Etiology Of Systemic Lupus Erythematosus Research Articles

Expression of Toll-like receptor 9 in renal podocytes in childhood-onset active and inactive lupus nephritis

Childhood-onset systemic lupus erythematosus (SLE) is frequently complicated with lupus nephritis (LN), which is characterized by the deposition of DNA-containing immune complex to the glomerulus. Toll-like receptor 9 (TLR9), capable of recognizing the microbially derived CpG oligonucleotide, plays a crucial role in the innate immunity. TLR9 is also assumed to be related to the aetiology of SLE in the recognition of anti-DNA antibody-containing immune complex, but this remains controversial. We conducted a study to elucidate the association between TLR9 and LN in childhood-onset SLE. We compared the expression and localization of TLR9 and the slit membrane-related protein in the biopsied kidney sample by immunostaining in four children with active or inactive LN. We also evaluated their laboratory findings, such as anti-DNA antibody, complement and proteinuria at biopsy, to assess the correlation to the findings of the immunostaining. TLR9 is not expressed in a normal control kidney. However, TLR9 develops in podocytes only in active LN but disappears in remission. Meanwhile, the slit membrane-related proteins such as nephrin, podocin and synaptopodin in podocytes express clearly and uniformly in remission, but their expression is markedly diminished in active LN, which results in podocyte injury. When TLR9 is expressed in podocytes, all the patients simultaneously showed hypocomplementaemia, high titre of anti-double-stranded DNA (dsDNA) antibody and proteinuria. Injured podocytes in active LN express TLR9. This expression could be associated with proteinuria and increased anti-dsDNA antibody. This is the first report indicating that TLR9 is involved in the aetiology of LN and that it may play some role in podocyte injury.

HLA-DRB1*15 Confers Susceptibility to Juvenile SLE But is Not Associated with Disease Presentation: An Egyptian Study

The etiology of Systemic lupus erythematosus (SLE) seems to be multifactorial including environmental as well as genetic factors. Major histocompatibility complex (MHC) genes especially HLA-DRB1 and HLA-DQB1 are strongly implicated in susceptibility to SLE. Moreover ethnicity has been found to have a significant role in both disease susceptibility and disease expression. This study was carried out to determine HLA-DRB1 allele association with SLE susceptibility and disease presentation in Egyptian children with juvenile onset SLE. HLA-DRB1 allele typing was done using polymerase chain reaction-sequence-specific oligonucleotide probe for 65 juvenile Egyptian SLE patients and 150 healthy controls. p-values were corrected for the number of the alleles tested (Pc). HLA-DRB1*15 g allele was significantly increased in SLE children versus controls (OR = 4.76; 95% CI = 1.83–12.4; p = 0.001 and Pc = 0.012). No HLA-DRB1 allele was found to be statistically significant associated with musculoskeletal, cutaneous, hematologic, cardiac or neuropsychiatric manifestations in SLE patients (p > 0.05). Moreover no statistically significant association was found between HLA-DRB1 alleles and clinical presentation or histologic classes of lupus nephritis. The current work suggests that HLA-DRB1*15g allele may be a susceptibility allele in Egyptian children with SLE but is not related to clinical presentation of SLE.

Assay of T- and NK-cell subsets and the expression of NKG2A and NKG2D in patients with new-onset systemic lupus erythematosus

