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At least 613 records · Page 34Linked to original sources
PubMed2005

Antibody-mediated rejection in human cardiac allografts: evaluation of immunoglobulins and complement activation products C4d and C3d as markers.

Antibody-mediated rejection (AMR) in human heart transplantation is an immunopathologic process in which injury to the graft is in part the result of activation of complement and it is poorly responsive to conventional therapy. We evaluated by immunofluorescence (IF), 665 consecutive endomyocardial biopsies from 165 patients for deposits of immunoglobulins and complement. Diffuse IF deposits in a linear capillary pattern greater than 2+ were considered significant. Clinical evidence of graft dysfunction was correlated with complement deposits. IF 2+ or higher was positive for IgG, 66%; IgM, 12%; IgA, 0.6%; C1q, 1.8%; C4d, 9% and C3d, 10%. In 3% of patients, concomitant C4d and C3d correlated with graft dysfunction or heart failure. In these 5 patients AMR occurred 56-163 months after transplantation, and they responded well to therapy for AMR but not to treatment with steroids. Systematic evaluation of endomyocardial biopsies is not improved by the use of antibodies for immunoglobulins or C1q. Concomitant use of C4d and C3d is very useful to diagnose AMR, when correlated with clinical parameters of graft function. AMR in heart transplant patients can occur many months or years after transplant.

Biomarkers↗
PubMed2006

C4d in acute rejection after liver transplantation--a valuable tool in differential diagnosis to hepatitis C recurrence.

Hepatitis C is the most common indication for liver transplantation. Recurrence of HCV is universal leading to graft failure in up to 40% of all patients. The differentiation between acute rejection and recurrent hepatitis C is crucial as rejection treatments are likely to aggravate HCV recurrence. Histological examination of liver biopsy remains the gold standard for diagnosis of acute rejection but has failed in the past to distinguish between acute rejection and recurrent hepatitis C. We have recently reported that C4d as a marker of the activated complement cascade is detectable in hepatic specimen in acute rejection after liver transplantation. In this study, we investigate whether C4d may serve as a specific marker for differential diagnosis in hepatitis C reinfection cases. Immunohistochemical analysis of 97 patients was performed. A total of 67.7% of patients with acute cellular rejection displayed C4d-positive staining in liver biopsy whereas 11.8% of patients with hepatitis C reinfection tested positive for C4d. In the control group, 6.9% showed C4d positivity. For the first time we were able to clearly demonstrate that humoral components, represented by C4d deposition, play a role in acute cellular rejection after LTX. Consequently C4d may be helpful to distinguish between acute rejection and reinfection after LTX for HCV.

Acute Disease↗
PubMed2006

C4d deposition and clearance in cardiac transplants correlates with alloantibody levels and rejection in rats.

Antibody-mediated rejection of human cardiac transplants is correlated with C4d deposits and macrophage infiltrates in capillaries of endomyocardial biopsies. We produced an antibody to rat C4d to study C4d deposition and clearance in Lewis rats that were sensitized with a blood transfusion from DA rats 7, 14 or 21 days before cardiac transplantation. Cyclosporin A (CsA) immunosuppression was initiated after transplantation at a dose that inhibited graft rejection, antibody production and C4d deposition in unsensitized recipients. Blood transfusion elicited high levels of circulating IgG alloantibodies, predominantly of the complement-activating IgG2b subclass, that peaked 14 days after transplantation. At this time, macrophages accumulated in capillaries, and C4d deposits were diffuse and intense on arteries, capillaries and veins. Grafts that survived 90 days in sensitized recipients still had deposits of C4d that were associated with increased interstitial fibrosis and vasculopathy in arteries. Clearance of C4d was determined by retransplanting DA cardiac allografts from Lewis recipients back to DA recipients. C4d deposits were decreased to minimal levels within 5 days after retransplantation. Thus, C4d deposition is not limited to the capillaries, but extends throughout the arterial tree, and despite formation of a covalent bond, C4d is cleared within days.

Animals↗
PubMed2006

Immunoadsorption in severe C4d-positive acute kidney allograft rejection: a randomized controlled trial.

Antibody-mediated rejection (AMR) frequently causes refractory graft dysfunction. This randomized controlled trial was designed to evaluate whether immunoadsorption (IA) is effective in the treatment of severe C4d-positive AMR. Ten out of 756 kidney allograft recipients were included. Patients were randomly assigned to IA with protein A (N = 5) or no such treatment (N = 5) with the option of IA rescue after 3 weeks. Enrolled recipients were subjected to tacrolimus conversion and, if indicated, 'anti-cellular' treatment. All IA-treated patients responded to treatment. One death unrelated to IA occurred after successful reversal of rejection. Four control subjects remained dialysis-dependent. With the exception of one patient who developed graft necrosis, non-responders were subjected to rescue IA, however, without success. Because of a high graft loss rate in the control group the study was terminated after a first interim analysis. Even though limited by small patient numbers, this trial suggests efficiency of IA in reversing severe AMR.

