Serum interleukin-17 levels are associated with nephritis in childhood-onset systemic lupus erythematosus

OBJECTIVES:

To determine the serum interleukin-17 (IL-17) levels in childhood-onset systemic lupus erythematosus patients and to evaluate the association between IL-17 and clinical manifestations, disease activity, laboratory findings and treatment.

METHODS:

We included 67 consecutive childhood-onset systemic lupus erythematosus patients [61 women; median age 18 years (range 11-31)], 55 first-degree relatives [50 women; median age 40 years (range 29-52)] and 47 age- and sex-matched healthy controls [42 women; median age 19 years (range 6-30)]. The childhood-onset systemic lupus erythematosus patients were assessed for clinical and laboratory systemic lupus erythematosus manifestations, disease activity [Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)], cumulative damage [Systemic Lupus International Collaborating Clinics/American College of Rheumatology (ACR) Damage Index] and current drug use. Serum IL-17 levels were measured by an enzyme-linked immunosorbent assay using commercial kits.

RESULTS:

The median serum IL-17 level was 36.3 (range 17.36-105.92) pg/mL in childhood-onset systemic lupus erythematosus patients and 29.47 (15.16-62.17) pg/mL in healthy controls (p=0.009). We observed an association between serum IL-17 levels and active nephritis (p=0.01) and migraines (p=0.03). Serum IL-17 levels were not associated with disease activity (p=0.32), cumulative damage (p=0.34), or medication use (p=0.63).

CONCLUSION:

IL-17 is increased in childhood-onset systemic lupus erythematosus and may play a role in the pathogenesis of neuropsychiatric and renal manifestations. Longitudinal studies are necessary to determine the role of IL-17 in childhood-onset systemic lupus erythematosus.     

Tumor necrosis factor gene polymorphisms are associated with systemic lupus erythematosus susceptibility or lupus nephritis in Mexican patients

The TNF -238G/A (rs361525) and -308G/A (rs1800629) polymorphisms have consistently been associated with systemic lupus erythematosus (SLE) in several populations; however, these findings have not been verified in all populations. Here, we aimed to examine whether the TNF -238G/A, -308G/A, -376G/A (rs1800750), and -1031T/C (rs1799964) polymorphisms confer SLE or lupus nephritis (LN) susceptibility in a Mexican population. Our study included 442 patients with SLE and 495 controls. For genotyping, we used the TaqMan 5′ allele discrimination assay. The TNF -238G/A and -1031T/C polymorphisms were associated with SLE susceptibility (odds ratio (OR) 2.1, p?=?0.0005 and OR 1.4, p?=?0.003, respectively). Gender stratification showed a strong association between TNF -238G/A and SLE in women (OR 2.2, p?=?0.00006), while TNF -1031T/C had an OR of 1.5 (p?=?0.007). With regard to the TNF -376G/A polymorphism, this also showed association with SLE susceptibility (OR 1.95, p?=?0.036) and LN (OR 3.5, p?=?0.01). In conclusion, our study provides the first demonstration of association between the TNF -376G/A polymorphism and SLE and LN susceptibility. In addition, our study is the second documenting an association of TNF -1031T/C with SLE susceptibility. We also observed a strong association between TNF -238G/A and SLE susceptibility. The TNF 308G/A polymorphism was not associated with SLE or LN.     

CD134 expression on CD4+ T cells is associated with nephritis and disease activity in patients with systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is characterized by a deviation of the immune system that involves T cell-dependent autoantibody production. The aim of this study was to investigate the role of co-stimulatory markers on T cells in this disease. Twenty-eight patients with SLE as defined by the American College of Rheumatology (ACR) criteria and 11 healthy controls were included into the study. Eleven patients had biopsy-proven lupus nephritis while 17 patients had no clinical evidence of lupus nephritis. Clinical disease activity was assessed according to the systemic lupus erythematosus disease index (SLEDAI). CD4+ T cell populations in the peripheral blood were analysed for the expression of co-stimulatory markers CD45RO, CD70, CD80, CD86, CD137, CD137L, CD134, CD152, CD154 and ICOS. SLE patients showed an increased frequency of peripheral CD4+ T cells expressing high levels of CD80, CD86 and CD134 compared to healthy controls (7.1 +/- 1.5% versus 1.7 +/- 0.9%; P < 0.005; 2.3 +/- 0.4% versus 1.0 +/- 0.2%; P = 0.008, 20.2 +/- 2.0% versus 10.6 +/- 1.9%; P < 0.005, respectively). Significantly higher levels of CD80 on CD4+ T cells were detected in SLE patients with lupus nephritis compared to patients without nephritis (11.9 +/- 3.3% versus 4.0 +/- 0.7%; P < 0.005). There was an increased presence of CD134+ CD4+ cells in SLE patients with lupus nephritis (27.5 +/- 4.0% versus 15.5 +/- 1.3%; P < 0.005). CD80 and CD134 expression was significantly correlated with SLEDAI (r = 0.42, P = 0.03; r = 0.56, P < 0.005). Co-stimulatory molecules on CD4+ T cells are associated with renal disease and disease activity in patients with systemic lupus erythematosus.     

