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The complement system plays a key role in pathogen immunosurveillance and tissue homeostasis. However, subversion of its tight regulatory control can fuel a vicious cycle of inflammatory damage that exacerbates pathology. The clinical merit of targeting the complement system has been established for rare clinical disorders such as paroxysmal nocturnal haemoglobinuria and atypical haemolytic uraemic syndrome. Evidence from preclinical studies and human genome-wide analyses, supported by new molecular and structural insights, has revealed new pathomechanisms and unmet clinical needs that have thrust a new generation of complement inhibitors into clinical development for a variety of indications. This review critically discusses recent clinical milestones in complement drug discovery, providing an updated translational perspective that may guide optimal target selection and disease-tailored complement intervention.

Emerging data indicate that complement and neutrophils contribute to the maladaptive immune response that fuels hyperinflammation and thrombotic microangiopathy, thereby increasing coronavirus 2019 (COVID-19) mortality. Here, we investigated how complement interacts with the platelet/neutrophil extracellular traps (NETs)/thrombin axis, using COVID-19 specimens, cell-based inhibition studies, and NET/human aortic endothelial cell (HAEC) cocultures. Increased plasma levels of NETs, tissue factor (TF) activity, and sC5b-9 were detected in patients. Neutrophils of patients yielded high TF expression and released NETs carrying active TF. Treatment of control neutrophils with COVID-19 platelet-rich plasma generated TF-bearing NETs that induced thrombotic activity of HAECs. Thrombin or NETosis inhibition or C5aR1 blockade attenuated platelet-mediated NET-driven thrombogenicity. COVID-19 serum induced complement activation in vitro, consistent with high complement activity in clinical samples. Complement C3 inhibition with compstatin Cp40 disrupted TF expression in neutrophils. In conclusion, we provide a mechanistic basis for a pivotal role of complement and NETs in COVID-19 immunothrombosis. This study supports strategies against severe acute respiratory syndrome coronavirus 2 that exploit complement or NETosis inhibition.

The complement cascade is a critical effector mechanism of the innate immune system that contributes to the rapid clearance of pathogens and dead or dying cells, as well as contributing to the extent and limit of the inflammatory immune response. In addition, some of the early components of this cascade have been clearly shown to play a beneficial role in synapse elimination during the development of the nervous system, although excessive complement-mediated synaptic pruning in the adult or injured brain may be detrimental in multiple neurogenerative disorders. While many of these later studies have been in mouse models, observations consistent with this notion have been reported in human postmortem examination of brain tissue. Increasing awareness of distinct roles of C1q, the initial recognition component of the classical complement pathway, that are independent of the rest of the complement cascade, as well as the relationship with other signaling pathways of inflammation (in the periphery as well as the central nervous system), highlights the need for a thorough understanding of these molecular entities and pathways to facilitate successful therapeutic design, including target identification, disease stage for treatment, and delivery in specific neurologic disorders. Here, we review the evidence for both beneficial and detrimental effects of complement components and activation products in multiple neurodegenerative disorders. Evidence for requisite co-factors for the diverse consequences are reviewed, as well as the recent studies that support the possibility of successful pharmacological approaches to suppress excessive and detrimental complement-mediated chronic inflammation, while preserving beneficial effects of complement components, to slow the progression of neurodegenerative disease.

There is an urgent need to develop effective therapies for COVID-19. Here, we urge immunologists and clinicians to consider the potential of targeting the complement system in these patients.This Comment article from Lambris and colleagues considers the therapeutic potential of targeting the complement system in patients with COVID-19.

Key Points Complement is a key component of immunity with crucial inflammatory and opsonic properties; inappropriate activation of complement triggers or exacerbates inflammatory disease. Complement dysregulation is a core feature of some diseases and contributes to pathology in many others. Approved agents have been developed for and are highly effective in some orphan applications, but their progress to use in more common diseases has been slow. Numerous challenges, such as target concentration or high turnover, limit the efficacy of these agents in humans. Numerous novel agents targeting different parts of the complement system in different ways are now emerging from pre-clinical studies and are entering Phase I/II trials; these agents bring the potential for more-effective and more-specific anti-complement therapies in disease. Other agents, both biologic and small molecule, are in Phase II or III trials for both rare and common diseases — administration routes include localized (for example, intravitreal) and systemic routes. There is an urgent need to develop biomarkers and imaging methods that enable monitoring of the effects and efficacy of anti-complement agents. The complement cascade, a key regulator of innate immunity, is a rich source of potential therapeutic targets for diseases including autoimmune, inflammatory and degenerative disorders. Morgan and Harris discuss the progress made in modulating the complement system and the existing challenges, including dosing, localization of the drug to the target and how to interfere with protein–protein interactions. The complement system is a key innate immune defence against infection and an important driver of inflammation; however, these very properties can also cause harm. Inappropriate or uncontrolled activation of complement can cause local and/or systemic inflammation, tissue damage and disease. Complement provides numerous options for drug development as it is a proteolytic cascade that involves nine specific proteases, unique multimolecular activation and lytic complexes, an arsenal of natural inhibitors, and numerous receptors that bind to activation fragments. Drug design is facilitated by the increasingly detailed structural understanding of the molecules involved in the complement system. Only two anti-complement drugs are currently on the market, but many more are being developed for diseases that include infectious, inflammatory, degenerative, traumatic and neoplastic disorders. In this Review, we describe the history, current landscape and future directions for anti-complement therapies.

