Systemic Lupus Erythematosus Disease Pathogenesis Research Articles

Autoimmune Disease Pathogenesis Exacerbates Inflammation Following Myocardial Infarction in a Rodent Model of Systemic Lupus Erythematosus

Patients with systemic autoimmune diseases such as systemic lupus erythematosus (SLE) have an increased risk of suffering a myocardial infarction (MI), and are also more likely to die, develop heart failure, or suffer a second cardiac event than patients without an autoimmune disease. SLE primarily affects women and is characterized by autoreactive T and B lymphocytes that lead to widespread production of autoantibodies to a variety of nuclear and cytoplasmic antigens. Autoantibody-antigen immune complexes deposit in tissues and activate downstream inflammatory pathways leading to end-organ damage to tissues such as the heart, lungs, kidneys, and vasculature. However, the mechanisms whereby SLE disease may exacerbate MI and lead to poor outcomes in autoimmune patients is not well understood. The purpose of the present study was to test the hypothesis that SLE disease pathogenesis contributes to worsened outcomes after MI because of systemic inflammatory processes taking place. To test this hypothesis, saline (control, n=7) and pristane-treated (SLE, n=8) C57BL/6 mice were subjected to permanent coronary artery ligation (MI) and studied at 7 days post MI. Left ventricular (LV) function was examined at baseline (D0) and D7 using echocardiography (VEVO 3100). Control and SLE mice had similar LV parameters at baseline, but SLE mice had significantly more wall thinning in the infarct area (Control: 0.54±0.05 vs. SLE: 0.36±0.03 mm, p=0.005) as well as in the remote area (Control: 0.59±0.07 vs. SLE: 0.38±0.03 mm, p=0.01). SLE mice also displayed increased LV dilation (Control: 61.7±5.3 vs. SLE: 78.9±3.8 μL, p=0.02) at 7 days post MI. Ejection fraction was significantly lower in SLE mice as well (Control: 26.3±2.0% vs. 19.0±2.5%, p=0.045). We examined expression of inflammatory cytokines and collagen subunit genes in infarcted heart tissue using qPCR. SLE mice had increased expression of several inflammatory cytokines, including IL-6 and IL-18, while other cytokines such as IL-1β and TNF-α were not significantly different between the groups. In addition, SLE mice had decreased expression of the Col1a1, which encodes the alpha subunit of Type I Collagen, and Cd31, an endothelial cell marker, suggesting impairment of scar formation and angiogenesis post MI in SLE mice. Flow cytometric analyses of infiltrating LV immune cells showed increased total CD45+ cells in the infarcted area of SLE mice (Control: 10.6±1.2% vs. SLE: 13.8±0.6%, p=0.03), and a trend for an increase in CD45R+ B cells (Control: 7.5±1.1% vs. SLE: 12.5±2.1%, p=0.05). Taken together, these data indicate that SLE disease impacted recovery post MI, possibly due to increased B cell infiltration in the heart. Future studies will assess outcomes at later time points and also examine the progression of renal injury post MI. NIH/NHLBI R00 HL146888 and U54 HL169191 to Taylor NHLBI R01 HL166737 and AHA CDA856365 to Mouton NIGMS P20 GM104357 and P30 GM149404 to Department of Physiology and Biophysics. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

B- and T-Lymphocyte Attenuator in Systemic Lupus Erythematosus Disease Pathogenesis.

B- and T-lymphocyte attenuator (BTLA; CD272) is an immunoglobulin superfamily member and part of a family of checkpoint inhibitory receptors that negatively regulate immune cell activation. The natural ligand for BTLA is herpes virus entry mediator (HVEM; TNFRSF14), and binding of HVEM to BTLA leads to attenuation of lymphocyte activation. In this study, we evaluated the role of BTLA and HVEM expression in the pathogenesis of systemic lupus erythematosus (SLE), a multisystem autoimmune disease. Peripheral blood mononuclear cells from healthy volunteers (N = 7) were evaluated by mass cytometry by time-of-flight to establish baseline expression of BTLA and HVEM on human lymphocytes compared with patients with SLE during a self-reported flare (N = 5). High levels of BTLA protein were observed on B cells, CD4+, and CD8+ T cells, and plasmacytoid dendritic cells in healthy participants. HVEM protein levels were lower in patients with SLE compared with healthy participants, while BTLA levels were similar between SLE and healthy groups. Correlations of BTLA-HVEM hub genes' expression with patient and disease characteristics were also analyzed using whole blood gene expression data from patients with SLE (N = 1,760) and compared with healthy participants (N = 60). HVEM, being one of the SLE-associated genes, showed an exceptionally strong negative association with disease activity. Several other genes in the BTLA-HVEM signaling network were strongly (negative or positive) correlated, while BTLA had a low association with disease activity. Collectively, these data provide a clinical rationale for targeting BTLA with an agonist in SLE patients with low HVEM expression.

