Pathogenesis Of Systemic Lupus Erythematous Research Articles

Role of T cells in the pathogenesis of systemic lupus erythematous: Focus on immunometabolism dysfunctions.

Evidence demonstrates that T cells are implicated in developing SLE, and each of them dominantly uses distinct metabolic pathways. Indeed, intracellular enzymes and availability of specific nutrients orchestrate fate of T cells and lead to differentiation of regulatory T cells (Treg), memory T cells, helper T cells, and effector T cells. The function of T cells in inflammatory and autoimmune responses is determined by metabolic processes and activity of their enzymes. Several studies were conducted to determine metabolic abnormalities in SLE patients and clarify how these modifications could control the functions of the involved T cells. Metabolic pathways such as glycolysis, mitochondrial pathways, oxidative stress, mTOR pathway, fatty acid and amino acid metabolisms are dysregulated in SLE T cells. Moreover, immunosuppressive drugs used in treating autoimmune diseases, including SLE, could affect immunometabolism. Developing drugs to regulate autoreactive T cell metabolism could be a promising therapeutic approach for SLE treatment. Accordingly, increased knowledge about metabolic processes paves the way to understanding SLE pathogenesis better and introduces novel therapeutic options for SLE treatment. Although monotherapy with metabolic pathways modulators might not be sufficient to prevent autoimmune disease, they may be an ideal adjuvant to reduce administration doses of immunosuppressive drugs, thus reducing drug-associated adverse effects. This review summarized emerging data about T cells that are involved in SLE pathogenesis, focusing on immunometabolism dysregulation and how these modifications could affect the disease development.

Sero-detection of Epstein-Barr virus and Cytomegalovirus Antibodies among patients with Systemic lupus Erythematous in Sudan

Infection by Cytomegalovirus (CMV) and Epstein - Barr virus (EBV) has been implicated in the pathogenesis of Systemic lupus Erythematous (SLE). The current study aimed to determine the frequency of EBV and CMV IgG among Sudanese patients with SLE. A case-control analytical study was conducted on 82 participants in Khartoum State during the period from 2017 to 2018. Serum from patients with SLE (n=62), and controls participants (n=20) were tested for IgG antibodies against EBV and CMV using the Avidity ELISA assay. Pretested questionnaire data were analyzed by SPSS software V.20 (IBM, Chicago,IL). Means and proportions of the demographic were calculated for SLE seropositive groups. Chi-square test and binary logistic regression analysis were used for SLE as a dependent factor while IgG seropositive groups of EBV and CMV as the independent variable and, SLE variables as dependent variables. Odds ratio (OR) with a 95% confidence interval was calculated and statistical significance was defined as a P value below 0.05. Eighty-two females with SLE volunteered to participate in this study, including 62 cases with systemic lupus erythematosus and 20 control participants. Average age means ± SD (34±1.4) for cases and (34±1.6) for controls. Original tribes in Sudan were screened Avidity assay for Western State 37(45.1%), Northern State 29(35.4%), Central State 17(20.7%), and Southern State1 (1.2%) respectively. Seropositivity of IgG by Avidity assay revealed high score for CMV 60 (96.8%) among cases vs 19(95%) among controls, (OR 1.579, CI -95% (0.136-18.4), P <0.05). Seropositivity for both EBV and Co-infection was 58 (98.3%) vs 16 (80.0%) among cases and controls, respectively (OR 3.625, CI -95% (0.227-2.708), P <0.05). Patients with SLE in Sudan have a high rate of infections by EBV and CMV as evidenced by the IgG avidity test indicating association.

Hsa_circ_0012919 promotes pyroptosis in CD4+T cells of systemic lupus erythematous by miR-125a-3p/GSDMD axis.

