Biological effects of C1 inhibitor

C1 inhibitor is a serine proteinase inhibitor (serpin) that regulates activation of both the complement and contact systems. Regulation of complement system activation takes place through inactivation of the classical pathway proteases, C1r and C1s, the lectin pathway protease, MASP2, and perhaps via inhibition of alternative pathway activation by reversible binding to C3b. Regulation of contact system activation takes place through inactivation of plasma kallikrein and coagulation factor XIIa. Deficiency of C1 inhibitor results in hereditary angioedema, which is characterized by recurrent episodes of localized angioedema of the skin, gastrointestinal mucosa or upper respiratory mucosa. A variety of clinical, in vitro and animal experiments indicate that the mediator of increased vascular permeability in hereditary angioedema is bradykinin. Animal models suggest that in addition to its utility in therapy of hereditary angioedema, C1 inhibitor may prove useful in a variety of other diseases including septic shock, reperfusion injury, hyperacute transplant rejection, traumatic and hemorrhagic shock, and the increased vascular permeability associated with thermal injury, interleukin-2 therapy and cardiopulmonary bypass. The therapeutic effect in these disease models very likely results from a combination of complement system activation, contact system activation and perhaps from other activities of C1 inhibitor. These other activities include a direct interaction with endotoxin, which may help to prevent endotoxic shock and an interaction with selectin molecules on endothelial cells, which may serve both to concentrate C1 inhibitor at sites of inflammation and to inhibit the transmigration of leukocytes across the endothelium.     

The potentiation of human C1-inhibitor by dextran sulphate is transient in vivo: studies in a rat model

C1-inhibitor (C1-Inh) is an important regulator of inflammatory reactions because it is a potent inhibitor of the contact and complement system. C1-Inh application in inflammatory disease is, however, restricted because of the high doses required. The glycosaminoglycan-like molecule dextran sulphate (DXS) enhances C1-Inh function in vitro. Hence, we investigated whether co-administration with dextran sulphate reduces the amount of C1-Inh required, through enhancement in vivo. C1-Inh potentiation was measured in a newly developed C1s-inactivation assay that is based on activation of C4 by purified C1s. Activated C4 in rat plasma was quantified with a newly developed ELISA. Human C1-Inh (2.5 microM) inhibited C1s in rat plasma 55-fold faster in the presence of dextran sulphate (15 kDa, 5 microM). To study the stability of the complex in vivo, rats were given a mixture of C1-Inh (10 mg/kg) and dextran sulphate (3 mg/kg). C1-Inh activity during 5 h was analyzed ex vivo with the C1s inactivation assay. The noncovalent C1-Inh-dextran sulphate complex resulted in a transient enhancement of the inhibitory capacity of C1-Inh, lasting for 60-90 min. Dextran sulphate did not affect plasma clearance of C1-Inh. We conclude that the enhanced inhibitory capacity of C1-Inh complexed to dextran sulphate is transient in vivo. Hence, co-administration of these compounds seems a feasible approach to achieve short-term inhibition of complement in vivo.     

The coagulation cascade in sepsis

Intravascular and extravascular fibrin formation are characteristic findings in patients with sepsis, suggesting that the activation of coagulation and the inhibiton of fibrinolysis are important in the pathogenesis of sepsis. Activation of coagulation during sepsis is primarily driven by the tissue factor (TF) pathway, while inhibition of fibrinolysis is primarily due to increases in plasminogen activator inhibitor -1(PAI-1). Downregulation of the anticoagulant Protein C pathway also plays an important role in the modulation of coagulation and inflammation in sepsis. Recent advances in the understanding of pathogenetic mechanisms of coagulation and fibrinolysis in sepsis may have therapeutic implications. Recombinant human activated protein C (rhAPC) is currently the only pharmacologic therapy that has been shown to reduce mortality in adults with severe sepsis, highlighting the importance of coagulation and fibrinolysis as a therapeutic target in sepsis. This review summarizes recent basic and clinical findings with regard to the role of the coagulation cascade in sepsis and explores potential therapeutic targets in the coagulation and fibrinolytic pathways in the management of sepsis.     

