A series of repletion experiments indicated that the opsonic defect for Pseudomonas was not due to the presence of inhibitors but was due to the lack of normal serum factor(s). Although both the level of immunoglobulins and complement components in the blister fluid was depressed, the cause of the opsoninopathy appeared to be due to local consumption of complement in the burn wounds. In addition to the opsoninopathy, both neutrophil chemotaxis and random migration were also depressed. In conclusion, a burn injury appears to cause severe impairment of both cellular and humoral local immunity, which could predispose these patients to burn wound sepsis.

Adolescent↗
PubMed1982

Determination of the half-life of C3 in patients and its relation to the presence of C3-breakdown products and/or circulating immune complexes.

Measurement of complement components in serum may not accurately assess the degree of activation of the complement system. An alternative approach is the measurement of conversion products of the complement components. The relation between the presence of an increased concentration of C3-conversion products and the metabolism of C3 was investigated. In a group of patients, circulating immune complexes were also measured (Clq-binding test) to see whether the combination of those markers yielded information on the C3 metabolism. In this study it is shown that static measurements of serum C3 levels is of no value for the degree of complement activation. Measurement of C3-conversion products may indicate C3 hypercatabolism (in 8 of the 11 patients with C3-conversion products), but it does not imply depressed C3 synthesis. Detection of circulating immune complexes by the C1q-binding assay did not always indicate a C3 hypercatabolism. Of 12 SLE patients studied, in 9 of them, a C3 hypercatabolism was detected, and 5 of these patients were clinically characterized by the presence of minor disease symptoms. Overall, the results indicated that detection of circulating immune complexes and/or C3-conversion products could not be used as an absolute measure for insight into the C3 metabolism.

Antigen-Antibody Complex↗
PubMed1988

Lumbar disc surgery and variations in C-reactive protein, erythrocyte sedimentation rate and the complement split product C 3 d.

Lumbar disc surgery was performed in fifty consecutive patients and variation in erythrocyte sedimentation rate (ESR), complement C 3 d, and C-reactive protein (CRP) levels before and after surgery were recorded. Preoperative values were within normal limits in all patients. Postoperatively, CRP increased immediately, with a maximum of 28.5 mg/l on the 2nd day and were normalized within 6 days. The maximum ESR elevation occurred after the 6th day and was followed by a slow decrease. After 12 weeks some patients still had an elevated ESR. Plasma C 3 varied pari passu with the ESR. Uncomplicated recovery after lumbar disc surgery seems to be indicated by a normalization of CRP, regardless of ESR values. Therefore, ESR may not be so useful as an indicator of disc space inflammation as previously accepted.

Adult↗
PubMedDate not supplied

Differences among acute, subacute, and chronic chorioamnionitis based on levels of inflammation-associated proteins in cord blood.

The serum concentration of inflammation-associated proteins and several complement components in the cord blood of 215 newborns with and without chorioamnionitis (CAM), who were delivered between 17 and 42 weeks of gestation, were measured. We investigated the relationship of levels of serum proteins to acute, subacute, and chronic CAM, and to subacute necrotizing funisitis (SNF). Complement components C3d, C3, and C4 levels increased in subacute CAM (P = 0. 0002, P = 0.0007, P = 0.0029, respectively), whereas factor B increased in each type of CAM (P = 0.0001, P = 0.0009, P = 0.0004, respectively). Among the immunoglobulins, IgG levels were unrelated to the presence or type of CAM, IgM levels increased in subacute CAM (P < 0.0001), and IgA levels increased in chronic CAM (P < 0.0001). Among the acute phase reactants (APR), haptoglobin and C-reactive protein (CRP) levels increased in acute (P < 0.0001, P = 0.0022, respectively) and chronic CAM (P = 0.0035, P = 0.0345, respectively), whereas orosomucoid levels increased in chronic CAM (P = 0.0003). IL-6 levels increased in acute (P = 0.0011) and subacute (P = 0. 0475) CAM. C3d (P = 0.0063), C3 (P = 0.0289), C4 (P = 0.0491), and IgM (P < 0.0001) levels were increased in SNF. These findings suggest that the histologic distinction of acute, subacute, and chronic CAM is a useful indicator of the inflammatory mediator status of the infants. The infants with SNF may have ended their initial active inflammatory states, but they still have subacute immune activation.

