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PubMed1984

Studies of four Japanese families with hereditary angioneurotic edema: simultaneous activation of plasma protease systems and exogenous triggering stimuli.

Forty-five relatives of 4 families with hereditary angioneurotic edema (HANE) were studied. Twenty-five, including 11 asymptomatic kindreds with the disposition, showed typical changes in complement system compatible with HANE. Follow-up study of HANE patients showed that, even in remission period, complement, coagulation and fibrinolytic systems can be activated. During edema attacks, moderate haemoconcentration and neutrophilia were encountered and kallikrein-kinin system was found to be also activated. Replacement therapy with C 1-inhibitor preparation for an edema attack revealed that clinical improvement paralleled the increase in blood levels of high molecular weight kininogen. Thus, HANE attack is considered to be elicited in kindreds with the hereditary disposition by activation of plasma protease systems, particularly by that of kallikrein-kinin system. On the other hand, exogenous triggers that can initiate activation of the protease systems can be classified into 2, neuro-humoral (sympathetic nerve response) and physico-chemical, categories. Hence, the edema attack of kindreds with the hereditary disposition can at least be modified by the biosynthesis of plasma factors and the individual susceptibility to the liberated catecholamines. These two different reaction processes are considered to be linked by the release of plasminogen activator and/or Hageman factor activating enzyme.

Angioedema↗

PubMed1987

[The immune system in coronary atherosclerosis].

A considerable imbalance in humoral and cellular factors of immunity characterized by high B-cell activity associated with a relative T-cell deficiency has been revealed in patients with coronary heart disease. Immunological imbalance is characteristic for all the clinically pronounced forms of coronary heart disease, forming long before obvious lesions of the coronary arteries. This makes it possible to regard patients without coronarographically documented atherosclerosis as having functional form of the process pathogenetically identical to atherosclerosis according to immunological criteria.

Adult↗

PubMed1994

Analysis of the IgG subclass distribution and inflammatory infiltrates in patients with anti-Hu-associated paraneoplastic encephalomyelitis.

Using immunohistochemistry, we studied the IgG subclass distribution of the anti-Hu antibody in serum, nervous system, and tumor of patients with anti-Hu-associated paraneoplastic encephalomyelitis/sensory neuropathy (PEM/PSN). The nervous system was also examined for deposits of complement and the distribution and type of inflammatory cells. IgG1 and IgG3 were the predominant isotypes of the anti-Hu IgG in serum, nervous system, and tumor. A few patients also had anti-Hu IgG2, but this isotype was not consistently present in all the regions of the nervous system studied. There was no correlation between neurologic symptoms and specific anti-Hu isotype, nor was there evidence that different anti-Hu isotypes recognized specific brain regions. Although IgG1 and IgG3 can activate complement, only weak complement reactivity was found, and that only in a few areas of the nervous system. This finding, in addition to the absence of natural killer (NK) cells, suggested that complement-mediated toxicity and antibody-dependent cell cytotoxicity mediated by NK cells are not pathogenic in PEM/PSN. Inflammatory infiltrates included CD19+ (B cells) and CD4+ (helper/inducer) cells in the perivascular spaces, and lymphocytes bearing CD8+CD11b- markers (cytotoxic T cells) in the interstitial spaces. Infiltrates of EBM11+ (monocyte/macrophage) cells were identified in the perivascular spaces (macrophage phenotype) and in those interstitial regions (microglial phenotype) with severe pathologic changes. The ability of the IgG1 and IgG3 isotypes to bind Fc receptors may have played a role in the recruitment of these monocyte/macrophage cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies↗

PubMedDate not supplied

[Local and systemic parameters in the synovial milieu].

Our own results as well as recent data from the literature confirm the already long known fact, that synovial fluid analysis allows only in very few diseases as for example a crystal synovitis a definite diagnosis in the individual case. In the majority of the patients this technique permits only to differentiate between inflammatory and non-inflammatory joint disease as well as an estimation of the local inflammatory activity of joint. The simultaneous histologic examination of synovial membrane according to our experience seems to bring no major additional information which exceeds the information given by each technique alone.

Acid Phosphatase↗

PubMed1995

Animal models for complement deficiencies.

