Serum protein oxidation and apolipoprotein CIII levels in people with systemic lupus erythematosus with and without nephritis

Increased oxidative stress is a hallmark of the autoimmune disease systemic lupus erythematosus (SLE). This study compares serum protein oxidation levels in SLE patients without and with renal involvement (lupus nephritis); the latter have a significantly poorer prognosis. Similar increases in protein carbonyls and decreases in protein thiols were observed in both SLE groups compared to controls. Protein carbonyl distribution, determined by Western blotting of 2D gels, was similar in both SLE groups, suggesting factors other than oxidation also play a role in SLE complications. 2D electrophoresis examined the serum proteome further. Six proteins were significantly decreased in non-renal SLE patients compared to controls; five were identified by mass spectrometry, including one isoform of pro-atherogenic apoCIII. Total apoCIII levels (assessed by ELISA) in lupus nephritis patients were significantly elevated compared to controls or non-renal SLE patients. Thus, levels of oxidized proteins and apoCIII may be useful biomarkers in SLE studies.     

Differences among immune complexes: association of C1q in SLE immune complexes with renal disease

Studies that made use of multiple assay systems demonstrated increased levels of immune complexes (IC) in patients with systemic lupus erythematosus (SLE), but no consistent correlations of IC concentration to patterns or activity of disease have been observed. Furthermore, consistent associations between qualitative differences in IC and disease manifestations have been elusive. IC interaction with erythrocytes and mononuclear phagocytic cells is another variable in SLE that may also mediate some of the biological effects of IC. The present report concerns studies of the composition of purified IC obtained from individuals with SLE and other rheumatic diseases; a 64,000 dalton component identified as the A-B subunit of C1q was detected in purified IC from 27 of 51 SLE patients (53%). The presence of this 64,000 dalton component was not related to either IC concentration or to the serum C1q level. However, the presence of the C1q component in isolated SLE IC did correlate with the presence of renal disease (p less than 0.02). These observations are interpreted relative to a recently described kinetic model of IC clearance.     

Early events in lupus humoral autoimmunity suggest initiation through molecular mimicry

The origins of autoimmunity in systemic lupus erythematosus (SLE) are thought to involve both genetic and environmental factors. To identify environmental agents that could potentially incite autoimmunity, we have traced the autoantibody response in human SLE back in time, prior to clinical disease onset, and identified the initial autoantigenic epitope for some lupus patients positive for antibodies to 60 kDa Ro. This initial epitope directly cross-reacts with a peptide from the latent viral protein Epstein-Barr virus nuclear antigen-1 (EBNA-1). Animals immunized with either the first epitope of 60 kDa Ro or the cross-reactive EBNA-1 epitope progressively develop autoantibodies binding multiple epitopes of Ro and spliceosomal autoantigens. They eventually acquire clinical symptoms of lupus such as leukopenia, thrombocytopenia and renal dysfunction. These data support the hypothesis that some humoral autoimmunity in human lupus arises through molecular mimicry between EBNA-1 and lupus autoantigens and provide further evidence to suspect an etiologic role for Epstein-Barr virus in SLE.     

Anti-C1q Antibodies as a Follow-Up Marker in SLE Patients

In cross-sectional studies autoantibodies against complement C1q (anti-C1q) were found to be highly associated with active lupus nephritis. The aim of this retrospective study was to determine the value of anti-C1q as follow-up marker of disease activity and renal involvement in patients with systemic lupus erythematosus (SLE). Fifty-two patients with SLE and a minimum of three anti-C1q measurements during follow-up were analyzed. Anti-C1q levels correlated with global disease activity scores. In subgroup analyses, patients without renal involvement did not show a significant correlation between anti-C1q levels and disease activity. In contrast, in patients with renal involvement, anti-C1q levels correlated well with global disease activity. In addition, a positive correlation with the urine protein-to-creatinine ratio and anti-dsDNA antibody levels as well as a negative correlation with complement levels was observed. Anti-C1q antibodies were found to strongly correlate with parameters of SLE disease activity during follow-up, in particular with regard to renal involvement.     

