Autoantibodies against Complement Classical Pathway Components C1q, C1r, C1s and C1-Inh in Patients with Lupus Nephritis (original) (raw)
Related papers
Relevance of Anti-C1q Autoantibodies to Lupus Nephritis
Annals of the New York Academy of Sciences, 2009
The first component of the classical pathway of the complement system (C1q) is considered to have a crucial role in the clearance of immune complexes (ICs) as well as in the removal of waste material originating from apoptotic cells. A prolonged exposure of C1q epitopes to the immune system could eventually lead to an autoimmune response against itself. Although autoantibodies against C1q are found in several diseases, their clinical interest originates from their strong association to active lupus nephritis (LN). Several studies indicate that anti-C1q autoantibodies could serve as a reliable serologic marker in the assessment of LN activity compared to other immunological tests. Additionally, it was suggested that anti-C1q autoantibodies could play a role in LN pathogenesis. Their potential pathogenic actions likely depend on genetic background, titers, Ig classes and subclasses, and specific epitopes of anti-C1q autoantibodies as well as C1q availability and allocation. It is still unclear which different types of anti-C1q autoantibodies dominate in each case and if their upregulation is pathogenic, an epiphenomenon of aberrant tissue damage, or compensatory to an uncontrolled immune response.
Journal of Biological Chemistry, 2015
Background: Autoantibodies against complement C3 are found in patients with the autoimmune disease systemic lupus erythematosus. Results: C3 autoantibodies are found in 30% of lupus nephritis patients and inhibit C3 interaction with the regulatory proteins Factor H and CR1. Conclusion: C3 autoantibodies have overt capability to overactivate complement. Significance: C3 autoantibodies can contribute to the pathological process in lupus nephritis. Lupus nephritis (LN) is a complication of the autoimmune disease systemic lupus erythematosus. Because the complement system plays a critical role in orchestrating inflammatory and immune responses as well as in the clearance of immune complexes, autoreactivity to complement components may have considerable pathological consequences. Autoantibodies against the central complement component C3 have been reported in systemic lupus erythematosus, but their molecular mechanism and functional relevance are not well understood. The objective of this study was to evaluate the frequency and the functional properties of the anti-C3 autoantibodies. Anti-C3 autoantibodies were measured in plasma of 39 LN patients, and identification of their epitopes on the C3 molecule was performed. By using surface plasmon resonance, we analyzed the influence of patient-derived IgG antibodies on the interaction of C3b with Factor B, Factor H, and complement receptor 1. The capacity of these antibodies to dysregulate the C3 convertase on the surface of endothelial cell was measured by flow cytometry. Here we report that the frequency of anti-C3 autoantibodies in LN is ϳ30%. They inhibited interactions of the negative complement regulators Factor H and complement receptor 1 with C3b. An enhanced C3 deposition was also observed on human endothelial cells in the presence of C3 autoantibodies. In addition, anti-C3 autoantibody levels correlated with disease activity. In conclusion, the anti-C3 autoantibodies in LN may contribute to the autoimmune pathology by their capacity to overactivate the complement system.
Rheumatology International, 2011
Associations of diVerent assays for antibodies to C1q (anti-C1q) and to dsDNA (anti-dsDNA) and of complements C3 and C4 with disease activity in patients with systemic lupus erythematosus (SLE) were studied. The clinical manifestations of 223 SLE patients were recorded, and the disease activity was assessed by the SLEDAI score. Anti-C1q were determined by two enzyme-linked immunosorbent assays (ELISA) and anti-dsDNA by a radioimmunoassay (RIA), a Crithidia immunoXuorescence (IF) assay and three ELISA assays using human telomere DNA, plasmid DNA circles, or calf thymus DNA as antigens, respectively. Complement C3 and C4 were determined by nephelometry. Control sera were obtained from 98 blood donors. In patients with SLE, the prevalence of anti-C1q was 17-18% and that of anti-dsDNA was 36-69%. Anti-C1q, anti-dsDNA, and complement C3 and C4 correlated well with the overall activity of SLE (r = 0.323-0.351, 0.353-0.566, and ¡0.372-0.444, respectively; P < 0.001). Sensitivity, speciWcity, positive predictive value, and negative predictive value for active lupus nephritis among SLE patients were 40-44, 92, 29, and 91-92% for anti-C1q and 48-68, 29-66, 11-16, and 86-91% for anti-dsDNA, respectively. Patients with active nephritis had higher levels of anti-C1q and lower levels of C3 and C4 than patients with inactive nephritis (P = 0.003-0.018). The corresponding associations of anti-dsDNA were somewhat weaker (P = 0.023-0.198). Hematological parameters reXecting disease activity correlated clearly better with anti-dsDNA and complement C3 and C4 than with anti-C1q. Anti-C1q is inferior to anti-dsDNA as a diagnostic test in SLE and in the evaluation of overall clinical activity of the disease. Anti-C1q together with complement C3 and C4 may oVer useful additional information to monitor lupus nephritis activity. There are no practical diVerences between diVerent assays for anti-C1q and anti-dsDNA.
