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PubMed1992

The human complement C4B/steroid 21-hydroxylase (CYP21) and complement C4A/21-hydroxylase pseudogene (CYP21P) intergenic sequences: comparison and identification of possible regulatory elements.

We determined the 1.8 kb intergenic sequences between the human complement C4B gene and the active steroid 21-hydroxylase gene in two subjects, and between the C4A gene and the steroid 21-hydroxylase pseudogene in one subject. Comparison of these sequences with each other and with published homologues revealed no differences which were unique to either intergenic region. Sequence analysis revealed two copies of an AGGTCA motif in all sequences. This motif is common to steroidogenic enzyme gene promoters and to the response elements for nuclear hormone receptors. Similarities with human enhancers were also found.

Bacteriophage lambda↗
PubMed1997

Temporal studies on the deposition of complement on human colostrum IgA and serum IgG immobilized on methylated silicon.

The temporal deposition of selected complement proteins from human serum onto immobilized human colostrum immunoglobulin (Ig)A and human IgG on hydrophobic silicon was studied by ellipsometry-antibody techniques after incubations at 37 degrees C for up to 1 h. In parallel experiments the serum soluble iC3b, C4d, and Bb were detected by enzyme-linked immunosorbent assay techniques. The IgA-coated surfaces showed activation via the alternative pathway, and displayed a lag phase in the deposition of increased amounts of serum proteins, and anti-C3c and antiproperdin. Anti-IgG, -C1q, -C4, -factor H and -factor B were not deposited at any time to IgA surfaces. Upon coating of the surface with IgG, the classical pathway was rapidly activated and bound, then anti-C3c, antiproperdin, and after short serum incubation times, also anti-C1q and anti-IgG. When factor B-depleted or heat-treated sera were used, the observation was that properdin deposited onto IgG-coated surfaces from both. Ellipsometry and antibody techniques offer a convenient and rapid way to indicate the activation of the complement system on solid surfaces and facilitates a time-resolved determination of the activation pathway(s).

Biocompatible Materials↗
PubMed2001

Intact B cell tolerance in the absence of the first component of the classical complement pathway.

A critical role for complement in the regulation of self tolerance has been proposed to explain the strong association between complement deficiency and autoimmunity. To elucidate the role of the classical pathway of complement in the maintenance of B cell tolerance, C1q-deficient (C1qa-/-) mice were bred with anti-hen egg lysozyme (HEL) immunoglobulin (Ig(HEL)) and soluble HEL (sHEL) transgenic mice. B cell tolerance was intact in C1qa-/- mice. In vivo, double-transgenic (Ig(HEL)/sHEL) C1qa-/- and wild-type control mice down-regulated surface immunoglobulin expression on splenocytes and equivalent numbers of HEL-binding B cells accumulated in the periphery. Maturation of B cells, evidenced by CD21 expression, was retarded to the same extent and at a similar time point. The frequency of anti-HEL-producing plasma cells and serum levels of anti-HEL immunoglobulin were comparably reduced in control and C1qa-/- double-transgenic mice compared to control Ig(HEL) and C1qa-/- Ig(HEL) mice. Furthermore, splenocytes from double-transgenic C1qa-/- or wild-type mice did not modulate intracellular calcium levels after stimulation with HEL in vitro. These data demonstrate that a stable form of B cell anergy persists in the periphery of C1qa-/- mice, suggesting that activation of the classical pathway by C1q is not essential for the maintenance of B cell tolerance in this transgenic model.

Animals↗
PubMed1995

Biphasic response of complement to heparin: fluid-phase generation of neoantigens in human serum and in a reconstituted alternative pathway amplification cycle.

