Serological and Genetic Evidence for Altered Complement System Functionality in Systemic Lupus Erythematosus: Findings of the GAPAID Consortium (original) (raw)
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Complement Cascade in Systemic Lupus Erythematosus
Annals of the New York Academy of Sciences, 2009
The complement (C') cascade is an important part of the innate immunity. It acts through three major pathways: classical (CP), alternative (AP) and mannose-bindinglectin (MP). C' reduction is a key feature in systemic lupus erythematosus (SLE), for its pathogenesis and for disease relapse. The aims of our study are to correlate C' variations with disease activity and verify the presence of C' deficiencies. We tested for three C' pathways 52 sera from 20 patients affected by SLE. A significant correlation between the ECLAM score and the degree of activation of the CP (Mann-Whitney; P = 0.001) was recorded, while the correlation with anti-dsDNA antibodies did not reach statistical significance (Mann-Whitney; P > 0.05). In conclusion, the ELISA assay can be considered well suited for testing SLE samples. We detected a significant link between the phases of lupus activity and the reduction of the CP.
Case reports in rheumatology, 2016
Activation of the classical pathway complement system has long been implicated in stimulating immune complex mediated tissue destruction in systemic lupus erythematosus (SLE). C3 and C4 complement levels are utilized as part of SLE diagnosis and monitoring criteria. Recently, cell bound complement activation products (CBCAPs) have shown increased sensitivity in diagnosing and monitoring lupus activity, compared to traditional markers. CBCAPs are increasingly utilized in rheumatology practice as additional serological markers in evaluating SLE patients. We report a case of a patient diagnosed with SLE that had chronically low C3 and C4, along with negative CBCAPs. We surmise that the patient has an inherited complement deficiency as the etiology of her SLE and that CBCAPs could be used to predict such deficiency.
Cell-Bound Complement Biomarkers for Systemic Lupus Erythematosus: From Benchtop to Bedside
Rheumatic Disease Clinics of North America, 2010
Systemic lupus erythematosus (SLE) is arguably the most clinically and serologically diverse autoimmune disease (1,2). Currently available information suggests that intricate interactions between environmental factors, hormonal factors, and disease susceptibility genes may predispose an individual to develop aberrant immune responses leading to SLE. Such aberrant responses, characterized by polyclonal activation of autoreactive lymphocytes, autoantibody production, immune complex formation, and complement activation, lead to acute and chronic inflammation in various tissue and organ systems. Owing to its complex etiopathogenesis, heterogeneous presentation, and unpredictable course, SLE remains one of the greatest challenges to both investigators and physicians. Currently, the diagnosis of SLE is primarily based on the presence or absence of American College of Rheumatology (ACR) criteria (3, 4). Disease activity in SLE patients is often assessed using indices such as the Systemic Lupus disease Activity Index (SLEDAI) (5), the Systemic Lupus Activity Measurement (SLAM) (6,7), and the British Isles Lupus Assessment Group (BILAG) index (8). The lack of easy-tomeasure, reliable and specific biomarkers for SLE not only hampers precise assessment of disease activity and accurate evaluation of response to treatment, but it also impedes the development of novel therapeutics targeting key pathogenic factors. Therefore, there is an urgent need for reliable, specific biomarkers in not only lupus patient care but also in research.
Lupus science & medicine, 2014
To compare the performance characteristics of cell-bound complement (C4d) activation products (CBCAPS) on erythrocyte (EC4d) and B cells (BC4d) with antibodies to double-stranded DNA (anti-dsDNA) and complement C3 and C4 in systemic lupus erythematosus (SLE). The study enrolled 794 subjects consisting of 304 SLE and a control group consisting of 285 patients with other rheumatic diseases and 205 normal individuals. Anti-dsDNA and other autoantibodies were measured using solid-phase immunoassays while EC4d and BC4d were determined using flow cytometry. Complement proteins were determined using immunoturbidimetry. Disease activity in SLE was determined using a non-serological Systemic Lupus Erythematosus Disease Activity Index SELENA Modification. A two-tiered methodology combining CBCAPS with autoantibodies to cellular and citrullinated antigens was also developed. Statistical analyses used area under receiver operating characteristic curves and calculations of area under the curve (...
Arthritis & Rheumatism, 2012
Methods. This was a multicenter cross-sectional study in which 593 subjects were enrolled (210 SLE patients, 178 patients with other rheumatic diseases, and 205 healthy subjects). Complement receptor 1 levels on erythrocytes (ECR1) together with complement C4d levels on erythrocytes (EC4d), platelets (PC4d), and B cells (BC4d) were determined using fluorescenceactivated cell sorting. Serologic markers were measured by enzyme-linked immunosorbent assay. Statistical analyses were performed using area under the curve (AUC), logistic regression, and calculations of diagnostic sensitivity and specificity.
Clinical and Developmental Immunology, 2012
CD55, CD59, CD46, and CD35 are proteins with complement regulatory (Creg) properties that ensure cell and tissue integrity when this system is activated. The aim of this study was to evaluate the Creg expression on peripheral blood cells from SLE patients and its association with cytopenia and disease activity. Flow cytometric analyses were performed on blood cells from 100 SLE patients and 61 healthy controls. Compared with healthy controls, we observed in SLE patients with lymphopenia and neutropenia decreased expression of CD55, CD59, and CD46 (P<0.05). In SLE patients with anemia, CD59 and CD35 were decreased on red blood cells. Furthermore, there was a negative correlation between CD55 and CD59 on neutrophils and the disease activity. The results suggest there is an altered pattern of Creg expression on the peripheral blood cells of SLE patients, and the expression is correlated with disease activity and/or with activation of the complement system.
