anti-C1q Antibodies Research Articles

Correlation Between Serum Anti-C1q Antibody Levels and Renal Pathological Characteristics and Prognostic Significance of Anti-C1q Antibody in Lupus Nephritis

To investigate the relationship between serum anti-C1q antibody levels and renal pathological characteristics in lupus nephritis as well as the prognostic significance of serum anti-C1q antibody. Seventy-three patients with biopsy-proven lupus nephritis were enrolled. Anti-C1q antibody was measured in serum samples taken within 7 days before renal biopsy and remeasured at the end of the first and the third month after treatment. All patients were followed at least once a month for 3 months. A cross-sectional study analyzed the relationship between serum anti-C1q antibody levels and renal histopathology and nephritic activity, while a longitudinal study evaluated the prognostic significance of anti-C1q antibody levels in lupus nephritis. Fifty-eight of 73 patients (79.5%) were reported as having positive baseline serum anti-C1q antibody, with a mean level of 95.3 (+/- 55.2) U/ml. Significant differences were found in serum anti-C1q antibody levels between each World Health Organization (WHO) classification of lupus nephritis. The serum anti-C1q antibody level of WHO class IV was the highest. Serum anti-C1q antibody was positively correlated with the active and chronic indices in renal pathology. Patients with persistent high levels or increased titers of serum anti-C1q antibody tended to develop delayed remission in nephropathy. Serum anti-C1q antibody levels before and after treatment were relevant to renal remission, but serum anti-C1q antibody at the end of the third month after treatment was a stronger predictor for the prognosis after adjustment in the Cox's proportional hazards regression model. Serum anti-C1q antibody is a valuable noninvasive biological marker for evaluation of renal involvement and lupus prognosis.

Anti-factor B autoantibody in dense deposit disease

Dense deposit disease (DDD), also known as membranoproliferative glomerulonephritis type II, is a rare kidney disorder that is associated with dysregulation of the alternative pathway of complement. Autoantibodies against the C3bBb convertase termed C3 nephritic factor are common in DDD patients. Here we report an autoantibody that binds to complement factor B in a DDD patient who was negative for C3 nephritic factor. This anti-factor B autoantibody recognized an epitope within the Bb fragment and was able to bind to the C3bBb convertase. Upon binding, the anti-factor B autoantibody stabilized the convertase against both intrinsic and factor H-mediated extrinsic decay and thus enhanced C3 consumption. Functional analyses demonstrated that, in contrast to C3 nephritic factor, the anti-factor B autoantibody inhibited complement-mediated lysis in vitro due to inhibition of the C5 convertase and the terminal complement pathway. Analysis of C5a plasma levels indicated that not all C5 convertases are inhibited by the autoantibodies in the patient in vivo. Antigen array experiments confirmed the presence of anti-factor B autoantibodies and also revealed complement activating anti-C1q antibodies in the patient's plasma. In summary, the present report describes a new autoantibody in DDD that binds to factor B and to the alternative pathway C3 convertase and alters the kinetics of complement activation and regulation.

Fc RIIA Genotypes and Its Association with Anti-C1q Autoantibodies in Lupus Nephritis (LN) Patients from Western India

To identify Fc γ RIIA genotypes in Systemic Lupus Erythematosus (SLE) patients and their association with anti-C1q antibodies. Methods. Fc γ RIIA genotyping was done in eighty Indian SLE patients and eighty healthy controls using allele-specific PCR. Anti-C1q antibodies were measured by ELISA. Results. LN patients showed higher SLEDAI (6–32) as compared to SLE patients without renal manifestations and had SLEDAI between 6–23. Fc γ RIIA polymorphic frequency in SLE patients was R131/H131 (67.5%), R131/R131 (20%) and H131/ H131 (12.5%) as against that of normal population (62.5%, 10%, and 27.5%), respectively. Sixty two patients (77.5%) showed positivity for anti-C1q antibodies. LN patients showed elevated levels of anti-C1q antibodies (258.2 u/ml ± 38.5 U/mL) as compared to SLE patients without nephritis (134.6 ± 24.6 U/mL). Among anti-C1q positive patients, 71% had R131/H131 genotype, 22.6% had R131/R131 and remaining 6.4%, patients had H131/H131 genotype. All anti-C1q positive patients with R131/R131 genotype had elevated levels of anti-C1q antibodies (>100 U/ml), whereas among anti-C1q negative patients, none had R131/R131 genotype. Conclusion. This first report on Indian SLE patients supports the hypothesis that Fc γ RIIA R131 variant over expression may constitute a susceptibility factor for development of severe SLE manifestations in LN patients.