The complement system plays a key role in host defense and in the development of autoimmunity. Three types of animal models of complement-mediated disease have traditionally been used: they involve normal animals, animals with spontaneously arising genetic deficiency, and animals treated with complement-inactivating agents. All of these approaches have had partial success in our attempts to understand complement mechanisms. Most animal models of genetic deficiency have been studied relatively little, as the availability of such animals is limited. C4, C2, and partial C3 deficiency in the guinea pig are well characterized, although only C4 deficiency in the guinea pig has been exclusively studied. C3 deficiency in the dog and C6 deficiency in the rabbit are well described, although studies are limited in number. C6 deficiency in the rat has been described recently and C5 deficiency in inbred mice strains has been studied fairly extensively. Factor H deficiency in the Yorkshire pig has also been described. Relatively few agents that inhibit complement are in use. Most widely used in animal studies is cobra venom factor. This inactivates the alternative complement pathway in the fluid phase and thereby depletes complement protein levels. The antigenicity of this protein, purified from the venom of cobras, limits its duration of use in most animal models. Complement-inhibiting agents are rare and, as yet, not widely used. We recently described the use of intravenous immune globulin for inhibiting complement in animal studies and present data on its use in animals, including discordant xenograft rejection, and its potential use in human disease. New developments in molecular biology provide the potential for a vast new array of deficiency models. A limited number of laboratories are actively engaged in the production of animals with inactivated genes. For example, gene knockout mice with no C3, and with no factor B, have been generated. Several complement control proteins have been prepared by genetic molecular biological techniques. Most promising among these is CR1, which limits complement damage in several animal models. Transgenic animals, which complement regulatory proteins expressed on their cells, have been prepared. As complement control proteins tend to be more efficient at regulating complement of the same species type as the regulatory protein, these animals may be useful in such areas as xenograft transplantation. The various animal models are reviewed and their potential application to understanding of human disease is emphasized.

Animals↗

PubMed2001

Complement-dependent platelet degradation and anaphylactoid shock in mice induced by lipopolysaccharide carrying the mannose homopolymer.

Intravenous injection of specified bacterial lipopolysaccharides (LPSs) induced anaphylactoid shock in mice of various strains, including LPS-resistant C3H/HeJ. The reaction was accompanied by occasional mortality of mice within 1 h. Prior to shock, rapid accumulation of blood platelets in the lungs and liver followed by degradation of platelets (or release of their contents) and tissue destruction were observed. In this study, LPS specimens carrying mannose-homopolymer (MHP), which markedly activate the human complement system through the lectin pathway, induced marked platelet degradation and anaphylactoid shock in BALB/c mice. In contrast, in C5-deficient DBA/2 mice, the platelet degradation and anaphylactoid reactions did not occur. Anti-complement agent K-76 COOH (C5 inhibitor) protected BALB/c mice from mortality in the anaphylactoid reaction. K-76 COOH also inhibited platelet degradation, but not accumulation, induced by LPS in mice. Based on these findings, we postulated that strong complement activation by specified LPS preparations induced degradation of platelets that have accumulated in the lungs and liver, resulting in acute inflammation accompanied by severe tissue destruction, especially in the lungs, which in turn leads to anaphylactoid reaction.

Anaphylaxis↗

PubMed1999

Targeting the complement system.

Interest has blossomed in the development of complement inhibitors, in parallel with a growth in our understanding of the biology of the complement cascade. The first generation of designed inhibitors was based on naturally occurring complement receptors and regulatory molecules. These agents provided useful tools for exploring the role of complement in experimental models of disease, but may have limited therapeutic application in humans because of their short half-lives, limited bioavailability and possible antigenicity. More recently, humanized antibodies and synthetic molecules that block the activation of complement have been developed, which look as though they may overcome some of these difficulties. The possibility for precision inhibition of a limited part of the complement cascade, or for inhibition confined to a single organ, may offer effective therapeutic results, while avoiding the disadvantages of nonselective complement blockade. This review examines the recent evidence that complement inhibition will reduce tissue damage resulting from organ transplantation, ischaemia-reperfusion injury, cancer, glomerulonephritis and the use of extracorporeal circuits.