Silver nanoparticles (AgNPs) have tremendous potentials in medical devices due to their excellent antimicrobial properties. Blood compatibility should be investigated for AgNPs due to the potential blood contact. However, so far, most studies are not systematic and have not provided insights into the mechanisms for blood compatibility of AgNPs. In this study, we have investigated the blood biological effects, including hemolysis, lymphocyte proliferation, platelet aggregation, coagulation and complement activation, of 20 nm AgNPs with two different surface coatings (polyvinyl pyrrolidone and citrate). Our results have revealed AgNPs could elicit hemolysis and severely impact the proliferation and viability of lymphocytes at all investigated concentrations (10, 20, 40 μg/mL). Nevertheless, AgNPs didn’t show any effect on platelet aggregation, coagulation process, or complement activation at up to ~40 μg/mL. Proteomic analysis on AgNPs plasma proteins corona has revealed that acidic and small molecular weight blood plasma proteins were preferentially adsorbed onto AgNPs, and these include some important proteins relevant to hemostasis, coagulation, platelet, complement activation and immune responses. The predicted biological effects of AgNPs by proteomic analysis are mostly consistent with our experimental data since there were few C3 components on AgNPs and more negative than positive factors involving platelet aggregation and thrombosis.

CD55 prevents convertase enzyme formation in the complement cascade, acting as a brake on complement activation. Inactivating mutations in CD55 result in hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy.

Excessive activation of blood coagulation and neutrophil accumulation have been described in several human cancers. However, whether hypercoagulation and neutrophilia are linked and involved in cancer development is currently unknown. Here we show that spontaneous intestinal tumorigenesis correlates with the accumulation of low-density neutrophils with a pro-tumorigenic N2 phenotype and unprompted neutrophil extracellular traps (NET) formation. We find that increased circulating lipopolysaccharide induces upregulation of complement C3a receptor on neutrophils and activation of the complement cascade. This leads to NETosis, induction of coagulation and N2 polarization, which prompts tumorigenesis, showing a novel link between coagulation, neutrophilia and complement activation. Finally, in a cohort of patients with small but not large intestinal cancer, we find a correlation between neutrophilia and hypercoagulation. This study provides a mechanistic explanation for the tumour-promoting effects of hypercoagulation, which could be used as a new biomarker or as a therapeutic target. It is unclear whether cancer-related hypercoagulation and neutrophilia contribute to tumorigenesis. In this study, the authors find that activation of the complement cascade causes hypercoagulation that leads to polarization of neutrophils in a mouse model of intestinal cancer, and show that blocking complement activation can reduce tumour formation.

Complement hyperactivation, angiopathic thrombosis and protein-losing enteropathy (CHAPLE disease) is a lethal disease caused by genetic loss of the complement regulatory protein CD55, leading to overactivation of complement and innate immunity together with immunodeficiency due to immunoglobulin wasting in the intestine. We report in vivo human data accumulated using the complement C5 inhibitor eculizumab for the medical treatment of patients with CHAPLE disease. We observed cessation of gastrointestinal pathology together with restoration of normal immunity and metabolism. We found that patients rapidly renormalized immunoglobulin concentrations and other serum proteins as revealed by aptamer profiling, re-established a healthy gut microbiome, discontinued immunoglobulin replacement and other treatments and exhibited catch-up growth. Thus, we show that blockade of C5 by eculizumab effectively re-establishes regulation of the innate immune complement system to substantially reduce the pathophysiological manifestations of CD55 deficiency in humans. CHAPLE disease is a lethal syndrome caused by genetic loss of the complement regulatory protein CD55. Lenardo, Ozen and their colleagues report that blockade of C5 complement activation in a small cohort of pediatric patients with CHAPLE disease reduced gastrointestinal pathology and restored their immunity and growth.

Polyethylenimine (PEI) is a gold standard polycationic transfectant. However, the highly efficient transfecting activity of PEI and many of its derivatives is accompanied by serious cytotoxic complications and safety concerns at innate immune levels, which impedes the development of therapeutic polycationic nucleic acid carriers in general and their clinical applications. In recent years, the dilemma between transfection efficacy and adverse PEI activities has been addressed from in-depth investigations of cellular processes during transfection and elucidation of molecular mechanisms of PEI-mediated toxicity and translation of these integrated events to chemical engineering of novel PEI derivatives with an improved benefit-to-risk ratio. This review addresses these perspectives and discusses molecular events pertaining to dynamic and multifaceted PEI-mediated cytotoxicity, including membrane destabilization, mitochondrial dysfunction, and perturbations of glycolytic flux and redox homeostasis as well as chemical strategies for the generation of better tolerated polycations. We further examine the effect of PEI and its derivatives on complement activation and interaction with Toll-like receptors. These perspectives are intended to lay the foundation for an improved understanding of interlinked mechanisms controlling transfection and toxicity and their translation for improved engineering of polycation-based transfectants. [Display omitted] Polycations such as polyethylenimines (PEIs) are widely used as non-viral transfectants, but they often induce cytotoxicity and may trigger immune reactions. Here we examine and discuss molecular events pertaining to dynamic and multifaceted PEI-mediated cytotoxicity and immune system modulation and their translation for improved and safer engineering of polycation-based transfectants.