Auto-antibody profile in systemic lupus erythematosus

Thirty cases of systemic lupus erythematosus (SLE) were selected on the basis of revised ARA criteria (American Rheumatology Association) and their sera examined for the presence of various auto-antibodies. The male to female ratio was 1:5 and joint manifestations were the commonest mode of presentation. The frequency of various manifestations was found to differ between the two sexes. Renal lesions were observed in 9 (nine) cases. ANF was detected in 28 of the 30 cases and the diffuse pattern was the commonest (11 cases) (37.7%). Six cases had very high titres (a titre of more than 1:1280) of antinuclear factor. Antibodies to DNA were detected in 9 cases (30%). These patients tended to have more severe disease, with high titres of ANF and low complement levels. Presence of antibodies to DNA, however, could not be correlated with the severity of renal lesions. Anti Sm antibody was found in 8 cases (26.7%), anti nRNP antibody in 19 cases (63.3%) and antihistone antibodies in 22 cases (73.3%). Patients harbouring any of these three antibodies tended to have a milder clinical disease.     

Genetic imprinting of autoantibody repertoires in systemic lupus erythematosus patients

Systemic lupus erythematosus (SLE) is an autoimmune disease distinguished by great heterogeneity in clinical manifestations and autoantibody expression. While only a handful of autoantibody specificities have proved useful for clinical diagnosis, to characterize complex lupus-associated autoantibody profiles more fully we have applied proteome microarray technology. Our multiplex microarrays included control ligands and 65-autoantigens, which represent diverse nuclear and cytoplasmic antigens recognized by disease-associated and natural autoantibodies. From longitudinal surveys of unrelated SLE patients, we found that autoantibody profile patterns can be patient-specific and highly stable overtime. From profiles of 38 SLE patients that included 14 sets of SLE twins, autoantibodies to the phospholipid neo-determinants, malondialdehyde (MDA) and phosphorylcholine (PC), which are exposed on apoptotic but not healthy cells, were among the most prevalent and highly expressed. We also found that immunoglobulin M (IgM) reactivity to MDA and PC ligands had significant direct correlations with DNA-containing antigens, while such a general relationship was not found with a panel of RNA-related antigens, or for IgG-autoantibodies. Significantly, hierarchical analysis revealed co-distribution/clustering of the IgM autoantibody repertoire patterns for six of 14 twin sets, and such patterns were even more common (10 of 14) for IgG autoantibody profiles. Our findings highlight the potentially distinct roles of IgM and IgG autoantibodies, as we postulate that the direct correlations for IgM autoantibodies to DNA antigens with apoptosis-related determinants may be due to co-expression arising from common pro-homeostatic protective roles. In contrast, the sharing of IgG autoantibody fingerprints by monozygotic twins suggests that lupus IgG autoantibodies can arise in predisposed individuals in genetically determined patterns.     

Detection of antiphospholipid autoantibody in systemic lupus erythematosus is temperature-dependent

Non-reactive SLE sera in an ELISA for anticardiolipin antibody (aCL) retested positive in the immunoassay when the sera were first heat-inactivated at 56 degrees C for 30 minutes. This was not a false positive phenomenon since the positive ELISA reactivity of the heated SLE sera was markedly reduced by inhibition with the cardiolipin antigen. Furthermore, the heat-potentiated ELISA reaction was abolished by prior IgG depletion of the SLE sera with Protein A preparation. The unmasked aCL in the heat-treated SLE sera also exhibited selective binding in ELISA to other negatively-charged phospholipids, namely phosphatidylserine and phosphatidic acid but not against either phosphatidylcholine or phosphatidyl-ethanolamine. The data strongly indicate an interaction between antiphospholipid antibodies and heat-sensitive serum component(s), a reduction of the latter resulting in the ELISA detection of the autoantibody.     