Animals↗

PubMed2002

Development of a novel cytomedical treatment that can protect entrapped cells from host humoral immunity.

Cell therapy is expected to relieve the shortage of donors needed for organ transplantation. When patients are treated with allogeneic or xenogeneic cells, it is necessary to develop a means by which to isolate administered cells from an immune attack by the host. We have developed "cytomedicine," which consists of functional cells entrapped in semipermeable polymer, and previously reported that alginate-poly-L-lysine-alginate microcapsules and agarose microbeads could protect the entrapped cells from injury by cellular immunity. However, their ability to isolate from humoral immunity was insufficient. It is well known that the complement system plays an essential role in rejection of transplanted cells by host humoral immunity. Therefore, the goal of the present study was to develop a novel cytomedical device containing a polymer capable of inactivating complement. In the screening of various polymers, polyvinyl sulfate (PVS) exhibited high anticomplement activity and low cytotoxicity. Murine pancreatic beta-cell line (MIN6 cell) entrapped in agarose microbeads containing PVS maintained viability and physiological insulin secretion, replying in response to glucose concentration, and resisted rabbit antisera in vitro. PVS inhibited hemolysis of sensitized sheep erythrocytes (EAs) and rabbit erythrocytes by the complement system. This result suggests that PVS inhibits both the classical and alternative complement pathways of the complement system. Next, the manner in which PVS exerts its effects on complement components was examined. PVS was found to inhibit generation of C4a and Ba generation in activation of the classical and alternative pathways, respectively. Moreover, when the EAC1 cells, which were carrying C1 on the EAs, treated with PVS were exposed to C1-deficient serum, hemolysis decreased in a PVS dose-dependent manner. These results suggest that PVS inhibits C1 in the classical pathway and C3 convertase formation in the alternative pathway. Therefore, PVS may be a useful polymer for developing an anticomplement device for cytomedical therapy.

Alginates↗

PubMed1993

Complement-dependent synergistic effects of rat monoclonal IgG antibodies in vivo.

We describe studies aimed at maximizing the effector mechanisms responsible for eliminating target erythrocytes from the circulation in a fully homologous opsonization system in vivo. The effects on the subsequent fate of target erythrocytes were examined in both normal and decomplemented rats preinjected with a variety of rat IgG monoclonal antibodies (mAb) directed against different epitopes on the RT1Aa, the classical class I major histocompatibiliy complex antigen of the DA rat. In general, the clearance of both DA and (DA x PVG)F1 erythrocytes in normal rats preinjected with various pairs of noncompetitive mAb was very rapid when compared with the overall clearance patterns seen with individual antibodies. With all mAb combinations containing IgG2b or IgG2a, an intact complement system was an essential requirement for augmenting the initial clearance and promoting hepatic sequestration of these target cells. The removal of (DA x PVG)F1 erythrocytes, expressing half as much antigen, was considerably slower than the DA cells for each antibody pair tested although a notable degree of heterogeneity was observed in the overall behavior of both types of target cells with different mAb combinations. Our results suggest that the limiting effects of low antigen density on the target cells combined with the use of mAb of an isotype like the rat IgG2a can be overcome using pairs of mAb that recognize different epitopes on the same target antigen.

Animals↗

PubMed2003

A novel cytomedical vehicle capable of protecting cells against complement.

We have developed "Cytomedicine," which consists of functional cells entrapped in semipermeable polymer, and previously reported that APA microcapsules could protect the entrapped cells from injury by cellular immune system. However, microencapsulated cells were not protected from humoral immune system. Here, we developed a novel APA microcapsule, in which APA microbeads (APA(Ba) microbeads) were modified to contain a barium alginate hydrogel within their centers in an attempt to make it more difficult for antibody and complement to permeate the microcapsules. The permeability of APA(Ba) microbeads was clearly less than that of APA microcapsules, presumably due to the presence of barium alginate hydrogel. Cells encapsulated within APA(Ba) microbeads were protected against treatment with xenogeneic anti-serum. Furthermore, murine pancreatic beta-cells encapsulated in APA(Ba) microbeads remained viable and continued to secrete insulin in response to glucose. Therefore, APA(Ba) microbeads may be a useful carrier for developing anti-complement device for cytomedical therapy.