Therapeutic modulation of coagulation and fibrinolysis in acute lung injury and the acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) are characterized by excessive intraalveolar fibrin deposition, driven, at least in part by inflammation. The imbalance between activation of coagulation and inhibition of fibrinolysis in patients with ALI/ARDS favors fibrin formation and appears to occur both systemically and in the lung and airspace. Tissue factor (TF), a key mediator of the activation of coagulation in the lung, has been implicated in the pathogenesis of ALI/ARDS. As such, there have been numerous investigations modulating TF activity in a variety of experimental systems in order to develop new therapeutic strategies for ALI/ARDS. This review will summarize current understanding of the role of TF and other proteins of the coagulation cascade as well the fibrinolysis pathway in the development of ALI/ARDS with an emphasis on the pathways that are potential therapeutic targets. These include the TF inhibitor pathway, the protein C pathway, antithrombin, heparin, and modulation of fibrinolysis through plasminogen activator- 1 (PAI-1) or plasminogen activators (PA). Although experimental studies show promising results, clinical trials to date have proven unsuccessful in improving patient outcomes. Modulation of coagulation and fibrinolysis has complex effects on both hemostasis and inflammatory pathways and further studies are needed to develop new treatment strategies for patients with ALI/ARDS.     

In vivo pharmacokinetics of calreticulin S-domain, an inhibitor of the classical complement pathway

Inhibition of the complement system is potentially therapeutic in diseases where uncontrolled or overshooting complement activation plays a significant role in the pathogenesis of the disorder. Calreticulin (CRT) is a multifunctional protein whose cell-surface form (ectocalreticulin) is reported to be a C1q receptor. A 124-residue domain within CRT, the S-domain, binds to C1q, prevents the formation of C1 and so inhibits activation of the classical pathway. To assess the usefulness of CRT S-domain as a complement inhibitor, recombinant S-domain was expressed, radiolabeled, and the fate of the radiolabeled peptide followed in vivo. In rats, CRT-S-domain shows a half-life of 1.21 +/- 0.34 and 40.5 +/- 2.7 min in the distribution and elimination phases from plasma, respectively. The peptide remains largely intact, and is cleared from the circulation by the kidneys, where it accumulates in the proximal convoluted tubules, but is not excreted. Much smaller amounts of the peptide accumulate in other tissues, and essentially none crosses the blood-brain barrier.     

Prevention of Cardiac Cell Injury During Acute Myocardial Infarction

The purpose of this article is to describe mechanisms of cell death in patients with acute myocardial infarction, particularly the activation of the complement system. Various pro-inflammatory cytokines, released by the inflamed tissue, play a role in the activation of the complement system. Several complement inhibitors have been developed to reduce tissue damage following ischemia. According to animal studies the deleterious effects of activators of the complement system can be diminished by complement inhibition. Several clinical studies have been conducted for the potential treatment of cell injury during actue myocardial infarction. C1 inhibitor dose-dependently inhibited complement activation and appeared to reduce myocardial injury after reperfusion therapy in patients with acute myocardial infarction. C1 inhibitor dose-dependently reduced plasma levels of C4 activation fragments. In addition, cardiac enzymes (troponin T and creatine kinase-MB) returned to baseline levels more rapidly among patients treated with C1 inhibitor, compared with controls. Furthermore, preliminary results from a placebo-controlled trial indicate that treatment with intravenous pexelizumab (anti-C5 antibody) was well tolerated in a large number of patients undergoing coronary artery bypass graft surgery. Further, more randomized trials are necessary to clarify the clinical significance of this new and innovative treatment with complement inhibition.     

C1-inhibitor: an anti-inflammatory reagent with therapeutic potential

Excessive activation of the protein cascade systems often leads to severe inflammatory tissue destruction with potential life-threatening outcome. These include clinical disorders, such as capillary leak syndrome, septic shock, myocardial infarction and other ischaemia/reperfusion injuries, trauma, burns, multiple organ failure, as well as graft rejection. A therapeutic substitution of appropriate regulators appears to be a reasonable approach to reduce undesirable inflammatory reactions. C1-inhibitor, a multifunctional regulator of the various kinin-generating cascade systems, is frequently reduced in patients suffering from severe inflammation. C1-inhibitor concentrate has been used for decades as a substitution therapy to treat acute attacks in patients with hereditary angioedema. Studies including pathophysiologically relevant animal models now provide sufficient evidence that C1-inhibitor may also serve as an effective means to protect against inflammatory tissue injury. Promising clinical results are emerging which support C1-inhibitor as a candidate for therapy in severe inflammatory disorders. Although treatment with C1-inhibitor is regarded as safe, recent reports on possible side effects in certain clinical situations emphasise the importance of controlled clinical studies. The following review will focus on the impact of C1-inhibitor treatment on diseases, where complement contributes to the pathogenesis.     