We describe a study of the effects of heparin on complement activation through the use of assays for fragment C4d, fragment Bb, and the S-C5b-9 complex (S-MAC). In sera from healthy volunteers, virtually no change was observed in C4d either as a function of time or of heparin concentration, whereas changes in Bb and S-MAC were biphasic. This observation was explored in greater detail in the heparin concentration range 0.001-5.0 u/ml (5 x 10(-3) to 25 micrograms/ml). For both Bb and S-MAC, a significant (P < 0.05) increase in production was noted in the heparin concentration range, 0.01-0.5 u/ml (5 x 10(-2) to 2.5 micrograms/ml). At higher heparin concentrations, Bb and S-MAC production decreased markedly (P < 0.05). We reconstituted the alternative pathway amplification cycle (C3, factor B, and factor D) and studied Bb generation. With reactants at concentrations one tenth those of normal serum, we observed a maximum generation of 13.2 micrograms/ml Bb. Control and heparin at 5 x 10(-4) micrograms/ml generated Bb concentrations of 6.8 and 6.1 micrograms/ml, respectively, for a 2-min incubation; at 5 x 10(-3) micrograms/ml heparin, Bb was increased to 9.8 micrograms/ml. Using isoelectric focusing to study anionic pI shifts in heparin-bound factors B and D, it was found that factor B bound heparin only at the highest heparin concentration studied, i.e., 50 micrograms/ml; factor D, however, bound heparin at a much lower concentration (0.05 micrograms/ml). We conclude that, at low concentrations, heparin activates complement due to potentiation of the alternative pathway amplification cycle in the fluid phase.

Adult↗
PubMed1989

Activation of the complement system in systemic sclerosis. Relationship to clinical severity.

Using newly developed techniques, we investigated the complement pathways and the extent of their activation in patients with systemic sclerosis (SSc) of both the diffuse cutaneous and limited cutaneous types. Plasma levels of the fragments C3d, C4d, and Ba were measured in patients with SSc and in matched control subjects. All fragments and ratios were higher in SSc patients than in controls (P less than 0.05), demonstrating that complement activation occurs in SSc. Levels of C3d, C3d:C3, Ba, and Ba:factor B were higher in patients with diffuse cutaneous SSc patients than in controls (P less than 0.01). C3d, C3d:C3, C4d, and C4d:C4 levels were also higher in patients with limited cutaneous SSc than in controls (P less than 0.05). These results show that complement activation occurs in SSc patients and that it reflects clinical severity. Complement activation may therefore have a pathogenetic role in SSc, and its measurement may prove useful in monitoring the disease.

Adult↗
PubMed1991

Synovial fluid levels of complement SC5b-9 and fragment Bb are elevated in patients with rheumatoid arthritis.

To determine whether complement turnover in synovial fluids of patients with rheumatoid arthritis (RA) reflects activation by the classical or alternative pathway, we used novel immunoassays to measure products of complement activation (the membrane attack complex SC5b-9 and the cleavage fragments Bb and C4d). Mean synovial fluid levels of SC5b-9 were more than 8 times higher in RA than in crystal-induced arthritis (gout and pseudogout) and over 16 times higher than in degenerative joint disease (DJD). Similarly, Bb levels were more than 3 times higher in RA synovial fluids than in crystal-induced arthritis and over 7 times higher than in DJD. Levels of C4d did not differ among the groups. SC5b-9 levels correlated with synovial fluid C3 anaphylatoxin (C3a), Bb, and C4d levels (r = 0.81, 0.62, and 0.51, respectively). In patients with RA, synovial fluid SC5b-9 levels correlated with C3a and Bb (r = 0.6 and 0.56, respectively) but not with C4d. Therefore, novel assays for complement activation indicate that both classical and alternative pathways are involved in complement turnover and that the alternative pathway contributes more to complement activation in RA than in DJD or crystal-induced arthritis.

Arthritis, Rheumatoid↗
PubMed1992

Activation of the alternative complement pathway accompanies disease flares in systemic lupus erythematosus during pregnancy.