Racial Differences in Plasma Microbial Translocation and Plasma Microbiome, Implications in Systemic Lupus Erythematosus Disease Pathogenesis.

Black groups have increased prevalence and accelerated pathogenicity of systemic lupus erythematosus (SLE) compared to other ethnic/racial groups. The microbiome and systemic microbial translocation are considered contributing factors to SLE disease pathogenesis. However, racial differences in the plasma microbiome and microbial translocation in lupus remain unknown. In the current study, we investigated plasma levels of microbial translocation (lipopolysaccharide [LPS] and zonulin) and the plasma microbiome using microbial 16S RNA sequencing of Black and White patients with SLE and Black and White healthy controls. Plasma microbial translocation was increased in Black patients versus in White patients and in patients with SLE versus healthy controls regardless of race. Compared to sex, age, and disease status, race had the strongest association with plasma microbiome differences. Black groups (Black controls and Black patients) had lower α-diversity than White groups (White controls and White patients) and more distinct β-diversity. Black and White patients demonstrated differences in plasma bacterial presence, including Staphylococcus and Burkholderia. Compared to White patients, Black patients had higher SLE Disease Activity Index (SLEDAI) scores and urinary protein levels as well as a trend for increased anti-double-stranded DNA (dsDNA) antibody levels consistent with the known increased severity of lupus in Black patients overall. Certain plasma bacteria at the genus level were identified that were associated with the SLEDAI score, urinary protein, and anti-dsDNA antibody levels. This study reveals racial differences in both quality and quantity of plasma microbial translocation and identified specific plasma microbiome differences associated with SLE disease pathogenesis. Thus, this study may provide new insights into future potential microbiome therapies on SLE pathogenesis.

Systemic Lupus Erythematosus: New Diagnostic and Therapeutic Approaches.

Systemic lupus erythematosus (SLE) is a devastating autoimmune disease that can result in substantial morbidity and mortality. Diagnosis and treatment of SLE are clinical challenges. Patient presentation and response to therapy are heterogeneous because of the complex immune dysregulation that results in SLE disease pathogenesis. An intricate interplay between genetic risk and skewing of adaptive and innate immune system responses leads to overproduction of type I interferons and other cytokines, complement activation, immune-complex deposition, and ultimately inflammation and tissue damage. Here, we review the classification criteria as well as standard and emerging diagnostic tools available to identify patients with SLE. We then focus on medical management, including novel therapeutics, nonpharmacologic interventions, and comorbidity management.

Sex bias in systemic lupus erythematosus: a molecular insight.

Acknowledging sex differences in immune response is particularly important when we consider the differences between men and women in the incidence of disease. For example, over 80% of autoimmune disease occurs in women, whereas men have a higher incidence of solid tumors compared to women. In general women have stronger innate and adaptive immune responses than men, explaining their ability to clear viral and bacterial infections faster, but also contributing to their increased susceptibility to autoimmune disease. The autoimmune disease systemic lupus erythematosus (SLE) is the archetypical sexually dimorphic disease, with 90% of patients being women. Various mechanisms have been suggested to account for the female prevalence of SLE, including sex hormones, X-linked genes, and epigenetic regulation of gene expression. Here, we will discuss how these mechanisms contribute to pathobiology of SLE and how type I interferons work with them to augment sex specific disease pathogenesis in SLE.

A Distinct Plasma Microbiome But Not Gut Microbiome in Patients With Systemic Lupus Erythematosus Compared to Healthy Individuals.