This study aims to explore the percentage of T-cell and NK-cell subsets, the expression of NKG2A and NKG2D on CD3+ T cells and CD3-CD56+ NK cells on the total lymphocytes in new-onset systemic lupus erythematosus (SLE) patients, and explore clinical significance of these cell subsets. Thirty-two SLE patients and 32 normal controls were enrolled. Flow cytometry was used to count T- and NK-cell subsets and to detect the expression of NKG2A and NKG2D on CD3+ T cells and CD3-CD56+ NK cells in patients with new-onset SLE. Results show that CD4+ T (t = 2.04, P < 0.05), CD4+/CD8+ T cell (t = 2.66, P < 0.05), CD4+ CD25+ T (t = 2.48, P < 0.05), CD3+CD56+ natural killer T (NKT) (t = 40.05, P < 0.01), CD3-CD56+CD16+ NK-cell subsets (t = 3.50, P < 0.01) were significantly decreased, CD8+ T-cell subsets was significantly increased in patients with new-onset SLE (t = 3.80, P < 0.01), as compared with healthy controls. CD8+ T-cell subset was significantly increased in patients with vasculitis (t = 2.47, P < 0.05), and CD3-CD56+CD16+ NK was increased in patients with arthritis (t = 3.21, P < 0.01). However, no statistically significant correlation was found among different PBMC subsets and SLEDAI activity scores. Patients with SLE had a lower expression of NKG2A (U = 2.42, P < 0.05) as well as NKG2A/NKG2D ratio (t = 2.61, P < 0.05) and a higher expression of NKG2D (t = 2.21, P < 0.05) on CD3+ T cells, compared with normal controls. However, they had a higher expression of NKG2A (t = 2.59, P < 0.05) as well as NKG2A/NKG2D ratio (t = 49.45, P < 0.01) and a lower expression of NKG2D (t = 3.05, P < 0.01) on CD3-CD56+ NK cells. Taken together, the findings indicate the decreased CD4+ T-cell, CD4+/CD8+ T-cell, CD4+CD25+ T-cell, CD3+CD56+ NKT-, and CD3-CD56+CD16+ NK-cell subsets, increased CD8+ T-cell subsets as well as the abnormal expression of NKG2A and NKG2D on CD3+ T and CD3-CD56 + NK cells may play a role in the etiology of SLE.

Three checkpoints in lupus development: central tolerance in adaptive immunity, peripheral amplification by innate immunity and end-organ inflammation

Although the etiology of systemic lupus erythematosus (SLE) remains to be fully elucidated, it is now apparent that multiple genetic and environmental factors are at play. Over the past decade, several studies have helped uncover genetic associations and susceptibility loci in human and murine lupus. In particular, recent genome-wide association studies have uncovered a large number of associated genes in human SLE. Given this plethora of candidate genes, the next challenge for lupus biologists is to fathom how these different genes operate to engender lupus. In this context, recent genetic studies in mouse models of lupus have been particularly informative. The purpose of this review is to overview three key genetically determined checkpoints in lupus development that have emerged from studies of NZM2410-derived congenic strains bearing individual lupus susceptibility loci. These three events include a breach in central tolerance in the adaptive arm of the immune system, peripheral amplification of the autoimmune response by the innate immune system and local processes in the target organ that facilitate end-organ disease. Collectively, murine congenic dissection studies provide a framework for understanding and analyzing the steady stream of gene candidates that are currently emerging from human lupus studies.

Apolipoprotein H Promoter Polymorphisms in Relation to Lupus and Lupus-related Phenotypes

Sequence variation in gene promoters is often associated with disease risk. We tested the hypothesis that common promoter variation in the APOH gene (encoding for ss(2)-glycoprotein I) is associated with systemic lupus erythematosus (SLE) risk and SLE-related clinical phenotypes in a Caucasian cohort. We used a case-control design and genotyped 345 women with SLE and 454 healthy control women for 8 APOH promoter single-nucleotide polymorphisms (SNP; -1284C>G, -1219G>A, -1190G>C, -759A>G, -700C>A, -643T>C, -38G>A, and -32C>A).Association analyses were performed on single SNP and haplotypes. Haplotype analyses were performed using EH (Estimate Haplotype-frequencies) and Haploview programs. In vitro reporter gene assay was performed in COS-1 cells. Electrophoretic mobility shift assay (EMSA) was performed using HepG2 nuclear cells. Overall haplotype distribution of the APOH promoter SNP was significantly different between cases and controls (p = 0.009). The -643C allele was found to be protective against carotid plaque formation (adjusted OR 0.37, p = 0.013) among patients with SLE. The -643C allele was associated with a ~2-fold decrease in promoter activity as compared to wild-type -643T allele (mean +/- standard deviation: 3.94 +/- 0.05 vs 6.99 +/- 0.68, p = 0.016). EMSA showed that the -643T>C SNP harbors a binding site for a nuclear factor. The -1219G>A SNP showed a significant association with the risk of lupus nephritis (age-adjusted OR 0.36, p = 0.016). Our data indicate that APOH promoter variants may be involved in the etiology of SLE, especially the risk for autoimmune-mediated cardiovascular disease.

