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.

Conflict of interest: JDL is the founder of Amyndas Pharmaceuticals, which develops complement inhibitors for therapeutic purposes; he has a broad portfolio of patents describing the use of complement inhibitors for therapeutic purposes (www.lambris.com/ patents), some of which are developed by Amyndas (US patents 8946145/9371365, 9630992) and Apellis (US patents 6319897, 7989589, 7888323). JDL is also the inventor of the compstatin technology licensed to Apellis Pharmaceuticals (i.e., 4(1MeW)7W/ POT-4/APL-1 and PEGylated derivatives such as pegcetacoplan and APL-9).

Neutrophils and complement are key sentinels of innate immunity and mediators of acute inflammation. Recent studies have suggested that inflammatory processes modulate thrombogenic pathways. To date, the potential cross-talk between innate immunity and thrombosis and the precise molecular pathway by which complement and neutrophils trigger the coagulation process have remained elusive. In this study, we demonstrate that antiphospholipid Ab-induced complement activation and downstream signaling via C5a receptors in neutrophils leads to the induction of tissue factor (TF), a key initiating component of the blood coagulation cascade. TF expression by neutrophils was associated with an enhanced procoagulant activity, as verified by a modified prothrombin time assay inhibited by anti-TF mAb. Inhibition studies using the complement inhibitor compstatin revealed that complement activation is triggered by antiphospholipid syndrome (APS) IgG and leads to the induction of a TF-dependent coagulant activity. Blockade studies using a selective C5a receptor antagonist and stimulation of neutrophils with recombinant human C5a demonstrated that C5a, and its receptor C5aR, mediate the expression of TF in neutrophils and thereby significantly enhance the procoagulant activity of neutrophils exposed to APS serum. These results identify a novel cross-talk between the complement and coagulation cascades that can potentially be exploited therapeutically in the treatment of APS and other complement-associated thrombotic diseases.

Complement has been implicated in liver repair after toxic injury. Here, we demonstrate that complement components are essential for liver regeneration, and mediate their effect by interacting with key signaling networks that promote hepatocyte proliferation. C3- or C5-deficient mice exhibited high mortality, parenchymal damage, and impaired liver regeneration after partial hepatectomy. Mice with dual C3 and C5 deficiency had a more exacerbated phenotype that was reversed by combined C3a and C5a reconstitution. Interception of C5a receptor signaling resulted in suppression of IL-6/TNFα induction and lack of C3 and C5a receptor stimulation attenuated nuclear factor–κB/STAT-3 activation after hepatectomy. These data indicate that C3a and C5a, two potent inflammatory mediators of the innate immune response, contribute essentially to the early priming stages of hepatocyte regeneration.

The increasing number of clinical conditions that involve a pathological contribution from the complement system — many of which affect the kidneys — has spurred a regained interest in therapeutic options to modulate this host defence pathway. Molecular insight, technological advances, and the first decade of clinical experience with the complement-specific drug eculizumab, have contributed to a growing confidence in therapeutic complement inhibition. More than 20 candidate drugs that target various stages of the complement cascade are currently being evaluated in clinical trials, and additional agents are in preclinical development. Such diversity is clearly needed in view of the complex and distinct involvement of complement in a wide range of clinical conditions, including rare kidney disorders, transplant rejection and haemodialysis-induced inflammation. The existing drugs cannot be applied to all complement-driven diseases, and each indication has to be assessed individually. Alongside considerations concerning optimal points of intervention and economic factors, patient stratification will become essential to identify the best complement-specific therapy for each individual patient. This Review provides an overview of the therapeutic concepts, targets and candidate drugs, summarizes insights from clinical trials, and reflects on existing challenges for the development of complement therapeutics for kidney diseases and beyond.

Progress in the beginning of the 21st century transformed our perception of complement from a blood-based antimicrobial system to a global regulator of immunity and tissue homeostasis. More recent years have witnessed remarkable advances regarding structure-function insights, mechanisms and locations of complement activation, thereby adding new layers of complexity in the biology of complement. This complexity is readily reflected by the multifaceted and contextual involvement of complement-driven networks in a wide range of inflammatory and neurodegenerative disorders and cancer. This Review provides an updated view of new and previously unanticipated functions of complement and how these impact immunity and disease pathogenesis.

Emerging data indicate that complement and neutrophils are involved in the maladaptive host immune response that fuels hyper-inflammation and thrombotic microangiopathy increasing the mortality rate in coronavirus disease 2019 (COVID-19). Here, we investigated the interaction between complement and the platelet/neutrophil extracellular traps (NETs)/thrombin axis, using COVID-19 clinical samples, cell-based inhibition studies and NETs/human aortic endothelial cell (HAEC) co-cultures. Increased plasma levels of NETs, TF activity and sC5b-9 were detected in patients. Neutrophils yielded high tissue factor (TF) expression and released NETs carrying functionally active TF. Confirming our ex vivo findings, treatment of control neutrophils with COVID-19 platelet-rich plasma generated TF-bearing NETs that induced thrombotic activity of HAEC. Thrombin or NETosis inhibition or C5aR1 blockade attenuated platelet-mediated NET-driven thrombogenicity. Serum isolated from COVID-19 patients induces complement activation in vitro, which is consistent with high complement activity in clinical samples. Complement inhibition at the level of C3 with compstatin Cp40 disrupted TF expression in neutrophils. In conclusion, we provide a mechanistic basis that reveals the pivotal role of complement and NETs in COVID-19 immmunothrombosis. This study supports emerging strategies against SARS-CoV-2 infection that exploit complement therapeutics or NETosis inhibition.

In tumour immunology, complement has traditionally been considered as an adjunctive component that enhances the cytolytic effects of antibody-based immunotherapies, such as rituximab. Remarkably, research in the past decade has uncovered novel molecular mechanisms linking imbalanced complement activation in the tumour microenvironment with inflammation and suppression of antitumour immune responses. These findings have prompted new interest in manipulating the complement system for cancer therapy. This Review summarizes our current understanding of complement-mediated effector functions in the tumour microenvironment, focusing on how complement activation can act as a negative or positive regulator of tumorigenesis. It also offers insight into clinical aspects, including the feasibility of using complement biomarkers for cancer diagnosis and the use of complement inhibitors during cancer treatment.