scholarly journals A Review of Complement Activation in SLE

2021 ◽  
Vol 23 (3) ◽  
Author(s):  
Arthur Weinstein ◽  
Roberta V. Alexander ◽  
Debra J. Zack
Keyword(s):  
Disease Activity ◽  
Lupus Erythematosus ◽  
Complement Activation ◽  
Alternative Pathway ◽  
Adverse Outcomes ◽  
Pathogenetic Mechanism ◽  
Activation Products ◽  
The Complement System ◽  
Anti Phospholipid Syndrome ◽  
Lupus Disease Activity

Abstract Purpose of Review Complement activation is a key event in the pathogenesis of tissue inflammation and injury in systemic lupus erythematosus (SLE). This review is aimed at comparing the usefulness of measurement of complement proteins in serum/plasma (C3, C4) to complement activation (split) products in plasma and on circulating blood cells for SLE diagnosis, disease monitoring, and prognosis. Recent Findings Complement split products, C3dg, iC3b, and C4d, are elevated in SLE, and C3dg/C3 and iC3b/C3 ratios correlate with active SLE. C4d also is higher in patients with lupus nephritis. An elevated level of the alternative pathway split product, Bb, in early lupus pregnancy is a predictor of adverse outcomes in SLE patients with antiphospholipid antibodies. Elevated levels of cell-bound complement activation products (CB-CAPs), namely, B cell-bound C4d (BC4d) and erythrocyte-bound C4d (EC4d), within a multiparameter assay panel, may predict transition to SLE more than other lupus biomarkers. EC4d better correlates with lupus disease activity than low plasma complement levels. Elevated platelet-bound C4d (PC4d) correlates with thrombosis in SLE. Both EC4d and PC4d are increased in primary and secondary anti-phospholipid syndrome, and anti-beta2glycoproteinI antibodies may directly activate the complement system. Summary Abnormal levels of plasma complement split products and CB-CAPs support complement activation as an important pathogenetic mechanism in SLE and the antiphospholipid syndromes. These tests show promise for the diagnosis of SLE and monitoring of disease activity.

Cell-bound complement activation products (CB-CAPs) have high sensitivity and specificity in pediatric-onset systemic lupus erythematosus and correlate with disease activity

Lupus ◽  
2018 ◽  
Vol 27 (14) ◽  
pp. 2262-2268 ◽  
Author(s):  
J S Hui-Yuen ◽  
Y Gartshteyn ◽  
M Ma ◽  
T O’Malley ◽  
J Conklin ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Disease Activity ◽  
Sensitivity And Specificity ◽  
Lupus Erythematosus ◽  
Complement Activation ◽  
Operating Characteristics ◽  
Systemic Lupus ◽  
Mixed Effect ◽  
Activation Products ◽  
Pediatric Onset

Objective Elevated levels of cell-bound complement activation products (CB-CAPs) (C4d deposition on B lymphocytes (BC4d) and/or erythrocytes (EC4d)) are sensitive and specific in diagnosis and monitoring of adult systemic lupus erythematosus (SLE). Our objective was to evaluate the role of CB-CAPs for diagnosis and monitoring of pediatric-onset SLE (pSLE). Methods A prospective cohort study of 28 pSLE and 22 juvenile arthritis patients was conducted. SLE disease activity was determined using a clinical Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) that excluded serologies. Autoantibodies were measured using solid-phase immunoassays, C3 and C4 using immunoturbidimetry, and CB-CAPs using quantitative flow cytometry. Abnormal CB-CAPs were defined as EC4d or BC4d above the 99th percentile for healthy adults (>14 and > 60 net mean fluorescence intensity (MFI), respectively). Performance characteristics of CB-CAPs were assessed using area under the curve (AUC) for receiver operating characteristics. Linear mixed effect models evaluated the correlation between CB-CAPs and clinical SLEDAI over 6 months. Results BC4d yielded higher AUC (0.91 ± 0.04) than C3 (0.63 ± 0.08) and C4 (0.67 ± 0.08) ( p < 0.05). Abnormal CB-CAPs were 78% sensitive and 86% specific for diagnosis of pSLE (Youden’s index = 0.64 ± 0.11). In contrast to BC4d, EC4d levels correlated with clinical SLEDAI ( p < 0.01). Conclusion CB-CAPs (EC4d and BC4d) have higher sensitivity and specificity than low complement in pSLE, and may help with diagnosis of pSLE. EC4d could provide a useful biomarker for disease activity monitoring.

