anti-C1q Antibodies Research Articles

CD8+ Treg Cells Associated with Decreasing Disease Activity after Intravenous Methylprednisolone Pulse Therapy in Lupus Nephritis with Heavy Proteinuria

We focus on the role of CD8+ Treg cell in Intravenous methyl-prednisolone (IVMP) pulse therapy in forty patients with active Class III/IV childhood lupus nephritis (LN) with heavy proteinuria. IVMP therapy for five days. From peripheral blood mononuclear cells (PBMCs) and renal tissues, we saw IVMP therapy definitely restoring both CD4+CD25+FoxP3+ and CD8+CD25+Foxp3+ Treg cell number plus greater expression with intracellular IL-10 and granzyme B in CD8+FoxP3+ Treg from PBMCs. IVMP-treated CD8+CD25+ Treg cells directly suppressed CD4+ T proliferation and induced CD4+CD45RO+ apoptosis. Histologically, CD4+FoxP3+ as well as CD8+FoxP3+ Treg cells appeared in renal tissue of LN patients before IVMP by double immunohistochemical stain. CD8+FoxP3+ Treg cells increased in 10 follow-up renal biopsy specimens after IVMP. Reverse correlation of serum anti-C1q antibody and FoxP3+ Treg cells in PBMNCs (r = −0.714, P<0.01). After IVMP, serum anti-C1q antibody decrease accompanied increase of CD4+FoxP3+ Treg cells. CD8+Treg cells reduced interferon-r response in PBMCs to major peptide autoepitopes from nucleosomes after IVMP therapy; siRNA of FoxP3 suppressed granzyme B expression while decreasing CD8+CD25+Treg-induced CD4+CD45RO+ apoptosis. Renal activity of LN by SLEDAI-2k in childhood LN was significantly higher than two weeks after IVMP (P<0.01). CD8+FoxP3+ Treg cells return in post-IVMP therapy and exert crucial immune modulatory effect to control autoimmune response in LN.Trial Registration DMR97-IRB-259

Anti-dsDNA, anti-nucleosome and anti-C1q antibodies as disease activity markers in patients with systemic lupus erythematosus

In spite of the growing number of reports on the study of anti-nucleosome and anti-C1q antibodies, there are still controversies on their significance as disease activity markers in patients with systemic lupus erythematosus (SLE) and their use in everyday clinical practice. Our aim was to assess the presence of anti-dsDNA, anti-nucleosome and anti-C1q antibodies in SLE patients, as well as to establish their sensitivity, specificity, positive and negative predictive value, and their correlation with SLE and lupus nephritis clinical activity. The study enrolled 85 patients aged 45.3 +/- 9.7 years on the average, with SLE of average duration 10.37 +/- 7.99 years, hospitalized at the Institute,,Niska Banja" during 2011, and 30 healthy individuals as controls. Disease activity was assessed using Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). In all examinees the levels of anti-dsDNA, anti-nucleosome and anti-C1q antibodies were measured using the ELISA method with Alegria Test Strips Orgentec (Germany). Patients with active lupus nephritis had a higher presence of anti-C1q antibodies and higher co-positivity of anti-dsDNA, anti-nucleosome, and anti-C1q antibodies compared to those with inactive lupus nephritis (77.77% vs. 21.74%; p < 0.01). SLE patients with SLEDAI > or = 11 had a higher presence of antinucleosome (93.75% vs. 64.15%; p < 0.01) and anti-C1q antibodies (46.87% vs. 22.64%; p<0.05), as well as a higher mean level of anti-nucleosome antibodies (107.79 +/- 83.46 U/ml vs. 57.81 +/- 63.15 U/ml; p < 0.05), compared to those with SLEDAI of 0-10. There was a positive correlation between the SLEDAI and the level of anti-dsDNA (r=0.290; p<0.01), anti-nucleosome (r = 0.443; p < 0.001), and anti-C1q antibodies (r = 0.382; p < 0.001). Only anti-C1q antibodies demonstrated correlation with proteinuria (r = 0.445; p < 0.001). Anti-nucleosome and anti-C1q antibodies demonstrated association with SLE and lupus nephritis activity, suggesting their potential usefulness in making predictions about lupus nephritis and assessment of disease activity.

