Etiology Of Systemic Lupus Erythematosus Research Articles

SLE: Another Autoimmune Disorder Influenced by Microbes and Diet?

Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease. Despite years of study, the etiology of SLE is still unclear. Both genetic and environmental factors have been implicated in the disease mechanisms. In the past decade, a growing body of evidence has indicated an important role of gut microbes in the development of autoimmune diseases, including type 1 diabetes, rheumatoid arthritis, and multiple sclerosis. However, such knowledge on SLE is little, though we have already known that environmental factors can trigger the development of lupus. 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 remain to be explored. Elucidation of the roles of gut microbes – as well as the roles of diet that can modulate the composition 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. In this review, we aim to compile the available evidence on the contributions of diet and gut microbes to SLE occurrence and pathogenesis.

JHDM1D and HDAC1-3 mRNA expression levels in peripheral blood mononuclear cells of patients with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic relapsing autoimmune disease characterized by production of autoantibodies against a series of nuclear antigens and by chronic inflammation. The etiology of SLE is the result of interactions between genetic, epigenetic, hormonal, and environmental factors. Changes in histone acetylation and methylation contribute to structural chromatin modifications. We studied the histone demethylase JHDM1D and histone deacetylases HDAC1, HDAC2, and HDAC3 transcript levels in peripheral blood mononuclear cells (PBMCs) from patients diagnosed with systemic lupus erythematosus (SLE). Furthermore, the association of JHDM1D, HDAC1, HDAC2, and HDAC3 transcript levels with gender, age, and major clinical manifestations were analyzed. Real-time quantitative polymerase chain reaction (RQ-PCR) analysis was used to determine JHDM1D, HDAC1, HDAC2, and HDAC3 mRNA expression levels in peripheral blood mononuclear cells (PBMCs) from 30 patients with SLE and 36 healthy controls. Significantly lower HDAC2 transcript levels (p = 0.006785) and significantly higher JHDM1D (p = 0.0000002) and HDAC1 (p = 0.010581) transcript levels in SLE patients were observed compared with healthy controls. Higher JHDM1D mRNA expression was detected in active SLE patients when compared with inactive patients (p = 0.005). Furthermore, the JHDM1D transcript levels were positively correlated with disease activity (r(s) = 0.368, p = 0.045), while HDAC2 mRNA expression was positively correlated with disease duration (r(s) = 0.502, p = 0.0047). Our analyses confirmed the importance of epigenetic alterations (histone demethylation and acetylation) in SLE etiology. Moreover, our results suggest that the presence of some clinical manifestations, like hematological disease and anti-Ro antibody, might be associated with the dysregulation of histone demethylase and deacetylases mRNA expression levels.

Cytokines and MicroRNAs as Candidate Biomarkers for Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease, with varied course and symptoms. Its etiology is very complex and not clearly understood. There is growing evidence of the important role of cytokines in SLE pathogenesis, as well as their utility as biomarkers and targets in new therapies. Other potential new SLE biomarkers are microRNAs. Recently, over one hundred different microRNAs have been demonstrated to have a significant impact on the immune system. Various alterations in these microRNAs, associated with disease pathogenesis, have been described. They influence the signaling pathways and functions of immune response cells. Here, we aim to review the emerging new data on SLE etiology and pathogenesis.