Alginates↗

PubMed1998

Pathogenetic and clinical aspects of C1 inhibitor deficiency.

People deficient in C1-INH present recurrent angioedema localized to subcutaneous or mucous tissues. The defect can be caused by impaired synthesis, due to a genetic defect (hereditary angioedema), or by increased catabolism (acquired angioedema). In our experience the majority of patients with acquired angioedema (16 of 18) have autoantibodies to C1-INH in their serum. These autoantibodies bind to C1-INH with different and generally low affinity. The vasopermeability mediator responsible for attacks is still undefined: bradykinin (derived from cleavage of high molecular weight kininogen) and a kinin-like peptide (derived from the second component of complement) still remain the two primary candidates. We examined the systems controlled by C1-INH (complement, contact system, fibrinolysis and coagulation) and found that all of them are activated during angioedema attacks. Activation of the coagulation leads to generation of thrombin whose vasoactive effect can thus influence edema formation. Treatment of severe angioedema attacks is satisfactorily performed with C1-INH plasma concentrate although patients with an acquired defect frequently need very high doses. Attenuated androgens effectively prevent attacks in hereditary angioedema, but their safety, on the very long-term, needs to be further assessed. Acquired angioedema generally fail to respond to these drugs, but can be treated prophylactically with antifibrinolytic agents.

Abdomen, Acute↗

PubMed2005

Complement-opsonized HIV: the free rider on its way to infection.

The complement system (C) is one of the main humoral components of innate immunity. Three major tasks of C against invading pathogens are: (i) lysis of pathogens by the formation of the membrane attack complex (MAC); (ii) opsonization of pathogens with complement fragments to favor phagocytosis; and (iii) attraction of inflammatory cells by chemotaxis. Like other particles, HIV activates C and becomes opsonized. To escape complement-mediated lysis, HIV has adopted various properties, which include the acquisition of HIV-associated molecules (HAMs) belonging to the family of complement regulators, such as CD46, CD55, CD59, and the interaction with humoral regulatory factors like factor H (fH). Opsonized virus may bind to complement receptor positive cells to infect them more efficiently or to remain bound on the surface of such cells. In the latter case HIV can be transmitted to cells susceptible for infection. This review discusses several aspects of C-HIV interactions and provides a model for the dynamics of this process.

Complement Inactivator Proteins↗

PubMed1983

In vivo demyelinating activity of sera from animals with chronic experimental allergic encephalomyelitis. Antibody nature of the demyelinating factor and the role of complement.

Sera from guinea pigs and rats with chronic experimental allergic encephalomyelitis were injected into the cerebrospinal fluid (CSF) of normal recipient rats. Guinea pig sera induced demyelination in the central and (or) peripheral nervous system, whereas injection of rat sera resulted in demyelination in the peripheral nervous system only. Control sera did not induce demyelination. Demyelinating activity in guinea pig sera was confined to the IgG-fraction; in rat sera the IgG- as well as the IgM-fraction were able to induce demyelination. The demyelinating activity was abolished when the sera were absorbed with with sensitising antigen (guinea pig spinal cord tissue) or when immunoglobulins were removed from the sera. When chronic EAE sera from rats were injected into the CSF of rats, complement was not required for the induction of demyeLination. The presence of complement, however, augmented the demyelinating activity. Decomplemented chronic EAE sera from guinea pigs failed to induce demyelination after injection into the CSF of rats. Injection of control and non-demyelinating or demyelinating EAE sera into the subarachnoid space of normal recipient rats induced a weak inflammatory response with increased numbers of large mononuclear cells in the meninges. It is discussed that in vivo a complex interaction of antibodies, complement and effector cells is responsible for induction of demyelination.

Animals↗

PubMed1986

The contact activation system: biochemistry and interactions of these surface-mediated defense reactions.

