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PubMedDate not supplied

Immunohistochemistry of complement response on human renal cell carcinoma biopsies.

The goal of the study was to characterize the complement humoral and cellular antitumor responses on primary renal cell carcinoma biopsies. As an original observation, complement activation was found on 11/22 cases. Classical complement pathway activation was characterized by tumor C1q complement protein and IgG deposition (5/22 cases). Alternative or nonimmune complement pathway activation was seen as tissue deposition of C3 (6/22 cases). The membrane attack complex was present in cases with alternative complement pathway activation at the sites of tumor necrosis. Renal cell carcinomas with complement activation overexpressed at least one of the complement regulatory factors (membrane cofactor protein, decay accelerating factor, membrane attack complex inhibitor) and major histocompatibility complex class II molecules. Tumor infiltrating lymphocytes were present in most of the renal cell carcinomas with complement activation (8/11). However, the number of tumor-infiltrating lymphocytes was correlated with the intensity of major histo-compatibility complex-II expression in 18/22 cases. Detection of complement activation and immune cell infiltrates on renal cell carcinoma primary biopsies may serve as a new predictive factor for immunotherapy.

Adult↗
PubMed1994

Absence of glomerulonephritis in guinea pigs deficient in the fourth component of complement.

Genetically determined deficiencies of the early components of the classical complement pathway (C1, C4, C2) or of the third component of complement (C3) in both human beings and experimental animals are known to be associated with renal disease, including glomerulonephritis. The current study was performed to examine the C4-deficient (C4D) guinea pig for the presence of renal disease. Eighteen C4D animals and 17 control animals (Crl:Hartley) (divided by sex into four age categories) were examined. Light microscopic examination revealed no differences in mesangium, glomerular cellularity, thickness of capillary loops, or presence of epithelial crescents in the kidneys of C4D guinea pigs as compared with control animals. Electron microscopic examination did not reveal glomerular or tubular immune complex deposits in either C4D or control animals. C4D guinea pigs apparently do not demonstrate glomerulonephritis.

Animals↗
PubMed2003

Intravenously applied IgG stimulates complement attenuation in a complement-dependent autoimmune disease at the amplifying C3 convertase level.

Intravenously applied normal human immunoglobulin G (IgG) has anti-inflammatory effects in the treatment of autoimmune diseases. Systemic inflammation can originate from an overreacting amplification loop of the complement system. In blood, C3b2-containing complexes maintain complement amplification much better than the extremely short-lived C3b. Therefore, in patients with the complement-dependent autoimmune disease, dermatomyositis, we studied whether intravenously applied normal human IgG (IVIG) stimulated in vivo inactivation of these complexes. In the course of IVIG treatment, clinically effective in 6 of 8 patients, the concentration of C3b2-containing complexes dropped to 37% +/- 14% (n = 6) of the pretreatment level when having infused 0.5 g IgG/kg body weight, increased marginally and in parallel to factor Bb thereafter until full-dose IgG was infused. By day 14 following infusion of 2 g IgG/kg body weight the concentration of C3b2-containing complexes was 66% +/- 19%. The plasma concentration of C3 remained constant in myopathic or increased by 15% to 20% in amyopathic patients. In contrast to this, IVIG infusion was associated with consumption of up to 40% of plasma C4 at day 1 to 2 after completion of IVIG infusion. Thus, IVIG had an immediate and long-lasting attenuating effect on complement amplification in vivo, despite the fact that it induced classical complement pathway activation.

Autoimmune Diseases↗
PubMed2005

Differential regulation of Abeta42-induced neuronal C1q synthesis and microglial activation.

