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Dense deposit disease and glomerulonephritis with isolated C3 deposits are glomerulopathies characterized by deposits of C3 within or along the glomerular basement membrane. Previous studies found a link between dysregulation of the complement alternative pathway and the pathogenesis of these diseases. We analyzed the role of acquired and genetic complement abnormalities in a cohort of 134 patients, of whom 29 have dense deposit disease, 56 have glomerulonephritis with isolated C3 deposits, and 49 have primary membranoproliferative glomerulonephritis type I, with adult and pediatric onset. A total of 53 patients presented with a low C3 level, and 65 were positive for C3 nephritic factor that was significantly more frequently detected in patients with dense deposit disease than in other histological types. Mutations in CFH and CFI genes were identified in 24 patients associated with a C3 nephritic factor in half the cases. We found evidence for complement alternative pathway dysregulation in 26 patients with membranoproliferative glomerulonephritis type I. The complement factor H Y402H variant was significantly increased in dense deposit disease. We identified one at-risk membrane cofactor protein (MCP) haplotype for glomerulonephritis with isolated C3 deposits and membranoproliferative glomerulonephritis type I. Thus, our results suggest a critical role of fluid-phase alternative pathway dysregulation in the pathogenesis of C3 glomerulopathies as well as in immune complex–mediated glomerular diseases. The localization of the C3 deposits may be under the influence of MCP expression.

Background This research explores complement activation products involvement and risk and protective polymorphisms in the complement alternative pathway genes in Shiga toxin-associated hemolytic uremic syndrome (STEC-HUS) pathogenesis. Methods We analyzed the levels of complement activation products, C3a, C5a and soluble C5b-9 (sC5b-9) and plasma concentrations of Factor H (FH) and FH-related protein 1 (FHR-1) in 44 patients with STEC-HUS, 12 children with STEC-positive diarrhea (STEC-D), and 72 healthy controls (HC). STEC-HUS cases were classified as “severe” or “non-severe”. Genetic analysis was performed for complement genes ( CFH , CFB , MCP , C3 ). Results No significant differences in the frequency of atypical HUS (aHUS) complement risk polymorphisms were found between groups. In severe STEC-HUS, the risk haplotypes CFH -H3 and MCP ggaac were identified in three patients each, all in homozygosity. Patients with STEC-HUS had significantly elevated C3a, C5a and sC5b-9 levels at admission compared to HC and STEC-D, with higher sC5b-9 levels in severe cases. Increased ratio between FHR-1 and FH (FHR-1/FH) was demonstrated in STEC-HUS vs. HC, with significantly higher FHR-1/FH ratio in severe STEC-HUS patients. Principal component analysis revealed significant changes in sC5b-9 direction and magnitude in STEC-HUS. Pearson correlation showed a significant relationship between FH and sC5b-9. Logistic regression indicated sC5b-9, leukocytosis, creatinine, and anuria duration as independent factors for severe STEC- HUS. Conclusions This study highlights the significant activation of the alternative complement pathway in STEC-HUS, particularly sC5b-9 in severe cases, and suggests a limited contribution of complement risk polymorphisms in STEC-HUS. FHR-1 may represent a promising target for future investigations related to STEC-HUS pathogenesis. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information

Membranoproliferative glomerulonephritis (MPGN) is a rare chronic kidney disease associated with complement activation. Recent immunofluorescence-based classification distinguishes between immune complex (IC)-mediated MPGN, with glomerular IgG and C3 deposits, and C3 glomerulopathies (C3G), with predominant C3 deposits. Genetic and autoimmune abnormalities causing hyperactivation of the complement alternative pathway have been found as frequently in patients with immune complex-associated MPGN (IC-MPGN) as in those with C3G. In the last decade, there have been great advances in research into the autoimmune causes of IC-MPGN and C3G. The complement-activating autoantibodies called C3-nephritic factors (C3NeFs), which are present in 40–80% of patients, form a heterogeneous group of autoantibodies that stabilise the C3 convertase or the C5 convertase of the alternative pathway or both. A few patients, mainly with IC-MPGN, carry autoantibodies directed against the two components of the alternative pathway C3 convertase, factors B and C3b. Finally, autoantibodies against factor H, the main regulator of the alternative pathway, have been reported in a small proportion of patients with IC-MPGN or C3G. The identification of distinct pathogenetic patterns leading to kidney injury and of targets in the complement cascade may pave the way for tailored therapies for IC-MPGN and C3G, with specific complement inhibitors in the development pipeline.