This review is intended to be a critical state-of-the-art overview of the activation and inhibition of the proteins (factor XII, prekallikrein, high molecular weight kininogen, and factor XI) of the contact phase of coagulation. Specifically, this review will reconsider the concept of the reciprocal activation of the proteases of the contact phase of coagulation, factor XII, and prekallikrein, in light of much recent evidence indicating that factor XII, itself, autoactivates when associated with negatively charged surfaces. In addition, the mechanisms for amplification of activation of the proteins of the contact phase of coagulation will be discussed from the pivotal role of high molecular weight kininogen, or one of its altered forms, serving as a cofactor to order the activation of the zymogens it is associated with. The role and relative importance of each of the naturally occurring plasma protease inhibitors (C1-inhibitor, alpha-2-macroglobulin, alpha-1-antitrypsin, antithrombin III, and alpha-1-antiplasmin) will be assessed as they relate to the dampening of contact phase activation. Finally, the contact phase of coagulation activation will be discussed not only as a plasma proteolytic mechanism, but also as it interacts with platelets.

Blood Coagulation↗

PubMed2005

APT070 (Mirococept), a membrane-localised complement inhibitor, inhibits inflammatory responses that follow intestinal ischaemia and reperfusion injury.

Activation of the complement system has been shown to play a major role in the mediation of reperfusion injury. Here, we assessed the effects of APT070 (Mirococept), a novel membrane-localised complement inhibitor based on a recombinant fragment of soluble CR1, on the local, remote and systemic injuries following intestinal ischaemia and reperfusion (I/R) in the rat. In a model of mild I/R injury (30 min of ischaemia and 30 min of reperfusion), APT070 dose-dependently (1-10 mg kg(-1)) inhibited the increase in vascular permeability of and neutrophil influx into intestine and lungs. Maximal inhibition occurred at 10 mg kg(-1). Following severe I/R injury (120 min of ischaemia and 120 min of reperfusion), APT070 (10 mg kg(-1)) markedly prevented neutrophil influx and the increase in vascular permeability both in the intestine and the lungs.APT070 also effectively suppressed the increase of tissue (intestine and lungs) and serum concentrations of TNF-alpha and IL-6, but not those of IL-1beta or IL-10. There was no significant reduction of mortality in the APT070 group. In conclusion, treatment with the membrane-targeted complement inhibitor APT070 significantly reduced the hyperinflammatory response after mild and severe ischaemia and reperfusion injury (I/RI) in rats. APT070 may be effective in therapeutic indications involving gut I/RI.

Animals↗

PubMed1994

Activation of the contact system and fibrinolysis in autoimmune acquired angioedema: a rationale for prophylactic use of tranexamic acid.

C1-inhibitor deficiency results in bouts of mucocutaneous edema and may be inherited (hereditary angioedema) or acquired (acquired angioedema [AAE]). The two forms have the same clinical picture but differ in the response to treatment. Prophylaxis with antifibrinolytic agents produces better results in the acquired form than in the inherited form, in which androgen derivatives are more effective. It is hypothesized that activation of the contact and fibrinolytic systems is involved in the pathogenesis of attacks. We evaluated these two systems in plasma from eight patients with AAE and anti-C1-inhibitor autoantibodies (autoimmune AAE) by measuring the cleavage of high molecular weight kininogen and the complexes formed by plasmin and its inhibitor alpha 2-antiplasmin. We also measured complement parameters, autoantibody titer, and cleaved C1-inhibitor (relative molecular mass = 96,000), because autoantibodies to C1-inhibitor are known to facilitate its cleavage by proteases. Plasma was obtained from patients in remission, during prophylactic treatment with the antifibrinolytic agent tranexamic acid (2 to 4.5 gm/day) and also from two patients during acute attacks of edema. Levels of cleaved high molecular weight kininogen and antiplasmin-plasmin complexes in patients with AAE were both higher in basal conditions, during treatment, and during acute attacks than those in normal subjects (p < 0.001). The cleaved inactive form of C1-inhibitor was also present in all patients in all three conditions. Therapy with antifibrinolytic agents reduced the frequency and intensity of symptoms without significantly changing any of the biochemical parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗

PubMed2023

Genome-wide screen in human plasma identifies multifaceted complement evasion of Pseudomonas aeruginosa.