Expression of C1q, an early component of the classical complement pathway, has been shown to be induced in neurons in hippocampal slices, following accumulation of exogenous Abeta42. Microglial activation was also detected by surface marker expression and cytokine production. To determine whether C1q induction was correlated with intraneuronal Abeta and/or microglial activation, D-(-)-2-amino-5-phosphonovaleric acid (APV, an NMDA receptor antagonist) and glycine-arginine-glycine-aspartic acid-serine-proline peptide (RGD, an integrin receptor antagonist), which blocks and enhances Abeta42 uptake, respectively, were assessed for their effect on neuronal C1q synthesis and microglial activation. APV inhibited, and RGD enhanced, microglial activation and neuronal C1q expression. However, addition of Abeta10-20 to slice cultures significantly reduced Abeta42 uptake and microglial activation, but did not alter the Abeta42-induced neuronal C1q expression. Furthermore, Abeta10-20 alone triggered C1q production in neurons, demonstrating that neither neuronal Abeta42 accumulation, nor microglial activation is required for neuronal C1q upregulation. These data are compatible with the hypothesis that multiple receptors are involved in Abeta injury and signaling in neurons. Some lead to neuronal C1q induction, whereas other(s) lead to intraneuronal accumulation of Abeta and/or stimulation of microglia.

Journal Article↗
PubMed2006

The tissue pentraxin PTX3 limits C1q-mediated complement activation and phagocytosis of apoptotic cells by dendritic cells.

Pentraxins (PTX) and complement belong to the humoral arm of the innate immune system and have essential functions in immune defense to microbes and in scavenging cellular debris. The prototypic long PTX, PTX3, and the first component of the classical complement pathway, C1q, are innate opsonins involved in the disposal of dying cells by phagocytes. Whether the interaction between various innate opsonins impacts on their function is not fully understood. We show here that characterized Toll-like receptor (TLR) ligands elicit the production of C1q and PTX3 by immature dendritic cells (DC). Moreover, these molecules bind to dying cells with similar kinetics, although they recognize different domains on the cell membranes. PTX3 binds in the fluid phase to C1q, decreasing C1q deposition and subsequent complement activation on apoptotic cells. C1q increases the phagocytosis of apoptotic cells by DC and the release of interleukin-12 in the presence of TLR4 ligands and apoptotic cells; PTX3 inhibits both events. Moreover, PTX3 inhibited the cross-presentation of the MELAN-A/melanoma antigen-reactive T cell 1 (MART-1) tumor antigen expressed by dying cells, even in the presence of C1q. These results suggest that interaction of C1q and PTX3 influences the clearance of apoptotic cells by DC. The coordinated induction by primary, proinflammatory signals of C1q and PTX3 and their reciprocal regulation during inflammation influences the clearance of apoptotic cells by antigen-presenting cells and possibly plays a role in immune homeostasis.

Antigen Presentation↗
PubMed2000

Toxic effects of SLE serum on normal monocytes in vitro: cell death induced by apoptosis related to complement dysfunction.

The aim of this study was to assess toxic effects of systemic lupus erythematosus (SLE) serum on blood peripheral mononuclear cells from healthy donors and to evaluate if complement activation was involved. Monocytes from a healthy donor were incubated with 20 sera from ten SLE patients in both high and low disease activity states. After incubation non-adherent cells were analysed by flow cytometry. Serum from six SLE patients induced an increased cell death, four in active disease only, one in the inactive state and one in the active and the inactive state. Five of these sera, three with high and two with low disease activity, induced an increased apoptosis in the monocytes. Proportion of apoptotic cells correlated inversely with C1q and C3 concentration in the active disease sera, but not with disease activity as evaluated by SLEDAI. Apoptosis could be induced by addition of active C1s or antigen/antibody complexes to normal serum before incubation. Serum with complexes added induced increased tumour necrosis factor-alpha secretion from mononuclear cells, but SLE patient sera did not. The results demonstrate that the toxic effect of serum from SLE patients on healthy monocytes is explained by induction of apoptosis. The induction process is suggested to be connected with complement activation in the serum.

Adolescent↗
PubMed2005

Clinical presentation and monitoring of lupus nephritis.