Autoantibodies against C1q as a Diagnostic Measure of Lupus Nephritis: Systematic Review and Meta-analysis.

ObjectivesTo evaluate the diagnostic accuracy of C1q autoantibodies in identifying lupus nephritis (LN) in patients with systemic lupus erythematosus (SLE).Data sources and methodsCitation indexes were searched and 370 articles published from 1977 to 2013 were evaluated. The 31 selected studies included in the meta-analysis were cross-sectional in design. Among the 31 studies, 28 compared anti-C1q antibodies in 2769 SLE patients with (n=1442) and without a history of LN (n=1327). Nine studies examined anti-C1q in 517 SLE patients with active (n=249) and inactive LN (n=268). Hierarchical summary receiver operating characteristic (HSROC) random effects models were fitted to pool estimates of accuracy across the studies.ResultsAnti-C1q antibodies discriminated between patients with and without a history of LN, with a median specificity of 73.5%. The HSROC model estimated the corresponding sensitivity to be 70.4%. A hypothetical patient with a 55% prior probability of having a history of LN as opposed to no history (the median prevalence across 28 eligible studies) would have a post-test probability of 76.4% following a positive test result (positive predictive value) or 33.0% following a negative test result (negative predictive value). For discriminating active from inactive LN the median specificity of anti-C1q antibodies was 80%, with a corresponding estimated sensitivity value 75.7% based on the HSROC model. A hypothetical patient with a 56% prior probability of active as opposed to inactive LN (the median prevalence across the 9 eligible studies) would have a post-test probability of 82.8% following a positive test result or 27.9% following a negative test result.ConclusionsAlthough C1q antibodies are associated with lupus nephritis the post-test probabilities are not sufficiently convincing to provide reasonable certainty of the presence or absence of history of disease/active disease.

Hypocomplementemic urticarial vasculitis syndrome – a case report

Hypocomplementemic urticarial vasculitis syndrome (HUVS) is a rare immune-complex small vessel systemic vasculitis involving kidney in about 50% of patients. Characteristic clinical features are recurrent urticaria, decreased serum complement, skin vasculitis, arthritis, eye inflammation, abdominal pain, glomerulonephritis and positive anti-C1q antibodies. We report a 36-year-old woman with a 12-year history of recurrent urticaria and 2 years of urticarial vasculitis. On admission, she also had arthritis, pleuritis and pericarditis, abdominal pain, pathologic urinalysis, low serum values of C3, C4 and CH50. All immunoserology was negative except for ANA 1:80 and anti-C1q 620 IU. ’Full-house’ immune complex vasculitis was demonstrated in skin and lung biopsies. A kidney biopsy showed diffuse proliferative segmental active and sclerosing glomerulonephritis with mesangial and endocapillary proliferation, neutrophil exudation, necrosis, extracapillary crescents and segmental and global glomerulosclerosis. ’Full-house’ glomerular and extensive extraglomerular vascular and tubulointerstitial immune deposits with dominant IgG, C3 and C1q were noted by immunofluorescence. Electron microscopy revealed electron dense deposits with an ultrastructural ’fingerprint’ pattern in the glomerular mesangium, transmembranous in capillary walls and in the arteriolar wall. Our patient fulfilled the criteria for HUVS and SLE, in accordance with the not infrequent clinical and immunoserological overlapping of the two diseases.

Serology of Lupus Erythematosus: Correlation between Immunopathological Features and Clinical Aspects

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the aberrant production of a broad and heterogenous group of autoantibodies. Even though the presence of autoantibodies in SLE has been known, for more than 60 years, still nowadays a great effort is being made to understand the pathogenetic, diagnostic, and prognostic meaning of such autoantibodies. Antibodies to ds-DNA are useful for the diagnosis of SLE, to monitor the disease activity, and correlate with renal and central nervous involvements. Anti-Sm antibodies are highly specific for SLE. Anti-nucleosome antibodies are an excellent marker for SLE and good predictors of flares in quiescent lupus. Anti-histone antibodies characterize drug-induced lupus, while anti-SSA/Ro and anti-SSB/La antibodies are associated with neonatal lupus erythematosus and photosensitivity. Anti-ribosomal P antibodies play a role in neuropsychiatric lupus, but their association with clinical manifestations is still unclear. Anti-phospholipid antibodies are associated with the anti-phospholipid syndrome, cerebral vascular disease, and neuropsychiatric lupus. Anti-C1q antibodies amplify glomerular injury, and the elevation of their titers may predict renal flares. Anti-RNP antibodies are a marker of Sharp's syndrome but can be found in SLE as well. Anti-PCNA antibodies are present in 5–10% of SLE patients especially those with arthritis and hypocomplementemia.