Protein array autoantibody profiles for insights into systemic lupus erythematosus and incomplete lupus syndromes

The objective of this study was to investigate the prevalence and clinical significance of a spectrum of autoantibodies in systemic lupus erythematosus and incomplete lupus syndromes using a proteome microarray bearing 70 autoantigens. Microarrays containing candidate autoantigens or control proteins were printed on 16-section slides. These arrays were used to profile 93 serum samples from patients with systemic lupus erythematosus (SLE (n = 33), incomplete LE (ILE; n = 23), first-degree relatives (FDRs) of SLE patients (n = 20) and non-autoimmune controls (NC; n = 17). Data were analysed using the significance analysis of microarray (SAM) and clustering algorithms. Correlations with disease features were determined. Serum from ILE and SLE patients contained high levels of IgG autoantibodies to 50 autoantigens and IgM autoantibodies to 12 autoantigens. Elevated levels of at least one IgG autoantibody were detected in 26% of SLE and 19% of ILE samples; elevated IgM autoantibodies were present in 13% of SLE and 17% of ILE samples. IgG autoantibodies segregated into seven clusters including two specific for DNA and RNA autoantigens that were correlated with the number of lupus criteria. Three IgG autoantibody clusters specific for collagens, DNA and histones, were correlated with renal involvement. Of the four IgM autoantibody clusters, two were correlated negatively with the number of lupus criteria; none were correlated with renal disease. The IgG : IgM autoantibody ratios generally showed a stepwise increase in the groups following disease burden from NC to SLE. Insights derived from the expanded autoantibody profiling made possible with the antigen array suggest differences in autoreactivity in ILE and SLE. Determining whether the IgM aurotreactivity that predominates in ILE represents an early stage prior to IgG switching or is persistent and relatively protective will require further longitudinal studies.     

Reduced anti-TNFalpha autoantibody levels coincide with flare in systemic lupus erythematosus

Deviating cytokine patterns, as a consequence of aberrant immunoregulation, is implicated to be of aetiopathogenetic importance in systemic lupus erythematosus (SLE). To evaluate the possibility of anti-cytokine autoantibody-mediated cytokine regulation/dysregulation, IgG class autoantibodies against cytokines (IL-1beta, IL-6, IL-10, TNFalpha and TGFbeta(1)) were analysed by enzyme-linked immunosorbent assay (ELISA) in serial serum samples from clinically well-characterized SLE patients and in normal human sera (NHS). Anti-TNFalpha autoantibody levels were lower in patients with active disease compared to inactive disease (P<0.001) as well as to NHS (P<0.001). The anti-TNFalpha antibody levels correlated inversely to the SLE disease activity index (SLEDAI) (r(2)=0.07, P<0.01), whereas anti-TGFbeta antibodies were raised in SLE and correlated positively to levels of complement factor C1q (r(2)=0.08, P<0.005). Generally raised anti-cytokine antibody levels and correlations to disease activity measures were found in one individual. Inverse correlations were found comparing SLEDAI scores and autoantibodies to TNFalpha (r(2)=0.92) and IL-6 (r(2)=0.86) and positive correlations were found between levels of anti-TNFalpha and C1q (r(2)=0.86) and C3 (r(2)=0.90). We show, for the first time, a coincidence between reduced anti-TNFalpha autoantibody levels and disease exacerbation in SLE, which is of interest regarding aetiopathogenesis and disease control.     

A cross-sectional hospital-based study of autoantibody profile and clinical manifestations of systemic lupus erythematosus in south Indian patients

Our study was aimed to analyze clinical manifestations, autoantibodies and other serological abnormalities in South Indian patients with systemic lupus erythematosus. Clinical history and findings on systemic examination were noted. Antinuclear antibodies (ANA), antibodies to double-stranded DNA (dsDNA) were detected by immunofluorescence and ANA profile by Immunoblotting. Arthritis was most common followed by fever and skin rash. Clinical manifestations vary according to geographical location of the patient. ANA was positive in 64.28% and anti-dsDNA in 89.36% of patients. All patients with lupus nephritis were positive for dsDNA. Detection of antibodies to dsDNA, RNP and anti-Smith (Sm) are of diagnostic and prognostic importance.     