Microarray to deep sequencing: transcriptome and miRNA profiling to elucidate molecular pathways in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease with diverse clinical manifestations and autoantibody repertoires. The etiology of SLE is multifactorial involving genetic, epigenetic and environmental factors. This complexity leads to poor prognosis, which poses major challenges in the treatment of SLE. Understanding the complex genetic pathways and regulatory mechanisms operative in SLE was feasible by utilizing several highly efficient molecular biological tools during the past few years. In this perspective, DNA microarray technology offered a high-throughput platform in unraveling SLE-associated genes. Additionally, extensive microarray analysis had demonstrated aberrant DNA methylation pattern and differential microRNAs, thus contributing to the knowledge of epigenetic modulators and posttranscriptional regulatory machinery in SLE. It was through the aid of these technologies that interferon signature was identified as an important contributor in SLE pathogenesis along with dysregulation of cytokine-, chemokine- and apoptosis-related genes. The emergence of next-generation sequencing technologies such as RNA sequencing has added new dimensions in understanding the dynamics of the disease processes. Compared with microarrays, deep sequencing has provided higher resolution in gene expression measurement along with identification of different splicing events, noncoding RNAs and novel loci in SLE. The focus, therefore, has now been shifted toward the identification of novel gene loci and their isoforms, and their implication in disease pathogenesis. This advancement in the technology from microarray to deep sequencing has helped in deciphering the molecular pathways involved in pathogenesis of SLE and opens new avenues to develop novel treatment strategies for SLE.

Neuro-ophthalmic complications in systemic lupus erythematosus: Case analysis and the literature review

SLE is an autoimmune connective tissue disease mostly occurs in women, affects various systems of the body with broad range of symptoms and complications. A 31 year old female was admitted in October 2013 with complaints of right lower limb weakness and inability to walk for 3 days and diagnosed to have systemic lupus erythematosus (SLE) remission. A detailed medical history revealed multiple admissions, initially with Parinauds syndrome due to an upper midbrain tectal lesion in December 2004 when she was Primigravida at 32 weeks and she developed SLE at 37 weeks. In subsequent admissions she was diagnosed to have transverse myelitis along with steroid induced diabetes mellitus (2005), obsessive compulsive disorder (2008) and optic neuritis (2009). On every admission patient has treated successfully; visual acuity is improving leisurely. Reviewed literature shows the relationship between SLE and its neuro-ocular complications. All the conditions diagnosed in the patient are related directly or indirectly with etiology and/or treatment of SLE; so this case would be helpful to understand pathogenesis, diagnosis and management of such cases.

T cells as a therapeutic target in SLE.

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by a loss of tolerance to multiple endogenous antigens. SLE etiology remains largely unknown, despite recent insight into the immunopathogenesis of the disease. T cells are important in the development of the disease by amplifying the immune response and contributing to organ damage. Aberrant signaling, cytokine secretion, and tissue homing displayed by SLE T cells have been extensively studied and the underlying pathogenic molecular mechanisms are starting to be elucidated. T-cell-targeted treatments are being explored in SLE patients. This review is an update on the T-cell abnormalities and related therapeutic options in SLE.

Awareness and Misconceptions of Female Students in King Saud University on Systemic Lupus Erythematosus

Objectives: To determine the level of awareness of systemic lupus erythematosus (SLE) among preparatory year program female students enrolling in King Saud University. Methods: The authors developed a self-administered questionnaire to estimate the level of awareness on SLE. According to their scores, respondents are classified as knowledge adequate if they could answer 11 (35.5%) of the question. Descriptive statistics were calculated in terms of mean and standard. Chi-square and T tests were used to compare different subgroups for nominal and continuous variables respectively. Results: Six hundred thirty participants completed the questionnaire. Mean age ± (SD) was 18.6 ± (1.17), 591(93.8%) were of Saudi nationality, and 607(96.3%) were single. The number of respondents in each university section was as follows: Humanity 228(36.2%), Health 201(31.9%), and Science 201(31.9%). One participant (0.02%) reported the diagnosis of SLE. Seventy-nine (12.5%) knew someone diagnosed with SLE. Two hundred fifty two (40%) have previously heard the term SLE. Of those, 73(29%) had adequate knowledge on SLE with a superior knowledge in participants who knew someone with SLE (p=0.018). In regards to the etiology of SLE, 71 (28.2%) identified it as an autoimmune disease. While 39(15.5%) thought it is infectious, 56(22.2%) attributed it to evil eye and 12(4.8%) believed it is the result of an act of sorcery or witch crafting. When asked about the preferred future source of knowledge, 476(75.6%) have chosen to obtain it directly from health care providers, while 183(29%) preferred social media. Conclusion: The awareness on SLE among university participants is low. Future educational campaigns are needed to increase awareness and rectify misconceptions.