OBJECTIVE: To assess the activity of systemic lupus erythematosus (SLE) during pregnancy and to distinguish it from preeclampsia. METHODS: We prospectively measured the complement activation products Ba, Bb, SC5b-9, and C4d, as well as the conventional complement determinants C3, C4, and CH50, during pregnancy in 14 patients with SLE and 10 women with preeclampsia. RESULTS: Four of the 14 SLE patients were considered to have disease flares, 3 occurring in the second trimester and 1 postpartum. In these patients, significant abnormalities of Ba, Bb, SC5b-9, and CH50 were noted. In contrast, measures of C4d did not distinguish between pregnant patients who had flares and those whose SLE remained stable. Although decreased values of C3 were rarely seen in the patients with stable disease, normal values of C3 during lupus pregnancy were not reliably associated with stable disease. Three of 10 non-SLE patients with preeclampsia had elevated levels of Ba; however, in each case, the CH50 level was close to or within the normal range. This was in sharp contrast to the findings observed in the 4 patients with active SLE, in whom high levels of plasma Ba were always associated with low CH50 values. Moreover, the ratio of CH50 to Ba was significantly lower in the patients with lupus flares than in the non-SLE patients with preeclampsia. CONCLUSION: While a decline in the CH50 level alone could otherwise be attributed to decreased synthesis of complement components, these data demonstrate that ongoing activation of the alternative complement pathway can accompany disease flares in pregnant women with SLE.

Complement Activation↗
PubMed1992

Assessment of disease activity and impending flare in patients with systemic lupus erythematosus. Comparison of the use of complement split products and conventional measurements of complement.

OBJECTIVE: To determine whether increased levels of the complement split products generated in the activation of the alternative or classical pathway accompany more severe disease activity in patients with systemic lupus erythematosus (SLE) and whether these measurements are useful in predicting flares of disease. METHODS: Levels of Ba, Bb, SC5b-9, and C4d were measured in 380 plasma samples obtained from 86 SLE patients who were prospectively followed up for 15 months. RESULTS: In the 20 patients who had inactive disease at the initiation of the study, the mean values of all of the complement split products at entry were within the normal range. In the 47 patients with stable or moderate disease activity, levels of Ba were significantly increased, while the mean values for Bb, SC5b-9, and C4d did not differ significantly from those in patients with inactive disease. The mean entry value of each analyte was highest in the group of 19 patients who had the most severe disease activity at initial evaluation. Traditional measurements of complement, i.e., C3, C4, and CH50, followed similar trends, but did not discriminate between the 3 groups of patients as well as did measurements of the split products. Analysis of the disease course in the patients with inactive or stable/moderate disease revealed that an elevated level of C4d had the most sensitivity with regard to subsequent flare, while an elevated Bb level had the highest specificity and the greatest predictive value. CONCLUSION: These data suggest that elevated levels of complement split products, particularly products of alternative and terminal pathway activation, more accurately reflect disease activity than do conventional measurements of complement in SLE and may be useful in the prediction of impending disease flares.

Complement C3 Convertase, Alternative Pathway↗
PubMed1996

Sensitivity and specificity of plasma and urine complement split products as indicators of lupus disease activity.

OBJECTIVE: To determine if measurement of serum complement split products (C4d, Bb, C5b-9) is better than conventional C3 and C4 measurements in distinguishing patients with varying degrees of lupus disease activity, and to determine if the presence of C3d in urine is helpful in distinguishing lupus patients with from those without early lupus nephritis. METHODS: Lupus disease activity was prospectively determined at 3 consecutive visits an average of 4 months apart, using the Systemic Lupus Activity Measure (SLAM), the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), and physician global assessment (PGA). Blood samples were evaluated for the presence of C4d, Bb, and C5b-9 by quantitative microassay plate enzyme immunoassay at each patient visit. We characterized urinary excretion of C3 fragments (with attention to C3d) by sodium dodecyl sulfate-polyacrylamide gel electrophoresis with Western blotting. RESULTS: Thirty-one SLE patients were enrolled in the study. The mean SLAM score and the mean SLEDAI score each correlated well with the PGA at all 3 visits. A SLAM score of 6 and a SLEDAI score of 4 had the best overall sensitivity and specificity for predicting moderate-to-severe disease activity by PGA (100% and 73%, respectively, for the SLAM and 86% and 94%, respectively, for the SLEDAI). Serum C4d and Bb were more sensitive indicators of current moderate-to-severe lupus disease activity at all 3 visits than were serum C5b-9, C3, and C4. C3 and C4 were more specific indicators of moderate-to-severe disease activity. Serum C4d and Bb were more sensitive at predicting moderate-to-severe disease activity at subsequent visits than were C5b-9, C3, and C4. Urine C3d was better than C3, plasma C4d, Bb, C5b-9 and anti-double-stranded DNA antibody in distinguishing patients with from those without acute lupus nephritis (P = 0.02). CONCLUSION: C4d and Bb are sensitive indicators of moderate-to-severe lupus disease activity and may be most helpful in situations where conventional measurements are not, such as in lupus patients whose C3 and C4 levels remain normal despite evidence of clinical disease activity. It appears from this study that detection of urine C3d may be a simple way of measuring complement activation in the setting of lupus renal disease. The availability of instruments for clinical disease activity measurement such as the SLAM and the SLEDAI may enable more consistent definition of lupus disease activity and may thus provide a means for better examining the role of complement activation products in predicting lupus disease activity in larger patient populations.