Familial aggregation and linkage analysis of autoantibody traits in pedigrees multiplex for systemic lupus erythematosus

Autoantibodies are clinically relevant biomarkers for numerous autoimmune disorders. The genetic basis of autoantibody production in systemic lupus erythematosus (SLE) and other autoimmune diseases is poorly understood. In this study, we characterized autoantibody profiles in 1,506 individuals from 229 multiplex SLE pedigrees. There was strong familial aggregation of antinuclear antibodies (ANAs), anti-double-stranded DNA (dsDNA), anti-La/SSB, anti-Ro/SSA, anti-Sm, anti-nRNP (nuclear ribonucleoprotein), IgM antiphospholipid (aPL) antibodies (Abs) and rheumatoid factor (RF) across these families enriched for lupus. We performed genome-wide linkage analyses in an effort to map genes that contribute to the production of the following autoantibodies: Ro/SSA, La/SSB, nRNP, Sm, dsDNA, RF, nuclear and phospholipids. Using an approach to minimize false positives and adjust for multiple comparisons, evidence for linkage was found to anti-La/SSB Abs on chromosome 3q21 (adjusted P=1.9 x 10(-6)), to anti-nRNP and/or anti-Sm Abs on chromosome 3q27 (adjusted P=3.5 x 10(-6)), to anti-Ro/SSA and/or anti-La/SSB Abs on chromosome 4q34-q35 (adjusted P=3.4 x 10(-4)) and to anti-IgM aPL Abs on chromosome 13q14 (adjusted P=2.3 x 10(-4)). These results support the hypothesis that autoantibody production is a genetically complex trait. Identification of the causative alleles will advance our understanding of critical molecular mechanisms that underlie SLE and perhaps other autoimmune diseases.     

Analysis of autoantibody specificities in selected systemic lupus erythematosus (SLE) sera

In order to design effective diagnostics for lupus, the heterogeneity in patient response must be understood. This heterogeneity in the anti-Sm and anti-U1-RNP response was examined via a frequency analysis of autoantibody fine specificities. Thus, 275 sera were studied by immunoprecipitation, immunoblotting, and immunodiffusion, and the frequency of occurrence of different autoantibodies to individual snRNP polypeptides and to other HeLa cell polypeptides was determined. The sera were found to contain autoantibodies reactive with denatured as well as native forms of HeLa-cell polypeptides. The common occurrence of several novel antibody fine specificities was noted, such as anti-p45 (different from anti-La/SS-B), anti-p105, and anti-p115. Another group of autoantibodies that is apparently not disease associated was observed in both lupus and normal sera.     

Common DNase I polymorphism associated with autoantibody production among systemic lupus erythematosus patients

DNase I could be the most important nuclease for the removal of DNA from nuclear antigens at sites of high cell turnover, and thus may also prevent systemic lupus erythematosus (SLE). Sixteen SNPs were identified by direct DNA sequencing, among which six were selected for genotyping in a larger investigation on the basis of linkage disequilibria among SNPs, their frequency, location and haplotype tagging status. Genetic associations of polymorphisms in DNase I with the risk of SLE and the production of common autoantibodies were examined in a Korean population (350 SLE patients and 330 controls). Although no significant associations with the risk of SLE were found, logistic regression analyses revealed that one non-synonymous SNPs in exon 8, +2373A>G(Gln244Arg), was significantly associated with an increased risk of the production of anti-RNP and anti-dsDNA antibodies among SLE patients. The frequency of the homozygous minor allele (Arg/Arg) was much higher in patients who had the anti-RNP antibody (31.3%) than in patients who did not have this antibody (14.4%) (P=0.0006, OR=2.86). In addition, the A/T mutation in exon 2 of DNase reported in two Japanese SLE patients was not present in SLE patients (n=350) or controls (n=330) in our Korean population, which combined with the results of previous reports strongly suggests that the mutation is not present in three major ethnic groups: Caucasian, African and Asian.     