Increased expression of costimulatory markers CD134 and CD80 on interleukin-17 producing T cells in patients with systemic lupus erythematosus

Introduction  

There is growing evidence that interleukin 17 (IL-17) producing T cells are involved in the pathogenesis of systemic lupus erythematosus (SLE). Previous studies showed that increased percentages of T-cell subsets expressing the costimulatory molecules CD80 and CD134 are associated with disease activity and renal involvement in SLE. The aim of this study was to investigate the distribution and phenotypical characteristics of IL-17 producing T-cells in SLE, in particular in patients with lupus nephritis, with emphasis on the expression of CD80 and CD134.     

Pregnancy-Related Systemic Lupus Erythematosus: Clinical Features,Outcome and Risk Factors of Disease Flares — A Case Control Study

Objective

To investigate the clinical features, outcome, and risk factors of disease flares in patients with pregnancy-related lupus (PRL).

Methods

Medical charts of 155 consecutive PRL inpatients were systematically reviewed, including demographic data, clinical features, laboratory findings, treatment, complications, and outcome.

Results

PRL cases were divided into active (a-PRL) (n = 82, 53.0%) and stable lupus (s-PRL) (n = 73, 47.0%). Compared with nonpregnant active female systemic lupus erythematosus (SLE) patients, a-PRL including new-onset lupus (n-PRL) and flare lupus (f-PRL) (n = 41 respectively), had a higher incidence of renal and hematological involvement but less mucocutaneous and musculoskeletal involvement (p<0.05). The incidence of preeclampsia/eclampsia, fetal loss, and preterm birth were significantly higher in a-PRL than in s-PRL (p<0.05). Despite receiving a more vigorous glucocorticoid treatment, a-PRL mothers had a poorer prognosis (p<0.001). Five (6.1%) of them died and 13 (15.9%) developed severe irreversible organ failure, whereas none of these events was observed in the s-PRL group. Multivariate logistic analysis indicated that a history of lupus flares and serological activity (hypocomplementemia and/or anti-dsDNA positivity) at the time of conception were associated with lupus flares in PRL mothers.

Conclusions

SLE patients with a flare history and serological activity at the time of conception were at an increased risk of disease flares during pregnancy and puerperium. a-PRL patients were more prone to renal and hematological involvement, pregnancy complications, and a poorer prognosis despite more vigorous glucocorticoid treatment.     

Serum levels of autoantibodies against C-reactive protein correlate with renal disease activity and response to therapy in lupus nephritis

Introduction  

Serum levels of C-reactive protein (CRP) seldom reflect disease activity in systemic lupus erythematosus (SLE). We have previously shown that autoantibodies against neo-epitopes of CRP often occur in SLE, but that this does not explain the modest CRP response seen in flares. However, we have repeatedly found that anti-CRP levels parallel lupus disease activity, with highest levels in patients with renal involvement; thus, we aimed to study anti-CRP in a material of well-characterized lupus nephritis patients.     

The inhibition of anti-DNA binding to DNA by nucleic acid binding polymers

Antibodies to DNA (anti-DNA) are the serological hallmark of systemic lupus erythematosus (SLE) and can mediate disease pathogenesis by the formation of immune complexes. Since blocking immune complex formation can attenuate disease manifestations, the effects of nucleic acid binding polymers (NABPs) on anti-DNA binding in vitro were investigated. The compounds tested included polyamidoamine dendrimer, 1,4-diaminobutane core, generation 3.0 (PAMAM-G3), hexadimethrine bromide, and a β-cylodextrin-containing polycation. As shown with plasma from patients with SLE, NABPs can inhibit anti-DNA antibody binding in ELISA assays. The inhibition was specific since the NABPs did not affect binding to tetanus toxoid or the Sm protein, another lupus autoantigen. Furthermore, the polymers could displace antibody from preformed complexes. Together, these results indicate that NABPs can inhibit the formation of immune complexes and may represent a new approach to treatment.     