Pseudomonas aeruginosa, an opportunistic Gram-negative pathogen, is a leading cause of bacteremia with a high mortality rate. We recently reported that P. aeruginosa forms a persister-like sub-population of evaders in human plasma. Here, using a gain-of-function transposon sequencing (Tn-seq) screen in plasma, we identified and validated previously unknown factors affecting bacterial persistence in plasma. Among them, we identified a small periplasmic protein, named SrgA, whose expression leads to up to a 100-fold increase in resistance to killing. Additionally, mutants in pur and bio genes displayed higher tolerance and persistence, respectively. Analysis of several steps of the complement cascade and exposure to an outer-membrane-impermeable drug, nisin, suggested that the mutants impede membrane attack complex (MAC) activity per se. Electron microscopy combined with energy-dispersive X-ray spectroscopy (EDX) revealed the formation of polyphosphate (polyP) granules upon incubation in plasma of different size in purD and wild-type strains, implying the bacterial response to a stress signal. Indeed, inactivation of ppk genes encoding polyP-generating enzymes lead to significant elimination of persisting bacteria from plasma. Through this study, we shed light on a complex P. aeruginosa response to the plasma conditions and discovered the multifactorial origin of bacterial resilience to MAC-induced killing.

Humans↗

PubMed2004

Anti-lipoprotein lipase antibodies: a new player in the complex atherosclerotic process in systemic lupus erythematosus?

OBJECTIVE: The novel description of antibodies to lipoprotein lipase (anti-LPL) associated with dyslipoproteinemia prompted us to analyze the association of anti-LPL with clinical and serologic features in patients with systemic lupus erythematosus (SLE) and its link to markers of inflammation that are known to be involved in atherogenesis. METHODS: Enzyme-linked immunosorbent assay was used to test for the presence of anti-LPL antibodies in 66 consecutive patients with SLE. Clinical and laboratory evaluation, including a fasting lipid profile, autoantibody screening, an assessment for markers of inflammation (C-reactive protein [CRP], erythrocyte sedimentation rate [ESR]), and the SLE Disease Activity Index (SLEDAI) were performed at the time of inclusion in the study. Exclusion criteria were any conditions that affect the lipid profile. SLE patients were categorized into 2 groups according to detection of these anti-LPL antibodies, as follows: anti-LPL+ and anti-LPL-. RESULTS: Anti-LPL antibody IgG was detected in 25 SLE patients (37.8%). Triglyceride levels were significantly higher in the anti-LPL+ group (112.4 +/- 50.2 versus 89.9 +/- 54.5 mg/dl in the anti-LPL- group; P = 0.033), but no significant differences between the 2 groups were detected for total, high-density lipoprotein, and low-density lipoprotein cholesterol levels. A higher frequency of elevated CRP levels and ESRs was observed in the anti-LPL+ group compared with the anti-LPL- group (44% and 17.1%, respectively [P = 0.023] and 52% and 19.5%, respectively [P = 0.013]). Moreover, SLE patients with anti-LPL antibodies also had significantly higher levels of CRP (11.1 +/- 16.4 versus 2.4 +/- 2.6 mug/ml; P = 0.036) and higher ESRs (33.4 +/- 29.8 versus 16.5 +/- 11.8 mm/hour; P = 0.020). Anti-LPL titers had a significant positive correlation with the CRP level (r = 0.56, P < 0.001), the ESR (r = 0.55, P < 0.001), the SLEDAI score (r = 0.45, P < 0.001), anti-double-stranded DNA (anti-dsDNA; r = 0.52, P < 0.001), and anticardiolipin IgG antibodies (r = 0.25, P = 0.04), and a significant negative correlation was detected with total hemolytic complement activity (CH100) (r = -0.34, P = 0.005). Reinforcing these findings, multiple regression analysis also revealed a significant association of anti-LPL with the CRP level (P = 0.025) and anti-dsDNA (P < 0.001). Importantly, a comparison of positive and negative anti-dsDNA sera revealed similar mean CRP levels (P = 0.56) and ESRs (P = 0.102), contrasting with the SLEDAI score (P = 0.004) and CH100 (P = 0.008). CONCLUSION: These data support the link between inflammation, immune response, and dyslipoproteinemia in SLE, introducing anti-LPL as a possible new player that may ultimately help in understanding the complex events of atherogenesis in this disease.

Adult↗