Anti-C1q autoantibodies from active lupus nephritis patients could inhibit the clearance of apoptotic cells and complement classical pathway activation mediated by C1q in vitro

Anti-C1q antibodies are prevalent in patients with active lupus nephritis and were found to be closely associated with renal involvement and predictive for a flare of nephritis. However, the pathogenesis of anti-C1q antibodies involved in human lupus nephritis remains unclear. C1q, which plays a key role in apoptotic cell and immune complex removal, is a very important functional molecule in the pathogenesis of SLE. The aim of this study was to investigate the influence of anti-C1q autoantibodies from active lupus nephritis patients on the bio-functions of C1q in vitro. We purified IgG autoantibodies against C1q from lupus nephritis patients, and found that they could recognize C1q bound on early apoptotic cells at 30 μg/ml, and could significantly decrease the phagocytosis by macrophages of early apoptotic cells opsonized by 50 μg/ml C1q in comparison with normal IgG. Levels of circulating immune complexes of the ten patients were measured by a circulating immune complexes (CIC)-C1q Enzyme Immunoassay Kit. Anti-C1q autoantibodies affinity purified by microtiter plates could significantly inhibit the deposition of C3c on CIC-C1q in a dose dependent manner in comparison with IgG from 10 healthy blood donors. The binding of opsonized immune complexes to RBCs was significantly inhibited by anti-C1q autoantibodies purified by microtiter plates in a dose dependent manner. Our observations suggest that serum anti-C1q autoantibodies from active lupus nephritis patients could interfere with some biological function of C1q in vitro.     

Association of monocyte chemoattractant protein 1 (MCP-1) gene polymorphism with lupus nephritis in Egyptian patients

Background and study aimMonocyte chemoattractant protein-1 (MCP-1) is a member of CC chemokine that plays an important role in the recruitment of monocytes/macrophages into renal tubulointerstitium. A biallelic A/G polymorphism at position ∼2518 in the MCP-1 gene was found to regulate MCP-1 expression. MCP-1 and its A/G gene polymorphism have been implicated in the pathogenesis of some renal diseases. The aim of the study was to investigate the role of the MCP-1 gene polymorphism as early predictors of the development of glomerulonephropathy in SLE patients. We also aimed to measure the serum and urinary levels of MCP-1 in patients with SLE, to find out its relation to clinical disease activity.Methods140 SLE patients (100 with nephritis and 40 without nephritis) and 80 controls were included in this study. MCP-1 gene polymorphism was analyzed by polymerase chain reaction. Serum and urine MCP-1 level were measured using high-sensitivity enzyme-linked immunosorbent assay.ResultsThe A/A genotype was more common in controls than in SLE patients, whereas both the A/G (P < 0.000) and G/G (P < 0.000) genotypes were more frequent in SLE patients. Carriers of G allele of the MCP-1 ∼2518 polymorphism had more than 7 fold increased risk to develop glomerulo-nephropathy in patients with SLE. High MCP-1 circulating levels production from patients with A/G and G/G genotypes was significantly higher than in A/A genotype. In addition there were significant differences in the mean levels of serum MCP-1 (P < 0.001) and urinary MCP-1 (P < 0.001) between patients and controls.ConclusionThe present study provides a new evidence that the presence of MCP-1 A (-2518) G gene polymorphism and high circulating MCP-1 levels can play an important role in the development of SLE and nephropathy in Egyptians.     

Tumor-associated antigens in systemic sclerosis and systemic lupus erythematosus: Associations with organ manifestations,immunolaboratory markers and disease activity indices