Association of FcγRIIB and FcγRIIA R131H gene polymorphisms with renal involvement in Egyptian systemic lupus erythematosus patients

Identification of the genetic basis of systemic lupus erythematosus (SLE) may contribute to the discovery of effective drugs before renal involvement. Our aim of this study was to estimate the association between Fc gamma receptor (FcγR) polymorphisms and SLE and renal involvement in Egyptian patients. FcγRIIB and FcγRIIA R131H gene polymorphisms were genotyped in 180 Egyptian adults. Genotyping for FcγRIIA R131H was performed using allele-specific PCR and FcγRIIB-Ile232 Thr polymorphism was genotyped using polymerase chain reaction restriction fragment length polymorphism (PCR–RFLP). The study showed that the homozygous genotype (Thr/Thr) of FcγRIIB significantly increased in all SLE patients (90 patients) and in SLE patients complicated with nephritis (61 patients). The Thr allele was significantly associated with an increased risk of the disease in all the patients and in patients complicated with nephritis. Our study demonstrated an association of FcγRIIB polymorphisms with SLE and lupus nephritis and a lack of association of FcγRIIA polymorphisms with SLE in the Egyptian patients.     

Autoantibodies against a specific nuclear RNP protein in sera of patients with autoimmune rheumatic diseases associated with myositis

Polymyositis is an autoimmune, inflammatory disease affecting human skeletal muscle. In the presence of concomitant vasculitis in the skin, the term dermatomyositis is used. In contrast, systemic lupus erythematosus (SLE) is a multisystem disease in which involvement of the skin, kidneys, joints, brain, and other organs may be found. The clinical manifestations vary according to the organ/system involved. It is clinical and therapeutic importance to define which organ/system is involved during the course of the disease. We approached this problem by studying the specificity of autoantibodies that are generated in patients with SLE and polymyositis/dermatomyositis. Among such antibodies are those directed against nuclear components including a variety of ribonucleoprotein (RNP) complexes. We have utilized mammalian nuclear preparations enriched with RNP particles as the antigenic source for immunoblotting studies to identify specific antigenic polypeptides. In the study reported here, sera from five groups of patients were examined: 10 patients with dermatomyositis/polymyositis; six patients with SLE and myositis; 12 lupus patients with cerebral and/or renal disease; eight patients with SLE but no myositis, renal, or cerebral disease; and 5) 11 patients with muscle weakness or muscle disease not due to myositis. In the first two groups of patients with myositis, antibodies against a nuclear RNP protein of 56 KD was identified in 12 of 16 sera. In contrast, such antibodies were found in the serum of only two of 20 patients with SLE but without muscle involvement (groups 3 and 4), and were not found at all in patients with other muscle diseases. This study has identified a new marker, antibodies against a nuclear RNP protein of 56 KD for detecting muscle involvement among the autoimmune rheumatic diseases.     

PSYCHOSIS AND SYSTEMIC LUPUS ERYTHEMATOSUS—A Review of the Literature and Case Reports

In a review of the literature of the last 60 years concerning the association between psychosis and systemic lupus erythematosus, reports of 227 cases of this association were found. The average incidence of psychosis in the various series of systemic lupus erythematosus that were reviewed was 22 per cent. In only 25 per cent of the cases in which the information was given was the psychosis associated with steroid therapy.The psychiatric manifestations are variable and may be associated with a neurological disorder. Psychosis may antedate by many years other features of lupus. The psychosis due to lupus may respond to steroid therapy. Since systemic lupus erythematosus sometimes may be an important differential diagnosis of functional psychosis, appropriate diagnostic studies should be carried out in psychotic patients who have an accelerated sedimentation rate or positive serological test for syphilis without apparent reason.     