Complement Activation In Patients with Isolated Antiphospholipid Antibodies (aPL) or Primary Antiphospholipid Syndrome (PAPS)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4216-4216
Author(s):  
Karen A Breen ◽  
Kiran Parmar ◽  
Beverley J Hunt
Keyword(s):  
Animal Models ◽  
Antiphospholipid Syndrome ◽  
Lupus Erythematosus ◽  
Complement Activation ◽  
Alternative Pathway ◽  
Oral Contraceptive Pill ◽  
Control Group ◽  
P Value ◽  
Primary Antiphospholipid Syndrome ◽  
Activation Products

Abstract Abstract 4216 Background: Increased complement activation has been implicated in the pathogenesis of APS. Most evidence to date comes from animal models of APS. Studies of murine APS models have demonstrated complement activation to be a mediator of thrombosis (Fischetti et al, 2005, Pierangeli 2007) and foetal loss (Girardi et al, 2003). Increased complement deposition was demonstrated in a study of placentae of APS pregnancies further supporting the findings in mice (Shamonki et al, 2007). Low levels of complement have been demonstrated in patients with APS which may be due to increased complement turnover (Oku et al, 2008). C3a-desArg is a stable product of C3a cleavage generated during complement activation; Bb is an activation fragment of Factor B, an alternative pathway component. Both have been evaluated as reliable markers of complement activation in patients. Objectives: To evaluate levels of complement activation products in patients with antiphospholipid syndrome by measuring the complement activation products Bb and C3a-desArg. Methods: Local ethics committee approval was obtained. Samples were obtained from patients attending clinics at our institution who had PAPS according to International Consensus statement criteria, or had persistent aPL without associated complications. Patients with systemic lupus erythematosus (SLE), intercurrent infection or malignancy were excluded. None of the patients were taking heparin. The control group were recruited from hospital staff who were not known to have aPL, were non smokers and not taking the oral contraceptive pill. Control samples were obtained from 18 healthy non-pregnant women (median age 37.5 (range 20–58) years). Patient blood samples were obtained from 39 women with apL and previous thrombosis, 5 of whom had previous pregnancy morbidity, 3 of whom were smokers and all of whom were on oral vitamin K antagonists (median 47 (23-61)), 15 women with obstetric APS and no history of thrombosis, 2 of whom were smokers (median 41 (32-54)), and 19 women with isolated aPL, 3 of whom were smokers (median 43.5 (19-73)). Blood was drawn by flawless venepuncture into tubes containing EDTA, immediately centrifuged at 3000 rpm for 15 min at 4°C and stored at -80°C until use. ELISA assays measuring complement fragments Bb and C3a-desArg levels were performed on plasma samples in one batch by one technician according to manufacturer's protocol (Quidel, Technoclone Dorking, UK). Intra-assay CV was 2.4% for Bb and 2.8% for C3a-desArg. Statistical analysis: The unpaired t-test was used to compare complement levels between groups. A p-value of <0.05 was considered to be statistically significant. Results: Results are shown below in table 1 and are described as means and standard deviations. Conclusions: Our results demonstrate evidence of increased complement activation in all patient groups with aPL. This supports recent findings in animal models and strongly suggests that all human individuals with aPL have complement activation. The role of complement activation in the pathogenesis of thrombotic and obstetric complications of APS is worthy of further study. Disclosures: Breen: NovoNordisk: Research Funding.

scholarly journals AB0421 EFFECT OF BODY WEIGHT ON COMPLEMENT LEVELS IN SYSTEMIC LUPUS ERYTHEMATOSUS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1510.3-1510
Author(s):  
L. Kondrateva ◽  
T. Popkova ◽  
E. Nasonov ◽  
A. Lila
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Disease Duration ◽  
Normal Weight ◽  
World Health ◽  
Systemic Lupus ◽  
Obesity Status ◽  
Health Organization ◽  
The Complement System