Hodgkin's disease associated with systemic lupus erythematosus

We report on the rare association of Hodgkin's disease with systemic lupus erythematosus. Two years after the diagnosis of systemic lupus erythematosus, the patient developed upper abdominal pain, jaundice, splenomegaly, and fever of unknown origin. He had a rapidly fatal clinical course, despite being treated for systemic lupus erythematosus, cholecystitis, and possible sepsis. Autopsy revealed Hodgkin's disease, lymphocyte-depletion type, involving lymph nodes, liver, spleen, and bone marrow. The awareness of the association of Hodgkin's disease with systemic lupus erythematosus and its modes of presentation will help in the early diagnosis and management of such patients.     

DNA-anti-DNA circulating complexes in the nephritis of systemic lupus erythematosus.

In order to determine whether circulating antigen-antibody complexes in systemic lupus erythematosus (SLE) consist of DNA and anti-DNA, cryoglobulins were isolated from the sera of 38 patients with SLE nephritis and analysed for DNA and anti-DNA. Cryoglobulins were detected in 36 of the 38 sera, and DNA was found in 30 of 33 examined by either fluorescence of ethidium bromide or a radioimmunoassay. Anti-DNA activity was not detectable in any of the whole cryoglobulins but anti-IgG activity was found in 17. Twenty cryoglobulins were therefore treated by acid dissociation and ultracentrifugation to obtain isolated immunoglobulins; IgG was isolated from all, and IgM from eight. Using a modified Farr assay to detect anti-dsDNA and an enzyme-linked immunoadsorption assay to detect anti-ssDNA, anti-dsDNA activity alone was found in five IgG fractions, anti-ssDNA activity alone in five, and both anti-ds- and anti-ssDNA activity in four. Anti-dsDNA activity was found in three of the IgM fractions. In all, anti-dsDNA activity was found in nine of these 20 cryoglobulins, and anti-DNA in 14. Analysis of these 14 cryoglobulins with anti-DNA Ig fractions showed that there was enrichment of the IgG anti-DNA activity in the cryoglobulin compared to the patient's serum in all but two cases. In six of the 20 cryoglobulins studied there was no detectable anti-DNA activity in isolated IgG or IgM fractions. We therefore concluded that DNA-anti-DNA complexes were present in most of our patients with SLE nephritis, but there was clearly a substantial minority in whom they were undetectable. In some of the latter who also had active disease the cryoglobulins had anti-IgG activity. Thus it would seem that SLE can occur in the absence of DNA-anti-DNA complexes, but with other complexes present. DNA was also found in cryoglobulins isolated from patients with idiopathic glomerulonephritis, but, in contrast to recent reports, anti-DNA activity was not detectable in immunoglobulins isolated from their cryoglobulins.     

Flares in patients with systemic lupus erythematosus are associated with daily psychological stress

BACKGROUND: The aetiology of systemic lupus erythematosus (SLE) remains unclear. Clinical observations and a small number of studies performed so far suggest an association between psychological stress and self-reported symptoms of SLE patients. This longitudinal study was designed to investigate whether daily psychological stress is associated with flares in SLE patients, measured by clinical and laboratory parameters. METHODS: Female SLE patients (n = 41) were followed over a period of six months. Daily stress was monitored by a hand-held PC diary programmed with 44 items based on standardized measures and clinical experience. Once every four weeks patients visited the outpatient clinic for medical evaluation. Disease activity was evaluated using the European Consensus Lupus Activity Measurement (ECLAM), laboratory parameters, and intake of steroids. RESULTS: Classification and regression tree (CART) patient-wise analyses revealed that SLE patients with vs. without flares using complement and ECLAM as activity measures show greater negative self-ratings in mood, and social duties (p < 0.01). In addition, mixed model analysis of variance showed that daily hassles with social relationships were significantly associated with flares in SLE measured by an increase in steroid medication >5mg/d (p < 0.01). CONCLUSIONS: These results suggest that psychological stress is associated with flares in SLE. Particularly daily stress with social relationships and social duties may be factors to be related to the course of disease activity in SLE.     