Blood microbiome has been analyzed in cancer patients using machine learning. We aimed to study whether the plasma microbiome represents the microbial community in the gut among patients with systemic lupus erythematosus (SLE) and healthy controls (HCs). Paired plasma and stool samples from female patients with SLE and female HCs were assessed for microbiome composition by microbial 16S ribosomal RNA sequencing. Decreased microbial alpha diversity in stool compared to plasma and distinct plasma and gut beta diversity were found in both HCs and patients with SLE. No difference in gut microbial diversity was found; however, plasma alpha diversity was decreased in patients with SLE compared to HCs. The predominant bacteria differed between plasma and stool in both groups. Although the predominant plasma and stool genus bacteria were similar in patients with SLE and HCs, some were clearly different. Compared to the gut, the plasma microbiome contained distinct community and greater heterogeneity, indicating that the predominant circulating microbiome may originate from sites (eg, oral or skin) other than the gastrointestinal tract. The decreased plasma but not gut alpha diversity in patients with SLE compared to HCs implies an altered plasma microbiome in SLE, which may be important for systemic immune perturbations and SLE disease pathogenesis.

Correlation Analysis between Gut Microbiota and Metabolites in Children with Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune-mediated diffuse connective tissue disease characterized by immune inflammation with an unclear aetiology and pathogenesis. This work profiled the intestinal flora and faecal metabolome of patients with SLE using 16S RNA sequencing and gas chromatography-mass spectrometry (GC-MS). We identified unchanged alpha diversity and partially altered beta diversity of the intestinal flora. Another important finding was the increase in Proteobacteria and Enterobacteriales and the decrease in Ruminococcaceae among SLE patients. For metabolites, amino acids and short-chain fatty acids were enriched when long-chain fatty acids were downregulated in SLE faecal samples. KEGG analysis showed the significance of the protein digestion and absorption pathway, and association analysis revealed the key role of 3-phenylpropanoic acid and Sphingomonas. Sphingomonas were reported to be less abundant in healthy periodontal sites of SLE patients than in those of HCs, indicating transmission of oral species to the gut. This study contributes to the understanding of the pathogenesis of SLE disease from the perspective of intestinal microorganisms, explains the pathogenesis of SLE, and serves as a basis for exploring potential treatments for the disease.

Arthritis in systemic lupus erythematosus is characterized by local IL-17A and IL-6 expression in synovial fluid.

SummaryArthritis is a common clinical feature of systemic lupus erythematosus (SLE) and is usually non‐erosive, as opposed to rheumatoid arthritis (RA). While RA synovial pathology has been extensively studied, little is known about the pathophysiology of lupus arthritis. Here, we aimed to explore the cytokine and cellular compartments in synovial fluids of SLE patients with arthritic manifestations. Acellular synovial fluid and paired serum samples from SLE patients (n = 17) were analyzed with cytokine bead array for T helper‐associated cytokines. From two SLE patients, synovial fluid mononuclear cells (SFMC) could also be captured and were analyzed by multiparameter flow cytometry to dissect T cell, B cell, monocyte and dendritic cell phenotypes. SLE‐derived SFMC were further stimulated in vitro to measure their capacity for producing interferon (IFN)‐γ and interleukin (IL)‐17A. All patients fulfilled the ACR 1982 classification criteria for SLE. Clinical records were reviewed to exclude the presence of co‐morbidities such as osteoarthritis or overlap with RA. IL‐17A and IL‐6 levels were high in SLE synovial fluid. A clear subset of the synovial CD4+ T cells expressed CCR6+, a marker associated with T helper type 17 (Th17) cells. IL‐17A‐production was validated among CD4+CCR6+ T cells following in‐vitro stimulation. Furthermore, a strong IFN‐γ production was observed in both CD4+ and CD8+ cells. Our study shows high IL‐17A and IL‐6 levels in synovial fluids of patients with lupus arthritis. The Th17 pathway has been implicated in several aspects of SLE disease pathogenesis and our data also point to Th17 involvement for lupus arthritis.