BackgroundSome tumor-associated antigens (TAAs) are expressed on inflammatory cells. We previously detected increased production of CA15-3, CA19-9 and CA125 in rheumatoid arthritis (RA). The production of some TAAs may also be increased in patients with systemic sclerosis (SSc), systemic lupus erythematosus (SLE) and other connective tissue diseases. Some of these TAAs contain sialylated carbohydrate motifs and they are involved in tumor-associated cell adhesion and metastasis.ObjectivesWe assessed levels of TAAs in the sera of SSc, SLE patients, patients with infectious diseases and healthy subjects. Serum TAA levels were correlated with each other, as well as with disease activity markers and organ involvement.MethodsTAAs including CEA, CA15-3, CA72-4, CA125 and CA19-9 were assessed by immunoassay in the sera of 92 patients with SSc, 40 patients with SLE, 50 age- and sex-matched healthy controls, as well as with 40 patients with current bacterial or viral infections. Normal upper limits for these TAAs were 3.4 mg/l, 25 kU/l, 6.9 kU/l, 35 kU/l and 34 kU/l, respectively.ResultsThere were significantly more SSc patients showing abnormally high levels of CA19-9 (8.8% vs 2.0%), CA125 (11.0% vs 6.0%) and CA15-3 (28.4% vs 14.0%) in comparison to controls (p < 0.05). In SLE, significantly more patients had elevated levels of CEA (32.5% vs 20.0%), CA19-9 (7.5% vs 2.0%), CA125 (15.0% vs 6.0%) and CA72-4 (15.0% vs 8.0%) than did controls (p < 0.05). The mean absolute serum levels of CEA (6.6 ± 1.7 vs 1.8 ± 1.4 mg/l) and CA15-3 (22.9 ± 1.8 vs 18.6 ± 2.2 kU/l) were also significantly higher in SSc compared to controls (p < 0.05). We found numerous correlations between the serum levels of different TAAs within the SSc and SLE population. Among SSc patients, serum CEA (R = 0.290; p = 0.005), CA15-3 (R = 0.260; p = 0.020) and CA19-9 (R = 0.257; p = 0.013) correlated with renal involvement. Serum CA15-3 also correlated with joint involvement (R = 0.329; p = 0.003), ANA positivity (R = 0.288; p = 0.010) and CRP levels (R = 0.407; p < 0.001). Within the SLE population, serum CA72-4 correlated with central nervous involvement (R = 0.624; p = 0.004) and CA125 correlated with the SLEDAI composite activity index (R = 0.666; p = 0.002). Patients with infections exerted serum TAA patterns similar to healthy controls.ConclusionThe concentration of some TAAs may be elevated in the sera of patients with SSc or SLE in comparison to healthy subjects. Pathogenically, most of these TAAs contain carbohydrate motifs and thus they may be involved in inflammation-associated adhesive events. Furthermore, the production of some TAAs may correlate with organ involvement or disease activity in scleroderma or lupus.     

Urinary TWEAK and the activity of lupus nephritis

The TNF superfamily cytokine TWEAK induces mesangial cells, podocytes, and endothelial cells to secrete pro-inflammatory chemokines including MCP-1, IP-10 and RANTES, which are crucial in the pathogenesis of lupus nephritis (LN). As TWEAK regulates the secretion of these inflammatory mediators, we studied whether urinary TWEAK (uTWEAK) levels might be predictive and/or diagnostic in LN.In a cross-sectional study of a large, multi-center cohort of systemic lupus erythematosus (SLE) patients, uTWEAK levels were higher in patients with active as compared to never or non-active nephritis (median (IQR): 16.3 (9.9–23.0) versus 5.5 (2.3–16.8) pg/mg creatinine, p = 0.001), and levels of uTWEAK correlated with the renal SLE disease activity index (rSLEDAI) score (r = 0.405, p < 0.001). uTWEAK levels were higher in patients undergoing a flare as compared to patients with chronic stable disease (11.1 (8.1–18.2) and 5.2 (2.3–15.3) pg/mg creatinine, respectively; p = 0.036). Moreover, uTWEAK levels were significantly higher in patients undergoing a renal flare, as opposed to a non-renal flare (12.4 (9.1–18.2) and 5.2 (3.0–11.9) pg/mg creatinine, respectively; p = 0.029).An accurate, non-invasive method to repeatedly assess kidney disease in lupus would be very helpful in managing these often challenging patients. Our study indicates that urinary TWEAK levels may be useful as a novel biomarker in LN.     

Polymyositis/dermatomyositis and nasopharyngeal carcinoma: The Epstein–Barr virus connection?

BackgroundPolymyositis (PM) and dermatomyositis (DM) are associated with high risk of nasopharyngeal carcinoma (NPC) in Asian countries. Epstein–Barr virus (EBV) might induce autoimmunity and malignancies in susceptible individuals.ObjectivesTo investigate the association of EBV with PM/DM and NPC in PM/DM patients.Study designSerum levels of anti-EBV viral capsid antigens (VCA) and anti-EBV-coded nuclear antigens-1 (EBNA-1) antibodies were measured by ELISA, and EBV DNA loads were determined using real-time PCR for 98 PM/DM patients, 94 systemic lupus erythematosus (SLE) patients and 370 healthy controls (HC). Anti-transfer-RNA synthetase antibodies (ASA) were determined by radioimmunoprecipitation for PM/DM patients.ResultsThirteen (13.3%) of PM/DM patients vs. none of SLE patients had detectable NPC. ASA were detectable in 31.7% of PM/DM without malignancy, while lack of ASA in any PM/DM patient with NPC. IgA anti-EBNA-1 were detectable in 30.6% of PM/DM patients and 31.9% of SLE patients, but only in 4.1% of HC (odds ratio [OR] 10.44 and 11.12 respectively, both p < 0.001). Significantly higher positivity for IgA anti-EBNA-1 were observed in PM/DM with NPC than in those without malignancy (OR 44.7, p < 0.01). Significantly higher positivity for EBV genome were observed in PM/DM with NPC than in those without malignancy (OR 43.9, p < 0.01), in SLE patients (OR 13.2, p < 0.05) and in HC (OR 99.4, p < 0.001). EBV DNA loads were significantly higher in PM/DM with NPC compared with those without malignancy and HC.ConclusionsOur results showed a positive association of EBV with PM/DM and NPC. PM/DM patients who have IgA anti-EBNA-1 or increased EBV DNA loads should be highly suspected to have occult NPC.     