The etiology of systemic lupus erythematous (SLE) remains unclear. Pyroptosis, a new model of programmed cell death, was poorly explored in the pathogenesis of SLE. We found cell pyroptosis in CD4+T cells of SLE patients and kidneys from MRL/lpr mice by examining caspase-1 and gasdermin D (GSDMD) in by RT-PCR, Western blot, and levels of IL-1β, IL-18 and TNF-α were detected by RT-PCR and Elisa. Expression of caspase-1 and GSDMD and levels of IL-1β, IL-18, TNF-α decreased significantly after downregulation of hsa_circ_0012919 (p < 0.05). Inhibition of miR-125a-3p enhanced expression of caspase-1 and GSDMD (p < 0.05), and increased the release of IL-1β, IL-18 and TNF-α (p < 0.05), thereby counteracting the effect of hsa_circ_0012919 knockdown on pyroptosis. Finally, we identified GSDMD as the target gene of miR-125a-3p. Silencing GSDMD reversed the effect of 5-aza-deoxycytidine in increasing release of IL-1β, IL-18, TNF-α and activating caspase-1, but it could be reversed by miR-125a-3p inhibitor. In conclusion, hsa_circ_0012919 regulated the pyroptosis in the CD4+ T cells of SLE patients by miR-125a-3p/GSDMD axis.

Overall Status of Epstein-Barr virus Infection, IFN-a, and TLR-7/9 in Patients with Systemic Lupus Erythematous.

Systemic lupus erythematous (SLE) is a multisystem autoimmune disorder. While studying the pathogenesis of SLE is prevalent, both infectious and non-infectious elements are regarded to exert an important impact on the disease's development. To explore the overall status of EBV, TLR7, TLR9, and IFN-α gene expression in 32 patients suffering from SLE and 32 healthy controls. Plasma and PBMCs were separated from fresh whole blood. To measure EBV DNA load and mRNA levels of IFN-a, TLR-7 and9 in PBMCs, molecular techniques were employed. The production of IFN-α, ds-DNA IgG antibody, and EBNA-1 IgG levels were also measured in plasma by ELISA. SLE patients showed significantly higher EBV load (p=0.001) and transcriptional levels of TLR7 (p=0.0001), IFN-α (p=0.0001), and TLR9 (p=0.0001) than controls. Moreover, the plasma levels of IFN-α (p=0.0002) and EBNA-1specific IgG antibodies (p=0.01) were significantly higher in SLE patients. The results stressed on the potential role of EBV infection and TLRs in SLE patients although more research is needed to determine the global impact that EBV infection can have on immune signature in patients with SLE.

Seroprevalence of HSV-1, HSV-2, and VZV with the possible role of CD8+ cell in pathogenesis of Systemic lupus Erythematous

Seroprevalence of HSV-1, HSV-2, and VZV with the possible role of CD8+ cell in pathogenesis of Systemic lupus Erythematous

IFNβ signaling inhibits osteogenesis in human SLE bone marrow.

Bone marrow mesenchymal stem cells are multipotent adult stem cells that can differentiate into osteoblasts, adipocytes, and chondrocytes. Our recently published data demonstrate that systemic lupus erythematous bone marrow mesenchymal stem cells produce increased quantities of interferon β based on a positive feedback loop involving the innate signaling molecule mitochondrial antiviral signaling protein. Moreover, this pathway contributes to human systemic lupus erythematous bone marrow mesenchymal stem cell senescence-like features. Here we investigate the differentiation defects of systemic lupus erythematous bone marrow mesenchymal stem cells and the potential for therapeutic interventions. The six systemic lupus erythematous patients recruited in this study satisfy the American College of Rheumatology 1997 classification criteria for systemic lupus erythematous. Systemic Lupus Erythematous Disease Activity Index-2K was used to determine disease activity. Systemic lupus erythematous bone marrow mesenchymal stem cells were isolated with Ficoll centrifugation and phenotyped using flow cytometry. In vitro studies included real-time polymerase chain reaction and western blotting. We compared six age-paired bone marrow aspirates from healthy controls and systemic lupus erythematous patients. Systemic lupus erythematous bone marrow mesenchymal stem cells display significantly reduced alkaline phosphatase staining, as well as reduced expression of osteogenic markers alkaline phosphatase, Runt-related transcription factor 2, and bone sialoprotein. When healthy bone marrow mesenchymal stem cells were treated with interferon β for 6 hours, expression of these same osteogenic markers was markedly reduced. Conversely the application of interferon β neutralizing antibody enhanced the expression of osteoblastogenesis markers. When the underlying mechanisms for interferon β inhibition of osteoblastogenesis were investigated, we found that IFNβ pre-treatment activates the inhibitory Smad6 and Smad7 expression through JAK1/STAT1, leading to reduced Smad1 phosphorylation and nuclear translocation. Our present work suggests that interferon β affects osteogenesis. By revealing the essential role of interferon β on systemic lupus erythematous bone marrow mesenchymal stem cell differentiation, our study sheds light on systemic lupus erythematous pathogenesis and provides a new potential therapeutic target for the bone complications found in systemic lupus erythematous.

