• Complement system
• IRI
• Immunological response

• Kidney Transplantation
• Humans
• Reperfusion Injury
• Graft Rejection/immunology
• Graft Rejection/prevention & control
• Complement System Proteins
• Animals
• Complement Activation

• FSGS
• complement
• gene expression
• progression
• tubulointerstitial fibrosis

• Animals
• Fibrosis
• Complement C3/metabolism
• Complement C3/genetics
• Mice
• Humans
• Disease Progression
• Epithelial-Mesenchymal Transition
• Male
• Mice, Inbred C57BL
• Epithelial Cells/metabolism
• Epithelial Cells/pathology
• Ureteral Obstruction/metabolism
• Ureteral Obstruction/pathology
• Ureteral Obstruction/genetics
• Kidney/pathology
• Kidney/metabolism
• Mice, Inbred BALB C
• Disease Models, Animal
• Mice, Inbred CBA
• Early Growth Response Protein 1/metabolism
• Early Growth Response Protein 1/genetics
• Kidney Diseases/metabolism
• Kidney Diseases/pathology
• Kidney Diseases/etiology
• Kidney Diseases/genetics
• Female

• Bolyai Scholarship BO/00304/20/5 Hungarian Academy of Sciences
• ÚNKP-22-5-SE-202206201434KG Hungarian Ministry of Innovation and Technology
• KP2024 Hungarian Society of Hypertension
• KFP2024 Hungarian Kidney Foundation

• alternative pathway
• classical pathway
• complement inhibitors
• hematophagy
• intestine
• salivary gland

• Animals
• Arthropods/physiology
• Arthropods/immunology
• Complement System Proteins/immunology
• Feeding Behavior
• Vertebrates/immunology
• Vertebrates/physiology
• Complement Activation
• Saliva/chemistry
• Saliva/immunology

• Fundação de Amparo à Pesquisa do Estado de Minas Gerais
• Conselho Nacional de Desenvolvimento Científico e Tecnológico
• Instituo Nacional de Ciência e Tecnologia em Entomologia Molecular

• Complement system
• Diabetic retinopathy
• Pathogenesis

• Humans
• Diabetic Retinopathy/immunology
• Complement System Proteins/metabolism
• Complement Activation/physiology

• Anemia
• Proteomics
• Total tannins of gei herba

• C3d
• complement
• factor H
• glomerular disease
• skin disease
• tissue-targeted

• Humans
• Mice
• Rats
• Animals
• Complement Factor H/genetics
• Complement C3d/metabolism
• Kidney Diseases/etiology
• Antibodies
• Complement Activation

• Syfovre
• age-related macular degeneration
• geographic atrophy
• intraocular inflammation
• occlusive
• pegcetacoplan
• retinal vasculitis
• vasculitis

• MASP-2
• complement
• lectin pathway
• narsoplimab
• pharmacodynamics
• pharmacokinetics

• Animals
• Humans
• Mannose-Binding Protein-Associated Serine Proteases/metabolism
• Lectins/metabolism
• Macaca fascicularis
• Serine Endopeptidases/metabolism

• Omeros Corporation

• CD55
• MAP-2
• complement inhibition
• complement regulation
• lectin pathway

• Animals
• Sheep
• Complement Activation
• Complement System Proteins
• CD55 Antigens/pharmacology
• Lectins/metabolism
• Transcription Factors
• Complement Inactivating Agents
• Mannose-Binding Protein-Associated Serine Proteases/metabolism

• autoimmune
• complement
• intracellular
• noncanonical

• Complement System Proteins
• Complement Activation

• R01 DK111222 NIDDK NIH HHS

• High-grade serous ovarian cancer
• immunotherapy
• prognosis
• tumor microenvironment
• tumor-associated macrophages

• Humans
• Female
• B7-H1 Antigen
• Immune Checkpoint Inhibitors/pharmacology
• Immune Checkpoint Inhibitors/therapeutic use
• Tumor Microenvironment
• Prognosis
• Ovarian Neoplasms/drug therapy

