Inherited C1q deficiency is associated strongly with the development of systemic lupus erythematosus (SLE). The aim of our study was to evaluate the ability of monocytes from SLE patients without inherited C1q deficiency to up-regulate C1q-mRNA upon stimulation. Furthermore, we wanted to elucidate the physiological stimulus for up-regulation of C1q-mRNA. Peripheral blood mononuclear cell (PBMC)-derived monocytes from 10 SLE patients, 10 patients with rheumatoid arthritis (RA) and 10 healthy controls (HC) were stimulated with dexamethasone (DXM), interferon-gamma or both. Additionally, purified monocytes from HC were stimulated with interleukin (IL)-10. C1q-mRNA expression was measured by quantitative reverse transcription–polymerase chain reaction (RT–PCR). C1q protein was detected using the standard alkaline phosphatase/anti-alkaline phosphatase (APAAP) technique. SLE monocytes were significantly less able to up-regulate C1q-mRNA when compared to RA or HC. IL-10 was identified as an important stimulus for C1q synthesis. In SLE patients there is a significant functional impairment of monocytes to synthesize C1q upon stimulation. As C1q is linked to the process of recognition and removal of apoptotic cells, this relative C1q deficiency is likely to contribute to the reduced phagocytosis of apoptotic material observed in SLE and thereby might be a central pathogenetic factor.
SUMMARY We measured in vitro C3 production by peripheral blood monocytes from patients with systemic lupus erythematosus (SLE), and found it to be significantly greater than that from normal controls. We also found that monocytes from SLE patients with active disease produced a markedly larger amount of C3 than those from SLE patients with inactive disease. Production of C3 by monocytes correlated with serum levels of anti-dsDNA antibodies and inversely correlated with serum C3 levels in SLE pat...
Background: Defects in phagocytosis of apoptotic cells have a role in the pathogenesis of autoimmune diseases. Decrease of phagocytosis of apoptotic cells occurs in systemic lupus erythematosus (SLE). Factors underlying this decrease are, presently, unknown. Objective: To analyse the expression of relevant membrane receptors of monocyte derived macrophages (MDM) from patients with SLE and assess their ability to phagocytose apoptotic cells in comparison with MDM from healthy controls. Additional...
Systemic lupus erythematosus (SLE) is a multifactorial disease and its pathogenesis and precise aetiology remain unknown. Under physiological conditions, neither apoptotic nor necrotic cell material is easily found in tissues because of its quick removal by a highly efficient scavenger system. Autoantigens are found in apoptotic and necrotic material and they are recognized by autoimmune sera from SLE patients. The clearance of dying cells is finely regulated by a highly redundant system of rece...
Purpose of review Systemic lupus erythematosus is characterized by overactive B cells that differentiate into autoantibody-forming cells, aberrant T cell function that provides help to B cells, and the production of pro-inflammatory cytokines. This article reviews recent studies unraveling the complex interplay between cytokines and lymphocytes in systemic lupus erythematosus. Recent findings In systemic lupus erythematosus, T cells are characterized by heightened calcium responses early after a...
Last. Marina Botto(Imperial College London)H-Index: 80
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C1q deficiency in both humans and mice is strongly associated with autoimmunity. We have previously shown that bone marrow transplantation (BMT) restored C1q levels in C1q-deficient (C1qa(-/-)) mice. Here, we studied the effect of BMT on autoimmunity in C1qa(-/-) mice. Following irradiation, young C1qa(-/-) or wild-type MRL/Mp mice received bone marrow cells (BMC) from strain-matched wild-type or C1qa(-/-) animals. C1q levels increased rapidly when C1qa(-/-) mice received BMC from wild-type mice...
Inflammation induced by circulating immunoglobulin G–immune complexes (ICs) characterizes many immune-mediated diseases. In this work, the molecular requirements for the deposition of circulating ICs and subsequent acute leukocyte recruitment in mice were elucidated. We show that after intravenous injection, preformed soluble ICs are rapidly deposited in the postcapillary venules of the cremaster microcirculation, secondary to increased vascular permeability. This deposition is dependent on comp...
Last. Anja Roos(LUMC: Leiden University Medical Center)H-Index: 49
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Deficiencies of early components of the classical complement pathway, particularly C1q, are strongly associated with susceptibility to systemic lupus erythematosus. Recent data link this predisposal to autoimmunity to an inappropriate clearance of apoptotic cells, which could lead to a loss of self-tolerance. In the present study, we demonstrate that opsonization of apoptotic cells with C1q and mannose-binding lectin allows and facilitates their uptake not only by macrophages but also by human i...
Dendritic cells (DCs) and complement are essential components of the innate immune system. Immature DCs (immDCs) and mature DCs (mDCs) can migrate to lymphoid areas inducing, respectively, tolerance and immune responses. Primary deficiency of complement component C1q (C1q) leads to autoimmunity, suggesting a role in the maintenance of tolerance. In the present study, we investigated the production of C1q by immDCs, mDCs, and macrophages. We demonstrated that monocyte-derived and CD34-derived int...
▪ Abstract Complement has both beneficial and deleterious roles in the pathogenesis of systemic lupus erythematosus (SLE). On the one hand, patients with SLE present with decreased complement levels and with complement deposition in inflammed tissues, suggestive of a harmful role of complement in the effector phase of disease. On the other hand, homozygous deficiency of any of the classical pathway proteins is strongly associated with the development of SLE. There are two main hypotheses to expl...