C1-inhibitor: an anti-inflammatory reagent with therapeutic potential

Excessive activation of the protein cascade systems often leads to severe inflammatory tissue destruction with potential life-threatening outcome. These include clinical disorders, such as capillary leak syndrome, septic shock, myocardial infarction and other ischaemia/reperfusion injuries, trauma, burns, multiple organ failure, as well as graft rejection. A therapeutic substitution of appropriate regulators appears to be a reasonable approach to reduce undesirable inflammatory reactions. C1-inhibitor, a multifunctional regulator of the various kinin-generating cascade systems, is frequently reduced in patients suffering from severe inflammation. C1-inhibitor concentrate has been used for decades as a substitution therapy to treat acute attacks in patients with hereditary angioedema. Studies including pathophysiologically relevant animal models now provide sufficient evidence that C1-inhibitor may also serve as an effective means to protect against inflammatory tissue injury. Promising clinical results are emerging which support C1-inhibitor as a candidate for therapy in severe inflammatory disorders. Although treatment with C1-inhibitor is regarded as safe, recent reports on possible side effects in certain clinical situations emphasise the importance of controlled clinical studies. The following review will focus on the impact of C1-inhibitor treatment on diseases, where complement contributes to the pathogenesis.     

Properdin and complement activation: a fresh perspective

The C3 convertases are the major proteases of the complement cascade and are assembled at the site of complement activation via several different pathways. Properdin's functional role in stabilizing the alternative pathway convertase has been long established; however, new evidence demonstrates that properdin can also bind to certain microbial surfaces, and provide a platform for de novo convertase assembly. Therefore, properdin participates in two distinct mechanisms for complement activation: the alternative pathway and a properdin-directed pathway. Previous work had implicated the alternative pathway in the initiation and/or progression of several autoimmune diseases and in the host defense against certain bacterial pathogens. Those conclusions were based on evidence that cannot distinguish effects of the alternative pathway from effects of the properdin-directed pathway. With the identification of the new role for properdin in C3 convertase assembly there became a pressing need to reassess the mechanisms of complement activation, determine the specific role of properdin in each of these pathways, and explore the new therapeutic avenues that could arise.     

Complement activation by carbon nanotubes and its influence on the phagocytosis and cytokine response by macrophages

Carbon nanotubes (CNTs) have promised a range of applications in biomedicine. Although influenced by the dispersants used, CNTs are recognized by the innate immune system, predominantly by the classical pathway of the complement system. Here, we confirm that complement activation by the CNT used continues up to C3 and C5, indicating that the entire complement system is activated including the formation of membrane-attack complexes. Using recombinant forms of the globular regions of human C1q (gC1q) as inhibitors of CNT-mediated classical pathway activation, we show that C1q, the first recognition subcomponent of the classical pathway, binds CNTs via the gC1q domain. Complement opsonisation of CNTs significantly enhances their uptake by U937 cells, with concomitant downregulation of pro-inflammatory cytokines and up-regulation of anti-inflammatory cytokines in both U937 cells and human monocytes. We propose that CNT-mediated complement activation may cause recruitment of cellular infiltration, followed by phagocytosis without inducing a pro-inflammatory immune response.From the Clinical EditorThis study highlights the importance of the complement system in response to carbon nanontube administration, suggesting that the ensuing complement activation may cause recruitment of cellular infiltration, followed by phagocytosis without inducing a pro-inflammatory immune response.     