The clinical characterisation of systemic lupus erythematosus in a Far North Queensland Indigenous kindred

The aetiology of systemic lupus erythematosus (SLE) is thought to involve both genetic and environmental factors. In other complex diseases, analysis of large multi-case families has resulted in insights into biological mechanisms. We have sought to characterise the members of an extended Indigenous family, five of whom have been diagnosed with SLE. Pedigree members were evaluated using the Lupus Screening Questionnaire, clinical interviews and medical records. Participants contributed blood and urine samples for laboratory analysis. A Mendelian pattern of inheritance was not observed. The five affected members (all female) shared two American College of Rheumatology criteria (positive ANA and arthritis) but showed a wide variety of other SLE manifestations. Disease onset, severity and progression were discordant. Including the five individuals with SLE, 15 blood relatives and two non-consanguineous spouses had autoimmune manifestations. Autoimmune haemolytic anaemia (one case), idiopathic thrombocytopenic purpura (ITP) (one case) and hypothyroidism (two cases) were observed in non-SLE affected individuals. Anti-nuclear antibodies were present in 12 blood relatives and one non-consanguineous spouse. Infections (especially of the skin) were observed to be common in the kindred. The lack of clear Mendelian inheritance or phenotypic concordance makes a rare monogenic explanation for SLE unlikely in this family. The finding of familial autoimmunity associated with SLE further supports the hypothesis that a common genetic pathway can precipitate autoimmunity, with further genes and possible environmental factors interacting to produce the eventual phenotype. Future genetic linkage studies may reveal a rare 'autoimmune gene' variant in this kindred.

Lupus-like autoantibody development in rabbits and mice after immunization with EBNA-1 fragments

Epstein–Barr virus has been implicated in the etiology of systemic lupus erythematosus (SLE) through serologic and immunologic studies. A potential mechanism for this influence is through molecular mimicry. The EBV nuclear antigen EBNA-1 contains a region, PPPGRRP, with considerable homology to the initial sequence targeted by antibodies in Sm B′ autoimmunity, PPPGMRPP. This study examined whether immunization of rabbits and mice with peptides containing the PPPGRRP sequence from EBNA-1 constructed on a poly-lysine backbone was able to drive the development of autoantibodies against the Smith antigen (Sm) and the related antigenic complex, the U1 nuclear ribonucleoproteins (nRNPs). PPPGRRP immunization, and immunization with an EBNA-1 fragment containing PPPGRRP, led to autoantibodies in both rabbits and mice at high frequency (83% of rabbits and 43% of mice). Five out of six immunized rabbits developed either leucopenia or lymphopenia or both. The fine specificity of antibody binding against the lupus-associated autoantigens Sm B′, nRNP A, and nRNP C after immunization with the EBNA-1-derived peptides was very similar to the early antibody binding patterns against these proteins in human SLE. This similarity, as well as the prevalence of autoimmunity after immunization with these peptides, identifies PPPGRRP as a strong candidate for molecular mimicry in SLE etiology.

Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus.

The TNFAIP3 (tumor necrosis factor alpha-induced protein 3) gene encodes a ubiquitin editing enzyme, A20, that restricts NF-kappaB-dependent signaling and prevents inflammation. We show that three independent SNPs in the TNFAIP3 region (rs13192841, rs2230926 and rs6922466) are associated with systemic lupus erythematosus (SLE) among individuals of European ancestry. These findings provide critical links between A20 and the etiology of SLE.

Apoptosis in the pathogenesis of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a prototype inflammatory autoimmune disease resulting from autoimmune responses against nuclear autoantigens. During apoptosis many lupus autoantigens congregate inside the cells and are susceptible to modifications. Modified nuclear constituents are considered foreign and dangerous. Therefore, apoptotic cells have to has to be efficiently removed to avoid the accumulation of apoptotic debris and the subsequently development of autoimmune responses. Hence, apoptosis and clearance of apoptotic cells/material are considered key processes in the aetiology of SLE. Clearance deficiencies may account for the development of autoimmunity by inducing a loss of tolerance in lymphoid tissues. Furthermore, phagocytosis of apoptotic cells may lead to a pro-inflammatory response in the presence of autoantibodies. This may sustain inflammatory conditions and the pathology found in overt lupus.