The microbiome and systemic lupus erythematosus

The microbiota, which is comprised of the collective of all microbes inhabiting the gut and its effect on the human host in which it resides, has become a growing field of interest. Various parameters of health and disease have been found to be associated with the variation in the human gut microbiome. In recent years, many studies have demonstrated an important role of gut microbes in the development of various illnesses including autoimmune diseases, such as type 1 diabetes, rheumatoid arthritis, and multiple sclerosis. Although the mechanism of the disease involves both genetic and environmental factors, lupus has been found to be affected by the composition of the microbes lining the intestines. Several recent studies have suggested that alterations of the gut microbial composition may be correlated with SLE disease manifestations, while the exact roles of either symbiotic or pathogenic microbes in this disease have yet to be explored. Elucidation of the roles of gut microbes in SLE will shed light on how this autoimmune disorder develops and provide opportunities for improved biomarkers of the disease and the potential to probe new therapies. This new knowledge, along with that enabling alteration in composition of the gut microbiome, via diet modification, antibiotic, and probiotics, may bring forward a new era in the future of lupus treatment.

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The genetics of systemic lupus erythematosus

There is considerable evidence that the development of systemic lupus erythematosus (SLE) has a strong genetic basis. For more than 20 years, much effort has been made to understand the genetics of SLE. Association studies in humans suggest the existence of genetic effects by the alleles encoded in the HLA, deficiencies in the complement genes and the low-affinity variants of Fcgamma-receptors. In mouse models of SLE at least 13 loci have been identified, including the MHC, linked to lupus-related phenotypes such as nephritis and production of autoantibodies. Recently, linkage studies have been performed in human SLE; one investigating a candidate region based on synteny to a murine susceptibility locus and four genome-wide linkage studies in various populations. Linkage was demonstrated to several chromosomal regions, some of which are syntenic to murine lupus susceptibility loci. Interestingly, many of the identified chromosomal regions co-localise with loci implicated in other autoimmune diseases.     

The pathogenesis of systemic lupus erythematosus

Many investigators believe that systemic lupus erythematosus is an autoimmune disease, perhaps caused by inadequate suppressor T lymphocyte activity, which permits the activation of autoantibody producing B lymphocytes. This paper discusses the testable hypothesis that a superoxide-generating, chromosome aberration-inducing factor (clastogenic factor), present in the lymphocytes of lupus patients but absent from normals, is responsible for such a suppressor cell defect. Superoxide or activated oxygen species derived from it, such as hydroxyl radical, may be the molecular mediators of CF activity.     

New therapies for systemic lupus erythematosus

In the past 40 years, prognosis for patients with systemic lupus erythematosus (SLE) has improved, with 10-year survival now approximately 90%. This is due probably to a combination of earlier disease diagnosis and diagnosis of milder disease, due in part to availability of multiple serological tests for SLE, use of steroids and other immunosuppressive agents, and availability of renal dialysis and transplantation. Despite this, however, the potential for significant morbidity and mortality remains in the group of patients with partially responsive or treatment resistant disease. More recently, advancements in the understanding of molecular mechanisms involved in the pathogenesis of SLE have translated to the development of novel therapies, offering possible alternatives to this patient cohort. Discussion of these pharmacological options and ongoing research forms the basis of this review.     