Complement activation is responsible for acute toxicities in rhesus monkeys treated with a phosphorothioate oligodeoxynucleotide

The objective of this study was to define the role of complement activation in the acute and transient toxicities associated with administration of phosphorothioate oligonucleotides in monkeys. In the absence of complement inhibitor, complement activation blocker-2 (CAB-2), i.v. infusion of 20 mg/kg ISIS 2302 produced increases in the concentrations of the complement split products Bb and C5a (100- and 7-fold, respectively). Monkeys also experienced marked changes in bloodpressure (hypertension and hypotension), clinical signs of toxicity (lethargy and periorbital edema), fluctuations in circulating neutrophil counts, and elevations in serum cytokine levels (45-, 12-, and 4-fold increases in IL-6, MCP-1, and IL-12, respectively). Changes occurred at or near the end of infusion and returned to normal over time. One of the three animals died approximately 4 h following infusion of 20 mg/kg ISIS 2302 alone. In contrast, prior treatment with CAB-2 effectively blocked complement activation, as well as the ISIS 2302-induced hemodynamic and clinical responses. Importantly, plasma concentration of ISIS 2302 were unaffected by CAB-2 pretreatment. Thus, the protection afforded by CAB-2 was due to its inhibition of complement activation rather than to any impact on the disposition of ISIS 2302. These results clearly demonstrate the causal relationship between activation of the alternative complement pathway and the hemodynamic and clinical responses associated with rapid infusion of phosphorothioate oligonucleotides. Demonstration of this relationship underscores the importance of avoiding complement activation in patients to ensure the continued safe use of phosphorothioate oligodeoxynucleotides.     

Interaction of anti-leprosy drugs with the rat serum complement system

Dapsone, clofazimine and rifampicin, the three most important constituents of multidrug therapy against leprosy, were studied with respect to their effects on the rat serum complement system, in vitro as well as in vivo. Of the three drugs only dapsone and clofazimine exhibited significant in vitro anti-complement activity and only at a very high, non-therapeutic dose of 0.24 mg/ml. On the contrary, rifampicin could not induce significant in vitro complement consumption. Furthermore, dapsone and clofazimine could reduce rat-serum-mediated rabbit erythrocyte haemolysis in the presence of Mg2+-EGTA, indicating that they could also affect the alternative pathway of complement activation. However, the latter pathway of complement consumption by these drugs seems to be insignificant because the factor-B-mediated complement-consumption system is minimal in rat sera. Immunoelectrophoretic study of mixtures of fresh rat sera and anti-leprosy drugs against specific anti-rat-C3 antisera demonstrated that dapsone and clofazimine could not cleave the C3 complement component. In a separate experiment we attempted to reconstitute the haemolytic complement activity consumed by dapsone and clofazimine by adding Crat-EDTA sera (a source of C3, C5, C6, C7, C8 and C9), but at most only 12% reconstitution of haemolytic activity could be achieved. We thus conclude that both dapsone and clofazimine could affect the complement system, predominantly through the earlier complement components and at very high, non-therapeutic doses. On the contrary, in-vivo experiments in rats showed that a combination of these three drugs, when given at a therapeutic dose or at 10 times the therapeutic dose for three months, did not affect the complement system.     

Interplay of complement and cytokines in the pathogenesis of septic shock.

Sepsis is a clinical syndrome that is usually induced by bacterial infections. It is generally assumed that the syndrome results from an excessive triggering of endogenous inflammatory mediators by the invading microorganisms. These mediators include substances released by activated monocytes, macrophages, endothelial cells and neutrophils such as cytokines, reactive oxygen species and proteases, as well as activation products of coagulation, fibrinolysis, contact and complement systems. Recent studies have suggested that cytokines and complement activation products may have overlapping biological activities. In addition, multiple interactions in vitro as well as in vivo between cytokines and complement have been described. Here we will review some of these recent studies and will discuss their relevance for the pathogenesis of sepsis and septic shock.     

Evolution of compstatin family as therapeutic complement inhibitors

Introduction: Therapeutic modulation of complement activation is considered as a promising approach for the treatment of host tissue damage in several inflammatory and autoimmune diseases. Complement component protein C3 is a particularly attractive drug target for complement inhibitors, due to its central role in three pathways of complement activation cascade.

Areas covered: The author provides a comprehensive review on compstatin family peptides which have been discovered and optimized as potent and selective C3 inhibitors via a combination of chemical, biophysical and computational approaches. New generations of the compstatin family with improved potency and therapeutic properties have been developed in recent years. Over two decades, compstatin demonstrated therapeutic potential as a first-of-its-kind complement inhibitor in a series of disease models, with encouraging efforts in clinical trials.

Expert opinion: Compstatin holds promise for new therapeutic implications in blocking the effect of the complement cascade in a variety of disease conditions. The development of cost-effective treatment options with suitable dosing route and schedule will be critical for patients with complement mediated chronic diseases.     