C3 glomerulonephritis (C3GN) is a recently described disorder that typically results from abnormalities in the alternative pathway (AP) of complement. Here, we describe the clinical features, kidney biopsy findings, AP abnormalities, glomerular proteomic profile, and follow-up in 12 cases of C3GN. This disorder equally affected all ages, both genders, and typically presented with hematuria and proteinuria. In both the short and long term, renal function remained stable in the majority of patients with native kidney disease. In two patients, C3GN recurred within 1 year of transplantation and resulted in a decline in allograft function. Kidney biopsy mainly showed a membranoproliferative pattern, although both mesangial proliferative and diffuse endocapillary proliferative glomerulonephritis were noted. AP abnormalities were heterogeneous, both acquired and genetic. The most common acquired abnormality was the presence of C3 nephritic factors, while the most common genetic finding was the presence of H402 and V62 alleles of Factor H. In addition to these risk factors, other abnormalities included Factor H autoantibodies and mutations in CFH, CFI, and CFHR genes. Laser dissection and mass spectrometry of glomeruli from patients with C3GN showed accumulation of AP and terminal complement complex proteins. Thus, C3GN results from diverse abnormalities of the alternative complement pathway leading to subsequent glomerular injury.

The hemolytic–uremic syndrome, which is characterized by nonimmune hemolytic anemia, thrombocytopenia, and renal impairment, occurs most frequently in young children. Most cases are secondary to infection with Escherichia coli O157:H7 and other Shiga-toxin–producing strains. However, approximately 10% of cases are atypical and not associated with infection. This article reviews current concepts about the pathobiology of atypical hemolytic–uremic syndrome and its diagnosis and management. Approximately 10% of cases of the hemolytic–uremic syndrome are atypical and not associated with infection. This article reviews current concepts about the pathobiology of atypical hemolytic–uremic syndrome and its diagnosis and management. The hemolytic–uremic syndrome is characterized by nonimmune hemolytic anemia, thrombocytopenia, and renal impairment. 1 The disorder occurs most frequently in children under the age of 5 years, with an annual incidence of 6.1 cases per 100,000 children under 5 years, as compared with an overall incidence of 1 to 2 cases per 100,000. The presentation is generally heralded by diarrhea, which is often bloody. 2 , 3 Most cases (including more than 90% of those in children) are secondary to infection with Escherichia coli serotypes O157:H7, O111:H8, O103:H2, O123, O26, or others, 1 which produce Shiga-like toxin (Stx), and several other bacteria, such as . . .

The complement system is important for the host defence against infection as well as for the development of inflammatory diseases. Here we show that C1q/TNF-related protein 6 (CTRP6; gene symbol C1qtnf6 ) expression is elevated in mouse rheumatoid arthritis (RA) models. C1qtnf6 −/− mice are highly susceptible to induced arthritis due to enhanced complement activation, whereas C1qtnf6 -transgenic mice are refractory. The Arthus reaction and the development of experimental autoimmune encephalomyelitis are also enhanced in C1qtnf6 −/− mice and C1qtnf6 −/− embryos are semi-lethal. We find that CTRP6 specifically suppresses the alternative pathway of the complement system by competing with factor B for C3(H 2 O) binding. Furthermore, treatment of arthritis-induced mice with intra-articular injection of recombinant human CTRP6 cures the arthritis. CTRP6 is expressed in human synoviocytes, and CTRP6 levels are increased in RA patients. These results indicate that CTRP6 is an endogenous complement regulator and could be used for the treatment of complement-mediated diseases. The complement system contributes to chronic inflammatory diseases. Here the authors show that CRTP6 suppresses the alternative complement pathway and reverses rheumatoid arthritis in a mouse model of the disease.