Indian Journal of Nephrology, 2012
and deposition of circulating immune complexes (CICs) that further leads to an intense inflammatory response and tissue damage. [1,2] Complement activation in SLE is predominantly due to the interaction of a C1q component with the immune complexes, which is the first component of a classical complement pathway. Deficiency of C1q leads to autoimmunity, associated with impaired apoptotic clearance and appearance of glomerular apoptotic bodies. Deficiency of classical complement components such as C1q and C4 is strongly associated with the pathogenesis of SLE. [3-6] Mannose-binding lectin (MBL), an acute phase protein, is responsible for complement activation via the lectin pathway. The MBL plays an important role in the clearance of immune complexes. The MBL is also reported to facilitate apoptotic cell clearance. In recent times, MBL deficiency has emerged as a probable cause for SLE susceptibility. [1,7] Anti-C1q antibodies are directed against the collagenlike region of C1q and are strongly correlated with
PloS one, 2016
Systemic lupus erythematosus is a chronic autoimmune disease with multifactorial ethiopathogenesis. The complement system is involved in both the early and late stages of disease development and organ damage. To better understand autoantibody mediated complement consumption we examined ex vivo immune complex formation on autoantigen arrays. We recruited patients with SLE (n = 211), with other systemic autoimmune diseases (n = 65) and non-autoimmune control subjects (n = 149). Standard clinical and laboratory data were collected and serum complement levels were determined. The genotype of SNP rs1143679 in the ITGAM gene was also determined. Ex vivo formation of immune complexes, with respect to IgM, IgG, complement C4 and C3 binding, was examined using a functional immunoassay on autoantigen microarray comprising nucleic acids, proteins and lipids. Complement consumption of nucleic acids increased upon binding of IgM and IgG even when serum complement levels were decreased due to con...
Lupus science & medicine, 2016
The relationship between cell-bound complement activation products (CB-CAPs: EC4d, EC3d), anti-C1q, soluble complement C3/C4 and disease activity in systemic lupus erythematosus (SLE) was evaluated. Per protocol, at baseline all SLE subjects enrolled in this longitudinal study presented with active disease and elevated CB-CAPs. At each monthly visit, the non-serological (ns) Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA-SLEDAI) and the British Isles Lupus Assessment Group (BILAG)-2004 index scores were determined as was a random urinary protein to creatinine ratio (uPCR). Short-form 36 (SF-36) questionnaires were also collected. All soluble markers were determined using immunoassays, while EC4d and EC3d were determined using flow cytometry. Statistical analysis consisted of linear mixed models with random intercept and fixed slopes. A total of 36 SLE subjects (mean age 34 years; 94% female) were enrolled and evaluated monthly for an average 11 visits per su...
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 (...
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.
Serum complement levels as prognostic marker for monitoring treatment response in lupus nephritis
BIRDEM Medical Journal, 2021
Background: Lupus nephritis (LN) is one of the most common and serious manifestations of systemic lupus erythematosus (SLE) that causes significant morbidity and mortality. Certain biomarkers for LN are sometimes able to assess treatment response in lupus nephritis. This study aimed to compare serum complement levels (C3 and C4) as markers of treatment response of LN and their relation to the LN class in renal biopsy. Methods: This prospective observational study was conducted in the Department of Nephrology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh from July 2018 to August 2019. Twenty seven patients who were diagnosed with LN after kidney biopsy were included in this study. Serum complement levels (C3 and C4), 24 hours urinary total protein (24-hr UTP) and anti-double-stranded DNA (anti-ds DNA) were measured in all patients at baseline, 3 months and 6 months after treatment initiation. These biomarker values before and after treatment were compared be...
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,