Acute Disease↗
PubMed1987

Reinvestigations into the formation and assay of C3bBbP complexes.

C3bBbP complex formation was studied by an enzyme linked immunosorbent assay (ELISA). Microtitre plates were coated with anti-P to trap the complexes and peroxidase labelled anti-C3 was used to detect them with the help of substrates of peroxidase. Incubation of normal serum pool (NSP) at 37 degrees C in the presence of high concentrations (greater than or equal to 0.5 mmol/l) of Mg2+, usually used in alternative pathway (AP) assay systems, caused the generation of C3bBbP complexes. This generation was not observed when NSP was incubated in the presence of low Mg2+ concentration (less than or equal to 0.2 mmol/l) or EDTA. The concentration of Mg2+ required for maximum complex formation was 2.0 mmol/l under the experimental conditions. Complexes could not be generated in B-depleted serum. Incubation of NSP with endotoxin or CoVF in the presence of 0.2 mmol/l Mg2+ caused the generation of the complexes. The generation was influenced by ionic strength in the incubation mixture. Endotoxin and Mg2+-dependent generation of complexes could not be detected when peroxidase-labelled anti-B was used instead of peroxidase-labelled anti-C3. Serum incubated with 0.2 mmol/l Mg2+ or EDTA apparently detected in vivo formed complexes whereas that incubated with 0.2 mmol/l Mg2+ and endotoxin reflected the complex forming capacity of the serum. The serum of a patient with Raynaud's phenomenon having 45% of normal AP activity did not show increased amounts of preformed complexes but had the ability to generate the complexes to a level of about 45% of that attainable by NSP. These observations suggest that the ELISA used here has the potential of detecting activation as well as the integrity of the AP under carefully controlled conditions.

Complement C3↗
PubMed1989

Preparation of monoclonal antibodies to C3b by immunization with C3b(i)-sepharose.

We have prepared and characterized four monoclonal antibodies (MAbs) to human C3b of high specificity and affinity. Our procedure did not require a purified source of C3b for immunization. Instead, C3b and C3bi were deposited on Sepharose 4B via the alternative pathway of complement activation in normal human serum, and this C3b(i)-Sepharose served as the immunogen. C3b(i)-Sepharose was also prepared from a number of primate and non-primate sources, and this allowed us to demonstrate that the anti-human C3b MAbs cross-reacted with primate-derived C3b, but not with C3b from non-primates. The procedures we have developed may be useful in the further investigation of species-specific C3 fragment-binding proteins from both primate and non-primate sources.

Animals↗
PubMed1989

Hairy leukoplakia: Epstein-Barr virus receptors on oral keratinocyte plasma membranes.

Hairy leukoplakia (HL) is an oral white lesion associated with, and probably caused by, the Epstein-Barr virus (EBV) among persons who are seropositive for infection with human immunodeficiency virus. A unique feature of HL is its localization to the lateral portion of the tongue. To determine site differences for EBV receptors according to epithelial phenotype, these receptors were mapped in oral mucosa with the use of monoclonal antibodies HB5 and B2(specific for the Complement Fraction 3d/EBV receptor on B lymphocytes). Immunoperoxidase and immunofluorescence techniques were employed with the use of both cytologic suspensions and frozen tissue sections of oral epithelium. Pericellular plasma membrane immunoreactants were localized to upper spinous layer cells of the parakeratin phenotype; basal and parabasilar layers as well as all strata of orthokeratinized epithelia were negative. Those cells harboring EBV DNA as detected by in situ hybridization corresponded to cells with C3d/EBV receptors.