Increased HERV-E clone 4\u20131 expression contributes to DNA hypomethylation and IL-17 release from CD4+ T cells via miR-302d/MBD2 in systemic lupus erythematosus

BackgroundIncreased human endogenous retroviruses E clone 4–1 (HERV-E clone 4–1) mRNA expression is observed in systemic lupus erythematosus (SLE) patients and associates with the disease activity. In this study, we want to further investigate the mechanism of HERV-E clone 4–1 mRNA upregulation and its roles in SLE progression.MethodsCD4+ T cells were isolated from venous blood of SLE patients or healthy controls and qRT-PCR was used to detect HERV-E clone 4–1 mRNA expression. We then investigated the regulation of Nuclear factor of activated T cells 1 (NFAT1) and Estrogen receptor-α (ER-α) on HERV-E clone 4–1 transcription and the functions of HERV-E clone 4–1 3′ long terminal repeat (LTR) on DNA hypomethylation and IL-17 release.ResultsWe found HERV-E clone 4–1 mRNA expression was upregulated in CD4+ T cells from SLE patients and positively correlated with SLE disease activity. This is associated with the activation of Ca2+/calcineurin (CaN)/NFAT1 and E2/ER-α signaling pathway and DNA hypomethylation of HERV-E clone 4–1 5’LTR. HERV-E clone 4–1 also takes part in disease pathogenesis of SLE through miR-302d/Methyl-CpG binding domain protein 2 (MBD2)/DNA hypomethylation and IL-17 signaling via its 3’LTR.ConclusionsHERV-E clone 4–1 mRNA upregulation is due to the abnormal inflammation/immune/methylation status of SLE and it could act as a potential biomarker for diagnosis of SLE. HERV-E clone 4–1 also takes part in disease pathogenesis of SLE via its 3’LTR and the signaling pathways it involved in may be potential therapeutic targets of SLE.

Adipokine interactions promote the pathogenesis of systemic lupus erythematosus

BackgroundAdipokines are chemical mediators released from adipose tissue involved in regulation of appetite, insulin sensitivity, immune system and inflammatory responses. Adipokines contributes to low grade inflammatory response in autoimmune disease like Systemic Lupus Erythematosus (SLE) but the pathophysiology is yet not clear. The aim of this study is to understand role of adipokine interactions in SLE disease pathogenesis. MethodsSixty newly diagnosed treatment naïve SLE patients fulfilling the ACR criteria and forty age-sex matched healthy subjects were enrolled in thiscase-control study. Disease activity in SLE patients was evaluated using SELENA-SLEDAI.Array of adipokines, C1q circulating immune complexes (C1q-CIC), anti-C1q, anti-ribososmal P0 (anti-RibP0) and anti-mitochondrial antibodies (AMA) levels were detected by ELISA. Antinuclear antibodies (ANA) and anti-dsDNA autoantibodieswere detected by Indirect Immunofluorescence (IIF), while antigen specificities were detected by Immunoassay blot. Serum levels of C3 and C4 complement factors were assessed by nephlometer. ResultsStatistically significant elevation in progranulin, adipsin and resistin levels was seen among SLE patients when compared to healthy controls (p < 0.0001). Leptin and omentin levels were significantly reduced in SLE patients (p < 0.0001). There was no statistically significant difference in serum adiponectin, chemerin and visfatin levels when these two groups were compared (p > 0.05). Adiponectin, adipsin and resistin levels were elevated in SLE patients with renal manifestations (p < 0.05). Reduced leptin levels were significantly associated with presence of renal manifestations (p < 0.05). Adiponectin levels positively correlated with disease activity (r = 0.294, p = 0.027) whereas negatively correlated with C3 levels (r = −0.439, p = 0.0007). A positive correlation was observed between hypocomplementemia and leptin levels (p < 0.05). Leptin levels were negatively correlated with disease activity, anti-dsDNA, C1q-CIC and anti-C1q levels (p < 0.05). A significant positive correlation was observed between progranulin levels and anti-ribosomal P0 antibodies (r = 0.499, p < 0.0001). ConclusionAdipokines levels and associated clinical manifestations suggest involvement of adipokines in disease pathogenesis of SLE. SLE disease activity and complement components may suggest regulatory effect of adipokines (adiponectin and leptin) on disease pathogenesis. Further studies on adipokines in SLE patients with renal manifestations may propose them as prognostic markers in renal damage.Trial Registration: NA

Differential expressions of plasma proteins in systemic lupus erythematosus patients identified by proteomic analysis.