• Alzheimer's
• CR1
• complement
• microglia

• Humans
• Alzheimer Disease/pathology
• Brain/metabolism
• Genome-Wide Association Study
• Microglia/metabolism

• MC_EX_MR/N50192X/1 Medical Research Council
• Alzheimer's Society
• UK Dementia Research Institute
• UK Medical Research Council

• Complement pathway
• complement component 5
• drug discovery
• neurodegenerative disease
• neuroinflammation

• C4BP, C4 binding protein
• Cardiac fibrosis. 1
• Complement C3
• DTBT, door-to-balloon time
• FB, Factor B
• FH, Factor F
• FI, Factor I
• IR, ischemia/reperfusion
• IRI, ischemia/reperfusion injury
• Ischemia/reperfusion injury (IRI)
• MBL, mannose binding lectin
• Necrosis
• TCC, terminal complement complex

• complement
• inflammation
• transplantation

• ASP
• Arrhythmogenic right ventricular cardiomyopathy
• Biomarker
• Heart failure
• Risk prediction

• Adult
• Antibodies, Monoclonal, Humanized
• Complement Inactivating Agents
• Fatigue
• Female
• Follow-Up Studies
• Hemoglobinuria, Paroxysmal/drug therapy
• Hemolysis
• Humans
• Immunologic Factors
• Male
• Peptides, Cyclic
• Quality of Life
• Treatment Outcome

• complement
• systemic lupus erythematosus
• lupus nephritis
• classical pathway
• lectin pathway
• alternative pathway

Traumatic brain injury, stroke, and neurodegenerative diseases represent a major cause of morbidity and mortality in Africa, as in the rest of the world. Traumatic brain and spinal cord injuries specifically represent a leading cause of disability in the younger population. Stroke and neurodegenerative disorders predominantly target the elderly and are a major concern in Africa, since their rate of increase among the ageing is the fastest in the world. Neuroimmunology is usually not associated with non-communicable neurological disorders, as the role of neuroinflammation is not often considered when evaluating their cause and pathogenesis. However, substantial evidence indicates that neuroinflammation is extremely relevant in determining the consequences of non-communicable neurological disorders, both for its protective abilities as well as for its destructive capacity. We review here current knowledge on the contribution of neuroinflammation and neuroimmunology to the pathogenesis of traumatic injuries, stroke and neurodegenerative diseases, with a particular focus on problems that are already a major issue in Africa, like traumatic brain injury, and on emerging disorders such as dementias.

• Aged
• Brain Injuries, Traumatic
• Humans
• Morbidity
• Neurodegenerative Diseases
• Neuroinflammatory Diseases
• Stroke

Inherited retinal dystrophies (IRDs) are a large group of genetically and clinically heterogeneous diseases characterized by the progressive degeneration of the retina, ultimately leading to loss of visual function. Oxidative stress and inflammation play fundamental roles in the physiopathology of these diseases. Photoreceptor cell death induces an inflammatory state in the retina. The activation of several molecular pathways triggers different cellular responses to injury, including the activation of microglia to eliminate debris and recruit inflammatory cells from circulation. Therapeutical options for IRDs are currently limited, although a small number of patients have been successfully treated by gene therapy. Many other therapeutic strategies are being pursued to mitigate the deleterious effects of IRDs associated with oxidative metabolism and/or inflammation, including inhibiting reactive oxygen species’ accumulation and inflammatory responses, and blocking autophagy. Several compounds are being tested in clinical trials, generating great expectations for their implementation. The present review discusses the main death mechanisms that occur in IRDs and the latest therapies that are under investigation.