The diversity of clinical presentations of lupus nephritis parallel the diversity of pathologic lesions seen in the kidneys of patients with SLE. Renal manifestations range from asymptomatic hematuria or proteinuria to overt nephritic and nephrotic syndromes, rapidly progressive glomerulonephritis, and chronic renal failure. Subclinical nephropathy both during presentation and during monitoring of disease activity is frequently missed because of the notorious unreliability of routine screening urinalyses performed in high-throughput clinical pathology laboratories. Requisitions for urine microscopy should be flagged for special attention in patients at risk for lupus nephritis. Depression of classic complement pathway components and high titers of anti-DNA, anti-nucleosome, or anti-Clq antibodies identify patients are increased risk of renal involvement or flares of nephritis. Several disease activity and damage indexes are available, but they are mostly used in clinical research setting and none has achieved wide use for standard clinical practice.

Humans↗
PubMed2005

Opportunities for new therapies based on the natural regulators of complement activation.

While the complement system is an essential component of immunity, shutting down all or part of it could be beneficial in a wide range of clinical situations. Designer, small-molecule, protease inhibitors and antagonists of protein-protein interactions are under development, while an approach based on a humanized monoclonal antibody to the C5 component works effectively against the later stages of complement activation and is close to completing clinical trials. The cobra venom factor depletes plasma of essential complement components, and a humanized (nonimmunogenic) version is being sought. Perhaps the most promising approach to comprehensive complement downregulation, however, is the exploitation of innate regulators of complement activation, with two products in clinical trials. The potential for more efficacious complement blockers of this kind is growing because of better targeting, but a deeper knowledge at the atomic level of mechanisms of action of these regulators is needed to underpin a rational approach to design of still more potent complement inhibitors.

Complement Activation↗
PubMed1979

The effect of human colostrum on neutrophil function.

Strains of Escherichia coli were opsonized in human colostrum via heat stable opsonins and the classic complement pathway, but colostrum lacked capacity to opsonize E. coli via the alternative pathway. There was no bacteriostatic activity against serum sensitive E. coli strains, although specific antibodies against the strains were present. Neutrophils suspended in colostrum had normal chemotaxis and this was not altered by treating the colostrum with HCl.

Chemotaxis, Leukocyte↗
PubMed2006

Cell surface expression of a chimeric protein containing mouse immunoglobulin G1 Fc domain and its immunological property.

Recently we reported that a chimeric molecule containing mouse transferrin receptor and immunoglobulin G1 (IgG1) Fc, mTR-Fc, induced higher immune responses and can be used as a vaccine adjuvant. In this study, the immunological property of the molecule was investigated. Although, the mTR-Fc did not activate complement classical pathway, it was recognized by activated macrophage as like intact IgG Fc, which is recognized by macrophage via Fcgamma receptor. In addition, we found that splenocyte simultaneously exposed to lipopolysaccaride (LPS) and mTR-Fc produced higher amount of interleukin-10, comparing to that exposed to only LPS. These results suggest that the mTR-Fc molecules conserved the IgG Fc property to biasing immune responses via modulation of cytokine production by antigen presenting cell.

Animals↗
PubMed1998

The complement cascade in Alzheimer's disease.

Numerous studies show that activated glial cells release increased amounts of several molecules that might contribute to the pathology of Alzheimer's disease (AD), including complement proteins. The complement proteins are particularly noteworthy because of their well-documented ability to induce inflammation, destroy foreign cells and, in certain circumstances, inflict damage to host tissue. There appears to be a general consensus that the early components of the classical complement pathway are found associated with senile plaques in AD brain; of some dispute is whether the later complement products are truly found in AD brain. An unequivocal demonstration of the terminal complement activation products in AD brain is important in strengthening the hypothesis that these products contribute to disease pathology. To date, it has been difficult to determine the extent to which complement activation contributes to the neuropathology of AD. Given the potential detrimental consequences of complement activation in AD brain, there is compelling reason to identify potential therapeutic agents that might attenuate complement activity in this disease. Based on the evidence that Abeta is a likely activator of complement in AD, and on the understanding of the nature of Abeta-C1q binding, it is possible that drugs might be developed that will slow complement activity in the AD brain without compromising this defense mechanism throughout the rest of the body.

Journal Article↗
PubMed2003

Inhibitors of the complement system currently in development for cardiovascular disease.