Pediatric Immunological Disorders Biorepository (PIDBioRep) at University of São Paulo Medical School, Brazil.

Pediatric Immunological Disorders Biorepository (PIDBioRep) at University of São Paulo Medical School, Brazil.

Glomerular C1q deposition and serum anti-C1q antibodies in anti-glomerular basement membrane disease

BackgroundAnti-glomerular basement membrane (GBM) disease is a well-known antibody-induced autoimmune disease. A few patients have glomerular C1q deposition, but it is usually absent on renal histopathology. The role of C1q deposition in kidney injury is unclear. Recently, anti-C1q antibodies are demonstrated to be pathogenic in the target organ damage of many autoimmune diseases, by facilitating C1q deposition and enhancing complement activation via classical pathway. In the current study, we investigated the associations between anti-C1q antibodies in sera and C1q deposition in kidney of patients with anti-GBM disease.ResultsIt was shown that the severity of kidney injury was comparable between patients with and without C1q deposition, including the prevalence of oliguria/auria, the median percentage of crescents in glomeruli and the mean concentration of serum creatinine. Serum anti-C1q antibodies were detected in 15/25 (60%) patients with a low titer. The prevalence of C1q deposition in kidney was comparable between patients with and without serum anti-C1q antibodies (26.7% vs. 30.0%, p > 0.05). No association was found between anti-C1q antibodies and the severity of kidney injury.ConclusionsThe classical pathway of complement may not play a pathogenic role in the kidney injury of human anti-GBM disease. Anti-C1q antibodies could be detected in more than half of patients, which need further investigations.

Anti-C1q antibodies as a follow-up marker in SLE patients

Anti-C1q antibodies as a follow-up marker in SLE patients

Effect of anti-C1q antibodies from SLE patients on complement activation

Effect of anti-C1q antibodies from SLE patients on complement activation

Immunoserological parameters in SLE: high-avidity anti-dsDNA detected by ELISA are the most closely associated with the disease activity

We assessed the relationship between the serum levels of antibodies against double-stranded DNA (dsDNA), C1q, nucleosomes, histones, C3 and C4 complement components with one another, with organ involvement and overall disease activity in patients with systemic lupus erythematosus (SLE). One hundred seventy-five sera from 99 patients with SLE, 31 sera of patients with other connective tissue diseases, and 20 sera from healthy blood donors were tested. SLE disease activity was assessed by modified SLEDAI-2K (M-SLEDAI-2K), not including complement and anti-dsDNA descriptors. Anti-dsDNA antibodies were measured by indirect immunofluorescence on Crithidia luciliae (CLIFT), standard enzyme-linked immunosorbent assay (ELISA) and ELISA for high-avidity antibodies. The most significant risk factor for renal involvement were anti-C1q antibodies (OR = 3.88, p < 0.05), high-avidity anti-dsDNA antibodies for polyserositis (OR = 7.99, p < 0.01), anti-histone antibodies for joint involvement (OR = 2.75, p < 0.05), and low C3 for cytopenia (OR = 11.96, p < 0.001) and mucocutaneous lesions (OR = 3.32, p < 0.01). Multiple linear regression analysis showed that disease activity in SLE could be predicted by the levels of antibodies against dsDNA determined by standard (p < 0.05) and high-avidity (p < 0.001) ELISA, and inversely associated with concentration of C3 (p < 0.001). Using stepwise method, high-avidity anti-dsDNA antibodies were found to be in the closest association to M-SLEDAI-2K. Moreover, positive test for high-avidity anti-dsDNA antibodies appeared as an independent risk factor for moderately to severely active disease (M-SLEDAI-2K>5) (OR = 5.5, p < 0.01). The presence of high-avidity anti-dsDNA antibodies represented a risk for renal, joint, and most importantly for serosal involvement. Our results suggest that simple and reliable ELISA for high-avidity anti-dsDNA antibodies is the test of good clinical utility for the assessment of global SLE activity.

