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Complement C1q is the activator of the classical pathway. However, it is now recognized that C1q can exert functions unrelated to complement activation. Here we show that C1q, but not C4, is expressed in the stroma and vascular endothelium of several human malignant tumours. Compared with wild-type (WT) or C3- or C5-deficient mice, C1q-deficient ( C1qa −/− ) mice bearing a syngeneic B16 melanoma exhibit a slower tumour growth and prolonged survival. This effect is not attributable to differences in the tumour-infiltrating immune cells. Tumours developing in WT mice display early deposition of C1q, higher vascular density and an increase in the number of lung metastases compared with C1qa −/− mice. Bone marrow (BM) chimeras between C1qa −/− and WT mice identify non-BM-derived cells as the main local source of C1q that can promote cancer cell adhesion, migration and proliferation. Together these findings support a role for locally synthesized C1q in promoting tumour growth. C1q is known to initiate the activation of the complement classical pathway. Here, the authors show the C1q is expressed in the tumour microenvironment and can promote cancer cell migration and adhesion in a complement activation-independent manner.

Patients with paroxysmal nocturnal hemoglobinuria who had a poor response to eculizumab therapy were found to have a genetic polymorphism in C5 that prevents binding by the antibody. Paroxysmal nocturnal hemoglobinuria (PNH) arises as a consequence of clonal expansion of hematopoietic stem cells that have acquired a somatic mutation in the gene encoding phosphatidylinositol glycan anchor biosynthesis class A ( PIGA ). 1 – 3 The resulting hematopoietic cells are deficient in glycosylphosphatidylinositol-anchored proteins, including the complement regulatory proteins CD55 and CD59; this accounts for the intravascular hemolysis that is the primary clinical manifestation of PNH. 4 – 6 PNH frequently develops in association with disorders involving bone marrow failure, particularly aplastic anemia. Thrombosis is a major cause of PNH-associated morbidity and mortality, particularly among white patients. 7 – 9 Eculizumab (Soliris, Alexion Pharmaceuticals) . . .

Complement activation is a relevant driver in the pathomechanisms of vasculitis. The involved proteins in the interaction between endothelia, complement, and platelets in these conditions are only partially understood. Thrombospondin-1 (TSP-1), found in platelet α-granules and released from activated endothelial cells, interacts with factor H (FH) and vWF. However, to our knowledge, direct regulatory interaction with the complement cascade has not yet been described. Our study shows that TSP-1 is a potent, FH-independent inhibitor of the alternative complement pathway. TSP-1 binds to complement proteins and inhibits cleavage of C3 and C5 and the formation of the membrane attack complex. We validated complement-regulatory function in blood samples from patients with primary complement defects. The physiological relevance of TSP-1 was demonstrated in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV) by significantly enhanced TSP-1 staining in glomerular lesions and increased complement activity and NETosis after TSP-1 deficiency in an in vitro and in vivo model of AAV. The complement-inhibiting function of TSP-1 represents an important mechanism in the interaction of endothelia and complement. In particular, the interplay between released TSP-1 and the complement system locally, especially on surfaces, influences the balance between complement activation and inhibition and may be relevant in various vascular diseases.

Osteoarthritis, the breakdown of cartilage in synovial joints, has long been viewed as the result of 'wear and tear', but this report shows that dysregulation of the complement system has an active role in the pathogenesis of this disease. Osteoarthritis, characterized by the breakdown of articular cartilage in synovial joints, has long been viewed as the result of 'wear and tear' 1 . Although low-grade inflammation is detected in osteoarthritis, its role is unclear 2 , 3 , 4 . Here we identify a central role for the inflammatory complement system in the pathogenesis of osteoarthritis. Through proteomic and transcriptomic analyses of synovial fluids and membranes from individuals with osteoarthritis, we find that expression and activation of complement is abnormally high in human osteoarthritic joints. Using mice genetically deficient in complement component 5 (C5), C6 or the complement regulatory protein CD59a, we show that complement, specifically, the membrane attack complex (MAC)-mediated arm of complement, is crucial to the development of arthritis in three different mouse models of osteoarthritis. Pharmacological modulation of complement in wild-type mice confirmed the results obtained with genetically deficient mice. Expression of inflammatory and degradative molecules was lower in chondrocytes from destabilized joints from C5-deficient mice than C5-sufficient mice, and MAC induced production of these molecules in cultured chondrocytes. Further, MAC colocalized with matrix metalloprotease 13 (MMP13) and with activated extracellular signal-regulated kinase (ERK) around chondrocytes in human osteoarthritic cartilage. Our findings indicate that dysregulation of complement in synovial joints has a key role in the pathogenesis of osteoarthritis.