Wnt/β-catenin signaling mediates the senescence of bone marrow-mesenchymal stem cells from systemic lupus erythematosus patients through the p53/p21 pathway

Recent studies have shown that allogeneic bone marrow (BM)-mesenchymal stem cell transplantation (MSCT) appears to be effective in systemic lupus erythematosus (SLE) patients and lupus-prone mice, contrary to studies in syngeneic BM-MSCT. These studies indicated that the abnormalities of BM-MSCs may be involved in the pathogenesis of SLE. Our studies and other previous studies have revealed that BM-MSCs from SLE patients exhibited early signs of senescence, such as flattened morphology, slow proliferation, increased senescence-associated β-galactosidase (SA-β-gal) activity, and so on. However, the mechanisms by which these cells senescences were still unclear. Previous studies have demonstrated that Wnt/β-catenin signaling plays an important role in stem cell senescence. In the current study, we investigated whether Wnt/β-catenin signaling mediates the senescence of BM-MSCs from SLE patients. We have found that Wnt/β-catenin signaling and the p53/p21 pathway were significantly hyperactivated in senescent SLE BM-MSCs. Treatment with 100 ng/mL Dickkopf-1 (DKK1), a Wnt/β-catenin signaling inhibitor or β-catenin siRNA for 48 h could reverse the senescent features of SLE BM-MSCs. Additionally, the expression levels of p53 and p21 were reduced in treated-SLE BM-MSCs compared with the untreated group. In summary, our study indicated that Wnt/β-catenin signaling may play a critical role in the senescence of SLE BM-MSCs through the p53/p21 pathway.     

Urine levels of HMGB1 in Systemic Lupus Erythematosus patients with and without renal manifestations

Introduction

Lupus nephritis (LN) is a severe and frequent manifestation of systemic lupus erythematosus (SLE). Its pathogenesis has not been fully elucidated but immune complexes are considered to contribute to the inflammatory pathology in LN. High Mobility Group Box 1 (HMGB1) is a nuclear non-histone protein which is secreted from different types of cells during activation and/or cell death and may act as a pro-inflammatory mediator, alone or as part of DNA-containing immune complexes in SLE. Urinary excretion of HMGB1 might reflect renal inflammatory injury. To assess whether urinary HMGB1 reflects renal inflammation we determined serum levels of HMGB1 simultaneously with its urinary levels in SLE patients with and without LN in comparison to healthy controls (HC). We also analyzed urinary HMGB1 levels in relation with clinical and serological disease activity.

Methods

The study population consisted of 69 SLE patients and 17 HC. Twenty-one patients had biopsy proven active LN, 15 patients had a history of LN without current activity, and 33 patients had non-renal SLE. Serum and urine levels of HMGB1 were both measured by western blotting. Clinical and serological parameters were assessed according to routine procedures. In 17 patients with active LN a parallel analysis was performed on the expression of HMGB1 in renal biopsies.

Results

Serum and urinary levels of HMGB1 were significantly increased in patients with active LN compared to patients without active LN and HC. Similarly, renal tissue of active LN patients showed strong expression of HMGB1 at cytoplasmic and extracellular sites suggesting active release of HMGB1. Serum and urinary levels in patients without active LN were also significantly higher compared to HC. Urinary HMGB1 levels correlated with SLEDAI, and showed a negative correlation with complement C3 and C4.

Conclusion

Levels of HMGB1 in urine of SLE patients, in particular in those with active LN, are increased and correlate with SLEDAI scores. Renal tissue of LN patients shows increased release of nuclear HMGB1 compared to control renal tissue. HMGB1, although at lower levels, is, however, also present in the urine of patients without active LN. These data suggest that urinary HMGB1 might reflect both local renal inflammation as well as systemic inflammation.     

Anti-dsDNA Antibody Isotypes in Systemic Lupus Erythematosus: IgA in Addition to IgG Anti-dsDNA Help to Identify Glomerulonephritis and Active Disease

Objectives

To evaluate the role of serum IgG, IgM and IgA anti-dsDNA antibody isotypes in the diagnosis of systemic lupus erythematosus (SLE), and their association with clinical features and disease activity, in a large cohort of SLE patients.