Controlled activation of the complement system is critical to the host-defense response of the immune system. Activated complement is responsible for the stimulation of a localized protective inflammatory response to either invading microorganisms or foreign molecules (toxins). However, the autologous activation of the complement system can have devastating consequences on many organ systems. This review discusses the various pathways involved in the activation of the complement system and the multiple levels of control established within the body to regulate activation. It also focuses on the role of complement activation in cardiovascular disease, especially myocardial ischemia and reperfusion injury as well as in cardiopulmonary bypass procedures. Lastly, this review also provides a comprehensive overview of both biologically derived proteins and chemically developed inhibitors of the complement system that range from those that are currently in the discovery stage to those that are in clinical development as novel therapeutic agents.

Animals↗
PubMed2001

Animal models of inherited complement deficiency.

The initial description of murine strains deficient in complement component C5 has been followed by the recognition in a range of animal species of a variety of natural complement component deficiencies, many of which have been characterized at the molecular level. The use of such species in inflammatory and infectious experimental models has led to significant progress in understanding the role of specific complement factors (and pathways) in disease pathogenesis. Deficiencies of early complement factors are characterized by impairment of immune response, possibly due to defective processing of immune complexes. Complete (but not partial) deficiency of the central component C3 predisposes affected animals to significant risk of infection and renal disease. Studies in species deficient in the terminal pathway component C6 are particularly relevant for investigating the pathogenetic role of the terminal membrane attack complex (MAC), implicating it as a causative agent in diverse inflammatory insults such as reperfusion injury, glomerular damage, and xenograft hyperacute rejection. Further investigations in such naturally deficient strains, added to results derived from studies in knockout animals, are likely to expand our understanding of the role of the activated complement system in experimental inflammatory disease, with significant potential implications for the treatment of human disease.

Animals↗
PubMed1997

Identification and characterisation of C1q-binding phage displayed peptides.

Five phage displayed peptide libraries were screened for binders to C1q, the recognition subunit of the classical complement pathway. Two rounds of panning resulted in the isolation and characterisation of several different phage displayed C1q-binding peptides from all five libraries. Two groups of the characterised peptides show sequence similarity with part of the metal ion dependent adhesion site (MIDAS) of integrin A-domains, and the site 187LRNPCPNKEKECQPPF of CD18 (integrin beta2), respectively. These results support binding of complement receptor 3 (CR3, CD11b/CD18, Mac1) to C1q and further suggest C1q binding sites in CR3. We also discuss sequence matches between the characterised peptides and proteins known to interact with C1q, as well as other proteins listed in the SwissProt databank. These findings are of interest for the study of the complement system and may lead to the development of peptides, fusion products or peptido-mimetics with C1q modulating potential.

Amino Acid Sequence↗
PubMed1988

Haemostasis contact system and fibrinolysis in hereditary angioedema (C1-inhibitor deficiency).

Factors of the classical complement pathway, the contact system and fibrinolysis were evaluated both with functional and immunochemical methods, in patients with inherited deficiency of C1-inhibitor. Evaluations were performed under basal conditions, during acute attacks and during prophylaxis with low doses of anabolic steroids. Patients in the basal state showed no significant abnormalities of any of the parameters that we investigated. During acute attacks a slightly reduced prekallikrein concentration was registered. During treatment with low doses of danazol and stanozolol, protein C and plasminogen were found to be increased. Our data suggest that C1-inhibitor deficiency per se does not lead to a derangement of the fibrinolysis and coagulation contact system, and that the kinin system may be involved during acute attacks of angioedema.

Adolescent↗
PubMed1995

Role of complement in the pathogenesis of postpartum thyroiditis: relationship between complement activation and disease presentation and progression.

