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PubMed1999

Complement activation in acute humoral renal allograft rejection: diagnostic significance of C4d deposits in peritubular capillaries.

The distinction between acute humoral rejection (AHR) and acute cellular rejection (ACR) in renal allografts is therapeutically important, but pathologically difficult. Since AHR is probably mediated by antibodies to the donor endothelium that activate the classical complement pathway, it was hypothesized that peritubular capillary C4d deposition might distinguish this group. Renal biopsies (n = 16) from 10 patients with AHR who had acute graft dysfunction, neutrophils in peritubular capillaries, and a concurrent positive cross-match were stained for C4d by immunofluorescence. Control biopsies for comparison showed ACR (n = 14), cyclosporin A toxicity (n = 6), or no abnormality (n = 4). Peribiopsy sera were tested for anti-donor HLA antibody. C4d deposited prominently and diffusely in the peritubular capillaries in all AHR biopsies (16 of 16). IgM and/or C3 were also present in 19 and 44%, respectively. With two-color immunofluorescence, C4d was localized in basement membranes (type IV collagen+) and in the endothelium (Ulex europaeus agglutinin-I+). In ACR, no more than trace C4d was found in peritubular capillaries (P < 0.0001 versus AHR), and no patient had anti-donor HLA antibodies (0 of 8); 27% had neutrophils in peritubular capillaries. One of six biopsies with cyclosporin A toxicity had similar C4d deposits, and circulating anti-donor class I antibody was detected. Grafts with AHR were lost (40%) more often than those with ACR (0%; P < 0.02). C4d in peritubular capillary walls distinguishes AHR from ACR, is more specific and sensitive than traditional criteria, and is a potentially valuable adjunct in the diagnosis of graft dysfunction.

Acute Disease↗
PubMed2002

Detection of the complement degradation product C4d in renal allografts: diagnostic and therapeutic implications.

The immunohistochemical detection of the complement degradation product C4d, a component of the classical complement pathway, offers a new and currently poorly defined tool in the evaluation of renal allograft biopsies. Our retrospective study aims at determining the diagnostic and clinical significance of C4d accumulation in kidney transplants, employing immunofluorescence microscopy. We analyzed 398 diagnostic allograft biopsies (n = 265 patients with 1 to 5 biopsies obtained 7 to 7165 d posttransplantation [tx]) and correlated the detection of C4d with 18 histologic changes, panel-reactive antibody titers, response to treatment, and outcome. One hundred twenty-five native kidney and baseline tx biopsies served as controls. Linear deposition of C4d along peritubular capillaries was only found in a subgroup (30%) of allografts post-tx, mainly during the early time-course (median, 38 d post-tx; range, 7 to 5646 d). There was no significant association with infections. C4d staining could change from negative to positive and vice versa within days to weeks. The accumulation of C4d was most tightly linked to a morphologic subtype of rejection, transplant glomerulitis (P < 0.0001). In addition, tubular MHC class II expression was correlated with C4d deposition (P < 0.0001). Both features are signs of "acute active rejection." In comparison with C4d-negative controls, 43% of C4d-positive patients showed increased (>10%) panel-reactive antibody titers (versus 19% in the negative group; P = 0.001). C4d positivity was frequently associated with higher serum creatinine levels at time of biopsy (compared with C4d-negative group; P < 0.01). More C4d-positive patients were treated with polyclonal antithymocyte globulins (ATG) or monoclonal anti-CD3 antibodies (OKT3) (P < 0.0001). Outcome did not significantly differ between C4d-positive and C4d-negative groups. In conclusion, the detection of C4d identifies a humoral alloresponse in a subgroup of kidney transplants, which is often associated with signs of cellular rejection, i.e. tx glomerulitis. Allograft dysfunction in C4d-positive rejection episodes is often more pronounced. We provide first evidence that C4d-positive rejection might benefit from intensive therapy, potentially preventing the previously reported high graft failure rate. In addition, we show that a subgroup of C4d-positive cases may not require any immediate therapeutic intervention. The presence of C4d is clinically relevant and should be reported in the histologic diagnosis.