Adult↗
PubMed2007

Subclinical acute antibody-mediated rejection in positive crossmatch renal allografts.

Subclinical antibody-mediated rejection (AMR) has been described in renal allograft recipients with stable serum creatinine (SCr), however whether this leads to development of chronic allograft nephropathy (CAN) remains unknown. We retrospectively reviewed data from 83 patients who received HLA-incompatible renal allografts following desensitization to remove donor-specific antibodies (DSA). Ten patients had an allograft biopsy showing subclinical AMR [stable SCr, neutrophil margination in peritubular capillaries (PTC), diffuse PTC C4d, positive DSA] during the first year post-transplantation; 3 patients were treated with plasmapheresis and intravenous immunoglobulin. Three patients had a subsequent rise in SCr and an associated biopsy with AMR; 5 others showed diagnostic or possible subclinical AMR on a later protocol biopsy. One graft was lost, while remaining patients have normal or mildly elevated SCr 8-45 months post-transplantation. However, the mean increase in CAN score (cg + ci + ct + cv) from those biopsies showing subclinical AMR to follow-up biopsies 335 +/- 248 (SD) days later was significantly greater (3.5 +/- 2.5 versus 1.0 +/- 2.0, p = 0.01) than that in 24 recipients of HLA-incompatible grafts with no AMR over a similar interval (360 +/- 117 days), suggesting that subclinical AMR may contribute to development of CAN.

Adult↗
PubMed1987

Heterogeneity of C4d and C3d and their complex formation with serum albumin.

High molecular weight (Mr around 175 KD) forms of C4d and C3d as well as free C4d and C3d (Mr about 40 KD) were demonstrable in normal human serum (NHS). Following in vitro C activation in NHS by delta IgG, the 40 KD C4d component increased markedly. By immunofixation it was shown that the high molecular forms of C4d and C3d reacted with biotinylated anti-human albumin IgG, whereas the 40 KD-free C4d and C3d fragments did not. Furthermore, the incorporation of anti-albumin IgG in the first dimensional gel in crossed immunoelectrophoresis caused retention of the 175 KD C4d component but not of free C4d. The 175 KD C4d had a distinctly higher electrophoretic migration velocity (post-albumin region) than the 40 KD C4d fragment. The C3d-, C4d-serum albumin complexes could not be dissociated by reducing agents (DTT, mercaptoethanol), a non-ionic detergent, or exposure to high and low ionic strength.

Complement Activation↗
PubMed1993

Activation of the complement system in baboons challenged with live Escherichia coli: correlation with mortality and evidence for a biphasic activation pattern.

Activation of the complement system was studied in baboons that were challenged with live Escherichia coli. In the group challenged with a lethal dose (n = 4), the complement activation parameters C3b/c, C4b/c, and C5b-9 increased 13, 5, and 12 times the baseline value, respectively, during the first 6 h after the E. coli infusion, whereas in the group challenged with a sublethal dose (n = 10), they increased only moderately, by 2 to 3 times the baseline value. However, in this latter group, a more pronounced activation occurred at 24 h. Subsequent experiments showed that this second phase in complement activation started at 6 h after the challenge, at which time infused microorganisms had been cleared from the circulation. The simultaneous increase in C-reactive protein with this second phase suggested an endogenous activation mechanism involving this acute-phase protein. Levels of inactivated (modified) C1 inhibitor also increased in both groups, with peak levels of 2.5 times the baseline value at 24 h in the sublethal group and of 4 times at 6 h after the challenge in the lethal group. Thus, activation of complement in this animal model for sepsis occurs in a biphasic pattern, the initial phase mediated by the bacteria and the later phase mediated by an endogenous mechanism possibly involving C-reactive protein. The differences in complement activation between animals with lethal or sublethal sepsis support the hypothesis that complement activation contributes to the lethal complications of sepsis.

Animals↗
PubMed2000

Treponema pallidum subsp. pertenue displays pathogenic properties different from those of T. pallidum subsp. pallidum.