C1q and anti-C1q antibody levels are correlated with disease severity in Chinese pediatric systemic lupus erythematosus

The aim of this study was to measure the level of serum complement lq(Clq) and anti-C1q antibodies (ClqAb) in pediatric systemic lupus erythematosus (PSLE), and then analyze the correlation between the levels of serum Clq and ClqAb with disease activity and kidney damage. We investigated 90 PSLE patients, including 43 patients in active stage and 47 patients in remission. Our results showed that the level of serum Clq of PSLE patients was significantly lower than the level of healthy children and children with other rheumatic diseases. In contrast, the level of ClqAb of PSLE patients was significantly higher than the other groups. The level of serum Clq was negatively correlated with systemic lupus erythematosus (SLE) disease active index (SLEDAI) and the level of ClqAb was positively correlated with SLEDAI and kidney damage. The sensitivity of using ClqAb levels to diagnose PSLE was 95.6% and the specificity was 97.5%. 93.0% SLE patients who had high C1qAb levels also showed kidney damage. Therefore, the levels of C1q and C1qAb in serum reflect the disease severity of SLE. Decreased Clq and increased C1qAb is closely correlated with lupus nephritis (LN) in children and may have diagnosis values for child LN.

Hypocomplementemic urticarial vasculitis syndrome

Hypocomplementemic urticarial vasculitis syndrome (HUVS) is an uncommon immune complex-mediated entity characterized by urticaria with persistent acquired hypocomplementemia. First described in 1973, HUVS is associated with several systemic findings including leukocytoclastic vasculitis, severe angioedema, laryngeal edema, pulmonary involvement, arthritis, arthralgia, glomerulonephritis, and uveitis. These manifestations should be present for at least 6 months. Laboratory findings include low complement levels of classical pathway, namely C1q, C2, C3, and C4. The disease marker is the serum presence of anti-C1q antibodies. Treatment, based on disease severity, involves corticosteroids and other immunosuppressive agents that have demonstrated some success. Patients may have significant morbidity and mortality, most commonly caused by chronic obstructive pulmonary disease and acute laryngeal edema.

Synergy between Ficolin-2 and Pentraxin 3 Boosts Innate Immune Recognition and Complement Deposition

The long pentraxin 3 (PTX3) is a multifunctional soluble pattern recognition molecule that is crucial in innate immune protection against opportunistic fungal pathogens such as Aspergillus fumigatus. The mechanisms that mediate downstream effects of PTX3 are largely unknown. However, PTX3 interacts with C1q from the classical pathway of the complement. The ficolins are recognition molecules of the lectin complement pathway sharing structural and functional characteristics with C1q. Thus, we investigated whether the ficolins (Ficolin-1, -2, and -3) interact with PTX3 and whether the complexes are able to modulate complement activation on A. fumigatus. Ficolin-2 could be affinity-isolated from human plasma on immobilized PTX3. In binding studies, Ficolin-1 and particularly Ficolin-2 interacted with PTX3 in a calcium-independent manner. Ficolin-2, but not Ficolin-1 and Ficolin-3, bound A. fumigatus directly, but this binding was enhanced by PTX3 and vice versa. Ficolin-2-dependent complement deposition on the surface of A. fumigatus was enhanced by PTX3. A polymorphism in the FCN2 gene causing a T236M amino acid change in the fibrinogen-like binding domain of Ficolin-2, which affects the binding to GlcNAc, reduced Ficolin-2 binding to PTX3 and A. fumigatus significantly. These results demonstrate that PTX3 and Ficolin-2 may recruit each other on pathogens. The effect was alleviated by a common amino acid change in the fibrinogen-like domain of Ficolin-2. Thus, components of the humoral innate immune system, which activate different complement pathways, cooperate and amplify microbial recognition and effector functions.