Anti-C1q autoantibodies

Autoantibodies to complement components are associated with various diseases. Anti-C1q antibodies are present in all patients with hypocomplementemic urticarial vasculitis, but also, with varying prevalence, in other conditions. In SLE, these antibodies are neither sensitive nor specific for this condition. They occur, however, more frequently in (proliferative) lupus nephritis, particularly during active disease. Furthermore, levels of anti-C1q rise, in many cases, prior to a relapse of lupus nephritis, suggesting a pathogenic role for the autoantibodies. Indeed, experimental studies strongly support a pathogenic role for anti-C1q in immune complex-mediated renal disease. In addition, anti-C1q may interfere with the clearance of apoptotic cells, so influencing induction and expression of autoimmunity.     

Correlation between the renal C1q deposition and serum anti-C1q antibody: a potential role of anti-C1q antibody in lupus nephritis

The anti-C1q antibody has been shown to be associated with lupus patients with renal involvement. We conducted a study to determine the relationship between the serum anti-C1q titer and the renal deposition of C1q. The serum anti-C1q was measured in 26 healthy controls and 47 systemic lupus erythematosus (SLE) patients who were divided into 2 groups as non-nephritis and nephritis SLE. We analyzed the relationship between the anti-C1q titers and SLE, renal C1q staining and the WHO classification for lupus nephritis. The result revealed that the serum anti-C1q was present in 50.8% of the SLE patients, that its levels in those with renal involvement were significantly higher than in the normal control group (61.540 +/- 87.720 U/ml vs 15.750 +/- 2.530 U/ml, p = 0.005). Besides, the serum anti-C1q levels were higher in the patients with lupus nephritis with C1q deposition in the kidney tissue (66.038 +/- 91.141 U/ml vs 16.652 +/- 3.097 U/ml, p < 0.01). There seems to be evidence supporting that the autoantibody anti-C1q might play a pathogenic role in lupus nephritis.     

Are anti-nucleosome antibodies a better diagnostic marker than anti-dsDNA antibodies for systemic lupus erythematosus? A systematic review and a study of metanalysis

BackgroundMethods to detect anti-nucleosome antibodies (ANuA) have been available for more than 10 years and the test has demonstrated its good sensitivity and high specificity in diagnosing systemic lupus erythematosus (SLE). Despite these data produced through clinical and laboratory research, the test is little used.ObjectiveTo verify the diagnostic performance of methods for measuring ANuA and to compare them with those for anti-dsDNA antibodies.Data sourcesA systematic review of English and non-English articles using MEDLINE and EMBASE with the search terms “nucleosome”, “chromatin”, “anti-nucleosome antibodies” and “anti-chromatin antibodies”. Additional studies were identified checking reference lists in the selected articles.Study selectionWe selected studies reporting on anti-nucleosome tests performed by quantitative immunoassays, on patients with SLE as the index disease (sensitivity) and a control group (specificity).A total of 610 titles were initially identified with the search strategy described. 548 publications were subsequently excluded based on abstract and title. Full-text review was undertaken as the next step on 62 publications providing data on anti-nucleosome testing; 25 articles were then excluded because they did not include either SLE patients or a control group, and 37 articles were selected for the metanalysis. Finally, a sub-metanalysis study was conducted on the 26 articles providing data on both ANuA and anti-dsDNA antibody assays in the same series of patients.Data extractionExtraction of data from selected articles was performed by two authors independently, using predefined criteria: the number of patients with SLE as the index case, and the number of healthy or diseased controls; specification of the analytical method used to detect anti-nucleosome and anti-dsDNA antibodies; the cut-off used in the study; and the sensitivity and specificity of the assay. Demographic and clinical data on the population investigated (adults or children; lupus patients with or without nephritis; patients with active or inactive disease) were also recorded and analyzed in a separate evaluation.ResultsThe systematic review and metanalysis showed that the overall sensitivity of the ANuA assay is 61% (confidence interval-CI, 60–62) and the specificity 94% (CI, 94–95). The overall positive likelihood ratio is 13.81 (CI, 9.05–21.09) and the negative likelihood ratio 0.38 (CI, 0.33–0.44). The odds ratio for having SLE in ANuA-positive patients is 40.7.The comparative analysis on anti-dsDNA antibodies conducted on the 26 studies which provided data for both antibodies showed that ANuA have greater diagnostic sensitivity (59.9% vs 52.4%) and a specificity rating only slightly higher (94.9% vs 94.2%). The probability that a subject with positive ANuA have SLE is 41 times greater than a subject with negative ANuA, while for anti-dsDNA the probability is 28 times greater.These figures are even more impressive in children, in whom ANuA have an odds ratio for the diagnosis of SLE of 146, compared to 51 for anti-dsDNA antibodies.In selected studies, ANuA (p < 0.0001) but not anti-dsDNA antibodies (p = 0.256) were significantly associated with disease activity measured by the international score systems. However, neither antibody appears to correlate with kidney involvement.ConclusionsData from the metanalysis have shown that ANuA have equal specificity but higher sensitivity and prognostic value than anti-dsDNA antibodies in the diagnosis of SLE. Despite a certain heterogeneity among the various studies, the use of ANuA appears more efficacious than anti-dsDNA.     