The present study described the susceptibility of C4D guinea pigs to cutaneous infection with Treponema pallidum subsp. pertenue Haiti B strain. The general manifestations of the disease in adults and neonates differ, to a certain degree, from those induced by T. pallidum subsp. pallidum Nichols strain. Noticeable differences between the infections were reflected in the character of the skin lesions, their onset and persistence, and the kinetics of the humoral response. The incidence and dissemination of cutaneous yaws lesions in very young guinea pigs were remarkably different from the low frequency observed in a similar age group of syphilis infection, 100 versus 17%, respectively. Moreover, as opposed to T. pallidum subsp. pallidum, T. pallidum subsp. pertenue does not cross the placenta. Offspring born to yaws-infected mothers did not produce immunoglobulin M antibodies and their organs, examined by PCR and rabbit infectivity test (RIT), were all negative. Examination of a large number of tissues and organs in adult, neonate, and maternal yaws by PCR and RIT clearly demonstrated that, unlike syphilis, there was a low incidence and short persistence of the yaws pathogen in internal organs. These findings stress the dermotropic rather than the organotropic character of yaws and provide further evidence of distinctive biological and pathological differences between yaws and venereal syphilis.

Age Factors↗
PubMed2003

Restoration of complement-enhanced neutralization of vaccinia virus virions by novel monoclonal antibodies raised against the vaccinia virus complement control protein.

The vaccinia virus complement control protein (VCP) is secreted by infected cells and has been shown to inhibit complement activation through interactions with C3b/C4b. It contains four short consensus repeat (SCR) domains. It has been suggested that all four SCRs are required for VCP's activity. To elucidate which SCR domains are involved in abolishing complement-enhanced neutralization of vaccinia virus virions, we generated and characterized a panel of mouse monoclonal antibodies (MAbs) raised against VCP. Ten MAbs were isolated and all recognized VCP on Western blots under reducing conditions as well as native-bound VCP in a sandwich enzyme-linked immunosorbent assay. Three of the 10 MAbs (2E5, 3D1, and 3F11) inhibited VCP's abolition of complement-enhanced neutralization of vaccinia virus virions. These MAbs blocked the interaction of VCP with C3b/C4b. The seven remaining MAbs did not alter VCP function in the complement neutralization assay and recognized VCP bound to C3b/C4b. To understand MAb specificity and mode of interaction with VCP, we mapped the MAb binding regions on VCP. The seven nonblocking MAbs all bound to the first SCR of VCP. One of the blocking MAbs recognized SCR 2 while the other two recognized either SCR 4 or the junction between SCRs 3 and 4, indicating that structural elements involved in the interaction of VCP with C3b/C4b are located within SCR domains 2 and 3 and 4. These anti-VCP MAbs may have clinical significance as therapeutic inhibitors of VCP's complement control activity and may also offer a novel approach to managing vaccinia virus vaccine complications that occur from smallpox vaccination.

Animals↗
PubMed1988

Correlation of the activation of the fourth component of complement (C4) with disease activity in systemic lupus erythematosus.

Levels of C4d, a fragment of C4 generated during activation of the classical complement pathway, were measured in the plasma of 48 patients with systemic lupus erythematosus, 11 with inactive (group 1), 23 with mildly active (group 2), 14 with moderately/severely active disease (group 3), and 30 healthy subjects. Levels of C3d, C4, and C3 were also measured and the C4d/C4 and C3d/C3 ratios calculated. C4d levels correlated with the degree of disease activity, being higher in group 3 than in group 2, in group 2 than in group 1, and in group 1 than in controls. C4d/C4 gave a similar result. Activation indices of the common complement pathway, C3d and C3d/C3, also correlated with disease activity, but in a non-linear relationship, failing to discriminate between patient groups. C4 and C3 showed no correlation with disease activity. These results indicate that indices of C4 activation, C4d and C4d/C4, provide a laboratory measure of disease activity in lupus patients, for whom an objective assessment of the severity of the disease is not readily available.

Adult↗
PubMed1992

A long-term immunological study of childhood onset systemic lupus erythematosus.