AB0123 CHANGES IN CELLULAR GLYCOSYLATION AS A KEY FACTOR IN THE IMMUNOPATHOGENESIS OF SYSTEMIC LUPUS ERYTHEMATOSUS

Background:Systemic Lupus Erythematous (SLE) is one of the most challenging autoimmune diseases as it may be presented as a severe, relapsing and disabling immune-mediated disorder still remaining incurable (1,2).Protein glycosylation is an essential post translational modification that participate in the correct recognition of cells by the immune system (3–5). Moreover, glycosylation changes in T cells (specifically loss of branchedN-glycans mediated by GnTV, encoded byMGAT5gene) have been shown to impact its intrinsic function and activity in a diverse panel of autoimmune diseases (3,4,6)Objectives:To evaluate the impact of glycans in the cellular and molecular mechanisms underlying the loss of immune-tolerance, envisioning the identification of a new targeted-specific mechanism.Methods:We have analysed the profile of cellular glycosylation of a subset of biopsy-proven lupus nephritis from SLE patients and normal kidney tissue (from two Porto Centre Hospitals), through immunohistochemistry (IHC) as well as by real time PCR using RNA extracted from paraffin tissues. Blood samples were collected and were analysed by flow cytometry.Mgat5null mice with 15-months old were monitored for autoimmune signs by evaluating proteinuria, weight loss and colon and kidney tissues were analysed by IHC and FACS.Results:SLE patients revealed a significant decreased expression of complexN-glycans in the renal parenchyma, when compared to healthy kidney. In addition, we have identified in lupus nephritis patients a unique subset of circulatory CD3+T cells with an abnormal glycosignature and displaying an increased expression of specific glycan-binding receptors. Interestingly,Mgat5null mice develop clinical signs compatible within autoimmune-like syndrome together with an increased infiltration of specific CD3+T cells subset identified in SLE patients.Conclusion:These findings point towards the identification of a novel immune player with increased ability to sense abnormalN-glycans, modulating the surrounding immune response. We propose glycosylation as a regulatory mechanism that tips the balance between homeostasis/self-tolerance and autoimmunity opening a potential novel targeted-specific mechanism in SLE pathogenesis.

Deletion of Dnase1L3 from Macrophages results in reduced serum Dnase activity in mice

Abstract Dnase1L3 deficiency leads to 100% penetrance of pediatric onset Systemic lupus erythematous (SLE) while reduce Dnase1L3 levels is seen in adult-onset. Dnase1L3 is an endonuclease primarily secreted by myeloid cells like macrophages into the serum, where it degrades apoptotic bodies and chromatin, which reduces auto antibody formation and prevents SLE in both humans and mice. Importantly, reduction in the Dnase1L3 protein levels occurs both in adult-onset SLE in humans, and in polygenic murine models. This suggests that different levels of Dnase1L3 contribute to SLE progression. Also, decreasing Dnase1L3 levels leads to progressively worse SLE. However, the amount of serum Dnase1L3 needed, or whether the impact of Dnase1L3 is analog or digital remains unknown. In order to reduce Dnase1L3 protein levels, we generated Dnase1L3fl/fl x LysM-cre+/− conditional knockout (cKO) mice on B6 background. We determined the contribution of macrophage Dnase1L3 by measuring the Dnase1L3 protein levels and enzymatic activity by Dnase activity assay. We found that cKO mice showed ~2-log reduction in the serum Dnase activity. These cKO mice represent a cell-specific model to study the impact of Dnase1L3 protein levels on SLE pathogenesis. Together these findings suggest that macrophage specific Dnase1L3 may be a key player in lupus, however there could be other nucleases involved which we plan to inhibit using certain specific inhibitors. Overall, our findings suggest that macrophage specific Dnase1L3 is critical to prevent autoantibody formation in protecting lupus onset