Atypical hemolytic uremic syndrome (aHUS) is frequently associated in humans with loss-of-function mutations in complement-regulating proteins or gain-of-function mutations in complement-activating proteins. Thus, aHUS provides an archetypal complement-mediated disease with which to model new therapeutic strategies and treatments. Herein, we show that, when transferred to mice, an aHUS-associated gain-of-function change (D1115N) to the complement-activation protein C3 results in aHUS. Homozygous C3 p.D1115N (C3KI) mice developed spontaneous chronic thrombotic microangiopathy together with hematuria, thrombocytopenia, elevated creatinine, and evidence of hemolysis. Mice with active disease had reduced plasma C3 with C3 fragment and C9 deposition within the kidney. Therapeutic blockade or genetic deletion of C5, a protein downstream of C3 in the complement cascade, protected homozygous C3KI mice from thrombotic microangiopathy and aHUS. Thus, our data provide in vivo modeling evidence that gain-of-function changes in complement C3 drive aHUS. They also show that long-term C5 deficiency is not accompanied by development of other renal complications (such as C3 glomerulopathy) despite sustained dysregulation of C3. Our results suggest that this preclinical model will allow testing of novel complement inhibitors with the aim of developing precisely targeted therapeutics that could have application in many complement-mediated diseases.

Respiratory failure can be a severe complication after polytrauma. Extensive systemic inflammation due to surgical interventions, as well as exacerbated post-traumatic immune responses influence the occurrence and progression of respiratory failure. This study investigated the effect of different surgical treatment modalities as well as combined inhibition of the complement component C5 and the toll-like receptor molecule CD14 (C5/CD14 inhibition) on the pulmonary microRNA (miRNA) signature after polytrauma, using a translational porcine polytrauma model. After induction of general anesthesia, animals were subjected to polytrauma, consisting of blunt chest trauma, bilateral femur fractures, hemorrhagic shock, and liver laceration. One sham group (n=6) and three treatment groups were defined; Early Total Care (ETC, n=8), Damage Control Orthopedics (DCO, n=8), and ETC + C5/CD14 inhibition (n=4). Animals were medically and operatively stabilized, and treated in an ICU setting for 72 h. Lung tissue was sampled, miRNAs were isolated, transcribed, and pooled for qPCR array analyses, followed by validation in the individual animal population. Lastly, mRNA target prediction was performed followed by functional enrichment analyses. The miRNA arrays identified six significantly deregulated miRNAs in lung tissue. In the DCO group, miR-129, miR-192, miR-194, miR-382, and miR-503 were significantly upregulated compared to the ETC group. The miRNA expression profiles in the ETC + C5/CD14 inhibition group approximated those of the DCO group. Bioinformatic analysis revealed mRNA targets and signaling pathways related to alveolar edema, pulmonary fibrosis, inflammation response, and leukocytes recruitment. Collectively, the DCO group, as well as the ETC + C5/CD14 inhibition group, revealed more anti-inflammatory and regenerative miRNA expression profiles. This study showed that reduced surgical invasiveness and combining ETC with C5/CD14 inhibition can contribute to the reduction of pulmonary complications.