The aim of this study was to assess whether the presentation and progression of autoimmune postpartum thyroiditis (PPT) was related to the degree of thyroid peroxidase autoantibody (TPO-ab)-mediated activation of the complement cascade. One hundred and forty-eight thyroid autoantibody-positive women have been followed during their postpartum year. Seventy-five women remained euthyroid during this time whilst the remaining 73 showed one or more episodes of thyroid dysfunction. Fourteen women showed hyperthyroid PPT, 23 showed a biphasic PPT and the remaining 36 showed hypothyroid PPT. Hyperthyroid PPT was always transient but 29 of the 59 women with hypothyroidism remained hypothyroid or still required thyroxine replacement therapy at the conclusion of the study. Thyroid autoantibodies were measured by enzyme-linked immunosorbent assay (ELISA), free triiodothyronine and free thyroxine by the Amerlex M methods and thyrotrophin by the Amerlite TSH (monoclonal) assay. Complement component C3b, immobilized as a result of classical complement pathway activation in the presence of TPO/TPO-ab complexes in vitro, was measured by ELISA. Bioactive TPO-ab were calculated as the product of the C3 index and TPO-ab level. Basal levels of complement C3 activation were seen in the euthyroid TPO-ab-positive women (C3 index 0.06 at delivery rising to 0.36 at 12 months postpartum; bioactive TPO-ab activity 0.4 kIU/l at delivery rising to 10.4 kIU/l at 12 months' postpartum (N = 75). These parameters were elevated progressively as the severity of the clinical syndrome increased. In 14 hyperthyroid PPT women the C3 index was 0.47 at 8 months' postpartum (bioactive TPO-ab activity = 20 kIU/I; p vs euthyroid group, NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Autoantibodies↗
PubMed2004

Involvement of C4 allotypes in the pathogenesis of human diseases.

The complement system is an important humoral defense mechanism that plays a relevant role against microbial agents, inflammatory response control, and immunocomplex clearance. Classical complement pathway activation is antibody-dependent. The C4 component participates in the initial step of activation, and C4 expression is determined by 2 pairs of allotypes: C4A and C4B. Deficiencies in C4 allotypes have been associated with several diseases. The aim of the present review is evaluate the reported data in the literature regarding specific C4A and C4B deficiencies and characterize their clinical relevance. We searched the MEDLINE and LILACS databases. Papers referring to total C4 deficiency without allotype evaluation and case reports of primary C4 deficiency were not included. Deficiencies in C4 allotypes have been associated with Mycobacterium leprae infection, erythema nodosum, systemic sclerosis with anti-topoisomerase I antibodies, intermediate congenital adrenal hyperplasia with DR5 genotype, diabetes mellitus type 1 with DR3,4 genotype, and diabetes mellitus with antibodies against islet cells. C4 allotype deficiency is also related to C4B deficiency and autoimmune-associated diseases, such as systemic lupus erythematosus, or diseases with an autoimmune component, such as autism. Some reports associate C4A with thyroiditis after delivery as well as limited and systemic sclerosis without anti-topoisomerase I antibodies. However, the studies with C4A and C4B have been concentrated in isolated populations, and some of the studies could not be reproduced by other authors.

Alleles↗
PubMed1994

Pathological proteins in senile plaques.

The beta-amyloid protein deposits of Alzheimer disease, whether in diffuse or consoliated form, are an agglomeration of many extracellular proteins. At least 35 have been reported as components of senile plaques, most of which also occur in diffuse deposits. More than half of these proteins are directly associated with the immune system. Since diffuse deposits are believed to be the precursors of senile plaques, it is important to define the precise molecular events that lead to the transition. Diffuse deposits share with senile plaques the presence of opsonizing components of complement, the complement activators beta-amyloid protein, amyloid P, thrombin, and apolipoprotein E. However, senile plaques contain, in addition, dystrophic neurites, agglomerates of activated microglia, components of the membrane attack complex, and the inhibitors of the membrane attack complex, clusterin, protectin and vitronectin. Microglial cells are professional phagocytes which possess the respiratory burst apparatus when activated. It produces extracellular superoxide molecules which can then form additional toxic products such as hydrogen peroxide and hydroxyl free radicals. It has long been known that opsonized zymosan is a powerful activator of the respiratory burst system. We found this activation could be inhibited by antibodies to complement receptors in the nanomolar range. Dapsone and indomethacin, two antiinflammatory agents that may have therapeutic potential in Alzheimer disease, were weakly inhibitory (10(-4) M range).(ABSTRACT TRUNCATED AT 250 WORDS)

Alzheimer Disease↗