Background:The complement system is a recognized biomarker for diagnosis or monitoring of disease activity in systemic lupus erythematosus (SLE) patients (pts). But on the other hand, it has been linked to insulin resistance and obesity in general population.Objectives:To find out whether overweight/obesity can modify C3 or C4 levels in SLE pts.Methods:A total of 92 SLE pts (83 women, 9 men, 39 [34;47] years old) were enrolled in the study. Median disease duration was 6[2;14] years, and SLE activity using SLEDAI-2K was 4[2;8]. SLE pts were treated with glucocorticoids (89%), hydroxychloroquine (78%), immunosuppressants (28%), biologics (10%). The overweight/obesity status was determined by World Health Organization criteria in patients with body mass index (BMI) ≥25kg/m2.Results:Overweight/obesity were established in 46% SLE pts. Overweight/obese SLE pts were older than pts with normal BMI (40[36;48] vs 37[31;44] years, р=0,02), and had lower SLEDAI-2K (3[2;6] vs 6[4;8], p<0,01). Lower C3 concentrations were found in 36% overweight/obese pts vs 68% pts with normal weight (р<0,01), decreased C4 levels - in 19% vs 30% pts (p=0,33), median C3 concentrations were 0,98[0,81;1,14] g/l vs 0,84[0,69;0;96] g/l (р<0,01), and C4 levels were 0,15[0,10;0,19] g/l vs 0,12[0,09;0,16] g/l, respectively (p=0,03). C3 and C4 levels negatively correlated with SLEDAI-2K (r=-0,5, p<0,01 for both), the effect was more strongly pronounced in patients with BMI≥25kg/m2 (r=-0,6, p<0,01 for both) than in those with normal weight (r=-0,2, p=0,09 for C3, r=-0,3, p=0,04 for C4).Conclusion:Overweight/obesity status in SLE pts was associated with increased levels of complement proteins, therefore decreased C3 or C4 levels in patients with BMI≥25kg/m2 are more likely related to disease activity and, can potentially induce SLE flares.Disclosure of Interests: :None declared

Optimal Frequency of Visits for Patients with Systemic Lupus Erythematosus to Measure Disease Activity Over Time

2010 ◽  
Vol 38 (1) ◽  
pp. 60-63 ◽  
Author(s):  
DOMINIQUE IBAÑEZ ◽  
DAFNA D. GLADMAN ◽  
ZAHI TOUMA ◽  
MANDANA NIKPOUR ◽  
MURRAY B. UROWITZ
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Activity Index ◽  
Disease Activity Index ◽  
Systemic Lupus ◽  
The Mean ◽  
Over Time ◽  
Measure Disease Activity ◽  
Lupus Disease Activity

Objective.Adjusted mean Systemic Lupus Erythematosus Disease Activity Index (SLEDAI; AMS) measures lupus disease activity over time. Our aim was to determine optimal visit frequency for calculating AMS.Methods.Patients followed monthly for 12 consecutive visits were included. AMS was calculated using all of the SLEDAI 2000 (AMSGOLD using all 12 visits), only quarterly visits (AMS3, using visits 3 months apart), semiannual visits (AMS6, using first, middle, and last visits only), and annual visits (AMS12, using only the first and last visits). Comparisons of AMS3, AMS6, and AMS12 with AMSGOLD are made using descriptive statistics.Results.Seventy-eight patients were included (92% women, mean age at SLE diagnosis 30.1 yrs and at study start 46.2 yrs). The mean (SD) AMSGOLD for the entire year was 2.05 (1.66), for AMS3 1.99 (1.65), for AMS6 2.12 (1.87), and for AMS12 2.08 (1.83). Mean (SD) of the absolute differences with AMSGOLD: for AMS3 0.29 (0.33), for AMS6 0.45 (0.59), and for AMS12 0.61 (0.58). Differences that were < 0.5 were considered minimal while those ≥ 1 were deemed important. Comparing AMSGOLD to AMS3, 82% of the differences were minimal and 3% were important. When comparing to AMS6, 68% were minimal and 10% were important, while comparing to AMS12, 50% were minimal and 21% were important.Conclusion.Usual clinic visits occurring quarterly offer a good estimation of disease activity over a 1-year period and are preferred over semiannual and annual visits.