Antibodies, Monoclonal↗
PubMedDate not supplied

Sequential occurrence of IgM, IgM/IgG, and gp120-IgM/IgG complement complexes on CD4+ lymphocytes in relation to CD4+ blood lymphocyte depletion in HIV+ hemophilia patients: results of a 10-year study.

The concept of autoimmune mechanisms playing an integral role in the pathogenesis of HIV disease is rapidly gaining ground. In this study, we determined IgM and IgG antibodies, complement fragments and gp120 on the surface of CD4+ lymphocytes using double-fluorescence flow cytometry. Sequential analysis demonstrated an inverse relationship of autoantibodies and CD4+ lymphocyte counts in the peripheral blood. HIV+ patients without autoantibodies (16/104 = 15%) had the highest CD4+ blood cell counts (324 +/- 264/microliters; mean +/- SD). CD4+ counts were successively lower in patients with complement-fixing IgM (243 +/- 240/microliter), complement-fixing IgG and IgM (139 +/- 138/microliter), or gp120-IgM/IgG complement complexes on the surface of CD4+ cells (38 +/- 45/microliter, P = 0.03). Individual patient profiles show that IgM autoantibodies typically are formed early after HIV infection and appear to deplete CD4+ lymphocytes very slowly, whereas complement-fixing IgG autoantibodies are generated at a later stage and deplete CD4+ lymphocytes more efficiently. The presence of both soluble gp120 and complement-fixing autoantibodies on CD4+ lymphocytes is associated with very low CD4+ cell counts and coincides with progression to terminal disease. Early during HIV infection autoantibody production is rather unstable, but it becomes more stable with disease progression and persists in advanced stages of the disease. These data suggest that autoantibody formation against CD4+ lymphocytes is a pathogenic mechanism for CD4+ cell depletion.

Antigen-Antibody Complex↗
PubMed1989

Effect of methylprednisolone on endotoxemia and complement activation during cardiac surgery.

The influence of high doses of methylprednisolone on complement activation and endotoxin concentration was investigated in two groups of eight patients undergoing coronary artery bypass grafting. Group 1 received methylprednisolone, 30 mg/kg, at the induction of anesthesia; group 2 served as the control group. The endotoxin concentrations increased significantly in both groups at the start of cardiopulmonary bypass. During cardiopulmonary bypass, the endotoxin concentrations were significantly higher in the steroid group compared with the control group (p less than 0.01). After completion of surgery, the endotoxin concentrations declined to almost zero within seven days in both groups. Complement activation was significantly reduced in the steroid-treated group during cardiopulmonary bypass compared with the control group (P less than 0.01). The clinical outcome after the first postoperative week was the same in the two groups. It appears that high-dose steroids can reduce complement activation during cardiopulmonary bypass, although the clearance of endotoxins may also be reduced.

Aged↗
PubMedDate not supplied

Role of Akata cell membrane fluidity in susceptibility to Epstein-Barr virus infection.

Infection by Epstein-Barr virus (EBV), a B lymphotropic human herpesvirus, of its target cells is initiated by the binding of the viral envelope glycoprotein gp350/220 to a 145-kDa cell membrane glycoprotein (CD21, CR2) which also serves as the receptor for the complement fragment C3d (Fingeroth et al., 1984; Nemerow et al., 1987). We used the fluorescent probe 1-6-diphenyl-1,3,5-hexatriene (DPH), extremely sensitive to the polar environment, in order to analyse the membrane viscosity distribution in single cells of two lymphoid cell lines, Raji and Akata. Lipid analysis on both cell lines showed a slightly lower cholesterol:phospholipid molar ratio on Akata than on Raji cells. Measurements of cell fluidity by DPH polarization in native cells and after cholesterol enrichment indicated that the apparent Akata membrane viscosity was lower than the viscosity of Raji cells. To examine the possibility that this difference could be correlated to a difference in the behaviour of Akata and Raji cells in expressing EBV early antigens, both lines were superinfected with the EBV non-transforming P3HR1 strain. We report here evidence that lipid composition can regulate EBV entry into cells.

