Complement activation and regulation in rheumatic disease

Dijkstra, Douwe J.; Joeloemsingh, Jivan V.; Bajema, Ingeborg M.; Trouw, Leendert A.

doi:10.1016/j.smim.2019.101339

Cited by 26 publications

(15 citation statements)

References 129 publications

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“…Accumulating evidence suggest that dysregulation of the complement system may play an important role in a number of diseases (5,34,35). Logically this drives the development of strategies to specifically inhibit complement in anti-inflammatory therapy (36).…”

Section: Discussionmentioning

confidence: 99%

Complement Receptor 2 Based Immunoassay Measuring Activation of the Complement System at C3-Level in Plasma Samples From Mice and Humans

et al. 2020

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We aimed at establishing a sensitive and robust assay for estimation of systemic complement activation at complement component C3 level in mouse and human plasma samples. In order to capture the activation products iC3b and C3dg in a specific and physiological relevant manner we utilized a construct consisting of the iC3b/C3dg-binding site of human complement receptor 2 (CR2) attached to an Fcpart of mouse IgG. This construct binds C3dg and iC3b from both mice and humans. We purified the CR2-IgG construct from mouse B myeloma cell line supernatants, J558L-CR2-IgG, by protein G affinity chromatography. The CR2-IgG construct was used for capturing C3 fragments in microtiter wells and an anti-mouse or an anti-human-C3 antibody was used for detection of bound C3 fragments. Initially we tested the specificity of the assays with the use of purified C3 fragments. Further, with the use of the CR2-based assay, we measured an up to threefold higher signal in activated mouse serum as compared to non-activated mouse serum, whereas activated serum from a C3 knockout mouse gave no signal. We tested in vivo generated samples from a mouse experiment; complement activation was induced by injecting cobra venom factor or heat aggregated IgG into C57bl6 mice, followed by withdrawal of EDTA blood samples at different time points and measurement of iC3b/C3dg. We observed a clear time-dependent distinction in signals between samples with expected high and low complement activation. Furthermore, with the use of the assay for human C3 fragments, we observed that patients with systemic lupus erythematosus (SLE) (n = 144) had significantly higher iC3b/C3dg levels as compared to healthy individuals (n = 144) (p < 0.0001). We present two functional immunoassays, that are able to measure systemic levels of the C3-activation products iC3b and C3dg in mice and

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Section: Discussionmentioning

confidence: 99%

Complement Receptor 2 Based Immunoassay Measuring Activation of the Complement System at C3-Level in Plasma Samples From Mice and Humans

et al. 2020

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“…RA is an autoimmune disease that has been confirmed to involve inappropriate complement activation in the joint cavity, making the delivery of anti-complement drugs into the joint cavity an ideal therapeutic strategy to relieve RA progression (Dijkstra et al, 2019). In animal models, intraarticular injection of complement inhibitors (such as soluble complement receptor 1 [sCR1], CD59 and anti-C5 neutralizing recombinant miniantibody) prior to disease onset or at the time of disease flares has been shown to alleviate joint swelling and the development of AIA by inhibiting the activation of complement system at different stages (Harris et al, 2002;Williams et al, 2004;Durigutto et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…Because of their strong immunomodulatory functions, some helminthderived proteins are sufficiently potent to treat a variety of allergies, autoimmune diseases, and other immune disorders (Wang et al, 2017;Wu et al, 2017). The complement system, consisting of more than 25 proteins, plays vital roles in defending against infections and is an important component of both innate and adaptive immunity (Dijkstra et al, 2019). Due to the complex impacts of the complement system on the immune system, it is a double-edged sword.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Efficacy of a Trichinella Spiralis Paramyosin-Derived Peptide Modified With a Membrane-Targeting Signal in Mice With Antigen-Induced Arthritis