PTPN22 polymorphisms,but not R620W,were associated with the genetic susceptibility of systemic lupus erythematosus and rheumatoid arthritis in a Chinese Han population

ObjectivesThe present study aimed to detect a possible association between PTPN22 gene polymorphisms and rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) in a Chinese Han population.Methods7 PTPN22 SNPs were genotyped in 358 patients with RA and 713 patients with SLE, as well as 564 RA controls and 672 SLE controls by Restriction Fragment Length Polymorphism (RFLP). Association analyses were conducted on the whole data set. Significant relationships were also examined between clinical features and SNPs for both RA and SLE.ResultsRs2476601 was lack of polymorphism with a ⩽0.1% frequency in both SLE and RA patients and healthy controls in our study. The two SNPs rs1217414 and rs3811021 of PTPN22 shown strong association with both SLE (rs1217414T: p_adj = 6.07e−004, OR = 0.57; rs3811021C: p_adj = 4.68e−005, OR = 0.65) and RA (rs1217414T: p_adj = 2.01e−008, OR = 0.26; rs3811021C: p_adj = 0.028, OR = 0.70). And the rs3765598 revealed a strong risk factor for SLE (p = 9.38e−009, p_adj = 6.57e−008, OR = 1.93), but not for RA (p = 0.48, OR = 1.12). Moreover, protective haplotype ACTTC in RA (p = 7.73e−016, p_adj = 5.51−015, OR[95%CI] = 0.02[0.002–0.10]) and SLE (p = 8.29e−018, p_adj = 5.80e−017, OR[95%CI] = 0.11[0.06–0.21]) were observed. In addition, the distribution of risk haplotypes ACGTC and GCTTT in RA (ACGTC: p = 0.0006, p_adj = 0.004, OR[95%CI] = 1.85[1.29–2.63]; GCTTT: p = 2.62e−005, p_adj = 1.85e−004, OR[95%CI] = 2.40[1.57–3.65]) and SLE (ACGTC: p = 0.0006, p_adj = 0.004, OR[95%CI] = 1.85[1.29–2.63]; ACGTC: p = 7.74e−011, p_adj = 6.81e−010, OR[95%CI] = 2.21[1.12–3.34]; GCTTT: p = 2.40[1.57–3.65], p_adj = 2.26e−006, OR[95%CI] = 2.64[1.79–3.87]) were significant different from that in controls. Furthermore, significant association was observed between the PTPN22 rs3765598 and antinuclear antibodies 1 (ANA1) in SLE.ConclusionsOur data provide strong evidence that the rs1217414 and rs3811021 in PTPN22 gene might be common protective factors contributed to SLE and RA susceptibility in the Chinese Han population. While, the rs3765598 might increase the genetic susceptibility of SLE, but not RA.     

Anti-C1q autoantibodies in murine lupus nephritis

Autoantibodies against C1q can be found in the circulation of patients with several autoimmune diseases including systemic lupus erythematosus (SLE). In SLE there is an association between the occurrence of these antibodies and renal involvement. How anti-C1q autoantibodies contribute to renal disease is currently unknown. Cohorts of MRL-lpr mice, which are known to develop age-dependent SLE-like disease, were used to study the relationship between levels of anti-C1q autoantibodies and renal disease. We collected serum, urine and renal tissue and analysed autoantibodies, complement levels and renal deposition as well as renal function. At 2 months of age all mice already had elevated levels of anti-C1q autoantibodies, and elution of kidneys revealed the presence of these antibodies in renal immune deposits in MRL-lpr mice and not in control MRL^+/+ mice. In conclusion, anti-C1q antibodies are already present in serum and immune deposits of the kidney early in life and therefore can play a role in nephritis during experimental SLE-like disease in mice.     