Antibodies↗
PubMed1981

Disruption of complement-mediated reactions by insoluble dentifrice ingredients.

It has been strongly suggested that the complement system plays a critical role in the pathological processes occurring in periodontal disease. Because individuals with this common disease are often instructed to brush their teeth more often and for longer periods of time, several commercial toothpastes were tested for their effects on complement-mediated reactions. In this study, six of the nine toothpastes tested activated the classical complement pathway, leading to C3 cleavage, as determined by crossed immunoelectrophoresis. The activating ingredients were contained in the insoluble fraction of the toothpastes. Of the toothpaste abrasives, Ca++ pyrophosphate was determined to have C3-converting activity. One of the toothpastes, which contains a particular type of amorphous silica abrasive, appeared to bind both native C3 and its conversion products. In general, disruption of complement-mediated functions in affected tissues could alter local immunological responses and interfere with healing. The in vitro studies described here suggest a need for clinical studies to ascertain the in vivo influences of dentifrice ingredients on complement-mediated reactions in periodontal disease.

Complement Activation↗
PubMed2005

Plasma levels of mannan-binding lectin in relation to periodontitis and smoking.

BACKGROUND: Mannan-binding lectin (MBL) is an important molecule of innate immunity; it acts as an opsonin and stimulates the classical complement pathway. Moreover, it has been suggested that MBL acts as a weak acute phase protein. We investigated whether MBL levels are increased in periodontitis, and we tested whether individuals deficient for MBL are more susceptible to periodontitis. METHODS: A total of 219 subjects participated in the study. Plasma samples from 115 periodontitis patients and 104 healthy controls were taken, and the MBL levels were measured by enzyme-linked immunosorbent assay (ELISA). MBL levels were analyzed in relation to periodontitis, taking into consideration age, gender, ethnic and educational background, and smoking status. In some analyses, subjects with MBL plasma levels <0.8 microg/ml were considered MBL deficient. RESULTS: MBL plasma concentrations were not significantly different in moderate and severe periodontitis compared to controls (1.6, 1.4, and 1.6 microg/ml, respectively). Also, the prevalence of MBL deficiency was not found to be different between controls and moderate and severe periodontitis (45%, 37%, and 36%). However, among all subjects and among the non-deficient subjects, MBL levels were markedly increased in heavy smokers (>10 cigarettes per day), irrespective of periodontal disease status, in comparison to non-smokers and light smokers. MBL plasma levels did not show a correlation with plasma C-reactive protein (CRP) and were also not related to the prevalence of specific periodontal pathogens. CONCLUSIONS: MBL levels were not elevated in periodontitis, and MBL deficiency was not related to susceptibility for periodontitis. The fact that MBL levels were higher among heavy smokers is the subject of further investigation.

Adult↗
PubMedDate not supplied

Complement-inhibiting activity of human seminal plasma and semen quality.

Human seminal plasma (SP) contains potent complement inhibitors. This study examined the complement-inhibiting activity of individual SP samples from 118 patients with infertility and analyzed them in relation to various semen parameters. When 25% complement-inhibiting activity was considered the cut off value, less than 1 SD unit from the mean percentage of inhibition of SP samples with normal semen quality, 32 samples (27%) showed low inhibiting activity. Among the lower group, incidences of patients with asthenozoospermia (66%) and oligozoospermia (31%) were significantly (p < .01) higher than those (36 and 10%) in the group whose SP showed significant inhibiting activity. Partial characterization revealed that the component responsible for complement inhibition was heat labile, trypsin resistant, high molecular weight (>10 kD) glycoprotein that can inhibit alternative as well as classical complement pathways. Furthermore, since in the majority of SP samples the anticomplementary activity was blocked by monoclonal antibody against membrane cofactor protein (MCP) or decay accelerating factor (DAF), the complement-inhibiting factors that were identified are likely to be MCP and/or DAF, which are known to be present in human SP. These results suggest that complement-regulatory proteins in SP such as MCP and DAF may protect sperm cells against complement attack in the male reproductive tract.

Complement Inactivator Proteins↗
PubMed2001

Circulating immune complexes induced by food proteins implicated in precocious myocardial infarction.