Clinical manifestations and analyses of the cytotoxic T-lymphocyte associated-4 gene in two Japanese families with systemic lupus erythematosus

Although still incompletely understood, the etiology of systemic lupus erythematosus (SLE) is considered to involve both genetic and environmental factors. We encountered two boys with severe SLE from unrelated families and analyzed the gene that encodes cytotoxic T-lymphocyte-associated (CTLA)-4, a protein important in T-cell activation and immune tolerance. Abnormal function of the gene may participate in causation of autoimmune disease, including SLE. In family 1, a boy showed serious cardiovascular complications associated with heart failure, and his mother also had clinically active SLE, including nephritis. A boy in family 2 developed severe renal complications and peripheral vasculitis accompanied by disseminated petechiae in the lower extremities. His paternal grandfather had died from fibrinous pneumonia caused by SLE. They showed high SLE Disease Activity Index (SLEDAI) score. Analysis of the CTLA-4 gene indicated that the boy in family 1 and his mother and the boy in family 2 possess a GG genotype in CTLA-4 exon 1 at +49 together with a 106-bp fragment length of the 3' untranslated region (UTR) in exon 4. No association with disease activity was found for polymorphism of the promoter region in exon 1 at -318 in either family. Disorders of the CTLA-4 gene, especially a GG genotype in exon 1 at +49 and/or 106-bp fragment length of the 3'UTR in exon 4, may be involved in early development of SLE in Japanese children, such as the boys described here.

Association of IL‐1 beta gene polymorphism with susceptibility to systemic lupus erythematosus

AbstractBackground: The IL‐1β exon5 (+3954) has been related to the pathogenesis of lupus, but the role of IL‐1 polymorphisms in the aetiology of systemic lupus erythematosus (SLE) is unknown.Method: We compare the IL‐1 beta +3954 (exon5) gene polymorphism among 52 SLE patients and healthy controls in north‐eastern Iran. Polymorphism of the gene for IL‐1 beta +3954 was typed after the genomic DNA was amplified by polymerase chain reaction‐sequence‐specific‐primers technique.Results: Comparing the results show no significant differences in the frequency of IL‐1 beta exon5 allels between patients with SLE and controls. Additionally, we did not detect any association of IL‐1 beta exon5 (+3954) genotype with clinical and laboratory profiles in SLE patients.Conclusion: The polymorphism of the IL‐1 beta exon5 allele is not associated with genetic susceptibility to SLE in north‐eastern of Iran.

Genetic association of interleukin-21 polymorphisms with systemic lupus erythematosus

Objective:The aetiology of systemic lupus erythematosus (SLE) is incompletely understood. Both genetic and environmental factors are implicated in the pathogenesis of the disease. Herein, we describe genetic association between SLE...

Altered Dynamics of Kv1.3 Channel Compartmentalization in the Immunological Synapse in Systemic Lupus Erythematosus

Aberrant T cell responses during T cell activation and immunological synapse (IS) formation have been described in systemic lupus erythematosus (SLE). Kv1.3 potassium channels are expressed in T cells where they compartmentalize at the IS and play a key role in T cell activation by modulating Ca(2+) influx. Although Kv1.3 channels have such an important role in T cell function, their potential involvement in the etiology and progression of SLE remains unknown. This study compares the K channel phenotype and the dynamics of Kv1.3 compartmentalization in the IS of normal and SLE human T cells. IS formation was induced by 1-30 min exposure to either anti-CD3/CD28 Ab-coated beads or EBV-infected B cells. We found that although the level of Kv1.3 channel expression and their activity in SLE T cells is similar to normal resting T cells, the kinetics of Kv1.3 compartmentalization in the IS are markedly different. In healthy resting T cells, Kv1.3 channels are progressively recruited and maintained in the IS for at least 30 min from synapse formation. In contrast, SLE, but not rheumatoid arthritis, T cells show faster kinetics with maximum Kv1.3 recruitment at 1 min and movement out of the IS by 15 min after activation. These kinetics resemble preactivated healthy T cells, but the K channel phenotype of SLE T cells is identical to resting T cells, where Kv1.3 constitutes the dominant K conductance. The defective temporal and spatial Kv1.3 distribution that we observed may contribute to the abnormal functions of SLE T cells.