Class IV-G and IV-S lupus nephritis in Chinese patients: a large cohort study from a single center

This study is to assess the difference between IV-G and IV-S in a large cohort of Chinese patients with lupus nephritis. The detailed data of patients with subclass IV-G and IV-S were retrospectively analyzed. Serum ANCA and anti-C1q antibodies were detected. A total of 172 cases were classified as class IV, including 152 cases with IV-G and 20 cases with IV-S. In IV-S, the level of haemoglobin was significantly higher (P = 0.024), proteinuria was milder (P = 0.003), serum creatinine was lower (P = 0.021), serum C3 was higher (P = 0.045) and the ratio of positive serum anti-cardiolipin antibodies was higher (P = 0.014). On pathological evaluation, the ratio of glomerular fibrinoid necrosis was significantly higher (P = 0.006) and the score of endocapillary hypercellualrity, interstitial inflammation and total activity indices was significantly lower (P < 0.001, P = 0.01, P = 0.006, respectively) in IV-S. The frequency of serum ANCA was significantly higher in IV-S than that in IV-G (20 vs 4.6%, P = 0.008). The frequencies of anti-C1q IgG1 and IgG3 subclass were significantly higher in IV-G (P = 0.006, P = 0.011, respectively). There are significant differences in clinical and pathological manifestations between IV-S and IV-G lupus nephritis which need further investigation.

Anti‐C1q Antibodies in Juvenile‐Onset Systemic Lupus Erythematosus

The objective of this study was to evaluate the presence of anti-C1q antibodies Hospital Israelita Albert Einstein Research Institute, São Paulo, Brazil in 67 juvenile systemic lupus erythematosus (JSLE) patients and 26 healthy controls and to assess the association of these antibodies with disease activity, nephritis, and presence of anti-double-stranded (ds)DNA. Anti-C1q antibodies were detected by ELISA. A higher frequency of anti-C1q antibodies was observed in JSLE patients compared to controls (20% vs. 0%, P = 0.016). Specificity of these antibodies was 100%[95% confidence interval (CI) 86.7-100%] and sensitivity was 19.4% (95% CI 10.7-30.8%) for a lupus diagnosis. The median anti-C1q antibodies was higher in JSLE patients compared to controls [median (range) 9.4 (5.5-127) vs. 7.3 (5-20) units, P = 0.004]. Remarkably, a positive Spearman's coefficient was found between anti-dsDNA and anti-C1q units (r = 0.42, P = 0.0004, 95% CI 0.19-0.60). Our results confirm a low frequency of anti-C1q antibody in our lupus populations, but the presence of anti-Clq antibodies appears to be a good marker for JSLE diagnosis.

Anti‐C1q Autoantibodies in Lupus Nephritis

Anti-C1q antibodies are found in a variety of diseases, in addition to systemic lupus erythematosus (SLE), and in 3-5% of normal individuals. In particular, anti-C1q antibodies are detected at a high titer in 100% of patients with hypocomplementemic urticarial vasculitis and in 30-48% of SLE patients. Their titer correlates with active renal disease with a sensitivity of 44-100% and a specificity of 70-92%. An increase in anti-C1q antibody titer has been suggested to be able to predict renal flares in lupus nephritis so that monitoring anti-C1q might be valuable for the clinical management of SLE patients as a noninvasive biological marker. Recently our group studied 228 patients affected by lupus nephritis and found that the association of anti-C1q, C3, and C4, in a multivariate analysis, provided the best prediction of renal flares, particularly in patients with focal and diffuse proliferative lupus nephritis and in the absence of antiphospholipid antibodies.

Which autoantibodies announce that lupus nephritis is on the way?

Systemic lupus erythematosus is characterized by a wide assortment of clinical traits, along with a profusion of autoantibodies. In practice, lupus nephritis is rather common, and dsDNA reactivity is crucial. Not only is this antibody a valuable asset for the diagnosis of systemic lupus erythematosus, but it may also contribute to its pathogenesis. Consistent with this view is that titer of anti-dsDNA antibody reflects the presence of lupus nephritis. However, this may rise or drop, before or during a renal flare. Other autoantibodies would thus be of use in monitoring the disease. These include anti-α-actinin, anti-C1q and antinucleosome antibodies. Yet, their prognostic value for lupus nephritis must be further investigated. The affinity of related autoantibodies for DNA should perhaps be taken into account, but more instrumental should be antinucleosome, anti-α-actinin and anti-C1q antibodies. They are associated together, but each may be combined with high-affinity anti-dsDNA, and particularly with an...