• C5aR
• IL-6
• OmpH
• TNF-α

To determine whether complement component 3 (C3) deficiency affects its receptor downstream-mediated inflammatory response, the current study was undertaken to measure alterations in the inducible nitric oxide synthase (iNOS)‑mediated cyclooxygenase‑2 (COX‑2) induction pathway, inflammasome pathway, nuclear factor-κB (NF-κB) activation, and inflammatory cytokine expressions in the mid colon of C3 knockout (KO) mice. Significant enhancement was observed in expressions of key components of the iNOS‑mediated COX‑2 induction pathway, and in the phosphorylation of mitogen‑activated protein (MAP) kinase members. A similar pattern of increase was also observed in the expression levels of inflammasome proteins in C3 KO mice. Moreover, compared to WT mice, C3 KO mice showed remarkably enhanced phosphorylation of NF-κB and Inhibitor of κB-α (IκB-α), which was reflected in entirety as increased expressions of Tumor necrosis factor (TNF), IL-6 and IL-1α. However, the levels of E-cadherin, tight junction channels and ion channels expressions were lower in the C3 KO mice, although myeloperoxidase (MPO) activity for neutrophils was slightly increased. Taken together, results of the current study indicate that C3 deficiency promotes inflammatory responses in the mid colon of C3 KO mice through activation of the iNOS‑mediated COX‑2 induction pathway, Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC)-inflammasome pathway and NF-κB signaling pathway, and the enhancement of inflammatory cytokine expressions.

• Alternative pathway
• C3
• Complement
• Convertase
• Inhibitor
• Structural biology

Elevated circulating levels of complement component 3 (C3) and C-reactive protein (CRP) have been linked with adverse pregnancy outcomes. Lifestyle interventions may hold potential to ameliorate these effects. We investigated the effect of an antenatal healthy lifestyle intervention on maternal C3 and CRP concentrations and assessed their relationship with maternal and fetal metabolic markers and outcomes.

Secondary analysis of data from the Pregnancy Exercise And Nutrition Research Study (PEARS) randomized controlled trial.

Women (n = 406) with C3 and CRP concentrations determined in early pregnancy (14–16 weeks) and/or late pregnancy (28-weeks) with corresponding fasting glucose, insulin, c-peptide, and lipid profiles were included in the analysis. Pregnancy outcomes included: diagnoses of gestational diabetes (GDM), pre-eclampsia (PET) or pregnancy induced hypertension (PIH), pre-term birth (delivery < 37 weeks), low birth weight (<2500 g), small-for-gestational age (SGA) defined using < 5th or 10th centile for birthweight and cord blood measures of glucose and lipid metabolism. T-tests investigated changes in C3 and CRP over time. Chi-square, Pearson’s’ correlations and multiple regression investigated relationships with outcomes.

The PEARS intervention did not influence maternal C3 or CRP concentrations in pregnancy. There was no relationship between CRP concentrations and any maternal or infant outcome. Women who developed GDM had higher C3 concentrations in early (p = 0.01) and late pregnancy (p = 0.02). Women who developed PIH/PET had lower C3 concentrations in early (p = 0.02), but not late (p = 0.10) pregnancy. Maternal C3 concentrations in early pregnancy were a small but significant predictor of maternal insulin concentrations in early (β = 0.40, 95% CI 0.27, 0.53; p < 0.001) and late (β = 0.30, 95% CI 0.17, 0.43p < 0.001) pregnancy, early total cholesterol (TC), and both early and late triglycerides, LDL and HDL Cholesterol concentrations (all p < 0.001). Women who delivered SGA babies (<10th centile) had lower C3 concentrations than women who did not in both early (p < 0.001) and late pregnancy (p = 0.01). No relationship between maternal C3 or CRP and fetal glucose concentrations or lipid profiles was observed.

Maternal C3 may play a role in multiple adverse pregnancy outcomes including cardiometabolic ill-health. Further research on this, and strategies to reduce C3 in a pregnant population, are warranted.