BACKGROUND: Circulating immune complexes (CIC) are frequently found in postinfarction patients. The constituents of these CIC are mostly unknown. AIM: The objective of the current study was to assess whether CIC containing alimentary proteins and antibodies against these proteins are implicated in precocious myocardial infarction (MI). METHODS: Seventy-six survivors (67 men and 9 women, mean age 39 years) of a first MI before the age of 45 years were enrolled in this study. Two control groups were included. One group consisted of age-matched, randomly selected, population-based healthy individuals, 79 men and 11 women, without features of coronary heart disease. An additional control group was used only for the determination of serum antibodies against some of the alimentary proteins and consisted of 139 healthy blood donors, 95 men and 44 women, with a mean age of 42 years. Sucrose density gradient centrifugation, gel filtration and precipitation by polyethylene glycol were used for the isolation of CIC, and enzyme-linked immunosorbent assay (ELISA) was used to measure the immunoglobulin levels and specific antibodies against alimentary proteins in both sera and isolated CIC. Sodium dodecylsulfate (SDS) polyacrylamide gel electrophoresis and Western blotting were used to determine alimentary proteins in the CIC. RESULTS: Alimentary antigens/antibodies were present in immune complex form in seven out of 14 (50%) postinfarction patients who had persistent high concentrations of CIC, the latter constituting 18% of the entire group. Antibodies of the IgG isotype predominated. A rise in CIC, signs of activation of the classical complement pathway, and a rise in plasma concentrations of von Willebrand factor antigen (vWFAg) were evident within 1 week in four patients subjected to a 2-week elimination diet followed by a single challenge with cow's milk. CONCLUSION: This study suggests that dietary proteins occasionally give rise to persistent CIC, which may predispose to MI at a young age.

Adult↗
PubMedDate not supplied

Early recipient-donor switch of the complement type after liver xenotransplantation.

Liver transplantation is an immunological peculiarity with respect to the resistance of the graft to humoral rejection. We undertook a kinetic analysis of molecules involved in humoral rejection for a period of one week following xenografting in the hamster to rat model system. A complement-dependent lymphocytotoxicity test (CDC) was used to detect anti-donor antibodies in the recipient rats. Complement was studied by two methods. Function of the classical complement pathway was evaluated with a hemolytic assay, and C3 was measured by radial immunodiffusion. Conversion of the major plasma proteins from recipient to donor profile was studied by zone electrophoresis on agarose. CDC showed antibody titers rose during the first week post-transplantation, and they were of complement-activating isotypes. Zone electrophoresis showed almost complete replacement of rat C3 by hamster C3 within 72 hours. Hemolytic assay of complement on day 6 post-transplant showed serum of the xenograft recipients could lyse erythrocytes sensitized with rat antibody with 80% of efficiency of normal rat serum. Our data show the effector molecules for humoral rejection, rat antibodies with anti-hamster specificity and a functional complement cascade, were present within the first week following transplantation. Rapid conversion of serum complement to hamster proteins maintains compatibility with the species-specific membrane inhibitors of complement activation expressed by the xenografted hepatocytes, and could limit complement-mediated damage.

Animals↗
PubMed1992

Aberrant expression of GM1 on lymph node cells of MRL/Mp-lpr/lpr mice: influences on the autoreactivities of anti-asialo GM1 antibodies.