DNA Methylation and Systemic Lupus Erythematosus

Several studies have indicated the importance of DNA hypomethylation in the etiology of systemic lupus erythematosus (SLE). Different enzymes linked to the DNA methylation process have been described. The identification of all these enzymes means that cells have the capacity to modify their methylation patterns. Therefore, to obtain a deeper understanding of the role this epigenetic mechanism may have on SLE, the enzymes involved in the DNA methylation mechanism must be thoughtfully analyzed. In fact, studies of enzymes (other than DNMT1) in this autoimmune disease are still lacking. We have recently investigated the simultaneous gene expression of DNMT1, DNMT3A, DNMT3B, MBD2, and MBD4 in SLE patients. Here we review some of the studies that focus on the relationship between DNA methylation and SLE as well as we report our recent findings in this field. We suggest some alternative hypothesis that could help to understand the causes of the global DNA hypomethylation observed in the CD4+ T cells of these patients.

Immunopathogenesis of systemic lupus erythematosus

There has been a substantial improvement in mortality and morbidity in patients with systemic lupus erythematosus (SLE) over the past 50 years. This change results from earlier diagnosis (with the aid of clinically useful biomarkers), development of disease monitoring and damage assessment methods, more effective pharmacotherapy, early recognition of side effects and efficient adjunctive therapies, including dialysis and renal transplant. Gene expression profiling and proteomic approaches may give insight into the etiology of SLE. Recent advances in the understanding of the various immunological defects in SLE have led to an era of therapeutic trials of agents, targeted at blocking effector mechanisms of either surface antigens, costimulatory molecules or cytokines.

Possible Role of DNA Methylation in the Induction of Systemic Lupus Erythematosus

Recent studies on epigenetics, including DNA methylation and its regulatory enzymes, seem to contribute to elucidation of the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE), although the relationship between DNA methylation and SLE has long been the subject of investigation. To obtain a deeper understanding of the role of DNA methylation in the induction of SLE, we reviewed the relationship between DNA methylation and SLE based on findings reported in the literature and our own data. Various studies, including ours, have indicated the possible importance of DNA methylation, especially hypomethylation, in the etiology of SLE. These epigenetic studies may give us clues towards elucidation of the pathogenesis of SLE and development of new therapeutic strategies for this disease. Keywords: Systemic lupus erythematosus, DNA methylation, CpG motif, human endogenous retroviruses, toll-like receptor

Gene–environment interactions in the aetiology of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a disease that displays a multitude of symptoms and a vast array of autoantibodies. The disease course may vary substantially between patients. The current understanding of SLE aetiology includes environmental factors acting on a genetically prone individual during an undetermined time period resulting in autoimmunity and finally surpassing that individual's disease threshold. Genetic differences and environmental factors may interact specifically in the pathogenetic processes and may influence disease development and modify the disease course. Identification of these factors and their interactions in the pathogenesis of SLE is vital in understanding the disease and may contribute to identify new treatment targets and perhaps also aid in disease prevention. However, there are several problems that need to be overcome, such as the protracted time frame of environmental influence, time dependent epigenetic alterations and the possibility that different pathogenetic pathways may result in a similar disease phenotype. This is mirrored by the relatively few studies that suggest specific gene-environment interactions. These include an association between SLE diagnosis and glutathion S-transferase gene variants combined with occupational sun exposure as well as variants of the N-acetyl transferase gene in combination with either aromatic amine exposure or hydralazine. With increased knowledge on SLE pathogenesis, the role of environmental factors and their genetic interactions may be further elucidated.