• C-reactive protein
• Complement component 3
• Lifestyle intervention
• Obese
• Overweight
• Pregnancy

Complement is one of the most ancient defense systems. It gets strongly activated immediately after acute injuries like trauma, burn, or sepsis and helps to initiate regeneration. However, uncontrolled complement activation contributes to disease progression instead of supporting healing. Such effects are perceptible not only at the site of injury but also systemically, leading to systemic activation of other intravascular cascade systems eventually causing dysfunction of several vital organs. Understanding the complement pathomechanism and its interplay with other systems is a strict requirement for exploring novel therapeutic intervention routes. Ex vivo models exploring the cross-talk with other systems are rather limited, which complicates the determination of the exact pathophysiological roles that complement has in trauma, burn, and sepsis. Literature reporting on these three conditions is often controversial regarding the importance, distribution, and temporal occurrence of complement activation products further hampering the deduction of defined pathophysiological pathways driven by complement. Nevertheless, many in vitro experiments and animal models have shown beneficial effects of complement inhibition at different levels of the cascade. In the future, not only inhibition but also a complement reconstitution therapy should be considered in prospective studies to expedite how meaningful complement-targeted interventions need to be tailored to prevent complement augmented multi-organ failure after trauma, burn, and sepsis.

This review summarizes clinically relevant studies investigating the role of complement in the acute diseases trauma, burn, and sepsis with important implications for clinical translation.

• Burn
• Clinical translation
• Complement activation
• Sepsis
• Systemic inflammation
• Thromboinflammation
• Trauma

• Alternative pathway
• C3b deposition
• Complement
• FBfr
• Factor B

Complement activation is a central mechanism in systemic inflammation and remote organ dysfunction following major trauma. Data on temporal changes of complement activation early after injury is largely missing. We aimed to describe in detail the kinetics of complement activation in individual trauma patients from admission to 10 days after injury, and the association with trauma characteristics and outcome.

In a prospective cohort of 136 trauma patients, plasma samples obtained with high time resolution (admission, 2, 4, 6, 8 h, and thereafter daily) were assessed for terminal complement complex (TCC). We studied individual TCC concentration curves and calculated a summary measure to obtain the accumulated TCC response 3 to 6 h after injury (TCC-AUC_3–6). Correlation analyses and multivariable linear regression analyses were used to explore associations between individual patients’ admission TCC, TCC-AUC_3–6, daily TCC during the intensive care unit stay, trauma characteristics, and predefined outcome measures.

TCC concentration curves showed great variability in temporal shapes between individuals. However, the highest values were generally seen within the first 6 h after injury, before they subsided and remained elevated throughout the intensive care unit stay. Both admission TCC and TCC-AUC_3–6 correlated positively with New Injury Severity Score (Spearman’s rho, p-value 0.31, 0.0003 and 0.21, 0.02) and negatively with admission Base Excess (− 0.21, 0.02 and − 0.30, 0.001). Multivariable analyses confirmed that deranged physiology was an important predictor of complement activation. For patients without major head injury, admission TCC and TCC-AUC_3–6 were negatively associated with ventilator-free days. TCC-AUC_3–6 outperformed admission TCC as a predictor of Sequential Organ Failure Assessment score at day 0 and 4.

Complement activation 3 to 6 h after injury was a better predictor of prolonged mechanical ventilation and multiple organ dysfunction syndrome than admission TCC. Our data suggest that the greatest surge of complement activation is found within the first 6 h after injury, and we argue that this time period should be in focus in the design of future experimental studies and clinical trials using complement inhibitors.

The online version contains supplementary material available at 10.1186/s10020-021-00286-3.

• Complement activation
• Complement membrane attack complex
• Humans
• Mortality
• Multiple organ failure
• Systemic inflammatory response syndrome
• Wounds and injuries

• Adult
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal, Humanized/adverse effects
• Antibodies, Monoclonal, Humanized/therapeutic use
• Complement C3/antagonists & inhibitors
• Complement C5/antagonists & inhibitors
• Complement Inactivating Agents/adverse effects
• Complement Inactivating Agents/therapeutic use
• Diarrhea/chemically induced
• Drug Therapy, Combination
• Erythrocyte Transfusion
• Hemoglobins/analysis
• Hemoglobinuria, Paroxysmal/blood
• Hemoglobinuria, Paroxysmal/drug therapy
• Hemoglobinuria, Paroxysmal/therapy
• Humans
• Injections, Subcutaneous/adverse effects
• Middle Aged
• Peptides/adverse effects
• Peptides/therapeutic use
• Peptides, Cyclic