et al. 2020

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Helminth-derived molecules have the ability to modulate the host immune system. Our previous study identified a tetradecapeptide derived from Trichinella spiralis paramyosin (Ts-pmy) that could bind to human complement component C9 to inhibit its polymerization, making the peptide a candidate therapeutic agent for complement-related immune disorders. Here, the peptide underwent an N-terminal modification with a membrane-targeting signal (a unique myristoylated peptide) to improve its therapeutic efficacy. We found that the modified peptide had a binding affinity to human C9 that was similar to that of the original peptide, as confirmed by microscale thermophoresis assays. The binding of the modified peptide to human C9 resulted in the inhibition of C9-related complement activation, as reflected by the decreased Zn2+-induced C9 polymerization and the decreased C9-dependent lysis of rabbit erythrocytes. In addition, the original and modified peptides could both bind to recombinant mouse C9 and inhibit the C9-dependent lysis of rabbit erythrocytes in normal mouse serum (NMS), which meant that the peptides could cross the species barrier to inhibit complement activity in mice. Further in vitro and in vivo analyses confirmed that the peptide modification increased the retention time of the peptide. Furthermore, intraarticular injection of the modified peptide markedly ameliorated knee swelling and joint damage in mice with antigen-induced arthritis (AIA), as assessed histologically. These results suggested that the Ts-pmy-derived peptide modified with a membrane-targeting signal was a reasonable candidate therapeutic agent for membrane attack complex (MAC)-related diseases [such as rheumatoid arthritis (RA)] and the study presented a new modification method to improve the potential therapeutic effects of the peptide.

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“…Существование тесной взаимосвязи между факторами внешней среды, генетическими дефектами свертывания крови и компонентов комплемента, воспалением и аутоиммунитетом в качестве патогенетических механизмов микротромбоза привлекает особое внимание к изучению ТМА при ИВРЗ, в первую очередь системной красной волчанке (СКВ), антифосфолипидном синдроме (АФС) [14,15] и склеродермическом почечном кризе [16,17]. Углубленные исследования этих заболеваний в перспективе могут иметь значение для расширения представлений о роли аутоиммун-ных механизмов патогенеза «критических» нарушений гемостаза в развитии заболеваний человека, разработки новых подходов к терапии [18][19][20][21] и позволяют обсуждать существование «аутоиммунного» субтипа ТМА (см. табл.…”

Section: тромботическая микроангиопатия в ревматологииunclassified

Thrombotic microangiopathy in rheumatology: a link between thrombosis and autoimmunity

Насонов¹,

Reshetnyak²,

Alekberova³

2020

Terapevticheskii arkhiv

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Uncontrolled hypercoagulation and inflammation (thromboinflammation), which are both independent and closely related and amplifying each other pathological processes, form the basis for pathogenesis of a wide range of diseases and complications, including immuno-inflammatory (autoimmune) rheumatic diseases, with the development of potentially fatal injuries of internal organs. Thrombotic microangiopathy is one of the most prominent prototypes of thromboinflammatory pathological conditions. The close link between environmental factors, hemostasis genetic defects and the complement system, inflammation and autoimmunity as pathogenetic mechanisms of microthrombosis draws particular attention to studying thrombotic microangiopathy in immuno-inflammatory rheumatic diseases, primarily systemic lupus erythematosus, antiphospholipid syndrome and scleroderma renal crisis. In future, these studies may be important for expanding the idea of the role of autoimmune mechanisms in pathogenesis of critical hemostasis disorders in human diseases, and for developing new approaches to therapy. Recently, special attention has been paid to the treatment of systemic lupus erythematosus and antiphospholipid syndrome with eculizumab, which is humanized monoclonal IgG2/4k antibody that blocks the complement component C5a and the membrane attack complex (C5b-9) formation, and which is registered for the treatment of atypical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria, as well as severe forms of myasthenia gravis and neuromyelitis optica. Further studies in this direction will create prerequisites for improving the prognosis not only in patients with orphan disorders, but also for widespread human diseases.

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Complement activation and regulation in rheumatic disease

Cited by 26 publications

References 129 publications

Complement Receptor 2 Based Immunoassay Measuring Activation of the Complement System at C3-Level in Plasma Samples From Mice and Humans

Complement Receptor 2 Based Immunoassay Measuring Activation of the Complement System at C3-Level in Plasma Samples From Mice and Humans

Therapeutic Efficacy of a Trichinella Spiralis Paramyosin-Derived Peptide Modified With a Membrane-Targeting Signal in Mice With Antigen-Induced Arthritis

Thrombotic microangiopathy in rheumatology: a link between thrombosis and autoimmunity

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