Elevated serum anti-endothelial cell autoantibodies titer is associated with lupus nephritis in patients with systemic lupus erythematosus.

BACKGROUND AND PURPOSE: Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disease associated with endothelial dysfunction and the existence of multiple species of autoantibodies. However, the association between endothelial dysfunction and renal manifestations remains unclear in Taiwanese SLE patients. METHODS: Serum samples were collected from SLE patients with biopsy-proven lupus nephritis (n = 32), stable SLE patients (n = 32) and healthy controls (n = 32). The SLE Disease Activity Index (SLEDAI) of SLE patients was scored, and levels of anti-endothelial cell antibodies (AECA) and anti-endothelial activities in serum samples were measured by cell-enzyme-linked immunosorbent assay and crystal violet assay, respectively, using cultured human endothelial EA.hy926 cells. RESULTS: Significantly higher AECA (p<0.001) and anti-endothelial activities (p<0.001) were found in sera from patients with lupus nephritis compared with that from stable SLE patients or controls. Moreover, AECA titers (p<0.001) and anti-endothelial activities (p<0.001) were strongly correlated with SLEDAI scores in these patients. CONCLUSION: The strong correlations of AECA and anti-endothelial activity with lupus nephritis activity support an endothelial origin for renal complications in Taiwanese SLE patients.     

Serological correlations with nephritis in systemic lupus erythematosus

Autoantibodies have long been thought to participate in the pathogenesis of lupus nephritis. In this regard, antibodies to double stranded (ds)DNA and ribosomal P protein have been studied the most intensively. We now report a new specificity, antibodies to lipoprotein lipase (LPL) that is strongly associated with lupus nephritis and has a powerful synergistic effect with anti-ribosomal P antibodies in its association with nephritis. The recognition of anti-LPL antibodies and their synergy with anti-P antibodies are discussed in terms of the pathogenesis of lupus nephritis.     

Incidental discovery of high systemic lupus erythematosus disease activity associated with cytomegalovirus viral activity

We try to find the association of cytomegalovirus (CMV) infection and anti-β2 glycoprotein 1 autoantibodies (anti-β2 GP1), a key antibody in antiphospholipid syndrome (APS), among systemic lupus erythematosus (SLE) and cerebral vascular accident (CVA) patients. This retrospective study enrolled serum samples obtained from 87 SLE and 97 CVA patients who have been checked for the existence of anti-β2 GP1. First, the prevalence rate of anti-CMV IgG and IgM in patients with and without anti-β2 GP1 were compared. Second, the prevalence of anti-CMV IgG and IgM were compared between SLE and CVA patients. Last, this study analyzed the clinical characteristics and disease activity in SLE patients with positive anti-CMV IgM and IgG. No difference existed in the prevalence rate of anti-CMV IgG and IgM between positive or negative anti-β2 GP1 serum samples in both SLE and CVA patients. However, the prevalence of anti-CMV IgM was significantly higher in the SLE group than in the CVA group. Severity of clinical features and SLEDAI scores were considerably higher in patients with positive anti-CMV IgM than in SLE patients with negative anti-CMV IgM. Very impressively, all IgM-positive SLE samples (9/9) carrying highest levels of anti-CMV IgG, indicated reactivation of the latent CMV infection. Hence, it suggests that CMV reactivation might contribute toward the disease flare in some SLE patients. In future, a prospective and longitudinal study is stongly indicated.     

HMGB1+ microparticles present in urine are hallmarks of nephritis in patients with systemic lupus erythematosus

Non‐classical monocytes infiltrate the kidney parenchyma and participate in tissue damage in patients with lupus nephritis (LN). Circulating microparticles (MPs) seem to play critical roles in the activation of monocytes in systemic lupus erythematosus (SLE) patients. This study aims to characterize the phenotypes of MPs and monocyte subsets in LN patients and to determine their potential to discriminate between SLE patients with and without LN. Blood and urine samples from SLE patients were collected. In monocyte subsets from whole blood samples several phenotypic markers were evaluated. MPs were isolated from platelet‐poor plasma and urine by centrifugation. This phenotypic marker characterization was performed using multiparametric flow cytometry. We observed that patients with active LN have lower counts of non‐classical monocytes than do those without renal involvement. All monocyte subsets exhibited lower expression of CX3CR1 and ICAM‐1 in LN than in patients without LN. High frequencies of MP‐HMGB1⁺ and MP‐HLA‐DR⁺ were detected in circulation and urine of LN patients. Although MP‐HMGB1⁺, MP‐HLA‐DR⁺, and MP‐CX3CR1⁺ from urine were able to discriminate between patients with and without LN, only urinary MP‐HMGB1⁺ were different between patients with active and inactive LN. Therefore, these vesicles may be useful as biomarkers of LN.     