Although changes in surface carbohydrate expression of abnormally expanded MRL/Mp-lpr/lpr (MRL/lpr) lymph node (LN) cells have previously been described, the composition and function of glycolipids present on these cells as well as the spectrum of specificity of anti-carbohydrate antibodies reactive with these cells remains obscure. Analysis of antibodies to a panel of 22 carbohydrate structures using a liposome immune lysis assay (LILA) showed that, except for anti-asialo GM2 (GA2) antibodies, marked reduction of antiglycolipid antibody levels was observed in sera from 4-mo-old MRL/lpr mice compared with these from MRL/Mp(-)+/+ (MRL/+) mice. Absorption experiments revealed that both anti-asialo GM1 (GA1) and globoside antibodies had binding capacity to MRL/lpr LN cells. To elucidate the glycolipid profiles of MRL/lpr LN cells, glycolipids were extracted from LN cells of both MRL/lpr and MRL/+ mice and analysed. A 30-fold elevation of GM1 was found in MRL/lpr LN cells compared with MRL/+ LN cells. From the results of LILA using GA1/GM1 mixed liposomes, aberrantly expressed GM1 inhibited the classical complement pathway but did not interfere with the binding of anti-GA1 antibodies to liposomal GA1. These findings suggest that a drastic GM1 increase on MRL/lpr LN cells would inhibit the action of anti-GA1 antibodies and complement on the cell surface. This may explain the escape of these cells from an activated self directed immune response.

Animals↗
PubMed1994

IgG3 reactive rheumatoid factor in rheumatoid arthritis: etiologic and pathogenic considerations.

Rheumatoid factor (RF) is a polyclonal autoantibody directed against the Fc portion of IgG. Although the role of RF in patients with rheumatoid arthritis (RA) is unclear, immune complexes that form between RF and IgG can activate the classical complement (C) pathway, leading to pathogenic outcomes involving inflammatory events and tissue damage. The specificity of serum RF and RF produced by rheumatoid synovial cells (RSC) is different. Serum RF has specificity for rabbit IgG and human IgG subclasses IgG1, 2, and 4, but binds poorly to IgG3. The affinity of serum RF for IgG Fc is low, having an association constant of 10(4)-10(5) M-1. RSC RF, however, has specificity for human IgG and high avidity for IgG3. Because of this greater specificity and avidity for IgG3, and because RSC RF may be pathogenically more important than serum RF, an important role for IgG3-reactive RF in RA may exist. Binding of RF to IgG may be dependent on the allotype and glycosylation of IgG. Infectious agents present in RA patients may directly or indirectly induce the production of certain RF. In this communication, we review and expand on several observations examining the role of IgG3-reactive RF in RA including: 1) binding differences between RF derived from RSC and serum; 2) glycosylation characteristics of IgG and its interaction with RF; 3) apparent allotype dependent binding of IgG3-reactive RF; and 4) possible relationship between infectious agents and the production of IgG3-reactive RF. Taken together, these observations suggest an important role for IgG3-reactive RF in better understanding the etiology and pathogenesis of RA.

Amino Acid Sequence↗
PubMed1995

Physiology and pathophysiology of complement: progress and trends.

The complement system comprises a family of at least 20 plasma and membrane proteins that interact in a tightly regulated cascade system to destroy invading bacteria and prevent the deposition of immune complexes in the tissues. This brief review addresses the basic mechanisms of complement activation and control and describes the active fragments produced during complement activation. The biological importance of the complement system is amply illustrated in patients with complement deficiencies, who are susceptible to bacterial infections and immune complex diseases. The involvement of complement in other immunological diseases is an expanding area of clinical research, supported by the development of new assays for the identification of complement activation. This area is discussed here with particular reference to neurological diseases. A promising new prospect involves the use of complement inhibitory molecules in therapy of complement-mediated disease and this exciting area is also discussed. Novel physiological roles of complement also are being revealed and new evidence that complement and complement receptors play an important role in reproduction is summarized. It is hoped that this brief overview will convey some of the enthusiasm currently pervading research in this underappreciated area of immunology.

Animals↗
PubMed1984

Complement and the host's defense against the pneumococcus.

The complement system plays a critical role in resistance to Streptococcus pneumoniae. In the last two decades, a great deal of new knowledge has been generated on both the complement system and on the pneumococcus. Not only has this new knowledge helped produce a better understanding of how the complement system serves the host in its defense against S. pneumoniae, but in a more general fashion, the lessons learned from the interaction of complement and the pneumococcus have also provided insight into how the complement system functions in the defense of the host against a wide variety of other microorganisms. The following review will attempt to summarize current knowledge about the complement system, how it interacts at the molecular level with the pneumococcus, the biologic consequences of that interaction, and their significance in pneumococcal infections.