Systemic lupus erythematosus (SLE) is a chronic and complex autoimmune disease with a wide range of clinical manifestations that affects multiple organs and tissues. Therefore the differential expression of proteins in the serum/plasma have potential clinical applications when treating SLE. We have compared the plasma/serum protein expression patterns of nineteen active SLE patients with those of twelve age-matched and gender-matched healthy controls by proteomic analysis. To investigate the differentially expressed proteins among SLE and controls, a 2-dimensional gel electrophoresis coupled with high-resolution liquid chromatography tandem mass spectrometry was performed. To further understand the molecular and biological functions of the identified proteins, PANTHER and Gene Ontology (GO) analyses were employed. A total of 14 significantly expressed (p<0.05, p<0.01) proteins were identified, and of these nine were up-regulated and five down-regulated in the SLE patients. The functional enrichment analysis assigned the majority of the identified proteins including alpha 2 macroglobulin, complement C4, complement factor H, fibrinogen beta chain, and alpha-1-antitrypsin were part of the complement/coagulation cascade, which is an important pathway that plays a crucial role in SLE pathogenesis. In addition to these proteins the differential expressions of ceruloplasmin, transthyretin, and haptoglobin play a potential role in the renal system abnormalities of SLE. Therefore, the identified differentially expressed proteins are relevant to SLE patient's cohort. Most importantly the up-regulated proteins might be the potential candidates for renal system involvement in SLE disease pathogenesis. In order to confirm the diagnostic/therapeutic potential of the identified proteins, future validation studies are required.

B-Cell-Attracting Chemokine CXCL13 As a Marker of Disease Activity in Systemic Lupus Erythematosus (SLE)

Abstract Background A correlation was detected between the chemokine CXC ligand 13 (CXCL13) and lupus nephritis, but there is no data recorded in the literature about a relationship with other disease manifestations in systemic lupus erythematosus (SLE). Therefore, we sought to investigate the relationship between CXCL13 and overall disease activity and other disease manifestations in SLE. Patients and Methods Fifty-seven SLE patients (51 female, 6 male) aged 18–60 years, fulfilling≥4 SLICC classification criteria for the classification of SLE, were enrolled in a cross-sectional study. Disease activity was scored using the SLE Disease Activity Index (SLEDAI) scoring system. The serological workup included routine lab investigations (full blood count, liver and kidney function tests, and urinalysis) as well as ESR, CRP, anti-ds DNA, C3, C4, 24-h urine protein, and creatinine clearance. Plasma CXCL13 levels were detected by ELISA. Results CXCL13 levels were elevated in active SLE patients. A significant positive correlation was found between the total score of SLEDAI and CXCL13 levels (r=0.547, p-value &lt;0.0001). A statistically significant difference was found regarding the mean CXCL13 levels between the patient groups (classified according to SLEDAI score) (inactive &lt;3, mild/moderate ≥3–12, severe ˃12) (p-value&lt;0.001). The anti-ds DNA antibody titre showed a significant positive correlation with CXCL13 levels (r=0.335, p-value&lt;0.05). The complement levels (C3, C4) showed a significant negative correlation with CXCL13 levels (p-value&lt;0.001). Also there was a significant positive correlation between 24-h urine protein and urinary casts and CXCL13 levels (p-value&lt;0.05). Conclusion Our study revealed elevated levels of serum CXCL13 in active SLE patients. We demonstrated a highly significant positive correlation between serum CXCL13 levels in active SLE patients and SLE disease activity, which supports the role of CXCL13 in the pathogenesis of SLE disease and its activity. Among the variants used in calculating the SLEDAI score, we detected significant relations between level of serum CXCL13 and each of total and extra-renal SLEDAI score.

Pentraxin-3 and its Association with C1q-CIC, hsCRP and Pro-Inflammatory Cytokines (TNF-Α and IL-1β) among SLE Patients from India