Clinical and Translational Science, 2009
Systemic lupus erythematosus (SLE) is arguably the most clinically and serologically diverse autoimmune disease, with more than 100 autoantibodies found in patients and disease spectra ranging from subtle symptoms to life-threatening multi-organ failure. 1-3 Owing to its complex etiopathogenesis, heterogeneous presentation, and unpredictable course, SLE remains one of the greatest diagnostic challenges to physicians, including rheumatologists. 4,5 Currently, the diagnosis of SLE is primarily based upon American College of Rheumatology (ACR) criteria, 6,7 many of which are subject to interpretation and may require years to evolve. Th e lack of specifi c, reliable, and validated biomarkers for SLE not only leads to misdiagnosis and misguided therapy, but also may result in fl awed clinical trials if patients in "lupus" treatment arms include false-positive diagnosis. Serum C3 and C4 levels have been measured for decades in attempts to monitor disease activity in patients with SLE; however, these complement assays are not considered useful for the diagnosis of SLE. 8-13 We have previously revisited the complement system as a source of SLE biomarkers and discovered that cell-bound complement activation products (CB-CAP) hold significant promise as diagnostic biomarkers for SLE. Specifi cally, erythrocyte-bound C4d (E-C4d), erythrocyte CR1 (E-CR1), and platelet-bound C4d (P-C4d) are highly sensitive and specifi c biomarkers for lupus diagnosis. 14,15 Initial studies indicate that these CB-CAP provide signifi cant added value to current diagnostic tests for SLE, and are capable of capturing the majority of patients who test negative for anti-double stranded DNA (dsDNA). 14 During these investigations, we found that patients with abnormal levels of E-C4d would not necessarily have abnormal levels of P-C4d and vice versa, suggesting a surprising and intriguing hematopoietic lineage specificity. Th ese observations lead to the hypothesis that lymphocyte-bound complement activation products (LB-CAP) may also serve as biomarkers for lupus diagnosis. Th is hypothesis was addressed in a cross-sectional study to determine and compare levels of LB-CAP in patients with SLE, patients with other diseases and healthy individuals. Patients and Methods Study participants All study participants were 18 years of age or older and provided written informed consent. No one was excluded based on gender or ethnicity. Ethnicity was self-reported by study participants. Th e University of Pittsburgh Institutional Review Board approved this study. Patients with SLE who met the ACR 1982 6 or 1997 7 revised classifi cation criteria were recruited for this study during routine visits to the University of Pittsburgh Lupus Patient Care and Translational Research Center. A total of 224 patients were studied from June 2004 through August 2007. As part of their routine care, all patients with SLE underwent routine blood work including complete blood count, erythrocyte sedimentation rate, serum levels of C3 and C4, antinuclear autoantibodies (ANA), and anti-dsDNA level. Tests for ANA (fl uorescent assay) and anti-dsDNA (fl uorescent assay using Crithidia lucillae or enzymelinked immunosorbent assay) were performed by certified clinical pathology laboratories. In addition, each of these patients underwent a history and physical examination by a physician (AHK or SM), who was blinded to the LB-CAP results. Disease activity was assessed at the time of the visit using the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) 16 and the Systemic Lupus Activity Measure (SLAM). 17 One hundred seventy-nine patients with non-SLE autoimmune or infl ammatory diseases, including scleroderma, idiopathic inflammatory myositis, Sjögren's syndrome,
Complement levels and risk of organ involvement in patients with systemic lupus erythematosus
Lupus science & medicine, 2017
Complement plays a major role in SLE. Complement participation has been linked to disease activity and damage. Our objective was to estimate the association of complement behaviour with clinical manifestations, visceral injury and mortality in patients with SLE. Complement determinations (C3 and C4 levels) were analysed in patients with SLE (fulfilling American College of Rheumatology (ACR) or Systemic Lupus International Collaborating Clinics (SLICC)criteria) seen at a university hospital between 2000 and 2013. Patients were grouped in those with permanent C3 and/or C4 low values (low complement group), those with C3 and C4 constant normal values (normal complement group) and those with fluctuant values (periods of normal and periods of low values: fluctuant group). Clinical characteristics and mortality were analysed and compared between groups. 270 patients with SLE were included (242 females, 89.6%), mean age at diagnosis was 34.2 years (SD 15.8). 75 patients had fluctuant level...
International Journal of Molecular Sciences
Autoantibodies against the complement component C1q (anti-C1q) are among the main biomarkers in lupus nephritis (LN) known to contribute to renal injury. C1q, the recognition subcomponent of the complement classical pathway, forms a heterotetrameric complex with C1r and C1s, and can also associate a central complement regulator and C1 Inhibitor (C1-Inh). However, the frequency and the pathogenic relevance of anti-C1r, anti-C1s and anti-C1-Inh autoantibodies remain poorly studied in LN. In this paper, we screened for anti-C1q, anti-C1r, anti-C1s and anti-C1-Inh autoantibodies and evaluated their association with disease activity and severity in 74 LN patients followed up for 5 years with a total of 266 plasma samples collected. The presence of anti-C1q, anti-C1r, anti-C1s and anti-C1-Inh was assessed by ELISA. IgG was purified by Protein G from antigen-positive plasma and their binding to purified C1q, C1r and C1s was examined by surface plasmon resonance (SPR). The abilities of anti...