Chimerism in systemic lupus erythematosus—three hypotheses

Systemic lupus erythematosus (SLE) is an immune-mediated disease characterized by the presence of autoantibodies and a wide array of clinical symptoms. Despite intensive research, the aetiology of SLE is still unknown and is probably multifactorial. Both genetic and environmental factors have been associated with SLE, but these factors alone are insufficient to explain the onset of SLE. Recently, it has been suggested that chimerism plays a role in the pathogenesis of autoimmune diseases, including SLE. Chimerism indicates the presence of cells from one individual in another individual. In an experimental mouse model, the injection of chimeric cells induces a lupus-like disease. In addition, chimerism is found more often in kidneys of women with SLE than in healthy controls. There are several mechanisms by which chimeric cells could be involved in the pathogenesis of SLE. In this review, three hypotheses on the role of chimerism in SLE are discussed. The first two hypotheses describe the possibilities that chimeric cells induce either a graft-vs-host reaction in the host (comparable with reactions seen after bone marrow transplantation) or a host-vs-graft reaction (comparable with reactions seen after solid organ transplantation). The third hypothesis discusses the possible beneficial role chimeric cells may play in repair mechanisms due to their stem cell-like properties. This review provides insights into the mechanisms by which chimerism may be involved in SLE and proposes several lines of inquiry to further investigate chimerism in SLE.

DNA methylation: its contribution to systemic lupus erythematosus

Recent studies on epigenetics, including the methylation of DNA and the enzymes regulating methylation, seem likely to contribute to understanding the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE). In fact, the relationship between DNA methylation and SLE has long been the subject of investigation. To obtain a deeper understanding of the role of DNA methylation in the onset of SLE, we reviewed the findings reported in the literature and our own data about DNA methylation and SLE. Various studies have indicated the possible importance of DNA methylation, especially hypomethylation, in the aetiology of SLE. Epigenetic studies may provide clues for elucidating the pathogenesis of SLE and for developing new strategies to treat this disease.

Systemic Lupus Erythematosus in Children and Adolescents

1. Beth S. Gottlieb, MD, MS* 2. Norman T. Ilowite, MD† 1. *Assistant Professor of Pediatrics, Albert Einstein College of Medicine; Chief, Division of Rheumatology, Schneider Children's Hospital, Hyde Park, NY 2. †Professor of Pediatrics, Albert Einstein College of Medicine; Chief, Division of Rheumatology, Children's Hospital at Montefiore, Bronx, NY After completing this article, readers should be able to: 1. List the most common presenting symptoms of systemic lupus erythematosus (SLE) in the pediatric population. 2. Describe the patient who is most likely to have secondary Raynaud phenomenon. 3. Recognize why antinuclear antibody testing lacks specificity. 4. Know the specific serologic markers for SLE. 5. Discuss the treatment for SLE. Systemic lupus erythematosus (SLE) is a multisystem, chronic but often episodic, autoimmune disease that is characterized by the presence of antinuclear antibodies (ANA). Because SLE can present with a number of signs and symptoms, the diagnosis often is considered in children who have prolonged unexplained complaints. Approximately 20% of all patients who have SLE are diagnosed in childhood. The onset of SLE is rare in those younger than 5 years of age; most pediatric patients are diagnosed in adolescence. SLE is considered a predominantly female disease, and although most affected patients are female, the ratio changes with age. Prior to puberty, the female-to-male ratio is 3:1; after puberty, the ratio becomes 9:1. Aside from this sex difference, there also are marked racial differences observed in SLE. Native Americans are most susceptible to developing SLE, followed by African-Americans, Hispanics, Chinese, and Filipinos. The disease tends to be more severe in African-Americans and Hispanics. SLE is a multigenic disease. A patient who has SLE is more likely to have a relative who has either SLE or another autoimmune disease such as thyroiditis or insulin-dependent diabetes. Epidemiologic, twin, and human leukocyte antigen data suggest a strong genetic contribution to the etiology of SLE, but the exact cause is unknown. Multiple factors confer risk, including abnormalities in the metabolism of sex hormones, particular foods that have been found to be immunostimulatory in animals, and infectious agents. Overall, it has been suggested that an environmental trigger is necessary in a …