The WHO recently endorsed an ambitious plan, “Defeating Meningitis by 2030”, that aims to control/eradicate invasive bacterial infection epidemics by 2030. Vaccination is one of the pillars of this road map, with the goal to reduce the number of cases and deaths due to Neisseria meningitidis, Streptococcus pneumoniae, Haemophilus influenzae and Streptococcus agalactiae. The risk of developing invasive bacterial infections (IBI) due to these bacterial species includes genetic and acquired factors that favor repeated and/or severe invasive infections. We searched the PubMed database to identify host risk factors that increase the susceptibility to these bacterial species. Here, we describe a number of inherited and acquired risk factors associated with increased susceptibility to invasive bacterial infections. The burden of these factors is expected to increase due to the anticipated decrease in cases in the general population upon the implementation of vaccination strategies. Therefore, detection and exploration of these patients are important as vaccination may differ among subjects with these risk factors and specific strategies for vaccination are required. The aim of this narrative review is to provide information about these factors as well as their impact on vaccination against the four bacterial species. Awareness of risk factors for IBI may facilitate early recognition and treatment of the disease. Preventive measures including vaccination, when available, in individuals with increased risk for IBI may prevent and reduce the number of cases.

• Haemophilus influenzae
• Neisseria meningitidis
• Streptococcus agalactiae
• Streptococcus pneumoniae
• complement
• genetic factors
• group B streptococci
• invasive bacterial infections
• susceptibility

The complement system is part of the innate immune response, where it provides immediate protection from infectious agents and plays a fundamental role in homeostasis. Complement dysregulation occurs in several diseases, where the tightly regulated proteolytic cascade turns offensive. Prominent examples are atypical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria and Alzheimer’s disease. Therapeutic intervention targeting complement activation may allow treatment of such debilitating diseases. In this review, we describe a panel of complement targeting nanobodies that allow modulation at different steps of the proteolytic cascade, from the activation of the C1 complex in the classical pathway to formation of the C5 convertase in the terminal pathway. Thorough structural and functional characterization has provided a deep mechanistic understanding of the mode of inhibition for each of the nanobodies. These complement specific nanobodies are novel powerful probes for basic research and offer new opportunities for in vivo complement modulation.

• complement system
• convertase
• inhibitor
• molecular mechanism
• proteolytic cascade
• structural biology

• Animals
• Antibodies, Monoclonal, Humanized/therapeutic use
• Atypical Hemolytic Uremic Syndrome/drug therapy
• Atypical Hemolytic Uremic Syndrome/immunology
• Complement Activation
• Complement C1/chemistry
• Complement C3-C5 Convertases/chemistry
• Complement System Proteins
• Epitopes/chemistry
• Hemoglobinuria, Paroxysmal/drug therapy
• Hemoglobinuria, Paroxysmal/immunology
• Humans
• Immunity, Innate
• Immunoglobulin G/immunology
• Inflammation
• Molecular Conformation
• Nanomedicine/methods
• Protein Binding
• Proteolysis
• Single-Domain Antibodies/chemistry

• pre-eclampsia
• proteomics
• protein-protein interaction networks
• molecular medicine

• Adult
• Biomarkers/blood
• Blood Coagulation/genetics
• Chromatography, Liquid
• Complement System Proteins/genetics
• Complement System Proteins/metabolism
• Endothelial Cells/metabolism
• Endothelial Cells/pathology
• Female
• Gestational Age
• Humans
• Pre-Eclampsia/blood
• Pre-Eclampsia/pathology
• Pregnancy
• Proteomics
• Tandem Mass Spectrometry

• Erasmus Programme
• Miguel Servet grant from the Instituto de Salud Carlos III
• Instituto de Salud Carlos III
• “la Caixa” Foundation
• Cerebra Foundation
• AGAUR 2017 SGR

• Anaphylatoxins
• biologic-therapy
• c5a
• complement
• immune checkpoint
• pattern recognition molecules (PRMs)
• sepsis
• t-cell dysfunction