Anti-C1q antibodies in hepatitis C virus infection

Autoantibodies against C1q have been described in many immune-complex diseases including hypocomplementaemic urticarial vasculitis and systemic lupus erythematosus (SLE). No study has focused on the role of anti-C1q antibodies in hepatitis C virus (HCV) infection. The aim of this study was (i) to evaluate the prevalence of anti-C1q antibodies in HCV infection; and (ii) to analyse the association of anti-C1q antibodies with clinical and biological features of HCV-mixed cryoglobulinaemia (MC) vasculitis. We searched for anti-C1q antibodies using an enzyme-linked immunosorbent assay (ELISA) test in 111 HCV patients (75 had cryoglobulin and 23 systemic vasculitis), 60 SLE patients and 109 blood donors. Anti-C1q antibodies were detected in 26% of HCV patients compared to 10% of healthy donors (P < 0.01), and 38% in patients with SLE. Although there was a higher prevalence of anti-C1q antibodies among HCV patients with type III cryoglobulin (50%, P < 0.01), the overall prevalence of anti-C1q antibodies was similar in HCV patients being cryoglobulin-positive or cryoglobulin-negative (26%versus 25%, P = 0.98). A significant association was found between anti-C1q antibodies and low C4 fraction of complement (P < 0.05). No association was found between anti-C1q antibodies and HCV genotype, severity of liver disease or with specific clinical signs of HCV-MC vasculitis. This study shows an increased prevalence of anti-C1q antibodies in HCV-infected patients. Anti-C1q antibodies were associated with low C4 levels. No association was found between anti-C1q antibodies and HCV-MC vasculitis, nor between anti-C1q antibodies and cryoglobulinaemia.     

Measurement of autoantibodies using multiplex methodology in patients with systemic lupus erythematosus

Autoantibodies are central to the diagnosis and assessment of systemic lupus erythematosus (SLE). A recent technique for the measurement of autoantibodies utilizes addressable laser bead immunoassay technology (BioPlex 2200) which permits the simultaneous detection of multiple autoantibodies and improved efficiency due to the shorter time to perform the assay and low volume of test samples and reagents. In the current study we have compared this technique to more traditional measures of autoantibody detection. The clinical and laboratory data and stored serum samples from the enrollment visit into a long-term lupus registry at a single academic medical center were used. Sera were examined for a panel of autoantibodies using the BioPlex ANA screen. The results were compared to the historical data on autoantibody profiles using indirect immunofluorescence (IIF) and ELISA. The association with global and organ specific SLE disease activity (nephritis) was also examined. The study consisted of 192 patients who were predominantly female (87%) and Caucasian (91%) with mean disease duration of 8.8 years. The frequency of ANA and anti-dsDNA by IIF and ELISA was 81.3% and 46.6% respectively and was higher than that found with BioPlex (75.5% and 31.8%). The latter detected a higher proportion of patients with autoantibodies to Sm (7.5% vs 16.7%), RNP (21.8% vs 24.0%), Ro (37.4% vs 41.7) and La (13.9% vs 23.4%). Overall agreement between assays varied between 71.4% and 92.5%. Additional autoantibodies identified by BioPlex were anti-chromatin antibodies which were similar in frequency to anti-dsDNA antibodies (33.9% and 31.8% respectively). There was a low frequency of anti-ribosomal P (6.8%), anti-Scl-70 (5.2%), anti-centromere B (3.7%) and anti-Jo-1 (0.5%). Several autoantibodies revealed significant associations with SLEDAI scores but in a multivariate analysis the only autoantibodies that approached statistical significance were anti-Sm (p = 0.094) measured by ELISA and anti-dsDNA (p = 0.082) measured by BioPlex. There was no association between any of the autoantibodies regardless of the method of detection and cumulative organ damage scores. Fifty-three patients (27.6%) had lupus nephritis of which 17 (32%) had active nephritis at the time of autoantibody determination. There was no significant association between a positive ANA (IIF) and any autoantibodies detected by ELISA with either the cumulative occurrence of lupus nephritis or active nephritis. In contrast, there was an association between BioPlex detected anti-dsDNA with the cumulative occurrence of nephritis (p = 0.074) which reached statistical significance with active nephritis at the time of antibody testing (p = 0.012). This was confirmed by multivariate analysis (p = 0.047). These results suggest reasonable agreement between the detection of lupus autoantibodies by ELISA and BioPlex. The latter demonstrated a better correlation with lupus nephritis.     