Association of S100B polymorphisms and serum S100B with risk of systemic lupus erythematous in a Chinese population.

The aim of this study was to investigate whether the S100B polymorphisms are associated with systemic lupus erythematous (SLE) in a Chinese population. A total of 313 SLE patients and 396 control subjects were enrolled in the present study. The genotypes of three SNPs (rs9722, rs881827 and rs1051169) in S100B gene were detected by single base extension polymerase chain reaction (SBE-PCR). Serum S100B levels were determined by enzyme-linked immunosorbent assay (ELISA). Rs1051169 was associated with an increased risk of SLE (C vs. G: adjusted OR=1.46, 95% CI, 1.18-1.80, p=0.001; CC vs. GG: adjusted OR=1.99, 95% CI, 1.32-3.02, p=0.001; CC+GC vs. GG: adjusted OR=1.54, 95% CI, 1.13-2.11, p=0.007; CC vs. GC+GG: adjusted OR=1.67, 95% CI, 1.16-2.42, p=0.006). Haplotype analysis showed that the G-G-C haplotype was associated with an increased risk of SLE (OR=1.50, 95% CI, 1.14-1.98, p=0.004). Stratified analyses showed that the rs1051169 polymorphism was associated with an increased risk of neurologic disorder in SLE patients (C vs. G: OR=1.78, 95% CI, 1.22-2.59, p=0.003; GC vs. GG: OR=2.33, 95% CI, 1.14-4.77, P=0.019; CC vs. GG: OR=3.02, 95% CI, 1.39-6.53, p=0.004; CC+GC vs. GG: OR=2.57, 95% CI=1.31-5.04, p=0.005). In addition, SLE patients with neurologic disorder carrying the rs1051169 GC/CC genotypes present a higher serum S100B levels compared with that carrying the GG genotype (p < 0.05). Our results indicate that the rs1051169 polymorphism may be involved in the pathogenesis of SLE.

Vitamin D in SLE: a role in pathogenesis and fatigue? A review of the literature.

Fatigue is a common, disabling problem that is highly prevalent in patients with systemic lupus erythematous (SLE). More recently, vitamin D status has been established as a potential contributor to SLE pathogenesis and manifestations, in particular fatigue. This review summarizes the literature regarding the role of vitamin D in SLE, and provides an overview of the recent literature examining the association between vitamin D and fatigue in patients with SLE. Finally, the role of vitamin D supplementation in the treatment of SLE-related fatigue is considered.

Association of clinical and serological parameters of systemic lupus erythematosus patients with Epstein-Barr virus antibody profile.

Epstein-Barr viral infection is one of the known environmental factors involved in development of Systemic Lupus Erythematous (SLE). Though not much is known about the exact role of Epstein-Barr virus (EBV) in SLE pathogenesis, the theory of switching of lytic and lysogenic cycles of EBV in memory B cells fits well with the periods of waning disease activity and intermittent flares in SLE patients. In this study, we investigate the association of EBV antibody profile with clinical and serological parameters in SLE. Eighty-seven clinically diagnosed SLE patients fulfilling the American College of Rheumatology (ACR) classification criteria and fifty healthy individuals were enrolled in this case control study. Anti-VCA IgM, anti-VCA IgG, and anti-EBNA IgG were detected by ELISA technique. Antibodies concentrations between two groups were compared using Mann-Whitney whereas the difference in categorical data was compared using Chi-square considering statistical significance at P < 0.05. This study demonstrated a significant increase in EBV VCA-IgG, VCA-IgM, and EBNA-IgG antibodies levels of SLE patients when compared to healthy controls (P < 0.05). High seroprevalence was seen in both the study groups for EBV VCA-IgG and EBNA-IgG antibodies when compared to VCA-IgM antibodies. A significant increase was noted in the anti-VCA-IgG levels with dsDNA autoantibody positivity (P < 0.05). Though there was no significant association between EBV antibody profile and clinical manifestations, 100% seropositivity for anti-VCA-IgG was seen in SLE patients with renal manifestations. Association of anti-VCA IgG levels with presence of anti-dsDNA antibodies suggests a possible role of EBV as an environmental trigger in pathogenesis of SLE.