Correlation of C3d fixing circulating immune complexes with disease activity and clinical parameters in patients with systemic lupus erythematosus

Using anti-C3d as a solid phase reagent, C3d fixing circulating immune complexes (CIC) were detected in sera from patients with systemic lupus erythematosus (SLE), rheumatoid arthritis, membranous nephropathy and IgA nephropathy. Particularly, sera from SLE showed the highest CIC levels and highest incidence of positivity among these diseases. In the 51 serum samples from 48 patients with SLE we studied, the CIC detected by the anti-C3d assay correlated well (P less than 0.01) with the CIC detected by the solid phase C1q assay, but not with those detected by the conglutinin assay. In addition, the CIC detected by the anti-C3d assay correlated more significantly (P less than 0.001) with disease activity, as well as some clinical parameters (serum anti-dsDNA antibodies, CH50 and C3 levels) than CIC detected by the other two assays of SLE sera. The anti-C3d binding materials were found to be of intermediate (8-19S) and small (7S) sizes in a small number of SLE sera which we analysed.     

BLK and BANK1 polymorphisms and interactions are associated in Mexican patients with systemic lupus erythematosus

Inflammation Research - The BLK and BANK1 genes have been consistently associated with systemic lupus erythematosus (SLE), primarily in European or Asian-derived populations. However, this finding...     

Serum adenosine deaminase activity is increased in systemic lupus erythematosus patients and correlated with disease activity

Adenosine deaminase (ADA) has been found to be involved in autoimmune disease progression. To assess the potential application of serum ADA activity in diagnosing systemic lupus erythematosus (SLE) and evaluating SLE disease activity, we investigated the serum ADA activity of 120 SLE patients and 120 healthy controls in the present study. The results showed that serum ADA activity in SLE patients was significantly increased (median (IQR)?=?14 (11–19) U/L) compared with that in healthy controls (median (IQR)?=?8 (7–10) U/L). Based on a receiver operating characteristic curve analysis, the optimal cut-off value for using serum ADA activity to diagnose SLE patients was 10.5 U/L (specificity, 84.2%; sensitivity, 78.3%). The diagnostic performance of serum ADA activity for SLE patients was better than that of other conventional haematology markers. Moreover, serum ADA activity displayed an increasing trend with increasing SLE disease activity. Spearman’s correlation analysis showed that serum ADA activity was positively correlated with SLE disease activity. These findings suggest that serum ADA activity could be a diagnostic marker for SLE; moreover, measuring serum ADA activity may be helpful for evaluating and monitoring the disease activity of SLE patients.     

Promoter polymorphisms of the TIM‐4 gene are correlated with disease activity in patients with systemic lupus erythematosus

Although the TIM gene family plays important roles in immune responses, little is known about TIM regulation in the development of systemic lupus erythematosus (SLE). This study aimed to investigate the association of two TIM‐4 single nucleotide polymorphisms (SNPs) rs6874202 (?1419G>A) and rs62382402 (?1609G>A) with SLE susceptibility in a Chinese Han population. The results showed no significant differences between patients with SLE and control group for rs6874202 and rs62382402 (p = .72, .53 respectively). However, the anti‐dsDNA levels in serum from SLE patients with GG genotype of TIM‐4 gene at ‐1419 site were significantly higher than those with GA and AA genotype (p = .0335), and C3 levels of SLE patients with GG and GA genotype were much lower than those with AA genotypes (p = .0187). Moreover, the apoptotic cell levels of SLE patients with AA and GG genotypes were significantly higher than those with GA genotypes in patients with SLE (p = .0393). In addition, the C3 concentration of SLE patients with the GG genotype of TIM‐4 gene at ‐1609 site was found to be significantly higher than those with the GA genotype (p = .0129). The results imply that GG genotype of the TIM‐4 gene at ‐1419 site might be associated with the disease activity of SLE.     

Myelosclerosis associated with systemic lupus erythematosus in patients in West Malaysia

Three cases of myelosclerosis associated with systemic lupus erythematosus are described. The probable role of systemic lupus erythematosus in the initiation of myelonecrosis and subsequent myelosclerosis is discussed.     