The Value of Complement Activation Products in the Assessment of Systemic Lupus Erythematosus Flares

1995 ◽  
Vol 74 (3) ◽  
pp. 283-288 ◽  
Author(s):  
J.M. Porcel ◽  
J. Ordi ◽  
A. Castro-Salomo ◽  
M. Vilardell ◽  
M.J. Rodrigo ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Complement Activation ◽  
Systemic Lupus ◽  
Activation Products

scholarly journals The Lectin Pathway of Complement Activation in Patients with Systemic Lupus Erythematosus

2018 ◽  
Vol 45 (8) ◽  
pp. 1136-1144 ◽  
Author(s):  
Anne Troldborg ◽  
Steffen Thiel ◽  
Marten Trendelenburg ◽  
Justa Friebus-Kardash ◽  
Josephine Nehring ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Pattern Recognition ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Complement Activation ◽  
Lectin Pathway ◽  
Classical Pathway ◽  
Systemic Lupus ◽  
Over Time ◽  
Repeated Samples

Objective.The pathogenesis of systemic lupus erythematosus (SLE) involves complement activation. Activation of complement through the classical pathway (CP) is well established. However, complement activation through pattern recognition not only happens through the CP, but also through the lectin pathway (LP). We investigated the hypothesis that the LP is activated in SLE and involved in the pathogenesis of the disease.Methods.Using immunoassays developed in-house, we measured concentrations of LP proteins in a cohort of 372 patients with SLE and 170 controls. We estimated complement activation measuring total C3, and investigated whether LP protein concentrations were associated with complement activation and disease activity. Protein changes and disease activity over time were assessed in a cohort of 52 patients with SLE followed with repeated samples over a 5-year period.Results.Concentrations of LP proteins in SLE were altered compared with controls. The differences observed in LP proteins associated with complement activation were reflected by a decrease in total C3. The pattern recognition molecules (M-ficolin, CL-L1, and CL-K1), the serine protease (MASP-3), and the associated protein (MAp19) displayed a negative correlation with disease activity. Changes in MASP-2 concentrations over time correlated significantly with increased disease activity. Association between active proteinuria and serum concentration was observed for MASP-3 and MAp19.Conclusion.In patients with SLE, we measured specific changes in LP proteins that are associated with complement activation and disease activity, indicating that the LP is activated in patients with SLE. These novel findings substantiate the involvement of the LP in SLE.

scholarly journals Complement activation predicts adverse pregnancy outcome in patients with systemic lupus erythematosus and/or antiphospholipid antibodies

2018 ◽  
Vol 77 (4) ◽  
pp. 549-555 ◽  
Author(s):  
Mimi Y Kim ◽  
Marta M Guerra ◽  
Elianna Kaplowitz ◽  
Carl A Laskin ◽  
Michelle Petri ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Complement Activation ◽  
Adverse Pregnancy Outcome ◽  
Alternative Pathway ◽  
Causative Factor ◽  
Healthy Controls ◽  
Systemic Lupus ◽  
Adverse Pregnancy ◽  
In Pregnancy

ObjectiveStudies in mouse models implicate complement activation as a causative factor in adverse pregnancy outcomes (APOs). We investigated whether activation of complement early in pregnancy predicts APOs in women with systemic lupus erythematosus (SLE) and/or antiphospholipid (aPL) antibodies.MethodsThe PROMISSE Study enrolled pregnant women with SLE and/or aPL antibodies (n=487) and pregnant healthy controls (n=204) at <12 weeks gestation and evaluated them monthly. APOs were: fetal/neonatal death, preterm delivery <36 weeks because of placental insufficiency or preeclampsia and/or growth restriction <5th percentile. Complement activation products were measured on serial blood samples obtained at each monthly visit.ResultsAPO occurred in 20.5% of SLE and/or aPL pregnancies. As early as 12–15 weeks, levels of Bb and sC5b-9 were significantly higher in patients with APOs and remained elevated through 31 weeks compared with those with normal outcomes. Moreover, Bb and sC5b-9 were significantly higher in patients with SLE and/or aPL without APOs compared with healthy controls. In logistic regression analyses, Bb and sC5b-9 at 12–15 weeks remained significantly associated with APO (ORadj=1.41 per SD increase; 95% CI 1.06 to 1.89; P=0.019 and ORadj=1.37 per SD increase; 95% CI 1.05 to 1.80; P=0.022, respectively) after controlling for demographic and clinical risk factors for APOs in PROMISSE. When analyses were restricted to patients with aPL (n=161), associations between Bb at 12–15 weeks and APOs became stronger (ORadj=2.01 per SD increase; 95% CI 1.16 to 3.49; P=0.013).ConclusionIn pregnant patients with SLE and/or aPL, increased Bb and sC5b-9 detectable early in pregnancy are strongly predictive of APOs and support activation of complement, particularly the alternative pathway, as a contributor to APOs.