THU0326 Association between Anti-C1 Q and Other Markers of Disease Activity with Nephritis in a Population of 160 Portuguese Patients with Systemic Lupus Erythematosus

BackgroundAnti-C1q autoantibodies have been described in patients with systemic lupus erythematosus (SLE) and their presence has been closely correlated with renal disease activity. Serum anti-C1q determination seems to be a...

AB0385 Anti-chromatin antibodies: a useful marker for early activity.

BackgroundThe anti-chromatin antibody is frequently is elevated in patients with active SLE and its titer correlates with activity.ObjectivesThe objective of this study is to determine the diagnostic value of anti-chromatin...

AB0688 Anti-C1Q antibody as a biomarker for systemic lupus erythematosus

BackgroundSLE is the prototype of the autoimmune systemic disease. It is characterized by the production of autoantibodies against the cell nucleus components in association with multiple clinical manifestations that affect...

AB0692 Anti-C1Q antibodies in correlation with lupus nephritis in patients treated by rituximab

ObjectivesThe aim of the study was to assess the levels of the antibody to C1q complement component (anti-C1q) in the sera of patients (pts) with lupus nephritis (LN) in relation...

SAT0473 Novel Biomarkers for the Assessment of Pediatric Systemic Lupus Erythematosus Nephritis (Preliminary Report)

BackgroundNephritis is the most common severe manifestation of pediatric Systemic Lupus Erythematosus (pSLE) and the major predictor of poor prognosis. Research for the detection of novel and accurate biomarkers, predictive...

C1q-targeted monoclonal antibody prevents complement-dependent cytotoxicity and neuropathology in in vitro and mouse models of neuromyelitis optica

Neuromyelitis optica (NMO) is an autoimmune disorder with inflammatory demyelinating lesions in the central nervous system, particularly in the spinal cord and optic nerve. NMO pathogenesis is thought to involve binding of anti-aquaporin-4 (AQP4) autoantibodies to astrocytes, which causes complement-dependent cytotoxicity (CDC) and downstream inflammation leading to oligodendrocyte and neuronal injury. Vasculocentric deposition of activated complement is a prominent feature of NMO pathology. Here, we show that a neutralizing monoclonal antibody against the C1q protein in the classical complement pathway prevents AQP4 autoantibody-dependent CDC in cell cultures and NMO lesions in ex vivo spinal cord slice cultures and in mice. A monoclonal antibody against human C1q with 11nM binding affinity prevented CDC caused by NMO patient serum in AQP4-transfected cells and primary astrocyte cultures, and prevented complement-dependent cell-mediated cytotoxicity (CDCC) produced by natural killer cells. The anti-C1q antibody prevented astrocyte damage and demyelination in mouse spinal cord slice cultures exposed to AQP4 autoantibody and human complement. In a mouse model of NMO produced by intracerebral injection of AQP4 autoantibody and human complement, the inflammatory demyelinating lesions were greatly reduced by intracerebral administration of the anti-C1q antibody. These results provide proof-of-concept for C1q-targeted monoclonal antibody therapy in NMO. Targeting of C1q inhibits the classical complement pathway directly and causes secondary inhibition of CDCC and the alternative complement pathway. As C1q-targeted therapy leaves the lectin complement activation pathway largely intact, its side-effect profile is predicted to differ from that of therapies targeting downstream complement proteins.

Hypocomplementemic urticarial vasculitis syndrome at the onset of systemic lupus erythematosus

Different autoimmune diseases can result in urticarial eruptions, in particular, in the form of such a rare immune disorder as hypocomplementemic urticarial vasculitis syndrome (HUVS). HUVS can be the debut of diffuse connective tissue disorders, in particular, systemic lupus erythematosus (SLE). To optimize the diagnostics of this syndrome, the authors describe the course of HUVS in a female patient aged 31 suffering from SLE and characterize particular features of the differential diagnostics of HUVS with skin disorders, in the first place, chronic urticaria. The syndrome is diagnosed clinically and confirmed by histology and laboratory examinations. In addition to urticarial eruptions, HUVS is also characterized by the severe course with systemic manifestations on the part of different organs, reduction in the level of the complimentary components in the serum and detection of specific markers of the disease such as anti-C1q antibodies.

Autoantibodies against complement C1q in patients with Behcet's disease: association with vascular involvement.