Adult↗
PubMed1992

Expression of genes encoding receptors for IgG (FcRIII) and for C3b/C4b (Crry) in rat sciatic nerve during development and Wallerian degeneration.

Northern blots were used to examine the expression of genes encoding receptors for IgG (FcRIII) and for C3b/C4b (Crry) in rat sciatic nerve during development and Wallerian degeneration. Steady state levels of FcRIII (1.4 kb) and Crry (1.9 and 2.1 kb) mRNAs were higher in adult rat nerves than in 6 day and 21 day postnatal rat nerves, indicating that the expression of these receptors is developmentally regulated. The FcRIII and Crry cDNA probes also hybridized with total RNA from 3 day old rat Schwann cells and from adult rat peritoneal macrophages. The size of the FcRIII mRNA expressed by cultured Schwann cells (1.6 kb) differed from that expressed by peritoneal macrophages (1.4 kb); the two may be splice variants of one transcript or products of related genes. Peritoneal macrophages contained approximately 100 times higher FcRIII mRNA levels than Schwann cells. In contrast, steady state levels of both 1.9 and 2.1 kb Crry mRNAs were similar in cultured Schwann cells and macrophages. Nerve transection induced a generalized increase in the level of sciatic FcRIII mRNA (1.4 kb) 3 days post-surgery, whereas the level of Crry mRNA was increased only in the nerve segment immediately to the cut. The increase of FcRIII mRNA that occurred in Wallerian degeneration was most likely due to infiltration of macrophages, as FcRIII mRNA-positive macrophages were demonstrated in the degenerating nerves by in situ hybridization. FcRIII mRNA-positive macrophages were not found in normal nerve. The functions of FcRIII and Crry in peripheral nerves are uncertain, but they may be of significance in phagocytosis, antibody-dependent cellular cytotoxicity, and in local immune regulation.

Aging↗
PubMed1999

Immune complex size and complement regulate cytokine production by peripheral blood mononuclear cells.

We have previously shown that immune complexes isolated from children with juvenile rheumatoid arthritis are heterogeneous in their size, composition, and proinflammatory capacities. The experiments described here were undertaken to clarify further the roles of size and composition in determining the proinflammatory effects of immune complexes. We incubated peripheral blood mononuclear cells (PBMCs) with different soluble immune complex preparations: opsonized complexes, which were formed in the presence of serum, unopsonized complexes, which were formed in the absence of serum, and immune precipitates solubilized by complement after their formation. ELISA assays showed that immune complexes formed in the presence of complement were less efficient than unopsonized complexes in inducing IL-1beta and IL-8 secretion from leukocytes. Solubilized immune precipitates showed intermediate capacity to stimulate the release of both cytokines. Complexes formed in heat-inactivated serum were as efficient as unopsonized complexes in eliciting cytokine secretion from the cells. The capacity of complement to regulate cytokine secretion from leukocytes was related, at least in part, to immune complex size. Sucrose density gradients showed unopsonized complexes and solubilized immune precipitates were larger than opsonized immune complexes. In contrast, fluid-phase binding of C4 to immune complexes, which did not appreciably change immune complex size, substantially increased IL-1beta secretion from PBMC.