Abstract 20959: Inhibition of Shp2 Ameliorates Systemic Lupus Erythematosus-Associated Cardiac Pathogenesis

Introduction: Systemic lupus erythematous (SLE) is a devastating autoimmune disorder affecting multiple tissues, including heart. However, the molecular mechanisms that cause cardiac effects in SLE remain unclear. PTPN11 , the gene encoding the SH2 domain-containing protein tyrosine phosphatase SHP2, is critical for development and is the first tyrosine phosphatase known to have a functional role in the adult heart. Moreover, gain-of-function mutations in SHP2 have been associated with onset of SLE. Here, sought to identify the mechanistic role for SHP2 in the cardiac pathogenesis of SLE. Methods and Results: We analyzed hearts from 18-week old female MRL/lpr (SLE-prone) and MRL/MpJ (control) mice. As compared to controls, MRL/lpr hearts showed substantial interstitial fibrosis and had elevated numbers of infiltrated CD11b + leukocytes. Moreover, MRL/lpr hearts displayed decreased fractional shortening and enlarged chamber dimensions, as measured by echocardiography. MRL/lpr heart lysates revealed significantly elevated SHP2 phosphatase activity, as compared to controls. Immunoprecipitation of SHP2 from MRL/lpr hearts revealed Focal Adhesion Kinase (FAK) in complex with SHP2. FAK is required to maintain cardiac function under conditions of stress. Significantly, SHP2 is a negative regulator of FAK, suggesting SHP2 may be involved in cardiac pathogenesis through dephosphorylation of FAK. Here, MRL/lpr heart lysates had decreased pY397-FAK activity, in conjunction with decreased p-ERK levels, suggesting that SHP2 may play a role in cardiac pathogenesis of SLE through aberrant FAK -mediated regulation of ERK. To test whether higher SHP2 activity contributes to the cardiac pathogenesis in lupus, we utilized a potent SHP2 inhibitor, 11a-1, to treat MRL/lpr mice for 6 weeks starting at 12 weeks of age. Hearts from these mice displayed improved cardiac structure and function, with reduced chamber dimensions, had decreased numbers of CD11b + leukocytes and lessened cardiac fibrosis. Moreover, pY397-FAK and p-ERK activities were both nearly normalized in response to treatment with the SHP2 inhibitor. Conclusion: These data suggest that SHP2 affects cardiac pathogenesis in SLE hearts through regulation of FAK and ERK signaling.

Genetic and Epigenetic Modifications in Systemic Lupus Erythematosus: Challenges to Homeostatic Immune Responses

Systemic lupus erythematous (SLE) is characterized by the body's lack of distinction between self- and nonself-antigens amounting to hyperactive immune reactions. In most cases, this type of autoimmune disorder has no exact known causal factor and can be caused by both genetic and epigenetic influences. One of the major points of interest in SLE research is understanding the disease biology from a wide landscape involving both the genome and epigenome of SLE patients. Availability of high-throughput gene sequencing, genome-wide association studies, and gene enrichment analysis has facilitated our understanding of the pathogenesis of SLE. However, the correlation of these genetic and epigenetic changes is still poorly understood, and therefore, this review makes a first overarching attempt to bridge the existing gap in the scientific domain.