Th-17 related regulatory network in the pathogenesis of Arab patients with systemic lupus erythematosus and lupus nephritis.

The present study aimed to identify the genes involved in the pathogenesis of systemic lupus erythematosus (SLE) in Arabs by investigating a panel of 84 genes related to the t helper (Th)17-related regulatory network and to further explore the expression levels of serum interleukin (IL)-17A and IL-17F in a studied cohort. A comparative analysis of gene expression profile in SLE and lupus nephritis (LN) patients against that of healthy controls (HC) was performed. A quantitative real-time polymerase chain reaction (PCR) (Th17 autoimmunity and inflammation) array analysis was performed in peripheral white blood cells of 66 SLE patients under specific medical treatment and 30 age/gender/ethnically matched healthy controls. Statistical analysis was carried out using the RT(2) Profiler TM PCR Data Analysis tool. The analysis of Th17 pathway revealed 14 genes (IL-17A, IL-17C, IL-17D, IL-17F, IL-18, IL-12RB2, IL-23R, CCL2, CCL20, CXCL5, MMP3, RORC, STAT4 and TRAF6) that are differentially expressed in SLE and HC (fold change [FC]<2, P<0.0006). No significant difference in expression profiles was observed between SLE and LN. A significant difference in serum concentration of IL-17A (P=0.002) and IL-17F (P=0.002) was observed between SLE (13.91±4.25) and LN (18.26±4.24). Our study is the first to investigate a panel of 84 genes related to Th17 regulatory pathway in Arab SLE subjects and the first to explore the effect of current immunosuppression regimens on Th17 regulatory pathway. It paves the way for understanding the etiology of SLE and autoimmune diseases in general.

Environmental influences on systemic lupus erythematosus expression.

The etiology of systemic lupus erythematosus (SLE) is unknown, but multiple genetic, epigenetic, and environmental risk factors have been implicated. The inheritance of genes alone is not sufficient for developing SLE, suggesting the influence of environmental triggers on disease expression. Despite the tremendous amount of progress in elucidating potential environmental risk factors for SLE, much more needs to be done. An interdisciplinary approach to studies of the causes and, ultimately, prevention of SLE is needed. This article reviews what is understood about the epidemiology of the relationship between environmental exposures and SLE, in addition to emerging areas of study.

Optimizing pharmacotherapy of systemic lupus erythematosus: the pharmacist role.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that can affect any part of the body. The management of the disease includes nonpharmacotherapy and pharmacotherapy. To provide an up-to-date review of the etiology, epidemiology, clinical features, diagnostic findings, and treatment options for SLE. METHODS DATA SOURCE: A PubMed search of English language journals using a combination of words--elderly, SLE, late onset SLE, etiology, screening, diagnosis, or treatment to identify original studies, guidelines, and reviews on SLE, SLE, late onset SLE published between 2000 and present. Overall, original studies, clinical reviews, references, and guidelines were obtained and evaluated on their clinical relevance. The literature included guidelines and considerations for the etiology, diagnosis, screening, and management of SLE, late onset SLE. SLE is a chronic autoimmune disorder, the exact etiology of which is unknown. SLE predominately affects younger women; however, it is reported to occur in up to 20 % of patients 50 years or older. In patients with SLE, nearly every system in the body is affected with varying degrees of severity ranging from subclinical to fatal. The hallmark feature of SLE is the production of autoantibodies directed primarily against nuclear antigens, but also against cytoplasmic components of cells. The diagnosis of SLE is based on criteria set by the American College of Rheumatology. Management is individualized and depends on presenting symptoms and reducing the likelihood of permanent damage to organs and tissues.