High concentrations of anti-caspase-8 antibodies in Chilean patients with type 1 diabetes

IntroductionDeregulation of apoptosis across the Fas–FasL pathway is an increasingly relevant phenomenon in the pathogenic mechanisms associated with autoimmune diseases. Caspase-8 initiates the activation of the apoptotic process and interacts directly with Fas in the membrane of the T lymphocyte.ObjectivesTo standardize an Elisa essay to measure the concentration of anti-caspase-8 antibodies in plasma of Type 1 Diabetes (T1D) patients and analyze their possible distribution and association with characteristics of the disease.Methods and subjects124 patients newly diagnosed with T1D and 132 controls: children and youngsters. ELISA test was standardized to detect anti-caspase-8 antibodies in plasma. It correlated the concentration of this antibody with classical markers of autoimmunity as anti-IA-2 and anti-GAD65, and the clinical characteristics at onset of diabetes mellitus. The statistical analysis was performed using logistic regression.ResultsPatients with T1D showed a higher concentration of anti-caspase-8 antibodies regarding the controls (87.5 ng/ml versus 24.3 ng/ml, p < 0.0001, values expressed as median). The proportion of patients with T1D and high concentrations of anti-caspase-8 (percentile 50–75) was significantly different from the control group (p < 0.0001). Anti-caspase-8 showed a strong association with positive anti-GAD65 (OR = 3.48, p < 0.035) and ketoacidosis (OR = 10.74, p < 0.0001) events, with glycemia and age at diagnosis as contributing variables.ConclusionThis is the first report in the literature of levels of anti-caspase-8 antibodies in T1D through ELISA. The high concentration in patients with T1D, and its strong correlation with anti-GAD65 auto-antibodies, suggests a potential role of anti-caspase-8 auto-antibodies as surrogate marker autoimmunity in T1D patients.     

Patterns of systemic lupus erythematosus expression in Europe

ObjectivesTo analyse the differences in disease expression of European SLE patients based on gender, age at diagnosis, and ethnicity.MethodsA two-year, retrospective, multicentre, observational study was carried out in five countries (France, Germany, Italy, Spain and the UK). Patients' clinical manifestations including disease activity, organ involvement, organ damage and flares were analysed.ResultsThirty-one centres enrolled 412 consecutive eligible patients (90.5% of women), with active disease, stratified by disease severity (half severe and half non-severe).Baseline characteristics included; mean (SD) age: 43.3 (13.6) years, SLE duration: 10.7 (8.0) years and age at disease diagnosis: 32.6 (13.0) years old. The mean (SD) SELENA-SLEDAI and SLICC/ACR scores were: 8.1 (6.7) and 0.82 (1.36), respectively. Over half of patients experienced flares (54.9%). The average number of annual flares was 1.01 (0.71) flares/year.In males compared to females, the renal system was more frequently active (53.8% vs 30.0%, p = 0.002), the mean SLICC/ACR score was higher (1.15 vs 0.79, p = 0.039) and the pulmonary system was more likely to be damaged (12.8% vs 3.8%, p = 0.010). Furthermore, patients diagnosed at younger age displayed more renal system activity (young: 56.3% vs adult: 33.4% vs elder: 8.9%, p < 0.001) and renal damage (25.0% vs 6.9% vs 2.2%, p = 0.018) compared to the others. The annual number of flares (1.13 vs 1.05 vs 0.81 flares/year, p < 0.0001), including the occurrence of severe flares (0.58 vs 0.51 vs 0.20, p < 0.0001), was also higher in these patients.Conversely, greater organ damage was observed in patients diagnosed at an older age compared to the others. The mean SLICC/ACR score was higher (1.31 vs young: 0.88 and adult: 0.78, p < 0.001) in patients diagnosed in the older age groups. The pulmonary (13.3% vs younger: 0% vs adult: 3.7%, p = 0.030) and cardiovascular (17.8% vs younger: 0% vs adult: 2.9%, p < 0.001) systems were more frequently damaged in these patients.Black African descents showed greater disease activity compared to Caucasian patients. They flared more often (77.1% vs 48.6%, p = 0.001) and experienced a greater number of annual flares (1.57 vs 0.89 flares/year, p < 0.0001), mainly more severe flares (0.89 vs 0.38/year, p < 0.0001). They also were more likely to experience renal system damage.ConclusionThe study showed clearly two patient subsets. The disease was the most active in Black African descents, and this phenomenon has never been described before in continental Europe. The disease was also more active in patients diagnosed at a younger or adult. Greater disease damage was observed in males and in patients diagnosed at an older age.     