Prognosis in systemic lupus erythematosus

Conclusions In SLE, morbidity is universal and fatality is significant. One cannot learn too much about the prognostic markers for this disorder. The identification by means of renal biopsy of subclasses of lupus nephritis spurred the development of new treatment regimens that have improved outcomes. While proliferative nephritis remains a marker of serious renal involvement, the newer indices that attempt to quantify the activity and chronicity of the renal lesion, as well as greater awareness of the importance of tubulointerstitial involvement and improvement in the amount of subendothelial electron-dense deposits with therapy, will likely permit further fine-tuning of the treatment of individual patients with lupus nephritis.Neuropsychiatric involvement in SLE is another major determinant of financial costs, morbidity and death. Unfortunately, our knowledge of the prognostic markers for this more heterogeneous group of manifestations is less advanced than for lupus renal involvement. Additional studies are needed urgently to determine the factors that predict the subsequent development of the different forms of neuropsychiatric lupus. The determinants will likely differ among the various forms of neuropsychiatric lupus, thereby permitting different preventative or treatment regimens to be developed.The role of social factors, particularly socioeconomic status, has attracted attention in the United States. The lessons are likely applicable elsewhere. Additional studies to identify social factors that can be modified may bring tangible benefits to SLE patients in this decade.Although not universally accepted, it does appear that as more SLE patients survive the acute disease, there is an inordinately high risk of developing vascular diseases, including coronary artery disease, stroke and peripheral vascular disease. As with neuropsychiatric lupus, the determinants may differ depending on the specific vascular disease. Better knowledge of these determinants will permit a further improvement in the overall prognosis for patients with SLE.     

An antibody profile of systemic lupus erythematosus detected by antigen microarray

Patients with systemic lupus erythematosus (SLE) produce antibodies to many different self‐antigens. Here, we investigated antibodies in SLE sera using an antigen microarray containing many hundreds of antigens, mostly self‐antigens. The aim was to detect sets of antibody reactivities characteristic of SLE patients in each of various clinical states – SLE patients with acute lupus nephritis, SLE patients in renal remission, and SLE patients who had never had renal involvement. The analysis produced two novel findings: (i) an SLE antibody profile persists independently of disease activity and despite long‐term clinical remission, and (ii) this SLE antibody profile includes increases in four specific immunoglobulin G (IgG) reactivities to double‐stranded DNA (dsDNA), single‐stranded DNA (ssDNA), Epstein–Barr virus (EBV) and hyaluronic acid; the profile also includes decreases in specific IgM reactivities to myeloperoxidase (MPO), CD99, collagen III, insulin‐like growth factor binding protein 1 (IGFBP1) and cardiolipin. The reactivities together showed high sensitivity (> 93%) and high specificity for SLE (> 88%). A healthy control subject who had the SLE antibody profile was later found to develop clinical SLE. The present study did not detect antibody reactivities that differentiated among the various subgroups of SLE subjects with statistical significance. Thus, SLE is characterized by an enduring antibody profile irrespective of clinical state. The association of SLE with decreased IgM natural autoantibodies suggests that these autoantibodies might enhance resistance to SLE.     

Dyslipidemia in systemic lupus erythematosus

Cardiovascular disease is one of the major causes of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Accelerated atherosclerosis is related to traditional (age, hypertension, diabetes mellitus, dyslipidemia, obesity, smoking, and positive family history) and non-traditional, disease-related factors. Traditional risk factors are still more prominent in patients with lupus, as both hypertension and hypercholesterinemia were independently associated with premature atherosclerosis in several SLE cohorts. In this work, the authors summarize the epidemiology of dyslipidemia in lupus patients and review the latest results in the pathogenesis of lipid abnormalities. The prevalence of dyslipidemia, with elevations in total cholesterol (TC), low-density lipoprotein (LDL), triglyceride (TG), and apolipoprotein B (ApoB), and a reduction in low-density lipoprotein (LDL) levels are about 30% at the diagnosis of SLE rising to 60% after 3 years. Multiple pathogenetic mechanism is included, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) can suppress HDL and increase TG, auto-antibodies can cause the injury of the endothelium, lipoprotein lipase (LPL) activity can be reduced by circulating inflammatory mediators and antibodies, and increased oxidative stress may trigger a wide range of pro-atherogenic lipid modifications. As a major risk factor, dyslipidemia should be treated aggressively to minimize the risk of atherosclerosis and cardiovascular events. Randomized controlled trials with statins are controversial in the detention of atherosclerosis progression, but can be favorable by inhibiting immune activation that is the arterial wall and by decreasing lupus activity.