Abstract 548: TLT-1 as a Possible Modulator of Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by immune system hyperactivity and autoantibody production that can affect almost any organ system. TREM like transcript-1 (TLT-1) is a membrane receptor found in platelets α-granules with activating properties. We have demonstrated that activated platelets release a soluble isoform of TLT-1 (sTLT-1) which is not found in the plasma of healthy individuals. Moreover, evaluation of patients suffering from inflammatory diseases, such as sepsis, reveals a significant increase of plasma sTLT-1 levels. It is not known if TLT-1 plays a role in auto immune diseases such as Lupus. In the present study we evaluate the potential that TLT-1 may play a role in the etiology of SLE. We assessed the plasma of 46 SLE patients and compared to 28 healthy controls by ELISA. Our results showed that SLE patients had a significant decrease in plasma sTLT-1 levels compared to healthy controls (9.0 [7.2] vs. 18.6 [22.3] ng/ml, p=0.008). A negative correlation was observed between TLT-1 levels and LupusPRO [lupus symptoms (r = -0.388, p = 0.055). Based on this data; we hypothesize that SLE patients produce autoantibodies against TLT-1 in serum which might correlate with clinical aspects of the disease . To address this question; TLT-1 antibodies levels in serum were measured by ELISA. Our data suggests that a sub-population of SLE patients have TLT-1 autoantibodies. This data was further confirmed by confocal microscopy. Using human embryonal kidney cells (HEKt) stably transfected with TLT-1, we evaluated the serum of SLE patients for the presence of TLT-1 autoantibodies using immunofluorescence. Our data confirms that a sub-population of SLE patients with active disease is expressing antibodies against TLT-1. These findings suggest a possible role for TLT-1 during the pathogenesis of SLE and targets new treatment possibilities for lupus patients.

Interplay of Infections, Autoimmunity, and Immunosuppression in Systemic Lupus Erythematosus

Infectious agents are considered to be crucial environmental factor in the etiopathogenesis of systemic lupus erythematosus (SLE). Infections may serve as initial trigger to the development of autoimmunity and carry an overall greater risk of morbidity and mortality than the general population. Initial presentation of SLE can mimic infections, and in turn infections can mimic disease flares in established SLE. Infections due to predisposition by commonly used immunosuppressive therapies are a significant cause of morbidity and mortality. In this review, viral, bacterial, fungal, and parasitic infections that contribute to the etiology of SLE, potentially mimic or precipitate flares, create diagnostic dilemmas, complicate treatment, or protect against disease, are discussed. Infection risks of current immunosuppressive therapies used in the treatment of SLE are outlined. Strategies to prevent infection, including vaccines, prophylactic antibiotic therapies, toll-like receptor antagonism, and antioxidant treatment that may decrease disease burden and improve quality of life in lupus patients will be discussed.

Elevated signal transducers and activators of transcription 1 correlates with increased C-C motif chemokine ligand 2 and C-X-C motif chemokine 10 levels in peripheral blood of patients with systemic lupus erythematosus.

IntroductionThe present study examines the levels of recently reported biomarkers, adenosine deaminase acting on RNA (ADAR), C-C motif chemokine ligand 2 (CCL2), C-X-C motif chemokine 10 (CXCL10), signal transducers and activators of transcription 1 (STAT1), and miR-146a in systemic lupus erythematosus (SLE) patients over multiple visits.MethodsPeripheral blood leukocytes were collected from 65 healthy donors and 103 SLE patients, 60 of whom had samples from 2 or more visits. Total RNA was isolated and analyzed for the expression of mRNA and microRNA using Taqman real time PCR assays. Relative expression of I-IFN signature genes, chemokines, and miR-146a were determined by the ΔΔCT method. Results were correlated with clinical data and analyzed by Wilcoxon/Kruskal-Wallis test and Fisher’s exact test.ResultsLevels of ADAR, CCL2, CXCL10, and STAT1 in SLE were significantly elevated compared with the healthy controls (P <0.0001). ADAR, CCL2, and CXCL10 showed significant correlation with IFN score in both healthy donors (P <0.0033) and SLE patients (P <0.0001). In SLE patients, miR-146a level was not significantly different from healthy controls nor correlated to the IFN score. Two STAT1 populations were identified: a low STAT1 and a high STAT1 group. High STAT1 patient visits displayed higher (P ≤0.0020) levels of CCL2 and CXCL10 than the low STAT1 patient visits. STAT1 levels correlated with IFN score in low STAT1 group but not in high STAT1 group. More importantly, high STAT1 levels appeared as an enhancer of CCL2 and CXCL10 as indicated by the significantly stronger correlation of CCL2 and CXCL10 with IFN score in high STAT1 patient visits relative to low STAT1 patient visits.ConclusionOur data indicate a novel role for STAT1 in the pathogenesis of SLE as an expression enhancer of CCL2 and CXCL10 in SLE patients with high levels of STAT1. Future study is needed to examine the exact role of STAT1 in the etiology of SLE.