Patients with C5 mutations are more susceptibility to Gram-negative bacterial infections, particularly species. To describe the phenotype and clinical features of a family carrying two C5 gene variants, including one novel mutation, and to assess their functional and genetic significance. We analyzed the clinical and genetic characteristics of a family with two compounds heterozygous C5 variants. Clinical features were assessed across affected and unaffected family members, and results were correlated with genetic and functional assays. Genetic testing revealed compound heterozygous variants in the C5 gene: c.713T>C (p.Ile238Thr) and c.1949G>T (p.Gly650Val). The p.Ile238Thr variant, located in exon 7, results in a substitution of isoleucine with threonine. The p.Gly650Val variant, located in exon 15, replaces glycine with valine. Sanger sequencing confirmed the variants were in trans (on separate alleles). The mother carried the same two variants as the patient. Two siblings carried one variant each (Gly650Val and Ile238Thr, respectively), and one sibling was homozygous for the Ile238Thr variant.Clinically, the patient, the mother, and the homozygous sibling had very low serum C5 protein and CH50 levels, correlating with increased susceptibility to infections. Siblings carrying only one variant had normal complement function. analysis and molecular modeling indicate that both amino acid substitutions (Ile238Thr and Gly650Val) may disrupt C5 protein structure. The Ile238Thr change introduces a polar residue in place of a hydrophobic one, disrupting the hydrophobic core and opening a loop between beta-sheets. The Gly650Val change substitutes a small residue with a larger one, causing steric hindrance that necessitates structural rearrangements, including shifts in a loop, alpha-helix, and beta-sheet. We describe a novel C5 variant (Gly650Val) a previously reported variant (Ile238Thr) in unique genotypic combinations (compound heterozygous and homozygous) associated with marked C5 deficiency and increased susceptibility to invasive Neisseria infections. Our findings underscore the importance of combining genetic, functional, and structural data for variant interpretation in complement deficiencies.

A variant on complement factor 3 is associated with age-related macular degeneration, with a population attributable risk of 22%. This finding underlines the importance of complement activation in the pathogenesis of the disease. A variant on complement factor 3 is associated with age-related macular degeneration, with a population attributable risk of 22%. Age-related macular degeneration is the leading cause of visual impairment in the elderly and the most common cause of blindness in Western countries. 1 It affects the macular region of the retina. The macula has a high density of photoreceptors and provides detailed central vision. In the early stages of the disease (referred to as age-related maculopathy), deposits called drusen develop between the retinal pigment epithelium and underlying choroid. 1 Later, the disease is manifested as either extensive atrophy of the retinal pigment epithelium and overlying photoreceptor cells (geographic atrophy) or aberrant choroidal angiogenesis (choroidal neovascularization). 1 Both of these conditions can lead . . .

This letter indicates that in a patient with long-standing dense-deposit disease, a variant of membranoproliferative glomerulonephritis, eculizumab can be useful in the resolution of the nephrotic syndrome. To the Editor: In 1999, an 11-year-old girl with the nephrotic syndrome received a biopsy-confirmed diagnosis of membranoproliferative glomerulonephritis. The level of plasma complement C3 was 7 mg per deciliter (normal range, 90 to 180). Glucocorticoids, administered for 5 years, were ineffective. We first saw the patient at that point. She had nephrotic-range proteinuria (urinary protein excretion, 4.8 g per 24 hours), a low level of C3 (12 mg per deciliter), and normal renal function. We withdrew glucocorticoid therapy and initiated treatment with ramipril plus losartan. She continued to have nephrotic-range proteinuria. Electron microscopy of a second biopsy specimen showed . . .

An excessively activated or dysregulated complement system has been proven to be a vital contributor to the pathogenesis of periodontitis. It has been previously hypothesized that inhibiting the activity of complement component C5 by targeting the C5a receptor is a powerful candidate for treating periodontitis. Here, we apply the drug target instrumental variable (IV) approach to investigate the therapeutic effect of genetically proxied inhibition of C5 on periodontitis. In our primary analysis, we used 26 independent 'cis' single nucleotide polymorphisms as IVs from the vicinity of the encoding locus of C5 that are associated with plasma C5 levels. In a secondary analysis, we assess the validity of our primary findings, exploring the involvement of alternative downstream biomarkers, interleukin 17 (IL-17), interleukin 1β (IL-1β), and tumor necrosis factor (TNF). Summary statistics of plasma levels (C5, IL-17, IL-1β, and TNF) were obtained from a genome-wide association study (GWAS) of 35,559 European descent individuals. We extracted association statistics from a GWAS of 17,353 clinical periodontitis cases and 28,210 European controls. Wald ratios were combined using inverse-variance weighted meta-analysis. In our primary approach, inhibiting C5 reduced the risk of periodontitis (Odds ratio 0.89 per 1 standard deviation reduction in C5; 95% confidence Interval 0.80-0.98, value=0.022). Our secondary analysis suggests an involvement of IL-17 within the potential causal pathway, but was inconclusive for other biomarkers. The findings from our study suggest that C5 inhibition may reduce the risk of periodontitis, prioritizing C5 inhibitors as a potential adjunctive therapeutic intervention in this disease.