Recent studies have found non-immunological roles of the classical complement pathway (CP) in brain development and its involvement in neuropsychiatric and neurodegenerative diseases. However, multiple complement activation pathways exist beyond the CP, but their expression and function remain poorly understood in the brain. Using MERFISH, we constructed a comprehensive spatial transcriptomic atlas of the complement system in mouse brains from late embryonic stage to adulthood. Here we show that most complement genes are expressed locally with a remarkable degree of cellular, spatial, and temporal heterogeneity and that complement regulatory mechanisms are distinct from the periphery. Beyond confirming the known expression of the CP, our measurements reveal endogenous expression of the alternative pathway (AP), notably the AP activator Masp3 in immature brains. Masp3 deficiency alters molecular structure of the brain and causes working spatial memory defects, indicating a role of Masp3 in brain maturation, potentially via modulation of AP activity. The complement cascade is increasingly recognized in the brain. Here, with MERFISH, the authors showed developmentally regulated brain endogenous expression of complement genes and a potential role of the alternative pathway in brain development.

The complement system, composed of the three activation pathways, has both protective and pathogenic roles in the development of systemic lupus erythematosus (or lupus), a prototypic autoimmune disease. The classical pathway contributes to the clearance of immune complexes (ICs) and apoptotic cells, whereas the alternative pathway (AP) exacerbates renal inflammation. The role of the lectin pathway (LP) in lupus has remained largely unknown. Mannose-binding lectin (MBL)-associated serine proteases (MASPs), which are associated with humoral pattern recognition molecules (MBL or ficolins), are the enzymatic constituents of the LP and AP. MASP-1 encoded by the gene significantly contributes to the activation of the LP. After the binding of MBL/ficolins to pathogens or self-altered cells, MASP-1 autoactivates first, then activates MASP-2, and both participate in the formation of the LP C3 convertase C4b2a, whereas, MASP-3, the splice variant of the gene, is required for the activation of the zymogen of factor D (FD), and finally participates in the formation of the AP C3 convertase C3bBb. To investigate the roles of MASP-1 and MASP-3 in lupus, we generated gene knockout lupus-prone MRL/ mice ( MRL/ mice), lacking both MASP-1 and MASP-3, and analyzed their renal disease. As expected, sera from MRL/ mice had no or markedly reduced activation of the LP and AP with zymogen forms of complement FD. Compared to their wild-type littermates, the MRL/ mice had maintained serum C3 levels, little-to-no albuminuria, as well as significantly reduced glomerular C3 deposition levels and glomerular pathological score. On the other hand, there were no significant differences in the levels of serum anti-dsDNA antibody, circulating ICs, glomerular IgG and MBL/ficolins deposition, renal interstitial pathological score, urea nitrogen, and mortality between the wild-type and MRL/ mice. Our data indicate that MASP-1/3 plays essential roles in the development of lupus-like glomerulonephritis in MRL/ mice, most likely activation of the LP and/or AP.

The complement system (CS) has recently been recognized as a bridge between innate and adaptive immunity that constitutes a very complex mechanism controlling the clearance of pathogens, cellular debris, and immune complexes. Out of three known pathways of complement activation, the alternative pathway (AP) plays a critical role in host defense by amplifying the complement response, independently of initiation pathway and continuously maintaining low-level activity in a process called ‘thick-over.’ A key molecule of the CS is C3, in which the AP is constantly activated. To prevent host cell destruction, a group of the AP regulators tightly controls this pathway of the CS activation. Acquired and genetic abnormalities of the CS may alter the delicate balance between enhancing and inhibiting the AP cascade. These can lead to the uncontrolled CS activation, inflammatory response, and subsequent tissue damage. Since complement components are locally produced and activated in the kidney, the abnormalities targeting the AP may cause glomerular injury. C3 glomerulopathy is a new entity, in which the AP dysregulation has been well established. However, recent studies indicate that the AP may also contribute to a wide range of kidney pathologies, including immune-complex-mediated glomerulonephritis (GN), pauci-immune GN, and primary membranous nephropathy (PMN). This article provides insight into current knowledge on the role of the AP in the pathogenesis of glomerular diseases, focusing mainly on various types of primary and secondary GN and PMN.