Detection of anti-C1q antibodies and anti-C1q globular head domain antibodies in sera from Chinese patients with lupus nephritis

Serum anti-C1q antibodies are associated with disease activity in patients with lupus nephritis. Recent studies showed that anti-C1q antibodies recognize both the collagen region and the globular head regions (gC1q) of individual A (ghA), B (ghB), and C (ghC) chains of C1q molecules. However, the clinical significance of anti-gC1q antibodies was not clear. This study is to investigate the frequency of antibodies against different parts of C1q molecule in sera from patients with lupus nephritis and their clinical significance. Sera from 83 patients with renal biopsy-proven lupus nephritis were collected at the day of renal biopsy. Sera from 30 patients with non-renal SLE (NR-SLE) and 100 healthy donors were used as controls, Serum anti-C1q antibodies, anti-collagen-like region (C1qCLR) antibodies, anti-globular head region (C1qGR) antibodies and anti-ghA, anti-ghB and anti-ghC antibodies were screened by ELISA using purified human C1q, C1qCLR, C1qGR and recombinant ghA, ghB and ghC as solid phase antigens. The association of these antibodies and clinical and histopathological features was further studied. The frequencies of positive anti-C1q and anti-C1qCLR antibodies in lupus nephritis group (46/83, 55.4%; 36/83, 43.4%, respectively) were significantly higher than that in patients with NR-SLE (4/30, 13.3%, P < 0.001; 5/30, 16.7%, P = 0.005, respectively) and healthy donors (5/100, 5.0%, P < 0.001; 4/100, 4%, P < 0.001, respectively). The levels of both SLE Disease Activity Index (SLEDAI) and renal biopsy Activity Index (AI) of patients were correlated with the levels of anti-C1q antibodies ( r = 0.520, P < 0.001; r = 0.321, P = 0.003, respectively) and anti-C1qCLR antibodies ( r = 0.387, P < 0.001; r = 0.261, P = 0.019, respectively). The levels of anti-C1q antibodies were closely correlated with that of anti-C1qCLR antibodies ( r = 0.588, P < 0.001). However, the prevalence of anti-C1qGR, anti-ghA, anti-ghB and anti-ghC antibodies in lupus nephritis group was only 1.2% (1/83), 3.6% (3/83), 2.4% (2/83) and 8.4% (7/83), respectively, which were comparable with that of NR-SLE and normal controls. In conclusion, serum anti-C1q antibodies and anti-C1qCLR antibodies are closely associated with disease activity in patients with lupus nephritis. However, gC1q might not be the dominant epitope of C1q molecule.

Antibodies Against Complement System in SLE and their Potential Diagnostic Utility

SLE is characterized by overproduction of various types of antibodies. Under certain circumstances, antibodies aiming some of the neoepitopes of the complement system can be seen. Neoepitopes are not present in the native proteins, but they appear after the structural change of the complement system. One of these antibodies binds the activated product C3 called iC3b; however, its possible part in the pathogenesis of a disease is unknown. Some of the antibodies to the component of the complement system are more significant. One of them is the C3 nephritic factor connected with partial lipodystrophy and with a certain form of mesangial glomerulonephritis. This factor also rarely appears in patients with SLE. Another antibody targets the C1 inhibitor and appears in some patients with lymphomas. Anti-C1q antibodies are present in approximately one third of the patients with lupus, who often have high clinical activity of the disease, and particularly, renal involvement. In the presence of high titers of anti C1q antibodies also the levels of C1q and C4 components of the complement system are also usually low. The levels of the C3 component of the complement system are only slightly lowered or sometimes not at all in SLE as already discussed above. However, according to the findings in our study, patients with higher anti-C1q antibodies seem to show the tendency to have lower serum levels of C3. 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 Urticar Vasculitis Syndrome), later in Felty´s syndrome, rheumatoid vasculitis, in hepatitis C or in aging population. The association between the presence of anti-C1q antibodies and the consumption of protein in the classic way of complement activation seen in SLE and in HUVS raises the question, whether these antibodies cause or amplify the classic way of complement activation. The alternative theory sees the anti-C1q antibodies as a mere product of this activation itself, which creates the neoepitopes in the molecule C1q.