Role of current and emerging antithrombotics in thrombosis and cancer

In the nearly 130 years since Trousseau first described migratory thrombophlebitis in cancer patients, thromboembolism has become a well-established presenting sign and complication of cancer. The coagulation system is activated in cancer and is further amplified by treatment with chemotherapy, radiation or surgery. Hypercoagulation is documented in virtually all cancer types, albeit at different rates, and is the second leading cause of death in cancer patients. The relationship between clotting activation and carcinogenesis supports the view of cancer as a hypercoagulable state and holds implications for the development of thrombosis, enhancement of tumor growth and risk of poor clinical outcomes. Although it is well recognized that cancer can activate the coagulation cascade, it is less well known that activation of the coagulation system may also support tumor progression. Additionally, platelet activation in cancer patients and its impact on tumor progression and metastasis further expand the role of the hemostatic system in malignancy. The problem of thrombosis in patients with metastatic diseases is a serious concern for clinicians. This review explores the mechanisms and clinical implications of coagulation and platelet activation in cancer. The prevention and treatment of venous thromboembolism in cancer will also be discussed by reviewing data from key clinical investigations. Finally, the emerging role of low-molecular-weight heparin as an antineoplastic agent will be explored. Warfarin and unfractionated heparin have been in clinical use for more than 50 years. Both are effective anticoagulants, but their use is associated with a number of impediments, including the need for intensive coagulation monitoring, wide variation in dose-response relationships, multiple drug interactions (in the case of warfarin), and serious immune-mediated thrombocytopenia (in the case of heparin). The introduction of low-molecular weight heparin advanced anticoagulation therapy by enhancing efficacy and eliminating the need for intensive coagulation monitoring. Fondaparinux, the first selective factor Xa inhibitor, represents yet another improvement in anticoagulation therapy. By binding rapidly and strongly to antithrombin, its sole physiologic target in plasma, fondaparinux catalyzes specifically the inhibition of factor Xa, which results in effective and linear dose-dependent inhibition of thrombin generation. Additionally, efficient inhibition of factor Xa activity impairs the activation of tissue factor/factor VIIa complex leading to downregulation of procoagulant state, pro-angiogenesis, and proinflammatory factors induced by tissue factor/factor VIIa. Furthermore, a number of orally active direct antithrombin and anti-factor Xa are in advanced clinical development for various thromboembolic disorders.     

Effect of medicinal preparations on the complement: inhibition of subcomponent C1q binding to a target

A method is developed for determining the inhibition constants of substances capable of acting on the complement system at the stage of target recognition (immune complexes) by the first component of the complement (and, hence, blocking activation of the classical pathway of the complement). The ability of some drugs to inhibit the binding of subcomponent C1q to a target has been studied. It is shown that some drugs possess a pronounced ability to block the complement activation. The inhibition constants are compared to the therapeutic dozes of drugs. Some of the investigated preparations (suramin, sodium deoxiribonucleate, curcumin, heparin, sulfetron, guttalax, lysozyme) upon administration can present in the blood flow in concentrations capable of blocking the complement. The method is useful in the search for preparations capable of inhibiting the complement and in the study of side effects of medicinal preparations.     

Tissue factor pathway inhibitor: an update of potential implications in the treatment of cardiovascular disorders

Tissue factor (TF) plays a crucial role in the pathogenesis of thrombotic, vascular and inflammatory disorders. Thus, the inhibition of this membrane protein provides a unique therapeutic approach for prophylaxis and/or treatment of various diseases. Tissue factor pathway inhibitor (TFPI), the only endogenous inhibitor of the TF/Factor VIIa (FVIIa) complex, has recently been characterised biochemically and pharmacologically. Studies in patients demonstrated that both TF and TFPI may be indicators for the course and the outcome of cardiovascular and other diseases. Based on experimental and clinical data, TFPI might become an important drug for several clinical indications. TFPI is expected to inhibit the development of post-injury intimal hyperplasia and thrombotic occlusion in atherosclerotic vessels as well as to be effective in acute coronary syndromes, such as unstable angina and myocardial infarction. Of special interest is the inhibition of TF-mediated processes in sepsis and disseminated intravascular coagulation (DIC), which are associated with the activation of various inflammatory pathways as well as of the coagulation system. A Phase II trial of the efficacy of TFPI in patients with severe sepsis showed a mortality reduction in TFPI- compared to placebo-treated patients and an improvement of organ dysfunctions. TFPI can be administered exogenously in high doses to suppress TF-mediated effects, alternatively high amounts of TFPI can be released from intravascular stores by other drugs, such as heparin and low molecular weight heparins (LMWH). Using this method high concentrations of the inhibitor are provided at sites of tissue damage and ongoing thrombosis. At present, clinical studies with TFPI are rather limited so that the clinical potential of the drug cannot be assessed properly. However, TFPI and its variants are expected to undergo further development and to find indications in various clinical states.     

