Preeclampsia (PE) generally manifests in the second half of pregnancy with hypertension and proteinuria. The understanding of the origin and mechanism behind PE is incomplete, although there is... Show morePreeclampsia (PE) generally manifests in the second half of pregnancy with hypertension and proteinuria. The understanding of the origin and mechanism behind PE is incomplete, although there is clearly an immune component to this disorder. The placenta constitutes a complicated immune interface between fetal and maternal cells, where regulation and tolerance are key. Stress factors from placental dysfunction in PE are released to the maternal circulation evoking the maternal response. Several complement factors play a role within this intricate landscape, including C1q in vascular remodeling and Factor H (FH) as the key regulator of alternative pathway complement activation. We hypothesize that decreased levels of C1q or FH, or disturbance of their function by autoantibodies, may be associated with PE. Autoantibodies against C1q and FH and the concentrations of C1q and FH were measured by ELISA in maternal sera from women with preeclamptic and normal pregnancies. Samples originated from cohorts collected in the Netherlands (n=63 PE; n=174 control pregnancies, n=51 nonpregnant), Finland (n=181 PE; n=63 control pregnancies) and Norway (n=59 PE; n=27 control pregnancies). Serum C1q and FH concentrations were higher in control pregnancy than in nonpregnant women. No significant differences were observed for serum C1q between preeclamptic and control pregnancy in any of the three cohorts. Serum levels of FH were lower in preeclamptic pregnancies compared to control pregnancies in two of the cohorts, this effect was driven by the early onset PE cases. Neither anti-C1q autoantibodies nor anti-FH autoantibodies levels differed between women with PE and normal pregnancies. In conclusion, levels of anti-C1q and anti-FH autoantibodies are not increased in PE. C1q and FH are increased in pregnancy, but importantly, a decrease in FH concentration is associated with PE. Show less
Bovenkamp, F.S. van de; Dijkstra, D.J.; Kooten, C. van; Gelderman, K.A.; Trouw, L.A. 2021
C1q is the recognition molecule of the classical pathway of the complement system. By binding to its targets, such as antigen-bound immunoglobulins or C-reactive protein, C1q contributes to the... Show moreC1q is the recognition molecule of the classical pathway of the complement system. By binding to its targets, such as antigen-bound immunoglobulins or C-reactive protein, C1q contributes to the innate defense against infections. However, C1q also plays several other roles beyond its traditional role in complement activation. Circulating levels of C1q are determined in routine diagnostics as biomarker in several diseases. Decreased C1q levels are present in several autoimmune conditions. The decreased levels reflect the consumption of C1q by complement activation and serves as a biomarker for disease activity. In contrast, increased C1q levels are present in infectious and inflammatory diseases and may serve as a diagnostic biomarker. The increased levels of C1q are still incompletely understood but are suggested to modulate the adaptive immune response as C1q is known to impact on the maturation status of antigen-presenting cells and C1q impacts directly on T cells leading to decreased T-cell activity in high C1q conditions. In this review, we provide a comprehensive overview of the current literature on circulating levels of C1q in health and disease, and discuss how C1q can both protect against infections as well as maintain tolerance by regulating adaptive immunity. Show less
In this thesis several aspects of complement proteins are described, from circulating levels in blood to their intracellular presence and from autoimmunity to the infectious disease tuberculosis.... Show moreIn this thesis several aspects of complement proteins are described, from circulating levels in blood to their intracellular presence and from autoimmunity to the infectious disease tuberculosis. We explored the local production of complement and we describe in Chapter 2 the production of C1q by chondrocytes. Additionally, studies addressing the potential intracellular C3 role are described in Chapter 3. The potential role of the complement system as biomarker was investigated by addressing the presence and concentrations of C1q in serum of patients with active tuberculosis and controls in Chapter 4. Like C1q, we also investigated the expression and concentration of the natural inhibitor C1-INH in Chapter 5. C1q protein was further analysed as biomarker for tuberculosis in experimental non-human primate models in Chapter 6. In this thesis, a newly identified case of a lupus patient is described with a complex medical history and a compound heterozygous deficiency of C1q in Chapter 7. To better comprehend a possible role of a prominent post-translational modification associated rheumatic disease, carbamylation, the interaction between carbamylated IgG was investigated in relation to the ability to activate the complement system. These studies are described in Chapter 8. Show less