Introduction: Systemic Lupus Erythematosus (SLE) is a prototype autoimmune disease with alternating periods of flares and remission. Disease pathogenesis involves vast inflammatory responses, characterized by impaired cell signaling and T-cell dysfunction with interplay of cytokines and a wide network of protein cascades. Aim of this study is to understand the correlation between PTX-3 and pro-inflammatory cytokines (TNF-α and IL-1β) and their role in disease pathogenesis of SLE. Materials and Methods: Sixty-three SLE patients classified as per ACR 1997 criteria were included, of which 36 had renal involvement (LN). Autoantibodies were detected by IFA and ANA BLOT techniques. Serum Complement levels and hsCRP (by nephelometer), Pentraxin-3 and C1q-CIC (by ELISA), TNF-α and IL-1β levels (by Multiplex immunoassay) were assessed. Results: ANA was present in 90.5% patients, anti-dsDNA antibodies were present in 87.3% patients. Reduced C3 ( 5 mg/L) in 49.2% patients. C1q-CIC levels were high (>50 μg/ml) in 50.8% patients. Serum PTX-3 levels and TNF-α levels were significantly higher in SLE patients than healthy controls (p<0.0001 and p<0.0001 respectively). It was observed that PTX-3 and IL-1β levels were significantly higher in LN patients as compared with nonLN patients (p=0.0107; p=0.0022 respectively). PTX-3 positively correlates with C1q-CIC and negatively correlates with hsCRP and IL-1β levels among SLE patients. Conclusion: This study suggests that serum PTX-3 though do not induce an immediate inflammatory response, its positive correlation with C1q-CIC levels, suggested its possible role in classical complement pathway activation. Further studies in this regard are needed to understand the role of PTX-3 in pathogenesis of SLE.

Heightened cleavage of Axl receptor tyrosine kinase by ADAM metalloproteases may contribute to disease pathogenesis in SLE

Systemic lupus erythematosus (SLE) is characterized by antibody-mediated chronic inflammation in the kidney, lung, skin, and other organs to cause inflammation and damage. Several inflammatory pathways are dysregulated in SLE, and understanding these pathways may improve diagnosis and treatment. In one such pathway, Axl tyrosine kinase receptor responds to Gas6 ligand to block inflammation in leukocytes. A soluble form of the Axl receptor ectodomain (sAxl) is elevated in serum from patients with SLE and lupus-prone mice. We hypothesized that sAxl in SLE serum originates from the surface of leukocytes and that the loss of leukocyte Axl contributes to the disease. We determined that macrophages and B cells are a source of sAxl in SLE and in lupus-prone mice. Shedding of the Axl ectodomain from the leukocytes of lupus-prone mice is mediated by the matrix metalloproteases ADAM10 and TACE (ADAM17). Loss of Axl from lupus-prone macrophages renders them unresponsive to Gas6-induced anti-inflammatory signaling in vitro. This phenotype is rescued by combined ADAM10/TACE inhibition. Mice with Axl-deficient macrophages develop worse disease than controls when challenged with anti-glomerular basement membrane (anti-GBM) sera in an induced model of nephritis. ADAM10 and TACE also mediate human SLE PBMC Axl cleavage. Collectively, these studies indicate that increased metalloprotease-mediated cleavage of leukocyte Axl may contribute to end organ disease in lupus. They further suggest dual ADAM10/TACE inhibition as a potential therapeutic modality in SLE.

Analysis of CD95 and CCR7 expression on circulating CD4+ lymphocytes revealed disparate immunoregulatory potentials in systemic lupus erythematosus

Emerging data have implicated a critical role for CD4 in the pathogenesis of systemic lupus erythematosus (SLE). This study was designed to delineate the contribution of CD4+ T cells in the pathogenesis of SLE disease. Forty-four patients (3 male: 41 female) and 20 healthy volunteers (4 male: 16 female) were included in the study. CD4+ lymphocytes analysis was done using three-color flow cytometry with antibodies against human-CD95, a prototype cell death receptor, and the chemokine receptor-7 (CCR7) after gating for lymphocytes based on the forward and side scatter. Serum levels of IL-6, IL-12, IL-17, TNF-α and IL-10 cytokines were assayed using ELISA. Disease activity was assessed using the SLE disease activity index (SLEDAI). Based on the expression of CCR7 and CD95, CD4+ lymphocytes were subdivided into three particular subsets; CD4+CD95+CCR7+ cells, CD4+CD95−CCR7+ cells and CD4+CD95+CCR7− cells. Percentage of CD4+CD95+CCR7+ cell subset was significantly higher in patients with SLE with active disease (SLEDAI>6) and inactive (SLEDAI<6) as compared with controls (P=0.005), and it showed a significant positive correlation with ANA titer (P=0.01), and a negative correlation with WBCs count (P=0.001). CD4+CD95+CCR7− cell subset was significantly higher in active SLE patients in comparison to patients with inactive disease and controls (P=0.05, P=0.005 respectively), and it correlates positively with SLEDAI, IL-6 and IL-17 levels (P=0.001, 0.05, 0.01 respectively), and negatively with blood WBCs counts (P=0.001). The third CD4+CD95−CCR7+cell subset was found significantly lower in SLE patients compared with controls, and it was found negatively correlated with IL-10, IL-6, and IL-17. The results show that CD4+CD95+subset lacking expression of CCR7 is associated with cell mediated inflammatory response as manifested by its correlation with signs of inflammation, inflammatory cytokines and disease activity index. Whereas, CD4+CD95+CCR7+ correlate more with antibody immune responses as manifested by association with serum ANA. These data suggest disparate roles of these cell subsets in the pathophysiology of SLE. A better understanding of the characteristics of CD4 cell subsets may shed light on the pathogenesis of autoimmune diseases, particularly SLE.