Antigen-Antibody Complex↗
PubMed1993

Alterations in C3, C4, factor B, and related metabolites in septic shock.

Forty subjects consisting of (i) patients with septic shock, (ii) patients with sepsis without shock, (iii) critically ill non-septic patients, and (iv) normal controls were studied for plasma C3, C4, factor B, iC3b, C4d, Bb, and SC5b-9 levels in an attempt to profile the pattern of complement activation in sepsis. Significant decreases in plasma C3 and C4 concentrations were observed in septic shock patients compared to normal as well as to critically ill subjects. When adjusted for illness severity, levels of C3 but not C4 showed significant differences between septic shock and critically ill patients. Concentrations of the complement metabolite Bb as well as the Bb to factor B ratio were significantly increased in septic shock patients. SC5b-9 levels were significantly higher in septic shock patients compared to normal as well as to critically ill subjects. No increases in C4d or iC3b were observed, but the iC3b to C3 ratio was higher in septic shock patients compared to that in normal subjects. In septic shock patients, there were significant correlations between SC5b-9 and Bb (P = 0.0213) concentrations and between C3 and Factor B concentrations (P = 0.0041). SC5b-9 levels also were correlated with lactate levels in septic shock patients (P = 0.0091). These findings demonstrate a metabolite pattern consistent with primarily alternative and terminal pathway activation in septic shock patients. Decreases in C4, a classical pathway component, may not be specific for septic shock and do not appear to be necessarily due to significant complement consumption/activation.

Adult↗
PubMed1995

Decreased levels of complement receptor 1 (CD35) on B lymphocytes in persons with HIV infection.

Previous studies have shown that complement receptor 1 (CR1) expression on erythrocytes is decreased under several conditions including HIV infection and autoimmune diseases. The goal of this study was to determine whether expression of CR1 on peripheral blood B cells, where this receptor plays a role during immune responses, is altered in persons with HIV infection. The B cells from rheumatoid arthritis (RA) patients were also assessed since this represents a group with known complement and B cell abnormalities. The CD19+ B cells from persons with either HIV infection or RA had significantly reduced levels of CR1 when compared with control donors (75 and 72% CR1+ versus 94% CR1+ for control donors). The reduction of B cell CR1 occurred in both the percentage of B cells positive for CR1 and the levels of CR1 found on positive cells. In contrast, CR1 on monocytes was not reduced. As shown in previous studies, CR2 was also found to be reduced on B cells from the HIV-infected persons and there was extensive overlap between the B cell subsets which lacked expression of CR1 and CR2. The complement receptor-negative B cells found in HIV-infected persons were not immature or activated as defined by their lack of expression of CD10 or B7, respectively. Elevated levels of C4d, a classical complement pathway-activation product, were detected in plasma from both HIV-infected and RA patients. These studies suggest that chronic complement activation occurring in persons with HIV infection or RA can affect the complement receptor phenotype of peripheral blood B cells. Since complement receptors are involved in activation of B cells, the subset that lacks CR1 may represent cells that have encountered immune complexes and may therefore be stimulated. Additionally, the downregulation of complement receptors may have significant effects on the ability of B cells to capture and present opsonized antigens.

Antigen-Antibody Complex↗
PubMed1997

Complement activation in severe Plasmodium falciparum malaria.