Antigen-specific H1N1 influenza antibody responses in acute respiratory tract infections and their relation to influenza infection and disease course

BackgroundEarly antibody responses to influenza infection are important in both clearance of virus and fighting the disease. Acute influenza antibody titers directed toward H1-antigens and their relation to infection type and patient outcomes have not been well investigated.ObjectiveUsing hemagglutination inhibition (HI) assays, we aimed to characterize the H1-specific antibody titers in patients with influenza infection or another respiratory infection before and after the H1N1-pandemic influenza outbreak. Among patients with acute influenza infection we related duration of illness, severity of symptoms, and need for hospitalization to antibody titers.MethodsThere were 134 adult patients (average age 34.7) who presented to an urban academic emergency department (ED) from October through March during the 2008–2011 influenza seasons with symptoms of fever and a cough. Nasal aspirates were tested by viral culture, and peripheral blood serum was run in seven H1-subtype HI assays.ResultsAcutely infected influenza patients had markedly lower antibody titers for six of the seven pseudotype viruses. For the average over the seven titers (log units, base 2) their mean was 7.24 (95% CI 6.88, 7.61) compared with 8.60 (95% CI 8.27, 8.92) among patients who had a non-influenza respiratory illness, p < 0.0001. Among patients with seasonal influenza infection, titers of some antibodies correlated with severity of symptoms and with total duration of illness (p < 0.02).ConclusionIn patients with acute respiratory infections, lower concentrations of H1-influenza-specific antibodies were associated with influenza infection. Among influenza-infected patients, higher antibody titers were present in patients with a longer duration of illness and with higher severity-of-symptom scores.     

Immune deposition of C1q and anti-C1q antibodies in the kidney is dependent on the presence of glomerular IgG

Anti-C1q autoantibodies are found frequently in patients with Systemic Lupus Erythematosus (SLE) and several studies indicate that these autoantibodies are associated with renal involvement. We have shown earlier that administration of anti-C1q antibodies to normal BALB/c mice results in the deposition of these antibodies and C1q in the kidney. In the present study we have investigated which factors are essential for this C1q-anti-C1q deposition. Injection of anti-C1q antibodies in C57BL/6 mice results in deposition of both C1q and anti-C1q in glomeruli, while administration of equal concentrations of anti-C1q to immunoglobulin deficient Rag2-/- mice did not result in deposition of anti-C1q antibodies. Analysis of renal sections of naive Rag2-/- mice revealed absence of mouse IgG and C1q in the glomeruli, while circulating C1q was within normal levels. Reconstitution of Rag2-/- mice with IgG, either by injection with purified mouse IgG or by splenocyte transfer, resulted in restored localization of mouse IgG together with C1q in the kidney. Subsequent injection of anti-C1q antibodies in these IgG reconstituted mice resulted in clear deposition of C1q together with anti-C1q in the kidneys comparable to that found in C57BL/6 mice receiving anti-C1q. We propose that the continuous presence of serum derived non-immune IgG in the glomerulus serves as a target for low affinity interactions with C1q, which then can serve as antigen for anti-C1q antibodies. Therefore we hypothesize that high and fluctuating levels of IgG as observed in patients with SLE may contribute to flares of renal inflammation in those patients with anti-C1q autoantibodies.     

Démarche diagnostique en auto-immunité : apport de la technologie Multiplex. Exemple de la gamme QUANTA Plex™ (Inova)

The detection of autoantibodies was often useful to diagnose and/or to classify autoimmune diseases.ObjectiveThe aim of this study was to compare the new Luminex^™ technology for anti-ENA, ANCA, anti-TPO and anti-TG antibodies detection with conventional methods.MethodsQUANTA Plex^™ SLE 8, ANCA and Thyroid Profile provided by Inova (Ménarini, France) were used to analyze 815 serum samples sent to the laboratory for the detection of anti-ENA (n = 400), ANCA (n = 161), anti-thyroid antibodies (n = 254).ResultsFor anti-ENA detection, the global concordance was 95.6%. For ANCA detection, the concordance was respectively 78.5 and 91.4% for anti-PR3 and anti-MPO. For thyroid antibodies, the concordance was respectively 90 and 88% for anti-TPO and anti-TG.ConclusionUse of QUANTA Plex^™ Profiles was easy to rapidly and simultaneously detect the most common autoantibodies in autoimmune diseases. These tests appear to be specific and sensitive and will be promute in diagnosis of autoimmune diseases.     