Immunological dysregulation is an important cause of the development of systemic lupus erythematosus (SLE). Serological evaluation has been useful in the clinical management of patients and as a prognostic indicator. Sixteen patients who developed SLE as children were followed up for more than three years and immunological data collected. The results showed that (a) complement C3 concentration was lower in the active stage of SLE, especially during a major clinical exacerbation, but rarely preceded a major flare up. The concentration was often normal during the mildly to moderately active stage. In contrast, a low complement C4 concentration often preceded a major clinical exacerbation and could be of longer duration, sometimes persisting regardless of disease activity. (b) A T cell subset distribution study showed persistently low CD4 positive T cells in the peripheral blood of patients with SLE during the long term follow up, strongly suggesting that the intrinsic defect is mainly localised in T helper/inducer cells. These abnormal cellular defects did not tend to return to normal even in long term remission. (c) The persistently higher serum interleukin 2 and interleukin 2 receptor concentrations in SLE strongly suggested that the T cells were preactivated in vivo and that these phenomena might persist even in remission. (d) The best single parameter for predicting active SLE was anti-dsDNA. It was highly correlated with disease activity in most patients, and the asymptomatic increase of anti-dsDNA (greater than or equal to 60 U/ml, radioimmunoassay) was often followed by a major clinical exacerbation, especially in patients with a simultaneously low complement C4 concentration, suggesting that it might be an important warning sign of a major flare up. High dose steroids are indicated in this group of patients.

Adolescent↗
PubMed1992

Association of Wegener's granulomatosis with HLA antigens and other genetic markers.

The frequencies of the HLA-A, B, C, DR, DQ antigens and of several other genetic markers in biopsy proved and well characterised patients with Wegener's granulomatosis were compared with control frequencies of the region. A highly significant increase in HLA-DR1 was found. The percentage combined frequency of DR1-DQw1 was significantly higher in patients than in the controls. Interestingly, association with the red cell enzyme GLOI and complement locus C4B was also seen. As both of these markers are either linked or within the major histocompatibility complex region (MHC) this is further evidence for the involvement of chromosome 6 in the pathogenesis of Wegener's granulomatosis. To understand the pathology of the disease fully molecular genetic studies of the MHC region are warranted.

Adult↗
PubMed1996

Association of complement alleles C4AQ0 and C4B5 with rheumatoid arthritis in Koreans.

OBJECTIVE: To investigate the association of complement C4 allotypes with rheumatoid arthritis in Koreans. METHODS: 65 rheumatoid arthritis patients and 255 controls were typed for C4 allotypes and HLA-A, B, C, DR, and DQ antigens. RESULTS: The frequencies of C4AQ0 (32.3% v 14.9%, P < 0.005) and C4B5 (29.2% v 12.2%, P < 0.005) were significantly increased in rheumatoid arthritis patients compared with healthy control subjects. Among rheumatoid patients, the frequency of C4AQ0 was significantly increased in both the rheumatoid factor (RF) positive (27.3%) and the RF negative (66.7%) subgroups. The frequencies of C4B5 and HLA-DR4 were significantly increased only in RF positive subgroup. C4B5 was strongly associated with HLA-DR4, whereas C4AQ0 did not show association with DR4. CONCLUSIONS: In Koreans, C4AQ0 and C4B5 are associated with susceptibility to rheumatoid arthritis, as in the Japanese. C4B5 is strongly associated with HLA-DR4. C4AQ0 is considered to be a DR4 independent risk factor, and a disease susceptibility allele in linkage disequilibrium with C4AQ0 is suggested in Korean patients with rheumatoid arthritis.

Adult↗
PubMed1994

Increased concentration of C4d complement protein in CSF in amyotrophic lateral sclerosis.

Plasma and CSF concentrations of C4d and the circulating immune complex to C1q were measured in 27 patients with amyotrophic lateral sclerosis (ALS) or cervical spondylosis. There was no significant difference among groups in plasma C4d or in plasma or CSF concentrations of the circulating immune complex to C1q. The ALS group, however, had a significantly higher CSF concentration of C4d than the group with cervical spondylosis, as well as a higher C4d index (CSF to plasma C4d ratio x serum to CSF albumin ratio). These results suggest that augmented complement activation in the CNS occurs in ALS. Increased CSF concentration of C4d or raised C4d index may serve as a basis for differentiating ALS from cervical spondylosis.

Adult↗
PubMed1985

Differences in susceptibility to infection with Treponema pallidum (Nichols) between five strains of guinea pig.

Groups of 10 young male guinea pigs of inbred strains 2 and 13 and outbred strains Hartley A, Hartley B, and one deficient in the fourth component of complement (C4D) were infected intradermally with 80 X 10(6) Treponema pallidum (Nichols). The course of infection and production of antitreponemal antibody were examined. Strain C4D guinea pigs were the most susceptible to infection (100%); inbred strains 2 and 13 and outbred strain Hartley B showed 80-90% symptomatic infection; and the Hartley A strain was the least susceptible to infection (10%). Strain 13 animals responded with the highest antitreponemal antibody activity, and the Hartley A strain with the lowest. The results suggest that genetic factors or complement, or both, may influence the degree of susceptibility to infection with T pallidum in guinea pigs.

Animals↗