Hemolytic assay for the measurement of functional human mannose-binding lectin: A modification to avoid interference from classical pathway activation

Diagnostic assays for measurement of functional mannose-binding lectin (MBL) in serum are widely performed as part of immune status assessment. Classical pathway mediated complement activity can interfere in these functional MBL assays. Here we describe classical pathway interference incidentally occurring in a previously described hemolytic MBL assay and the modification of this assay to prevent this artifact by addition of anti-C1q antibodies. Classical pathway interference in functional MBL assays can and should be inhibited to prevent that MBL deficiency is overlooked and patients are misdiagnosed.

Anti‐C1q antibodies: association with nephritis and disease activity in systemic lupus erythematosus

Anti-C1q antibodies have been described in systemic lupus erythematosus (SLE) as well as in other connective tissue diseases. They have been considered as a marker for disease activity and presence of nephritis. The aim of this study was to determine the prevalence of anti-C1q antibodies in Brazilian lupus patients as well as analyze their association with different clinical and serologic parameters. Sera from 81 SLE patients, based on the American College of Rheumatology (ACR) criteria, were collected from a lupus referral outpatient clinic in Salvador, Brazil. Antibodies to C1q were detected by an enzyme-linked immunoassay (ELISA) kit and antibodies to other cellular antigens identified by indirect immunofluorescence on HEp-2 cell substrate (ANA), or Crithidia luciliae (dsDNA), and to nucleosome by ELISA. A cutoff of 20 U was established for anti-C1q and anti nucleosome assays. Anti-C1q antibodies were detected in 39.5% (32/81) of SLE sera. The presence of anti-C1q antibodies was associated with proteinuria (P=0.028) but not with other laboratory or clinical features, such as anti nucleosome or anti-dsDNA antibodies, hematuria, urinary casts or renal failure, leukopenia, pericarditis, pleuritis, malar rash, seizures, and psychosis. There was a positive correlation between the titers of anti-C1q antibodies and the systemic lupuis erythematosus disease activity index (SLEDAI) score (r=0.370; P=0.001). This study in Brazilian SLE patients confirms previous findings of the association of anti-C1q antibodies with nephritis and disease activity.

The expressions of Toll-like receptor 9 and T-bet in circulating B and T cells in newly diagnosed, untreated systemic lupus erythematosus and correlations with disease activity and laboratory data in a Chinese population

Toll-like receptor 9 (TLR9) plays a controversial role in the pathogenesis of systemic lupus erythematosus (SLE). T-bet may be involved in the processes between the initiation of TLR9 activation and the antibodies’ production. To clarify the paradox of TLR9, we investigated the intracellular expressions of TLR9 and T-bet in B and T cells in peripheral blood samples from 35 newly diagnosed, untreated patients with SLE and 16 healthy subjects by flow cytometry (FCM). And we collected the clinic laboratory data obtained from the same individual blood sample tested by FCM each time. And the correlations among the expression levels of the two proteins and SLE laboratory data were calculated. We found the percentages of B cells expressing TLR9 and T-bet and of T cells expressing TLR9 were significantly elevated in SLE patients when compared with healthy controls. There was a significantly negative relationship between the proportion of B cells expressing TLR9 and SLE Disease Activity Index (SLEDAI) score. The serum levels of anti-dsDNA antibody reversely correlated with the mean fluorescence intensity (MFI) of B cells co-expressing T-bet and TLR9. The serum levels of anti-C1q antibody significantly associated with the proportion of B cells expressing T-bet. Also, the serum levels of IgM and IgA antibodies both significantly correlated with TLR9 and T-bet expressions in T and B cells. According to the immunological pathway knowledge and the mutually verified associations, the following conclusions are made. Expressions of TLR9 and T-bet were increased in patients with SLE. TLR9 may have a role to play in protecting against lupus. And the increase of the co-expression of TLR9 and T-bet may be of benefit to the protective antibodies’ production and pathogenic antibodies’ decline, and could be regarded as a good sign for lupus demission and/or treatment.