Anti-C1q in chronic hepatitis C Virus genotype IV infection: association with autoimmune rheumatologic manifestations

A growing body of evidence suggests that anti-complement-1q (anti-C1q) antibodies are elevated in a variety of autoimmune disease. Therefore, we investigated their prevalence and clinical significance in plasma of patients with hepatitis C virus (HCV) genotype IV in the presence and absence of autoimmune extra hepatic manifestations in comparison to normal healthy individuals. Plasma Anti-C1q Abs levels were assessed by an Enzyme Linked Immunosorbant Assay in 91 chronic HCV-infected patients (51 with and 40 without autoimmune rheumatic manifestations) and 40 healthy volunteers matched for age and gender. Epidemiological, clinical, immunochemical and virological data were prospectively collected. Positive Anti-C1q antibodies were more frequent among HCV patients with extra-hepatic autoimmune involvement, than those without and healthy control subjects. No significant correlations were found between Anti-C1q levels with either the liver activity or the fibrosis scores. In HCV-patients with autoimmune involvements, plasma Anti-C1q levels were significantly higher in patients with positive cryoglobulin, and in those with lymphoma than in those without. These results were confirmed by multivariate analysis. Further large scale longitudinal studies are required to assess and clarify the significance and the pathogenic role of anti-C1q antibodies among HCV infected patients with positive cryoglobulinaemia and lymphoma.     

Hierarchical cluster and survival analyses of antisynthetase syndrome: Phenotype and outcome are correlated with anti-tRNA synthetase antibody specificity

The clinical phenotype and evolution of antisynthetase syndrome (ASS) are heterogeneous. This study was therefore undertaken to identify subgroups of ASS patients with similar clinico-biological features and outcomes. This retrospective multicentric study included 233 consecutive patients with three different anti-aminoacyl-tRNA-synthetase antibodies (anti-ARS): anti-Jo1 (n = 160), anti-PL7 (n = 25) and anti-PL12 (n = 48). To characterise ASS patients, bivariate, multiple correspondence (MCA), cluster and survival analyses were performed.Interstitial lung disease (ILD) and myositis were the most common ASS manifestations. However, their respective frequencies were correlated to anti-ARS specificity: ILD was more frequent (80% and 88% vs 67%, p = 0.014) whereas myositis was less common (44% and 47% vs 74%, p < 0.001) in patients with anti-PL7 and anti-PL12 compared to anti-Jo1. The MCA suggested that anti-PL7 and anti-PL12 phenotypes were close to one another and distinct from anti-Jo1. The clustering analysis confirmed these data, identifying subgroups strongly defined by the anti-ARS specificity and other clinical features. Cluster 1 (n = 175, 86% of anti-Jo1) defined patients with the most diffuse phenotype, whereas patients from cluster 2 (n = 48, 96% of anti-PL12 and anti-PL7) exhibited a disease more restricted to the lung. Patient survival was also conditioned by the anti-ARS specificity, and was significantly lower in patients with anti-PL7/12 rather than anti-Jo1 (p = 0.012). Other factors associated with poor survival were mostly related to pulmonary involvement, including severe dyspnea (p = 0.003) and isolated ILD (p = 0.009) at diagnosis. In patients with ASS, the phenotype and the survival were correlated with the anti-ARS specificity.     

Development of anti-hepatitis B surface (HBs) antibodies after HBs antigen loss in HIV-hepatitis B virus co-infected patients

BackgroundHepatitis B surface antigen (HBsAg)-seroconversion, or loss of HBsAg and acquisition of anti-hepatitis B surface (HBs) antibodies, defines functional cure of chronic hepatitis B virus (HBV) infection. After HBsAg-loss, little is known regarding the development of anti-HBs antibodies and even less so in individuals co-infected with HIV.ObjectivesTo determine anti-HBs antibody kinetics after HBsAg-loss and explore determinants of HBsAg-seroconversion in HIV-HBV co-infected patients.Study designPatients enrolled in the French HIV-HBV cohort were included if they had >1 study visit after HBsAg-loss. Individual patient kinetics of anti-HBs antibody levels were modeled over time using mixed-effect non-linear regression, whereby maximum specific growth rate and maximal level of antibody production were estimated from a Gompertz growth equation.ResultsFourteen (4.6%) of 308 co-infected patients followed in the cohort exhibited HBsAg-loss, all of whom were undergoing antiretroviral therapy. Nine (64.3%) of these patients achieved HBsAg-seroconversion during a median 3.0 years (IQR = 1.1–5.1) after HBsAg-loss. Across individuals with HBsAg-seroconversion, the fastest rates of antibody growth ranged between 0.57–1.93 year⁻¹ (population maximum growth rate = 1.02) and antibody production plateaued between 2.09–3.66 log₁₀ mIU/mL at the end of follow-up (population maximal antibody levels = 2.66). Patients with HBsAg-seroconversion had substantial decreases in HBV DNA viral loads (P = 0.03) and proportion with elevated ALT levels (P = 0.02) and HBeAg-positive serology (P = 0.08). No such differences were observed in those without HBsAg-seroconversion.ConclusionsMost co-infected patients with HBsAg-seroconversion produced and maintained stable antibody levels, yet kinetics of anti-HBs production were much slower compared to those observed post-vaccination or after clearance of acute HBV-infection.