Gene-function studies in systemic lupus erythematosus

The aetiology of systemic lupus erythematosus (SLE) is complex and is known to involve both genetic and environmental factors. In a small number of patients, single-gene defects can lead to the development of SLE. Such genes include those encoding early components of the complement cascade and the 3'-5' DNA exonuclease TREX1. In addition, genome-wide association studies have identified single-nucleotide polymorphisms that confer some susceptibility to SLE. In this Review, we discuss selected examples of genes whose products have distinctly altered function in SLE and contribute to the pathogenic process. Specifically, we focus on the genes encoding integrin αM (ITGAM), IgG Fc receptors, sialic acid O-acetyl esterase (SIAE), the catalytic subunit of protein phosphatase PP2A (PPP2CA) and signalling lymphocytic activation molecule (SLAM) family members. Moreover, we highlight the changes in epigenetic signatures that occur in SLE. Such epigenetic modifications, which are abundantly present and might alter gene expression in the presence or absence of susceptibility variants, should be carefully considered when deconstructing the contribution of individual genes to the complex pathogenesis of SLE.

Association of HLA-DRB1*15 and HLA-DQB1* 06 with SLE in Saudis

BACKGROUND AND OBJECTIVESSystemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by humoral autoimmunity. The etiology of SLE is thought to be multifactorial including environmental, hormonal, and genetic factors. The human leukocyte antigen (HLA) has extensively been associated with the susceptibility to SLE; however, the association is heterogeneous among different ethnic groups. The aim of this study was to determine the association of HLA-A, HLA-B, HLA-DRB1, and HLA-DQB1 with SLE susceptibility in the Saudi population.DESIGN AND SETTINGSA total of 86 consecutive SLE patients attending the rheumatology clinic at King Abdulaziz Medical City, Riyadh, were recruited for this study.METHODSHLA types were determined by the polymerase chain reaction sequence-specific oligonucleotide (PCR-SSP) method in 86 patients and 356 control subjects.RESULTSThe following HLA alleles were found to be positively associated with SLE: HLA-A*29 (OR=2.70; 95% CI=1.03–7.08; P=.0035), HLA-B*51 (OR=1.81; 95% CI=1.17–2.79; P=.0066), HLA-DRB1*15 (OR=1.45; 95% CI=0.98–2.29; P=.063), and HLA-DQB1*06 (OR=1.67; 95% CI=1.19–2.36; P=.0032), whereas HLA-DRB1*16 was negatively associated with the disease (OR=0.18; 95% CI=0.02–1.3; P=.055). HLA-DRB1*15 haplotypes were significantly associated with SLE (OR=2.01, 95% CI=1.20–3.68, P=.008); this was mainly due to the HLA-DRB1* 15-DQB1*06 association.CONCLUSIONSOur data suggest an association between MHC class I and class II (HLA-A*29, HLA-B*51, HLA-DRB1*15, and HLA-DQB1*06) and susceptibility to SLE in the Saudi population. HLA-DRB1*15-DQB1*06 haplotype showed the highest risk factor for the disease that is similar to what was seen in the African American patients, suggesting shared susceptibility genetic factors among these ethnic groups.

Variable association of reactive intermediate genes with systemic lupus erythematosus in populations with different African ancestry.