Correcting the expression of miRNA-155 represses PP2Ac and enhances the release of IL-2 in PBMCs of juvenile SLE patients.

MicroRNA-155 is involved in immune cell, differentiation, maturation and function. MiR-155 showed variable dysregulated expression in autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) patients. MiR-155 was previously confirmed to directly target CAMP response element binding protein (CREB), which was previously identified as a positive regulator of protein phosphatase 2A (PP2A). PP2A is a key negative regulator of interleukin-2, which is an important immune modulator and was previously shown to be decreased in SLE. In this study we aimed at investigating the regulation of PP2A by miR-155 and hence its role in juvenile SLE disease pathogenesis. MiR-155 showed significant downregulation in PBMCs from juvenile SLE and juvenile familial Mediterranean fever (FMF) and significant upregulation in PBMCs from juvenile idiopathic arthritis (JIA) patients. In SLE, miR-155 expression was negatively correlated with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score and proteinuria and was positively correlated with white blood cell (WBC) count. The mRNA of the catalytic subunit of PP2A (PP2Ac) showed significant upregulation in PBMCs from SLE and FMF but not in JIA patients. Additionally, the relative expression of PP2Ac mRNA was positively correlated with SLEDAI score. Forced expression of miR-155 led to decreased relative expression of PP2Ac mRNA and increased IL-2 release in cultured-stimulated PBMCs. This study suggests for the first time the possible role of an miR-155-PP2Ac loop in regulating IL-2 release and identifies miR-155 as a potential therapeutic target in juvenile SLE disease through relieving IL-2 from the inhibitory role of PP2A.

Sex Differences in monocytes and TLR4 associated immune responses; implications for systemic lupus erythematosus (SLE).

It has been shown that TLR7 and TLR9 signaling play a role in SLE pathogenesis. Our recent study revealed that estrogen receptor α knockout mice have impaired inflammatory responses to TLR3, TLR4, TLR7 and TLR9 ligand stimulation in DCs, B cells and whole spleen cells. These findings indicate that estrogen receptor mediated signaling may impact universal TLR responsiveness. Whether estrogen has a direct or indirect effect on TLR responsiveness by immune cells is not clear. There is evidence of a role of TLR4 in SLE disease pathogenesis, such as the kidney damage, the induction of CD40 and autoantibodies, the suppression of regulatory T cells, and the role of pro-inflammatory cytokines (e.g., IL-6, IL-1β, TNF-α) in SLE pathogenesis that can be induced by TLR4-mediated monocyte activation, suggesting that TLR4 and TLR4 responsiveness are also important for SLE disease. This review will focus on TLR4 responses and monocytes, which are understudied in systemic autoimmune diseases such as SLE.

Spleen Tyrosine Kinase (Syk) Regulates Systemic Lupus Erythematosus (SLE) T Cell Signaling

Engagement of the CD3/T cell receptor complex in systemic lupus erythematosus (SLE) T cells involves Syk rather than the zeta-associated protein. Because Syk is being considered as a therapeutic target we asked whether Syk is central to the multiple aberrantly modulated molecules in SLE T cells. Using a gene expression array, we demonstrate that forced expression of Syk in normal T cells reproduces most of the aberrantly expressed molecules whereas silencing of Syk in SLE T cells normalizes the expression of most abnormally expressed molecules. Protein along with gene expression modulation for select molecules was confirmed. Specifically, levels of cytokine IL-21, cell surface receptor CD44, and intracellular molecules PP2A and OAS2 increased following Syk overexpression in normal T cells and decreased after Syk silencing in SLE T cells. Our results demonstrate that levels of Syk affect the expression of a number of enzymes, cytokines and receptors that play a key role in the development of disease pathogenesis in SLE and provide support for therapeutic targeting in SLE patients.