• Adult
• Anemia, Hemolytic/drug therapy
• Anemia, Hemolytic/etiology
• Anemia, Hemolytic/prevention & control
• Antibodies, Monoclonal, Humanized/adverse effects
• Antibodies, Monoclonal, Humanized/therapeutic use
• Bilirubin/blood
• Chemical and Drug Induced Liver Injury/etiology
• Complement C3/antagonists & inhibitors
• Complement C5/antagonists & inhibitors
• Drug Substitution
• Female
• Fever/chemically induced
• Hemoglobins/analysis
• Hemoglobinuria, Paroxysmal/blood
• Hemoglobinuria, Paroxysmal/drug therapy
• Hemoglobinuria, Paroxysmal/immunology
• Hemolysis/drug effects
• Humans
• L-Lactate Dehydrogenase/blood
• Male
• Middle Aged
• Pancreatitis/chemically induced
• Prospective Studies
• Reticulocyte Count

The initiating protease of the complement classical pathway, C1r, represents an upstream and pathway-specific intervention point for complement-related autoimmune and inflammatory diseases. Yet, C1r-targeted therapeutic development is currently underrepresented relative to other complement targets. In this study, we developed a fragment-based drug discovery approach using surface plasmon resonance (SPR) and molecular modeling to identify and characterize novel C1r-binding small-molecule fragments. SPR was used to screen a 2000-compound fragment library for binding to human C1r. This led to the identification of 24 compounds that bound C1r with equilibrium dissociation constants ranging between 160–1700 µM. Two fragments, termed CMP-1611 and CMP-1696, directly inhibited classical pathway-specific complement activation in a dose-dependent manner. CMP-1611 was selective for classical pathway inhibition, while CMP-1696 also blocked the lectin pathway but not the alternative pathway. Direct binding experiments mapped the CMP-1696 binding site to the serine protease domain of C1r and molecular docking and molecular dynamics studies, combined with C1r autoactivation assays, suggest that CMP-1696 binds within the C1r active site. The group of structurally distinct fragments identified here, along with the structure–activity relationship profiling of two lead fragments, form the basis for future development of novel high-affinity C1r-binding, classical pathway-specific, small-molecule complement inhibitors.

• complement inhibitors
• fragment-based drug discovery
• surface plasmon resonance

• Aneurysm
• aortic aneurysm
• dissecting
• inflammation mediators
• interleukin-6
• pharmacogenetics

• effusion
• hypoxia
• inflammation
• otitis media
• transcript

To investigate the role of complement C3 (C3) convertase on the strain difference for C3 protein expression in three inbred mice strains, we compared the levels of C2, C3 and C4 mRNA, as well as C3 protein and C3 convertase activity in the serum and liver tissue of FVB/N, C3H/HeN and C57BL/6N mice. The level of mRNA, inactive form (InACF) and active form (ACF) for C3 showed a regular pattern, which they were higher in the FVB/N and C57BL/6N mice than C3H/HeN mice. However, the level of C3b fragments (C3bα and β) derived from C3 protein were constantly maintained in the liver of FVB/N, C3H/HeN and C57BL/6N mice in spite of the strain difference on the transcriptional and translation level of C3. Especially, a reverse pattern of the level of mRNA, InACF and ACF for C3 was observed on the activity level of C3 convertase activity. The highest level of C3 convertase activity was measured in C3H/HeN mice, followed by C57BL/6N and FVB/N mice. In case of C3 convertase components, the level of C2 mRNA was higher in C3H/HeN mice than FVB/N and C57BL/6 N mice, while levels of C4 mRNA were higher in FVB/N and C57BL/6N mice than C3H/HeN mice. The current study results provide the first scientific evidence that C3 convertase may play complementary role to overcome the strain difference on the C3 protein expression in FVB/N, C3H/HeN and C57BL/6N mice.

• C3H/HeN
• C57BL/6N
• Complement C3
• Convertase activity
• FVB/N