Methods

Sera of 200 SLE patients (mean age 34±10.3 years; 26 male and 174 female; median duration of disease 115 months, range 7–378), and of 206 controls, including 19 Sjögren''s syndrome, 27 rheumatoid arthritis, 26 psoriatic arthritis, 15 idiopathic inflammatory myopathies (IIM), 13 systemic sclerosis, 49 infectious diseases and 57 healthy subjects, were tested for anti-dsDNA IgG, IgM and IgA isotypes.

Results

Selecting a cutoff corresponding to 95% specificity, the sensitivity of IgG, IgM and IgA anti-dsDNA antibodies in SLE was 55%, 30% and 49%, respectively; 12.5%, 1% and 7.5% of SLE patients had positive IgG, IgM or IgA isotype alone, respectively. SLE patients with glomerulonephritis showed higher levels of IgA anti-dsDNA (p = 0.0002), anti-dsDNA IgG/IgM (p = 0.001) and IgA/IgM (p<0.0001) ratios than patients without renal disease. No significant associations have been found between anti-dsDNA isotypes and other clinical features. IgA anti-dsDNA (p = 0.01) (but not IgG or IgM) and IgG/IgM ratio (p = 0.005) were significantly higher in patients with more active disease (ECLAM score >4).

Conclusions

The detection of IgA anti-dsDNA autoantibodies seems to improve our ability to diagnose SLE and to define lupus nephritis phenotype and active disease. By contrast, IgM anti-dsDNA antibodies might be protective for renal involvement. These data support the hypothesis that anti-dsDNA antibody class clustering may help to refine SLE diagnosis and prognosis.     

The new era of autoimmune disease research

Recent genome-wide association studies have advanced our understanding of genetic factors that underlie systemic lupus erythematosus (SLE), a multifactorial autoimmune disease characterized by various clinical manifestations. SLE also has an environmental component, which can trigger or exacerbate the disease. Despite extensive efforts aimed at elucidating the cellular and biological abnormalities that arise in the immune system of patients with SLE, its pathology remains unclear. Lee and colleagues recently carried out gene expression profiling of patients with SLE followed by bioinformatics analysis and discovered the existence of abnormal regulatory networks and potential key molecules. The authors found that ATP synthesis and DNA repair pathways may be involved in the pathogenesis, providing a potential explanation for photosensitivity experienced by patients with SLE.     

Pathogenic idiotypes of autoantibodies in autoimmunity: lessons from new experimental models of SLE

Systemic lupus erythematosus (SLE) is considered a classical autoimmune disease that involves many biological systems. Similar to other autoimmune conditions, its etiology is multifactorial entailing genetic, environmental, hormonal, and immunologic factors. In this review we demonstrate that by using a pathogenic idiotype of anti-DNA autoantibodies, it is possible to explain some of the pathogenesis and diversity of clinical and serological manifestations reported by SLE patients. The 16/6 idiotype (Id) is a representative pathogenic idiotype of anti-DNA autoantibodies. The serum titers of 16/6 Id in SLE patients correlate with clinical activity of the disease, and are deposited in afflicted tissues in SLE patients. SLE was experimentally induced in naive mice after immunization with 1 microgram of the Id. The disease is characterized clinically (proteinuria), serologically (e.g., anti-dsDNA, anti-Sm antibodies), and by pathological findings (e.g., deposition of 16/6 Id in the kidneys). The condition can be induced by other human and mouse antibodies carrying the 16/6 Id, as well as by mouse antimonoclonal-16/6 Id and by T cell lines and clones specifically reactive with 16/6 Id. There are strain-dependent differences in susceptibility to the induction of systemic lupus erythematosus (SLE). Induction of SLE is directly correlated with the ability to respond to the 16/6 idiotype (or 16/6 Id)2 by anti-Id antibody production. It is easier to induce the disease in females, and it can be modulated by manipulation of sex hormones. Being able to identify the pathogenic idiotype allowed us to generate T suppressor (Ts) cells specific for the 16/6 Id. Treatment of mice with these T cells abrogated the disease. Our studies point to the importance of pathogenic idiotypes of autoantibodies in autoimmunity, which suggests that SLE may represent a dysregulation of a functional network of idiotypes-anti-idiotypes interactions among autoreactive B cells, T helper cells, and T suppressor cells.     