Complement-mediated injury of human glomerular endothelial cells by anti-C1q antibodies

Complement-mediated injury of human glomerular endothelial cells by anti-C1q antibodies

Occurrence of anti-C1q antibodies in type I hereditary angioedema

Occurrence of anti-C1q antibodies in type I hereditary angioedema

Are laboratory tests useful for monitoring the activity of lupus nephritis? A 6-year prospective study in a cohort of 228 patients with lupus nephritis

Objectives:To evaluate the role of immunological tests for monitoring lupus nephritis (LN) activity.Methods:C3, C4, anti-dsDNA and anti-C1q antibodies were prospectively performed over 6 years in 228 patients with LN.Results:In membranous...

Anti-C1q antibodies and IgG subclass distribution in sera from Chinese patients with lupus nephritis

Objective. Anti-C1q antibodies are common in sera from patients with lupus nephritis (LN) and are associated with disease activity. The current study aimed to further investigate the prevalence of serum IgG anti-C1q antibody, its subclass distribution and their clinical and pathological association in patients with LN. Sera were collected from 150 patients with renal biopsy-proven LN, diagnosed from 2000 to 2006 in our hospital, 30 patients with systemic lupus erythematosus (SLE) without clinical evidence of renal involvement (non-renal SLE, NR-SLE) and 63 healthy donors. ELISA was used to detect serum IgG anti-C1q antibody and its subclass. Their clinical and pathological associations were further analysed. The prevalence of IgG anti-C1q antibody in LN (84/150, 56%) was significantly higher than that in NR-SLE (6/30, 20%) and healthy controls (3/63, 4.8%) (P < 0.005, P < 0.001, respectively). The prevalence of anti-C1q antibody in patients with diffuse proliferative renal lesions (class IV) (59/82, 71.95%) was significantly higher than that in those with non-diffuse proliferative renal lesions (class II + III) (12/26, 46.15%, P = 0.016) and class V (13/42, 30.95%, P < 0.001). The prevalence of IgG2 (60/135, 44.44%) was significantly higher than that of IgG1 (37/135, 27.41%) and IgG3 (25/135, 18.52%) (P < 0.005, P < 0.001, respectively). IgG2 was associated with the occurrence of arthritis (P < 0.05), higher serum creatinine (P < 0.05) and lower serum C3 (P < 0.05). Of the 38 LN patients with sera both in active phase and in remission, 17 were anti-C1q antibody-positive in active phase and the antibody levels decreased in all and turned to negative in 9 (52.94%) in remission. Meanwhile, the ratio of turning negative of IgG1, IgG2 and IgG3 anti-C1q was 33%(2/6), 53.85% (7/13) and 100% (7/7), respectively. Anti-C1q antibodies are prevalent in LN and are closely associated with diffuse proliferative lesions. IgG2 anti-C1q might be pathogenic and IgG3 anti-C1q might be a more specific biomarker for monitoring disease activity.

Antibodies against C1q in anti-glomerular basement membrane nephritis

The prevalence of antibodies against the collagen-like region of the subcomponent of the first component of complement, C1q, was investigated in 11 patients with anti-glomerular basement membrane (GBM) nephritis. Anti-C1q antibodies (anti-C1qAb) were detected in seven patients. IgG anti-C1qAb were found in four and IgA anti-C1qAb in five patients. During follow up of the patients a relationship was observed between the levels of IgG anti-C1qAb and the levels of anti-GBM antibodies (anti-GBMAb). Gelfiltration experiments indicated that both IgG anti-C1qAb as well as IgG anti-GBMAb were monomeric and that binding also occurred with the F(ab')2 fragments of the antibodies. Although anti-C1qAb and anti-GBMAb are both directed against a collagen-like structure, it was demonstrated by means of inhibition experiments that anti-C1qAb and anti-GBMAb are directed against different antigenic sites. Comparison of patients with anti-GBM nephritis with and without anti-C1qAb revealed that there were no differences in disease activity or disease severity. Therefore, the results of this study suggest that anti-C1qAb do not play a direct pathogenetic role in anti-GBM nephritis.