#1Udo S. Gaipl(FAU: University of Erlangen-Nuremberg)H-Index: 21
#2Thomas Beyer(FAU: University of Erlangen-Nuremberg)H-Index: 14
Last. Martin Herrmann(FAU: University of Erlangen-Nuremberg)H-Index: 85
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Objective The efficient uptake of dying cells by phagocytes is essential to the avoidance of chronic inflammation. Some human autoimmune responses are thought to be driven by autoantigens from apoptotic or necrotic cells. We analyzed the role of C1q and DNase I in the disposal of necrotic cell–derived chromatin because deficiencies in these serum factors predispose to the development of systemic autoimmune disorders, such as systemic lupus erythematosus. Methods Human necrotic peripheral blood l...
Uncontrolled inflammation is a leading cause of many clinically relevant diseases. Current therapeutic strategies focus mainly on immunosuppression rather than on mechanisms of inflammatory resolution. Glucocorticoids (GCs) are still the most widely used anti-inflammatory drugs. GCs affect most immune cells but there is growing evidence for cell type specific mechanisms. Different subtypes of monocytes and macrophages play a pivotal role both in generation as well as resolution of inflammation. ...
Last. Leendert A. Trouw(LUMC: Leiden University Medical Center)H-Index: 61
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IntroductionC1q is an essential part of the classical pathway of complement activation. Genetic deficiencies, caused by homozygous mutations in one of the C1q genes, are rare and are strongly assoc...
Last. Zhanguo Li(PKU: Peking University)H-Index: 32
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Although rare variant C1Q deficiency was identified as causative risk for systemic lupus erythematosus (SLE), there are limited and inconsistent reports regarding the common polymorphisms of C1Q genes in SLE susceptibility. Furthermore, there are no reports concerning polymorphisms of C1S, C1R, and C1RL and whether they confer susceptibility to SLE. We therefore evaluated 22 SNPs across six C1-complex genes in two independent case-control cohorts, and identified four novel SNPs that confer prote...
#2Fionnuala Lundy('QUB': Queen's University Belfast)H-Index: 20
Last. Imad About(AMU: Aix-Marseille University)H-Index: 32
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Abstract Fibroblasts represent the most abundant population within the dental pulp. Although other cell types such as odontoblasts and stem cells have been extensively investigated, very little attention was given to the fibroblasts, which have major roles in regulating the pulp biology and function under normal and pathologic conditions. Indeed, although pulp fibroblasts control the pulp vascularization and innervation under physiological conditions, these cells synthesize growth factors that e...
Last. Veronika Grau(University of Giessen)H-Index: 22
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Recently, we discovered a cholinergic mechanism that inhibits the ATP-dependent release of interleukin-1β (IL-1β) by human monocytes via nicotinic acetylcholine receptors (nAChRs) composed of α7, α9 and/or α10 subunits. Furthermore, we identified phosphocholine and dipalmitoylphosphatidylcholine as novel nicotinic agonists that elicit metabotropic activity at monocytic nAChR. Interestingly, phosphocholine does not provoke ion channel responses at conventional nAChRs composed of subunits α9 and α...
: Antibodies against C1q (anti-C1q) are frequently found in patients with systemic lupus erythematosus (SLE). The anti-C1q antibodies strongly correlate with the occurrence of lupus nephritis and low-circulating C1q levels. Previous studies have demonstrated that myeloid cells, i.e., dendritic cells and macrophages, are a major source of C1q. However, a direct effect of anti-C1q on C1q secretion by macrophages has not yet been established. In the present study, we investigated the C1q secretion ...
#1Zejun Zhou(MUSC: Medical University of South Carolina)H-Index: 6
#2Miao Ding(MUSC: Medical University of South Carolina)H-Index: 2
Last. Wei Jiang(MUSC: Medical University of South Carolina)
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Abstract Monocytes are precursors of macrophages and key players during inflammation and pathogen challenge in the periphery, whereas intestinal resident macrophages act as innate effector cells to engulf and clear bacteria, secrete cytokines, and maintain intestinal immunity and homeostasis. However, perturbation of toll-like receptor signaling pathway in intestinal macrophages has been associated with tolerance breakdown in autoimmune diseases. In the present review, we have summarized and dis...
#1Jefte M. Drijvers(Ragon Institute of MGH, MIT and Harvard)H-Index: 6
#2Shiv Pillai(Ragon Institute of MGH, MIT and Harvard)H-Index: 65
While there is some knowledge about the mechanisms that might contribute to an increase in both circulating chromatin as a source of antigen and chromatin containing immune complexes in lupus subjects, less is understood regarding how B-cell tolerance is broken in this disease. The role of inherited genetic variants and accumulating chromatin immune complexes in enhancing type I interferon levels in patients is well appreciated. It has been postulated that the increased levels of type I interfer...
#2Nina A. Daha(LUMC: Leiden University Medical Center)H-Index: 14
Last. Leendert A. Trouw(LUMC: Leiden University Medical Center)H-Index: 61
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Abstract Introduction C1q deficiency is a rare genetic disorder that is strongly associated with development of systemic lupus erythematosus (SLE). Several mutations in the coding regions of the C1q genes have been described that result in stop-codons or other genetic abnormalities ultimately leading to C1q deficiency. Here we report on a Dutch boy suffering from recurrent infections with a complete C1q deficiency, without any SLE symptoms. Methods The presence of C1q in serum was assessed using...
Last. Imad About(AMU: Aix-Marseille University)H-Index: 32
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The complement system is an efficient plasma immune surveillance system that controls tissue injury and infection. Although the liver constitutes the primary circulating complement protein synthesis site, extrahepatic synthesis is known to optimize local tissue inflammatory reaction. Because dentin–pulp regeneration is known to be regulated locally, we investigated activation of the local complement system within the dental pulp and its role in initiating the regeneration process. Membrane attac...