Infection and Lupus: Which Causes Which?

Infection is a leading cause of morbidity and mortality among patients with systemic lupus erythematous (SLE). Dysfunction of the innate and adaptive immune systems increases the risk of infection in patients with SLE. Infectious agents have also been theorized to play a role in the pathogenesis of SLE. This article summarizes our current knowledge of the infectious risk SLE patients face as a result of their underlying disease including abnormal phagocytes and T cells as well as the increased risk of infection associated with immunosuppressive agents used to treat disease. Pathogens thought to play a role in the pathogenesis of disease including EBV, CMV, human endogenous retroviruses (HERVs), and tuberculosis will also be reviewed, as well as the pathologic potential of microbial amyloids and the microbiome.

Leptin-related polymorphisms and SLE

Leptin is a hormone/cytokine that is mainly produced by adipocytes and has a range of actions that span from the control of metabolic balance to the modulation of adaptive and innate immune responses. Many investigations have indicated that the pro-inflammatory activities of leptin can contribute significantly to the promotion and maintenance of autoimmune responses. It is not known whether the abnormal elevation of leptin in patients with systemic lupus erythematous (SLE) - an autoimmune disease characterized by multi-organ involvement and the presence of autoantibodies – can reflect the chronic inflammatory status of the disease or contributes to the pathogenesis of the disease. To partly address this question, a recent investigation analyzed several leptin-related gene polymorphisms in SLE in large numbers of individuals from different ancestral groups. The study identified weak associations with certain SNPs that did not remain significant after correction for multiple testing. This review discusses the implications of those findings for the pathogenesis of SLE and for the possibility of leptin-based modalities of therapeutic intervention in the disease.

Expression of TLR2 and TLR4 on CD14 Monocytes in Female SLE Patients E

Background: Systemic Lupus Erythematous (SLE) is a prototype autoimmune disease of multifactorial origin mainly assigned to defects in the adaptive immune system. However, evidences supported the crucial role of the innate immune system in its pathogenesis. Toll-like receptors (TLRs) have been proposed as important pathways in disease development. This relatively new idea holds promise for new therapeutic strategies. The aim of this work is to measure surface expression of TLR2 and TLR4 on CD14+ monocytes in SLE patients and compare it with healthy controls, also to find out their relation with disease activity and damage. Subjects and methods: The current study was carried out on Forty Egyptian female SLE patients and 20 matched control subjects. Disease activity was assessed by the SLE disease activity index (SLEDAI) and damage assessed by the Systemic Lupus International Collaborating Clinics (SLICC) index. Expression of TLR2 and 4 on CD14+ monocytes was studied using flow cytometry. Results: The age of the patients ranged between 16-56 years with a mean ± SD of 31.6 ± 9.2 years. Significant increase of TLR2 surface expression and a significant decrease of TLR4 surface expression on CD14+ monocytes in SLE patients compared to the control group (p=0.006, 0.004, respectively) were observed. No statistically significant associations were detected with both activity and damage indices. Conclusion: This study suggests that TLR2 and 4 plays a role in the pathogenesis of SLE but have no impact on disease activity.

Key issues in the management of patients with systemic lupus erythematosus: latest developments and clinical implications.

Systemic lupus erythematous (SLE) is a chronic multisystem disease with significant associated morbidity and mortality. A deeper understanding of the pathogenesis of SLE has led to the development of biologic agents, primarily targeting B cells and others inhibiting costimulatory molecules, type I interferons and cytokines such as interleukin-6. Several of these agents have been studied in clinical trials; some have shown promise while others have yielded disappointing results. Economic and regulatory issues continue to hamper the availability of such therapies for SLE patients. With increasing recognition that recurrent flares of disease activity lead to long-term damage accrual, one of the most important recent developments in patient management has been the concept of treat-to-target in SLE while minimizing patient exposure to excessive corticosteroid and other immunosuppressive therapy. This article reviews these key issues in SLE management, outlining recent developments and clinical implications for patients.