Increased expression of FcγRI/CD64 on circulating monocytes parallels ongoing inflammation and nephritis in lupus

Introduction  

The high-affinity receptor for IgG Fcγ/CD64 is critical for the development of lupus nephritis (LN). Cross-linking Fc receptor on recruited monocytes by IgG-containing immune complexes is a key step in immune-complex-mediated nephritis in systemic lupus erythematosus (SLE). The goal of this study was to determine whether expression of Fc receptor (FcγR) I on circulating monocytes is associated with systemic inflammation and renal disease in SLE patients.     

TWEAK as a target for therapy in systemic lupus erythematosus

Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a recently identified proinflammatory cytokine of the TNF superfamily. Through activation of the fibroblast growth factor-inducible 14 (Fn14) receptor, TWEAK regulates cell proliferation, cell death and inflammation. The available evidences have indicated that TWEAK might be a target for therapeutic intervention in renal, vascular injury and neuropathy. Since renal, vascular and neuropsychiatric complications are frequently encountered in systemic lupus erythematosus (SLE)—a systemic autoimmune disease, TWEAK-Fn14 pathway may be implicated in the pathogenesis of SLE. In this review, we will discuss the TWEAK-Fn14 pathway and the therapeutic potential of modulating this pathway in SLE.     

Presence of antibodies against cyclic citrullinated peptides in patients with 'rhupus': a cross-sectional study

'Rhupus' is a rare condition sharing features of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). If rhupus is a distinctive entity, an overlap between RA and SLE or a subset of SLE is currently debated. This study was performed to explore the prevalence of antibodies against cyclic citrullinated peptides (anti-CCP antibodies) in rhupus. Patients meeting American College of Rheumatology criteria for RA, SLE, or both were included. Clinical and radiographic features were recorded and sera were searched for anti-CCP antibodies, rheumatoid factor, antinuclear antibodies, anti-extractable nuclear antigens, and antibodies against double-stranded DNA (anti-dsDNA antibodies). Seven patients for each group were included. Clinical and serological features for RA or SLE were similar between rhupus and RA patients, and between rhupus and SLE patients, respectively. Values for anti-CCP antibodies obtained were significantly (p < 0.05) higher in RA (6/7) and rhupus (4/7) than in SLE patients (0/7) and healthy subjects (0/7). Our data support the possibility that rhupus is an overlap between RA and SLE, because highly specific autoantibodies for RA (anti-CCP) and for SLE (anti-dsDNA and anti-Sm) are detected in coexistence.     

Lupus eritematoso sistémico en el anciano

Late-onset systemic lupus erythematosus (SLE) usually appears in patients older than 65 years and has clinical features different from the classical form observed in younger patients. In the elderly, SLE represents 10-20% of all SLE cases, shows a different and less aggressive clinical evolution and the first manifestations are non-specific. A significantly higher incidence of late-onset SLE in males, and the fact that postmenopausal women have a more benign disease, suggests that the estrogenic status may influence the activity of the disease. Owing to the insidious onset and the non-specific clinical manifestations on presentation, there is commonly a delayed diagnosis of late-onset SLE. Furthermore, the presence of comorbidities and concomitant therapies in elderly patients may limit the therapeutic options for SLE. The treatment of choice of joint symptoms and serositis includes non-steroidal anti-inflammatory drugs and low-dose steroids for short periods. In addition to the need for adopting a multidisciplinary approach, it is fundamental to obtain information about the functional, cognitive and social status of these patients in order to make appropriate healthcare decisions.