In the current thesis, we provide novel insights in antigen uptake, storage, processing, and sustained cross-presentation mechanisms in dendritic cells (DCs) in vitro and in vivo. We have studied... Show moreIn the current thesis, we provide novel insights in antigen uptake, storage, processing, and sustained cross-presentation mechanisms in dendritic cells (DCs) in vitro and in vivo. We have studied antigen handling functions by dendritic cells in three different antigen delivery routes: antibody targeting involving Fcγ receptors and complement factor C1q, C-type lectin receptor targeting, and toll-like receptor ligand targeting systems. Our data highlights that antigen storage in specialized compartments in DCs, despite the chosen uptake route, is beneficial for prolonged antigen cross-presentation by DCs and sustained T cell activation. Further in vivo studies in different antigen presenting cell (APC) subsets confirmed the presence of antigen storage compartments by isolating APC subsets after in vivo antigen uptake. Besides, we revealed a dominant role of C1q in antigen-antibody immune complex uptake and cross-presentation in vivo in contrast to the crucial role of Fcγ receptors in vitro. Furthermore, we demonstrated that autophagosomes have a negative impact on the storage of antigen in those specialized compartments and thereby affecting DC cross-presentation efficiency. With the current studies, we unraveled some mechanics of antigen processing in DCs which contribute to future vaccine designs against diseases such as cancer. Show less
Objective: Inflammation and innate immune responses may contribute to development and progression of Osteoarthritis (OA). Chondrocytes are the sole cell type of the articular cartilage and produce... Show moreObjective: Inflammation and innate immune responses may contribute to development and progression of Osteoarthritis (OA). Chondrocytes are the sole cell type of the articular cartilage and produce extracellular-matrix molecules. How inflammatory mediators reach chondrocytes is incompletely understood. Previous studies have shown that chondrocytes express mRNA encoding complement proteins such as C1q, suggesting local protein production, which has not been demonstrated conclusively. The aim of this study is to explore C1q production at the protein level by chondrocytes.Design: We analysed protein expression of C1q in freshly isolated and cultured human articular chondrocytes using Western blot, ELISA and flow cytometry. We examined changes in mRNA expression of collagen, MMP-1 and various complement genes upon stimulation with pro-inflammatory cytokines or C1q. mRNA expression of C1 genes was determined in articular mouse chondrocytes.Results: Primary human articular chondrocytes express genes encoding C1q, C1QA, C1QB, C1QC, and secrete C1q to the extracellular medium. Stimulation of chondrocytes with pro-inflammatory cytokines upregulated C1QA, C1QB, C1QC mRNA expression, although this was not confirmed at the protein level. Extracellular C1q bound to the chondrocyte surface dose dependently. In a pilot study, binding of C1q to chondrocytes resulted in changes in the expression of collagens with a decrease in collagen type 2 and an increase in type 10. Mouse articular chondrocytes also expressed C1QA, C1QB, C1QC, C1R and C1S at the mRNA level.Conclusions: C1q protein can be expressed and secreted by human articular chondrocytes and is able to bind to chondrocytes influencing the relative collagen expression. (C) 2019 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. Show less
ObjectivesTo examine the relation between serum C1q levels and blood type-1 interferon signature (type-1 IFN signature) in active pulmonary tuberculosis (APTB) and to determine whether combined... Show moreObjectivesTo examine the relation between serum C1q levels and blood type-1 interferon signature (type-1 IFN signature) in active pulmonary tuberculosis (APTB) and to determine whether combined measurement of serum C1q and type-1 IFN signature may add to the diagnosis of QuantiFERON-positive (QFT(+)) patients with uveitis of unknown cause.MethodsC1q was determined (ELISA) in serum from two distinct Indonesian cohorts, and in total, APTB (n = 72), QFT(+) uveitis of unknown aetiology (n = 58), QFT(-) uveitis (n = 51) patients and healthy controls (HC; n = 73) were included. The type-1 IFN signature scores were previously determined.ResultsSerum C1q was higher in APTB than HC (P < 0.001). APTB patients with uveitis had higher serum C1q than APTB patients without uveitis (P = 0.0207). Serum C1q correlated inversely with type-1 IFN signature scores in APTB (P = 0.0036, r(2) = 0.3526), revealing that these biomarkers for active TB disease can be mutually exclusive. Stratification of QFT(+) patients with uveitis of unknown cause, by serum C1q and type-1 IFN signature, yielded four groups with different likelihood of suffering from active TB uveitis.ConclusionSerum C1q is elevated in APTB, especially in those cases with uveitis. We propose that combined measurement of blood type-1 IFN signature and serum C1q may provide added value in the diagnosis of active TB disease. Combined measurement of type-1 IFN signature and serum C1q in QFT(+) patients without signs of active TB disease, but suffering from uveitis of unknown cause, may be of help to identify cases with low or high likelihood of having active TB uveitis, which may facilitate clinical management decisions. Show less
O'Flynn, J.; Kotimaa, J.; Faber-Krol, R.; Koekkoek, K.; Klar-Mohamad, N.; Koudijs, A.; ... ; Kooten, C. van 2018
The complement system is an important part of the innate immune system and can be divided in three different pathways; the classical, the lectin and the alternative pathway. In this thesis the... Show moreThe complement system is an important part of the innate immune system and can be divided in three different pathways; the classical, the lectin and the alternative pathway. In this thesis the role of C1q is investigated, which is the recognition molecule of the classical pathway. With the usage of epidemiological projects the clinical presentation of C1q deficient patients is investigated and the association of C1q in patients with Neuropsychiatric Systemic Lupus Erythematosus. Furthermore, using cellular based project the production and secretion of C1q by (non) immune cells is determined. Overall, this thesis is a nice overview about the importance of C1q in keeping the homeostasis and the role of C1q in disease. Show less