Anemia, Sickle Cell↗
PubMed1990

A newly developed LDL-binding material.

Results of in vitro and ex vivo experiments with a newly developed LDL-binding material are presented. This material consists of macroporous bead cellulose which is capable to bind selectively LDL. LDL-cholesterol is considerably decreased after contacts of plasma or serum samples with this bead cellulose. On the other hand high density lipoproteins (HDL) and other plasma components (proteins, enzymes, electrolytes, and metabolic substances) remained high or unchanged. Triglycerides (TG)--transported by very low density lipoproteins--are also bound up to a certain degree. 1 g of the adsorbent wet mass binds at least 20 mg cholesterol. The capacity suffices to decrease two- to threefold increased cholesterol and LDL plasma levels to the low normal range following passage of the sevenfold plasma volume' through two the three LDL adsorbent columns (results of perfusion experiments). In vitro and dog experiments revealed only slight drops of the hemolytic capacities of the classic complement pathway and moderate decreases of the alternative one. But no detectable side effects were noticed in the dog experiments.

Adsorption↗
PubMed1976

Serum and blister fluid anticomplementary activity in pemphigus and bullous pemphigoid. Sucrose density gradient studies.

By sucrose density gradient ultracentrifugation and standard hemolytic complement assays, complement fixing activity of about 19 S and greater was found in blister fluids of one patient with pemphigus and three of five patients with bullous pemphigoid. Control blister fluids, including experimentally induced blisters, lacked such activity. Complement fixing activity was apparent, however, in 6 of 10 pemphigus sera and in two of five bullous pemphigoid sera tested. The material present in both pemphigus and bullous pemphigoid appears to activate the classical complement pathway.

Antigen-Antibody Complex↗
PubMed2001

Complement component C3 is not required for full expression of immune complex glomerulonephritis in MRL/lpr mice.

Complement activation and tissue deposition of complement fragments occur during disease progression in lupus nephritis. Genetic deficiency of some complement components (e.g., Factor B) and infusion of complement inhibitors (e.g., Crry, anti-C5 Ab) protect against inflammatory renal disease. Paradoxically, genetic deficiencies of early components of the classical complement pathway (e.g., C1q, C4, and C2) are associated with an increased incidence of lupus in humans and lupus-like disease in murine knockout strains. Complement protein C3 is the converging point for activation of all three complement pathways and thus plays a critical role in biologic processes mediated by complement activation. To define the role of C3 in lupus nephritis, mice rendered C3 deficient by targeted deletion were backcrossed for eight generations to MRL/lpr mice, a mouse strain that spontaneously develops lupus-like disease. We derived homozygous knockout (C3(-/-)), heterozygous (C3(+/-)), and C3 wild-type (C3(+/+)) MRL/lpr mice. Serum levels of autoantibodies and circulating immune complexes were similar among the three groups. However, there was earlier and significantly greater albuminuria in the C3(-/-) mice compared with the other two groups. Glomerular IgG deposition was also significantly greater in the C3(-/-) mice than in the other two groups, although overall pathologic renal scores were similar. These results indicate that C3 and/or activation of C3 is not required for full expression of immune complex renal disease in MRL/lpr mice and may in fact play a beneficial role via clearance of immune complexes.

Albuminuria↗
PubMed2001

Novel small molecule inhibitor of C1s exerts cardioprotective effects in ischemia-reperfusion injury in rabbits.