We determined indices of plasma complement activation (C3, C4, Bb, C4d, iC3b, and SC5b-9), levels of tumor necrosis factor (TNF) and interleukin-6, and the APACHE II score in 23 patients with complicated Plasmodium falciparum malaria. On admission, plasma concentrations of Bb, SC5b-9, and C4d were markedly increased compared to healthy control subjects (n = 24) (4.5 +/- 1.9 vs 1.5 +/- 0.6 mg/L; 1125.7 +/- 496.9 vs 183.2 +/- 76.5 microg/L; and 15.7 +/- 5.7 vs 7.2 +/- 1.4 mg/L, P < 0.01 for all). In contrast C3 and iC3b concentrations were decreased (631.4 +/- 247 vs 947.3 +/- 243.2 and 105 +/- 17.9 vs 151.3 +/- 14.5 mg/L; P < 0.01 for both). Plasma C4 concentrations in malaria were not different from normal controls. Plasma Bb, C3, and iC3b levels normalized on day 7 of treatment, whereas SC5b-9 and C4d levels remained elevated. A significant correlation between elevated TNF levels and Bb (r = 0.507) and SC5b-9 (r = 0.448, P < 0.01 for both) and a negative correlation between iC3b and SC5b-9 and TNF levels existed (r = -0.537 and r = -0.466, P < 0.01 for both). In addition, a significant correlation between C3 and iC3b (r = 0.689) and C4 and C4d (r = 0.737) existed. However, no relation between clinical disease severity and complement fragments existed. The results demonstrate that both the classical and the alternative pathways of the complement system are profoundly activated in complicated malaria.

Adult↗
PubMed2002

Complement activated C4d immunoreactive oligodendrocytes delineate small cortical plaques in multiple sclerosis.

C4d-immunoreactive complement-activated oligodendrocytes (C4d-CAOs) have been described in several neurodegenerative diseases but have not been studied in multiple sclerosis (MS). Here we report that such CAOs delineate miniature MS plaques of 300-500 mum diameter. They are devoid of myelin and are surrounded by a rim of activated microglia intermingled with the C4d-CAOs. Although C4d-immunostained periaxonal oligodendroglial processes are often swollen, the axons of passage appear undamaged and extend through the demyelinated plaque area. No immunostaining with other components of the complement cascade (C1q-C9) was observed in association with these miniature plaques. However, in large MS lesions, C1q-C9 immunoreactive fibers were present, indicating complete activation of the complement cascade in these more developed lesions. It is possible that the miniature plaques, bordered by C4d-CAOs, represent the earliest stage of plaque development, preceding even the larger, transient plaques frequently observed in serial MRI studies. The association of CAOs with miniature areas of demyelination suggests a direct attack on oligodendroglial cells by the early complement components as an initiating event in MS. Incomplete complement activation indicates that this step may be reversible, whereas full and persistent activation as observed in large MS lesions may lead to death of oligodendroglia with permanent axonal damage.

Aged↗
PubMed1992

Possible association of the extended MHC haplotype B44-SC30-DR4 with autism.

We previously reported that the complement C4B null allele appears to be associated with infantile autism. Since the C4B null allele is known to be part of the extended or ancestral haplotype [B44-SC30-DR4], we investigated the incidence of [B44-SC30-DR4] in 21 autistic children and their parents. This extended haplotype was increased by almost six-fold in the autistic subjects as compared with healthy controls. Moreover, the total number of extended haplotypes expressed on chromosomes of autistic subjects was significantly increased as compared with those expressed on chromosomes of healthy subjects. We conclude that a gene related to, or included in, the extended major histocompatibility complex may be associated with autism.

Adolescent↗
PubMed1992

Increases in immunoglobulin and complement in patients with esophageal or gastric cancer.

Based on data providing evidence that the enhancement of serum IgG and IgA is associated with the occurrence of infectious complications following surgery in patients with esophageal cancer, we examined the possible factors contributing to alterations in the serum IgG, IgA, IgM, C3, C4, and CH50 levels. A multiple linear regression analysis was made on data obtained from 71 patients with esophageal cancer and 57 with gastric cancer. In the patients with esophageal cancer, age and protein-calorie malnutrition (PCM) were related to the elevation of IgG levels while the stage of cancer was linked to that of IgA. The sex and IgM levels were also seen to be related. Age and the stage of cancer were associated with reductions in C3, C4, and CH50 levels, although in the patients with gastric cancer, the stage of cancer and elevations of these complement levels were related. Thus, age, PCM, and tumor malignancy are all factors related to the enhancement of IgG or IgA in patients with esophageal cancer.

Adenocarcinoma↗