Little is known about the genetic etiology of systemic lupus erythematosus (SLE) in individuals of African ancestry, despite its higher prevalence and greater disease severity. Overproduction of nitric oxide (NO) and reactive oxygen species are implicated in the pathogenesis and severity of SLE, making NO synthases and other reactive intermediate-related genes biological candidates for disease susceptibility. We analyzed variation in reactive intermediate genes for association with SLE in 2 populations with African ancestry. A total of 244 single-nucleotide polymorphisms (SNP) from 53 regions were analyzed in non-Gullah African Americans (AA; 1432 cases and 1687 controls) and the genetically more homogeneous Gullah of the Sea Islands of South Carolina (133 cases and 112 controls). Single-marker, haplotype, and 2-locus interaction tests were computed for these populations. The glutathione reductase gene GSR (rs2253409; p = 0.0014, OR 1.26, 95% CI 1.09-1.44) was the most significant single SNP association in AA. In the Gullah, the NADH dehydrogenase NDUFS4 (rs381575; p = 0.0065, OR 2.10, 95% CI 1.23-3.59) and NO synthase gene NOS1 (rs561712; p = 0.0072, OR 0.62, 95% CI 0.44-0.88) were most strongly associated with SLE. When both populations were analyzed together, GSR remained the most significant effect (rs2253409; p = 0.00072, OR 1.26, 95% CI 1.10-1.44). Haplotype and 2-locus interaction analyses also uncovered different loci in each population. These results suggest distinct patterns of association with SLE in African-derived populations; specific loci may be more strongly associated within select population groups.

Znaczenie czynników środowiskowych w etiologii tocznia rumieniowatego kładowego

Toczeń rumieniowaty układowy (TRU) jest układową chorobą tkanki łącznej o zróżnicowanym obrazie klinicznym, w której występują liczne zaburzenia serologiczne. U podłoża tej choroby leżą czynniki genetyczne, hormonalne i środowiskowe, które sprzyjają zaburzeniom odpowiedzi immunologicznej. W artykule omówiono znaczenie czynników środowiskowych, takich jak ekspozycja na UVB, infekcje, leki, czynniki chemiczne, dietetyczne, socjoekonomiczne i psychospołeczne, niedobór witaminy D, estrogeny egzogenne, nikotynizm, szczepienia ochronne oraz środowisko in utero w etiologii TRU i chorób z kręgu TRU.

Identification of IRF8, TMEM39A, and IKZF3-ZPBP2 as Susceptibility Loci for Systemic Lupus Erythematosus in a Large-Scale Multiracial Replication Study

Systemic lupus erythematosus (SLE) is a chronic heterogeneous autoimmune disorder characterized by the loss of tolerance to self-antigens and dysregulated interferon responses. The etiology of SLE is complex, involving both heritable and environmental factors. Candidate-gene studies and genome-wide association (GWA) scans have been successful in identifying new loci that contribute to disease susceptibility; however, much of the heritable risk has yet to be identified. In this study, we sought to replicate 1,580 variants showing suggestive association with SLE in a previously published GWA scan of European Americans; we testeda multiethnic population consisting of 7,998 SLE cases and 7,492 controls of European, African American, Asian, Hispanic, Gullah, and Amerindian ancestry to find association with the disease. Several genes relevant to immunological pathways showed association with SLE. Three lociexceeded the genome-wide significance threshold: interferon regulatory factor 8 (IRF8; rs11644034; p(meta-Euro) = 2.08× 10(-10)), transmembrane protein 39A (TMEM39A; rs1132200; p(meta-all) = 8.62× 10(-9)), and 17q21 (rs1453560; p(meta-all) = 3.48× 10(-10)) betweenIKAROS family of zinc finger 3 (AIOLOS; IKZF3) and zona pellucida binding protein 2 (ZPBP2). Fine mapping, resequencing, imputation, and haplotype analysis of IRF8 indicated that three independent effects tagged by rs8046526, rs450443, and rs4843869, respectively, were required for risk in individuals of European ancestry. Eleven additional replicated effects (5× 10(-8) < p(meta-Euro) < 9.99× 10(-5)) were observed with CFHR1, CADM2, LOC730109/IL12A, LPP, LOC63920, SLU7, ADAMTSL1, C10orf64, OR8D4, FAM19A2, and STXBP6. The results of this study increase the number of confirmed SLE risk loci and identify others warranting further investigation.