Myocardial ischemia-reperfusion injury can be related to complement activation with generation of chemotactic agents, adhesion molecule expression, release of cytokines and oxygen-derived free radicals, and subsequent neutrophil accumulation. In the present study the cardioprotective effects of a novel highly selective small molecule C1s inhibitor (C1s-INH-248, Knoll) were examined in a rabbit model of myocardial ischemia (I) and reperfusion (R; i.e., 60 min I + 180 min R). In in vitro tests (enzyme activity and SRBC lysis) C1s-INH-248 demonstrated profound inhibitory potency. In vivo C1s-INH-248 (1 mg/kg body weight) administered 5 min before reperfusion significantly attenuated myocardial injury (31.9 +/- 2.5 vs 8.9 +/- 1.6% necrosis/area at risk; p < 0.01). The cardioprotective effect was dose dependent. The reduction of myocardial injury was also observed as diminished plasma creatine kinase activity in C1s-INH-248-treated animals (70.7 +/- 6.8 vs 45.1 +/- 3.9 U/g protein after 3 h of reperfusion, p < 0.05). Further, cardiac myeloperoxidase activity (i.e., a marker of PMN accumulation) in the ischemic and necrotic area was significantly reduced following C1s-INH-248 treatment (1.31 +/- 0.23 vs 0.4 +/- 0.05 U/100 mg tissue in necrotic area, p < 0.01). Thus, blocking the classical complement pathway with a highly specific and potent synthetic inhibitor of the activated C1 complex appears to be an effective mean to preserve ischemic myocardium from injury following reperfusion.

Animals↗
PubMed2002

Characterization of a de novo conversion in human complement C4 gene producing a C4B5-like protein.

Complement C4 is a highly polymorphic protein essential for the activation of the classical complement pathway. Most of the allelic variation of C4 resides in the C4d region. Four polymorphic amino acid residues specify the isotype and an additional four specify the Rodgers and Chido determinants of the protein. Rare C4 allotypes have been postulated to originate from recombination between highly homologous C4 genes through gene conversions. Here we describe the development of a de novo C4 hybrid protein with allotypic and antigenic diversity resulting from nonhomologous intra or interchromosomal recombination of the maternal chromosomes. A conversion was observed between maternal C4A3a and C4B1b genes producing a functional hybrid gene in one of the children. The codons determining the isotype, Asp(1054), Leu(1101), Ser(1102), Ile(1105) and His(1106), were characteristic of C4B gene, whereas the polymorphic sites in exon and intron 28 were indicative of C4A3a sequence. The protein produced by this hybrid gene was electrophoretically similar to C4B5 allotype. It also possesses reversed antigenicity being Rodgers 1, 2, 3 and Chido-1, -2, -3, 4, -5, and -6. Our case describes the development of a rare bimodular C4B-C4B haplotype containing a functional de novo C4 hybrid gene arisen through gene conversion from C4A to C4B. Overall the data supports the hypothesis of gene conversions as an ongoing process increasing allelic diversity in the C4 locus.

Complement C4a↗
PubMed2002

Protection from Streptococcus pneumoniae infection by C-reactive protein and natural antibody requires complement but not Fc gamma receptors.

Streptococcus pneumoniae is an important human pathogen and the most common cause of community-acquired pneumonia. Both adaptive and innate immune mechanisms provide protection from infection. Innate immunity to S. pneumoniae in mice is mediated by naturally occurring anti-phosphocholine (PC) Abs and complement. The human acute-phase reactant C-reactive protein (CRP) also protects mice from lethal S. pneumoniae infection. CRP and anti-PC Ab share the ability to bind to PC on the cell wall C-polysaccharide of S. pneumoniae and to activate complement. CRP and IgG anti-PC also bind to Fc gamma R. In this study, Fc gamma R- and complement-deficient mice were used to compare the mechanisms of protection conferred by CRP and anti-PC Ab. Injection of CRP protected wild-type, FcR gamma-chain-, Fc gamma RIIb-, and Fc gamma RIII-deficient mice from infection. Complement was required for the protective effect of CRP as cobra venom factor treatment eliminated the effect of CRP in both gamma-chain-deficient and wild-type mice, and CRP failed to protect C3- or C4-deficient mice from infection. Unexpectedly, gamma-chain-deficient mice were extremely sensitive to pneumococcal infection. This sensitivity was associated with low levels of natural anti-PC Ab. Gamma-chain-deficient mice immunized with nonencapsulated S. pneumoniae produced both IgM- and IgG PC-specific Abs, were protected from infection, and were able to clear the bacteria from the bloodstream. The protection provided by immunization was eliminated by complement depletion. The results show that in this model of systemic infection with highly virulent S. pneumoniae, protection from lethality by CRP and anti-PC Abs requires complement, but not Fc gamma R.

Animals↗