Evaluation of endothelial protein C receptor in patients with systemic lupus erythematosus: correlation with disease activity and lupus nephritis

Systemic lupus erythematous (SLE) is a systemic, multifaceted inflammatory disease with clinical manifestations is protean and follows a relapsing and remitting course. Lupus Nephritis (LN) is one of the most frequent and serious manifestation. Endothelial protein C receptor (EPCR) is a transmembrane receptor that is shed into soluble form (sEPCR) in inflammatory status. It is demonstrated as a part of the pathobiology of the SLE disease. To assess correlation of sEPCR level in SLE patients to the disease activity in these patients and to relate sEPCR to LN. Serum level of sEPCR using enzyme-linked immunosorbent assay (ELISA), chemical and immunological markers of SLE were measured in 30 SLE patients and 30 age and sex matched apparently healthy controls. SLE patients were subgrouped into 20 patients without LN and 10 with LN. Disease activity was assessed using SLE Disease Activity Index (SLEDAI). A significantly higher sEPCR level was found on comparing SLE patients to controls with statistically highly significant difference (z = 4.8, P < 0.001). Moreover, there was a significantly higher sEPCR level on comparing SLE patients with LN to those without LN with statistically highly significant difference (z = 3.9, P < 0.001). Serum sEPCR had a highly significant positive correlation with SLEDAI in SLE patients (r = 0.66, P < 0.01). sEPCR has a possible role in the pathogenesis of SLE and particularly LN diseases, reflecting disease activity in SLE patients.

Association between IRF5 polymorphisms and autoimmune diseases: a meta-analysis.

In this study, we investigated the association between 5 interferon regulatory factor-5 (IRF5) single nucleotide polymorphisms (SNPs) and autoimmune diseases using the Medline citation index. Twenty-eight studies with 74 comparisons, including 16 rheumatoid arthritis (RA), 43 systemic lupus erythematous (SLE), 2 juvenile idiopathic arthritis (JIA), 6 multiple sclerosis (MS), and 5 systemic sclerosis (SSc) studies, were examined in the meta-analysis. The SNP rs2004640 was significantly associated with SLE, MS, and SSc, but not with JIA [odds ratio (OR)=1.06, 95% confidence interval (CI)=0.90-1.24, P=0.48] or RA (OR=1.03, 95%CI=0.95-1.11, P=0.44). A significant association was observed between rs2280714 and SLE, MS, and SSc, but not RA (OR=1.01, 95%CI=0.94-1.09, P=0.80). Rs10954213 was associated with the pathogenesis of SLE, RA, MS, and SSc. rs2070197 and the exon 6 insertion were significantly associated with SLE. Haplotypes containing rs2004640T and rs2280714T were significantly associated with an increased risk of SLE, but not with RA. This meta-analysis certified that IRF5 polymorphisms confer susceptibility to SLE, MS, and SSc. To further confirm the correlations between polymorphisms of IRF5 and autoimmune disease susceptibility, studies involving a larger number of patients worldwide are necessary.

Lipid-Antigen Presentation by CD1d+ B Cells Is Essential for the Maintenance of Invariant Natural Killer T Cells

SummaryB cells perform many immunological functions, including presenting lipid antigen to CD1d-restricted invariant natural killer T (iNKT) cells, known to contribute to maintaining tolerance in autoimmunity. Patients with systemic lupus erythematous (SLE) display dysregulated B cell responses and reduced peripheral iNKT cell frequencies. The significance of these defects and how they relate to SLE pathogenesis remain elusive. We report that B cells are essential for iNKT cell expansion and activation in healthy donors but fail to exert a similar effect in SLE patients. Defective B cell-mediated stimulation of iNKT cells in SLE patients was associated with altered CD1d recycling, a defect recapitulated in B cells from healthy donors after stimulation with interferon-α (IFN-α) and anti-immunoglobulin (Ig). iNKT cell number and function were restored in SLE patients responding to anti-CD20 treatment upon normalization of CD1d expression exclusively in repopulated immature B cells. We propose that healthy B cells are pivotal for iNKT cell homeostasis.