Clinical significance of circulating immune complex assay in patients with systemic lupus erythematosus

Circulating immune complexes (IC) were assayed in 65 patients with systemic lupus erythematosus (SLE), 34 patients with rheumatoid arthritis (RA), 40 patients with progressive systemic sclerosis (PSS), 35 patients with chronic glomerulonephritis (GN) and 30 healthy controls. Immunoglobulin components of PEG-precipitated IC from 10 patients with SLE were also determined. Cryoglobulins isolated from 11 patients with SLE were assayed for their IC-like activity. The effect of corticosteroid treatment on IC levels were also studied in SLE patients with nephritis. IC levels significantly increased in all groups but those of SLE patients were the highest values. The SLE patients with nephritis had higher levels than those without renal involvement. IgG- d IgM- but no IgA-components were found in 100% and, 90%, respectively, of IC preparations. IC-like activity of cryoglobulins were found to correlate with disease severity and appeared to be characteristic of clinical manifestations. Corticosteroid therapy significantly decreased IC levels, however, related to the entire patient group, the mean of IC level was still higher than that of healthy controls. The degree of IC level decrease (as percentage), but not absolute values, appeared to be significant in assessing disease activity. The clinical significance of IC determination and IC activity of cryoglobulins are discussed.     

HLA-C1 ligands are associated with increased susceptibility to systemic lupus erythematosus

Recently, the role of killer cell immunoglobulin-like receptor (KIR) in autoimmune diseases has received increasing attention. The present study was undertaken to determine the association of KIR genes and the human leukocytes antigen (HLA) ligands with Systemic Lupus Erythematosus (SLE) and accompanying oxidative stress. Presence or absence of 17 KIR and 5 HLA loci was performed using the polymerase chain reaction-sequence specific primer (PCR-SSP) method by case-control study. A total of 45 SLE patients, and 60 healthy controls, all of Sicilian descent, were enrolled. Plasma values of the anti-oxidant molecule Taurine were determined in all subjects by capillary electrophoresis UV detection. The carrier frequency of the KIR2DS2 gene was significantly increased in SLE patients compared to healthy controls (73.3 versus 45.0%; OR?=?3.36; 95% CI?=?1.46–7.74; p?=?.005) suggesting a role of KIR2DS2 gene in the susceptibility to disease. We also observed a strong positive association between the presence of HLA-C1 ligands group and the disease (82.2% in SLE patients versus 41.7% in controls; OR?=?6.47, 95% CI?=?2.58–16.26; p?<?.0001). Stepwise logistic regression analysis supported the effect of the HLA-C1 ligands in SLE patients (OR?=?7.06, 95% CI?=?0.07–2.19; p?=?.002), while the KIR genes were no longer significant. Interestingly, we found that SLE patients HLA-C1 positive showed significantly decreased plasma levels of antioxidant activity marker Taurine (69.38?±?28.49?μmol/L) compared to SLE patients HLA-C1 negative (108.37?±?86.09?μmol/L) (p?=?.03). In conclusion, HLA-C1 ligands group was significantly associated with an increased risk of SLE as well as an increased oxidative stress status overall in SLE patients.     

Autoantibodies against monomeric C-reactive protein in sera from patients with lupus nephritis are associated with disease activity and renal tubulointerstitial lesions

Serum levels of C-reactive protein (CRP) often remain low despite high disease activity in systemic lupus erythematosus (SLE). Sera from 96 patients with renal biopsy-proven active lupus nephritis, 24 of 96 patients in remission, and 49 patients with SLE with negative urinalysis (nonrenal SLE) was collected. Immunoglobulin G autoantibodies against monomeric CRP (mCRP) were screened by enzyme-linked immunosorbent assay with purified human CRP. Associations with clinical features, pathological data, and laboratory findings were investigated. The prevalence of mCRP autoantibodies in active lupus nephritis (57/96, 59.4%) was significantly higher than that in patients with SLE without clinical evidence of kidney involvement (20/49, 40.8%, p = 0.034). For the 13 patients with positive mCRP autoantibodies and sequential sera, their positive mCRP autoantibodies in active phase turned negative in remission (13/13, 100%). Patients with mCRP autoantibodies had significantly higher SLEDAI scores than patients without mCRP autoantibodies (18.3 +/- 5.2 vs 15.8 +/- 4.0, p = 0.013), who were more likely to experience acute renal failure (14/55 vs 2/33, p = 0.022), oral ulcer (15/57 vs 3/39, p = 0.022), and delayed activated partial thromboplastin time (18/52 vs 2/38, p = 0.001). Positive correlations between levels of mCRP autoantibodies and semiquantitative scores of renal histologic features were first observed in lupus nephritis as follows: interstitial inflammation (r = 0.328), tubular atrophy(r = 0.276), interstitial fibrosis (r = 0.211), and chronicity index score (r = 0.243). Autoantibodies against mCRP are prevalent in patients with lupus nephritis and are associated with disease activity and renal tubulointerstitial lesions.