Increased IgG on cell‐derived plasma microparticles in systemic lupus erythematosus is associated with autoantibodies and complement activation

To quantify immunoglobulin and C1q on circulating cell-derived microparticles (MPs) in patients with systemic lupus erythematosus (SLE) and to determine whether immunoglobulin and C1q levels are correlated with clinical and serologic parameters. Sixty-eight clinically well-characterized SLE patients, 38 healthy controls, 6 patients with systemic sclerosis (SSc), and 6 patients with rheumatoid arthritis (RA) were included. The numbers of annexin V-binding MPs displaying IgG, IgM, or C1q were enumerated by flow cytometry. MP protein levels were determined by mass spectrometry in clinically defined subsets of SLE patients and controls. The MP IgG load was determined by flow cytometric analysis of all samples from SLE patients and healthy controls. SLE patients had significantly increased total and relative numbers of IgG-positive MPs (P = 0.0004), with a much higher average IgG load per MP (P < 0.0001) than healthy controls. Quantitative mass spectrometry of purified MPs verified significantly increased IgG, IgM, and C1q levels in SLE patients. In RA and SSc patients, the average IgG load per MP was significantly lower than in SLE patients (P = 0.006 and P = 0.05, respectively). Also, the IgM load and C1q load per MP were significantly higher in SLE patients than in the control groups (P < 0.05), except for IgM in the RA group. IgG-positive MPs were significantly associated with the presence of anti-double-stranded DNA, anti-extractable nuclear antigen, and antihistone antibodies, with total IgG, and with decreased leukocyte counts. Average IgG load per MP was associated with lower concentrations of MPs, the presence of anti-C1q antibodies, and complement consumption. Our findings indicate that circulating cell-derived MPs in SLE patients carry increased loads of IgG, IgM, and C1q and that IgG MPs are associated with autoantibodies and complement activation. The findings link immunologic reactions on MPs with the etiology of SLE.

Functional single-nucleotide polymorphisms in the DEFB1 gene are associated with systemic lupus erythematosus in Southern Brazilians

Systemic lupus erythematosus (SLE) is an autoimmune disease that results in inflammation and tissue damage. The etiology of SLE remains unknown, but recent studies have shown that the innate immune system may have a role in SLE pathogenesis through the secretion of small cationic peptides named defensins. The aim of the study was to determine the possible involvement in SLE of three functional single nucleotide polymorphisms (SNPs) (c.-52G>A, c.-44C>G and c.-20G>A) in the 5'UTR region of DEFB1 gene, by analyzing them in a population of 139 SLE patients and 288 healthy controls. The c.-52G>A SNP showed significant differences in allele and genotype frequency distribution between SLE patients and controls (p = 0.01 and p = 0.02 respectively) indicating protection against SLE (A allele, OR = 0.68, AA genotype OR = 0.51). Significant differences were also observed for c.-44C>G SNP, the C/G genotype being associated with susceptibility to SLE (OR = 1.60, p = 0.04). Moreover, statistically significant differences between patients and controls were found for two DEFB1 haplotypes (GCA and GGG, p = 0.01 and p = 0.02 respectively). When considering DEFB1 SNPs and SLE clinical and laboratory manifestations, significant association was found with neuropsychiatric disorders, immunological alterations and anti-DNA antibodies. In conclusion, our results evidence a possible role for the c.-52G>A and c.-44C>G DEFB1 polymorphisms in SLE pathogenesis, that can be considered as possible risk factors for development of disease and disease-related clinical manifestations. Additional studies are needed, to corroborate these results as well as functional studies to understand the biological role of these SNPs in the pathogenesis of SLE.