Beyond antibody-mediated rejection: hyperacute lung rejection as a paradigm for dysregulated inflammation

The use of animal organs for transplantation in humans is seen as a potential solution to the short supply of human donor organs available for clinical transplantation. However, to develop this therapeutic option as clinical reality will require surmounting formidable obstacles. The primary immunologic barrier to pig-to-human xenotransplantation is hyperacute rejection (HAR), a phenomenon previously characterized as resulting from antibody binding and complement activation. This article will first review recent progress in the development of specific strategies to overcome hyperacute lung rejection (HALR), through production of genetically engineered pig organs, modification of the host innate immunity and control of antibody and complement. Additional therapeutic targets identified in HALR are reviewed, with particular emphasis on recent studies describing a critical role for the coagulation cascade in HAR.     

Roles of coagulation pathway and factor Xa in chronic kidney disease (CKD)

Considering that fibrin deposition is observed in glomerulonephritis as well as in diabetic nephropathy, we performed studies to clarify the roles of the coagulation pathway and the active type of coagulation factor X (factor Xa) in the development of chronic kidney disease (CKD) using animal models. Factor Xa activates various cell types through protease-activated receptor 2 (PAR2). Several in vitro studies have demonstrated that PAR2 can mediate factor Xa signaling, but not thrombin signaling. Coagulation processes proceed together with the extracellular matrix (ECM) accumulation through factor V expression in rat Thy-1 nephritis. DX-9065a, a factor Xa inhibitor, suppresses this type of glomerulonephritis. The factor Xa inhibitor danaparoid ameliorated proteinuria, cellular proliferation, and fibrin deposition in lipopolysaccharide (LPS)-triggered activation of High IgA (HIGA) strain of ddY mice. Another factor Xa inhibitor, fondaparinux, suppressed urinary protein, glomerular hypertrophy, and connective tissue growth factor (CTGF), and ECM protein deposition together with angiogenesis in diabetic db/db mice. Finally, in the model of peritoneal fibrosis, fondaparinux treatment decreased the thickness of submesothelial fibrotic tissue and angiogenesis. In consideration of the results to potential human therapy, factor Xa regulation may be promising for the treatment of the aggravation in glomerulonephritis and of the early phase of diabetic nephropathy. In the near future, novel factor Xa inhibitors with the characteristics of oral administration and biliary elimination may appear in the clinical use for treatment of cardiovascular diseases.     

Inhibition of the complement system by glutathione: molecular mechanisms and potential therapeutic implications

Glutathione (GSH), a component of the antioxidant defence system, plays a role in autoimmunity and the complement system is often responsible for tissue damage in autoimmune diseases. The aim of this study is to evaluate the effects of GSH on the complement system. The complement system was examined in the normal human sera (NHS) of 30 healthy subjects. Increasing quantities of GSH (1, 2, 10, 20 mg) were incubated in 1 ml of each NHS. The mixtures were evaluated for complement activities (THC, CPA and APA) and for the presence of cleavage fragments of activation of C3 and B. GSH was also incubated with human complement in the presence of classical and alternative pathway activators. The results showed an inhibitory effect of GSH on the complement system starting from a dosage of GSH≥1 mg/ml. Indeed, when NHS was incubated with GSH at such dosage, a significant reduction of the complement activities THC, CPA, and APA was observed (P<0.0001, P<0.005, P=NS, respectively), and no cleavage fragments of C3 or B were found. Further analysis demonstrated that the inhibition was exerted on C3-9 and to a lower extent on classical and alternative pathway C3-convertases. Our results indicate that GSH is capable of inhibiting the complement system. These findings are relevant for the design of interventions aimed at modulation of GSH metabolism to inhibit complement-mediated damage in autoimmune diseases.