Antigens, Viral↗
PubMed1996

Aortobifemoral surgery induces complement activation and release of interleukin-6 but not tumour necrosis factor-alpha.

The aim of the present study was to determine the inflammatory response by an extended analysis of complement in 16 patients undergoing aortobifemoral bypass surgery. The patients were randomized to receive either a bifurcated expanded polytetrafluoroethylene graft (n = 8; group I) or a collagen-impregnated knitted Dacron graft (n = 8; group II) to determine whether differences in graft surface properties might influence the inflammatory response during and after the procedure. The following components of complement: C1q, C4, C3, C3d, C5a and terminal complement complexes were all analysed. C-reactive protein and interleukin-6 were also determined to assess the acute phase response. The complement data were corrected for haemodilution, which was assessed from alpha 2-macroglobulin concentrations. A significant decrease of C1q (P < 0.0001) and an increase in C5a (P < 0.0005) was observed in both groups. C4 and C3 levels showed slight fluctuations in group I, whereas in group II these proteins increased significantly (P < 0.05, P < 0.005, respectively) between 2 and 7 days after surgery. Terminal complement complexes remained unchanged in both groups. Interleukin-6 levels peaked at 12-24 h and the C-reactive protein at 24-72 h. Higher interleukin-6 levels (P < 0.05) were found in group II 6 h after surgery compared with group I; no release of tumour necrosis factor-alpha was identified. An early inflammatory response was found in all patients. The patterns of the complement proteins varied with a C1q depletion and a C5a increase, interpreted as complement activation. Whether the variations between the two graft groups represent any differences in graft surface properties has to be further elucidated.

Aged↗
PubMedDate not supplied

The covalent interaction of C3 with IgG immune complexes.

Antigens (Ags) are converted into immune complexes (antigen-antibody complexes, IC) as soon as they encounter their specific antibodies (Abs). In fluids containing complement, the process of IC formation and fixation of complement components occur simultaneously. Hence, the formation of Ag-Ab-complement complexes is the normal way of eliminating Ags from a host. C3b-C3b-IgG covalent complexes are immediately formed on interaction of serum C3 with IgG-IC. These C3b-C3b dimers constitute the core for the assembly of C3/C5-convertase on the IC, which are subsequently converted into iC3b-iC3b-IgG by the complement regulators. These complexes are detected on SDS-PAGE by two bands of molecular composition, C3alpha65-C3alpha43 (band A) and C3alpha65-heavy chain of the Ab (band B), which correspond to C3b-C3b and C3b-IgG covalent interaction respectively, and that identify opsonized IC (C3b-IC). C3b can attach to Fab and Fc regions of the Ab molecule with similar efficiency. The presence of multiple C3b binding regions on IgG is considered an advantageous characteristic that facilitates the elimination of Ags in the form of C3b(n)-IC. Ab molecules on the IC recognize the Ag, and also serve as a very good acceptor for C3b binding. In this way, Ags, even if they have no acceptor sites for C3b, can be efficiently processed and removed. When C3 is activated in serum by IC or other activators, secondary C3b-IgG covalent complexes are generated, with bystander monomeric circulating IgG, and thus constitute, physiological products of complement activation. These complexes gain importance when IgG concentration is extremely high as in cases of infusion of intravenous IgG (IVIG) in several pathologies. The covalent attachment of activated complement C3 (C3b, iC3b, C3 d,g) to Ags or IC links innate and adaptative immunity by targeting Ags to different cells of the immune system (follicular dendritic cells, phagocytes, B cells). Hence C3b marks Ags definitively, from the earliest contact with the innate immune system until their complete elimination from the host.

Amino Acid Sequence↗