AIM: The aim of our study was to determine the prevalence of anti-C1q antibodies and their possible association with clinical presentation in Behcet's disease (BD) patients with special emphasis for patients with vascular involvement. METHODS: Plasma anti-C1q Abs levels were measured using an enzyme-linked immunosorbent assay in 51 BD patients and 25 age- and gender-matched healthy controls. RESULTS: We found elevated concentrations of anti-C1q more frequently in patients with BD (18%) than in healthy controls (8%). The highest prevalence was found in patients with vascular BD (42%) which was significantly higher than patients without vascular BD and healthy controls (p=0.025). Furthermore, patients with vascular BD had the highest mean anti-C1q levels when compared to BD patients without vascular involvement or healthy control subjects (p=0.015). We did not find significant differences in the prevalence of any other organ involvement between BD patients with elevated vs. normal anti-C1q ab levels. Anti-C1q ab levels positively correlated with ESR (r=0.383, p=0.006) and negatively with C4 (r=-0.304, p=0.030). CONCLUSION: In conclusion, we found an increased prevalence of anti-C1q autoantibodies in BD patients with vascular involvement. Further large scale longitudinal studies are required to assess and clarify the significance and the pathogenic role of anti-C1q antibodies in BD and other autoimmune diseases in which vasculitis is a component.

Complement system in SLE as a target for antibodies.

SLE is characterized by overproduction of various types of autoantibodies. Under certain circumstances, antibodies targeting some of the neoepitopes of the complement system can be seen. The most studied among antibodies directed against a component of the complement system is anti-C1q. Anti-C1q antibodies are present in approximately one third of the patients with lupus, who often have high clinical disease activity and in particular renal involvement. In the presence of high titers of anti-C1q antibodies also the levels of C1q and C3 and C4 components of the complement system are also usually low. The presence of the anti-C1q antibodies is not limited or specific just for SLE or lupus nephritis. For the first time, they were described in HUVS (Hypocomplementemic Urticarial Vasculitis Sydrome), later in Felty´s syndrome, rheumatoid vasculitis, hepatitis C, poststreptococcal glomerulonephritis or aging population.

Serum levels and renal deposition of C1q complement component and its antibodies reflect disease activity of lupus nephritis

BackgroundLupus nephritis is considered to be a principal cause of morbidity and mortality in SLE. Few studies focus on the association between anti-C1q antibodies in circulation and renal C1q deposition in human lupus nephritis. In this study, we detected the serum levels of C1q, presence of anti-C1q antibodies in circulation, renal C1q deposition and further analyzed their associations with clinical and pathological activity in a large cohort of Chinese lupus nephritis patients.MethodsSera and renal biopsies from 218 consecutive patients with lupus nephritis with long-term follow up data were studied. Sera were tested for levels of C1q and anti-C1q autoantibodies. Associations of levels of C1q, anti-C1q autoantibodies with renal deposition of C1q, clinical and histopathological data and renal outcome were further investigated.ResultsThe levels of serum C1q were significantly lower in lupus nephritis than that in normal controls [33.81 ± 20.36 v.s. 61.97 ± 10.50 μg/ml (P < 0.001)]. The prevalence of anti-C1q antibodies, ratios of glomerular and vascular deposition of C1q in patients with lupus nephritis were 42.7% (93/218), 71.6% (156/218) and 86.2% (188/218), respectively. The serum C1q levels and anti-C1q antibodies were associated with SLEDAI scores (P < 0.001, P = 0.012, respectively), renal total activity indices scores (P < 0.001, P < 0.001, respectively). Granular positive staining of C1q and IgG by immunofluorescence was co-localized almost completely along the glomerular capillary wall and mesangial areas. Patients with anti-C1q antibodies presented with significantly lower serum C1q levels than those without it (23.82 [0.60, 69.62] μg/ml v.s. 37.36 [0.64, 82.83] μg/ml, P < 0.001). The presence of anti-C1q antibodies was associated with the presence of glomerular C1q deposition (P < 0.001), but not with the presence of renal vascular C1q deposition (P = 0.203).ConclusionAnti-C1q autoantibodies were closely associated with serum levels of C1q and glomerular deposition of C1q. Kidney is at least one of the target organs of anti-C1q autoantibodies.