A study on anti-mannose binding lectin (anti-MBL) antibodies and serum MBL levels in Indian systemic lupus erythematosus patients

Systemic lupus erythematosus (SLE) is a prototype autoimmune disease characterized by systemic inflammation and autoantibody production. Anti-MBL autoantibodies have been studied in SLE for their possible effect on MBL levels and functional activity. This study aimed at detection of anti-MBL autoantibodies in Indian SLE patients and evaluates their relationship with related immunological parameters. Two hundred diagnosed SLE patients from Western India were included in the study where 87 patients were lupus nephritis (LN) (43.5 %) and remaining (56.5 %) were non-LN. Disease activity was assessed using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Anti-MBL autoantibodies to IgG and IgM isotypes, anti-C1q autoantibodies, MBL levels and circulating immune complex levels were detected by ELISA. C3, C4 and CRP levels were detected by nephelometer. Anti-MBL autoantibodies were detected in 52 % SLE patients, where 55 % had IgG-anti-MBL, 33.8 % had IgM-anti-MBL and 11.3 % had both subclasses. Low MBL levels were present in 64.4 % anti-MBL positives as compared with 61.5 % in anti-MBL negatives. Among anti-MBL positives, 74 % had anti-C1q antibodies, whereas 41.7 % of anti-MBL negatives had anti-C1q autoantibodies (p = 3.45E06). An inverse correlation was observed between serum MBL and CIC levels. A statistically significant difference was noted between anti-MBL positives and anti-MBL negative patients with hsCRP levels (p = 0.002). Occurrence of infections was higher among anti-MBL positives (65 %) as compared with anti-MBL negatives (35 %). The difference between SLEDAI scores among anti-MBL positive and negative groups was statistically insignificant. Anti-MBL autoantibodies in SLE patients can influence functional activity of MBL and have a significant role in SLE disease pathogenesis.

A study on anti-mannose binding lectin (anti-MBL) antibodies and serum MBL levels in Indian systemic lupus erythematosus patients

Systemic lupus erythematosus (SLE) is a prototype autoimmune disease characterized by systemic inflammation and autoantibody production. Anti-mannose binding lectin (anti-MBL) autoantibodies have been studied in SLE for their possible effect on mannose binding lectin (MBL) levels and functional activity. This study aimed at the detection of anti-MBL autoantibodies in Indian SLE patients and evaluates their relationship with related immunological parameters. Two hundred diagnosed SLE patients from Western India were included in the study where 87 patients were lupus nephritis (LN) (43.5 %) and remaining (56.5 %) were non-LN. Disease activity was assessed using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Anti-MBL autoantibodies to IgG and IgM isotypes, anti-C1q autoantibodies, MBL levels and circulating immune complex levels were detected by ELISA. C3, C4 and CRP levels were detected by nephelometer. Anti-MBL autoantibodies were detected in 52 % SLE patients, where 55 % had IgG-anti-MBL, 33.8 % had IgM-anti-MBL and 11.3 % had both subclasses. Low MBL levels were present in 64.4 % anti-MBL positives as compared to 61.5 % in anti-MBL negatives. Among anti-MBL positives, 74 % had anti-C1q antibodies, whereas 41.7 % of anti-MBL negatives had anti-C1q autoantibodies (p = 3.45E06). An inverse correlation was observed between serum MBL and CIC levels. A statistically significant difference was noted between anti-MBL positives and anti-MBL negative patients with hsCRP levels (p = 0.002). Occurrence of infections was higher among anti-MBL positives (65 %) as compared to anti-MBL negatives (35 %). The difference between SLEDAI scores among anti-MBL-positive and anti-MBL-negative groups was statistically insignificant. Anti-MBL autoantibodies in SLE patients can influence functional activity of MBL and have a significant role in SLE disease pathogenesis.