Inherited complement deficiencies

1984 ◽  
Vol 306 (1129) ◽  
pp. 419-430 ◽  
Keyword(s):  
Immune Complex ◽  
Complement System ◽  
Lupus Erythematosus ◽  
Alternative Pathway ◽  
Strong Association ◽  
Factor H ◽  
Complement Deficiency ◽  
Classical Pathway ◽  
The Complement System

Isolated genetic deficiencies of individual components of the complement system have been described in man for all the components of the classical pathway and the membrane attack complex as well as for Factor I, Factor H and properdin. It is only for Factor B and Factor D of the alternative pathway that homozygous deficiency states are not so far known. Complement deficiency states provide the most direct way of looking at the role of the complement system in vivo and emphasize the importance of complement in resistance to bacterial infection and in particular to infection with Neisseria . This association is not unexpected since in vitro studies have shown complement to be an efficient enhancer of phagocytosis and inflammation. The particularly frequent occurrence of neisserial infection may be ascribed to the ability of these organisms to survive in phagocytic cells so that the plasma cytolytic activity provided by complement is needed to kill them. On the other hand the strong association between complement deficiencies and immune-complex diseases - especially systemic lupus erythematosus — was unexpected and seems paradoxical in view of the large part played by complement in the pathogenesis of immune complex mediated tissue damage. The paradox can be explained in part by the necessity for an intact complement system in the solubilization and the proper handling of immune complexes. It is also likely that complement deficiency can allow the persistence of low virulence organisms that produce disease solely by an immune complex mechanism. Recently described deficiencies of complement receptors and their effects in vivo are described.

scholarly journals Influence of Mannan and Glucan on Complement Activation and C3 Binding by Candida albicans

2009 ◽  
Vol 78 (3) ◽  
pp. 1250-1259 ◽  
Author(s):  
Gayle M. Boxx ◽  
Thomas R. Kozel ◽  
Casey T. Nishiya ◽  
Mason X. Zhang
Keyword(s):  
Candida Albicans ◽  
Complement System ◽  
Complement Activation ◽  
Alternative Pathway ◽  
Surface Expression ◽  
Human Neutrophils ◽  
Intact Cells ◽  
Independent Mechanism ◽  
The Complement System ◽  
Wall Components

ABSTRACT The complement system is important for host resistance to hematogenously disseminated candidiasis. However, modulation of complement activation by cell wall components of Candida albicans has not been characterized. Although intact yeast display mannan on the surface, glucan, typically located in the interior, becomes exposed during C. albicans infection. We show here the distinct effects of mannan and glucan on complement activation and opsonophagocytosis. Previous studies showed that intact cells are resistant to initiation of complement activation through the alternative pathway, and antimannan antibody reverses this resistance via an Fc-independent mechanism. The present study shows that this mannan-dependent resistance can be overcome by periodate-borohydride conversion of mannose polysaccharides to polyalcohols; cells treated with periodate-borohydride initiate the alternative pathway without the need for antibody. These observations identify an inhibitory role for intact mannan in complement activation. Next, removal of the surface-displayed mannan by acid treatment of periodate-borohydride cells exposes glucan. Glucan-displaying cells or purified β-glucan initiate the alternative pathway when incubated with the purified proteins of the alternative pathway alone, suggesting that C. albicans glucan is a natural activator of the alternative pathway. Finally, ingestion of mannan-displaying cells by human neutrophils requires anti-mannan antibody, whereas ingestion of glucan-displaying cells requires complement. These results demonstrate a contrasting requirement of natural antibody and complement for opsonophagocytosis of C. albicans cells displaying mannan or glucan. Thus, differential surface expression of mannan and glucan may influence recognition of C. albicans by the complement system.

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