Disease Activity In SLE Patients Research Articles

Immunogenicity and Adverse Events after Covid-19 Vaccination in Patients with Systemic Inflammatory Autoimmune Diseases

Abstract Background The first cases of COVID-19 began in Wuhan, Hubei Province china, in December 2019. Since then, this disease caused by a highly pathogenic virus, severe acute respiratory syndrome coronavirus (SARS-COV-2), has been labelled as a global pandemic. It is believed that the primary means of viral spread is via respiratory droplets during close-range, human-to-human contact. Aim of the Work To assess immunogenicity and to compare adverse effect following COVID-19 vaccinations in patients with systemic inflammatory autoimmune diseases vs matched healthy controls. Patients and Methods This is a cross sectional study. Two groups of subjects were enrolled in the study after consideration of both inclusion and exclusion criteria. Group A: patients with systemic inflammatory auto immune disease (60 subjects) including (30 patients with systemic lupus erythematosus, 30 patients with rheumatoid arthritis) who received two doses of COVID-19 vaccine. Group B: age-matched healthy controls who received two doses of COVID-19 vaccine (30 Subjects). All patients were recruited from the outpatient clinic of department of Internal Medicine – Rheumatology division at Ain Shams University Hospital. Control group were recruited from medical and non-medical staff working at Ain Shams University Hospital. Results There was no statistically significant difference in the titre of anti-spikes antibodies with the use of different immune suppressive drugs in RA group such as methotrexate and leflunomide with p-value =0.935,0.257, respectively,also in SLE patients there was no statistically significant difference in the titre of anti-spikes antibodies with the use of different immune suppressive drugs in SLE group such as azathioprine, mycophenolate mofetil and cyclophosphamide with p-value = 0.317, 1.000 and 0.513 respectively,(all patients in our study were on corticosteroids and hydroxychloroquine). There was statistically significant difference as regarding disease activity in RA patients before and after covid-19 vaccine with p-value = 0.001,with a total percentage of 26.70% of patients developed mild disease activity,13.30% developed moderate disease activity while 3.3% of patients developed severe activity and as regarding SLE patients there was statistically significant difference as regarding disease activity in SLE patients before and after covid-19 vaccine with p-value = 0.002,with a total percentage of 23.3% of patients developed mild disease activity,6.7% developed moderate disease activity while 10% of patients developed severe activity. Conclusion Comparable side effects in both control and patients group with only minor side effects were reported. The Sinopharm BIBP COVID-19 vaccine was immunogenic in the majority of patients in comparison to control group, with an acceptable safety profile. The use of different immune suppressive therapies (methotrexate, azathioprine, mycophenolate mofetil,cyclophosphamide) didn’t affect humoral response after two doses of the vaccine. Apparent impact on disease activity of both SLE and RA patients but mainly in the form of mild disease activity.

Immunogenicity and Adverse Events after Covid-19 Vaccination in Patients with Systemic Inflammatory Autoimmune Diseases

Abstract Background The first cases of COVID-19 began in Wuhan, Hubei Province china, in December 2019. Since then, this disease caused by a highly pathogenic virus, severe acute respiratory syndrome coronavirus (SARS-COV-2), has been labelled as a global pandemic. It is believed that the primary means of viral spread is via respiratory droplets during close-range, human-to-human contact. Aim of the Work To assess immunogenicity and to compare adverse effect following COVID-19 vaccinations in patients with systemic inflammatory autoimmune diseases vs matched healthy controls. Patients and Methods This is a cross sectional study. Two groups of subjects were enrolled in the study after consideration of both inclusion and exclusion criteria. Group A: patients with systemic inflammatory auto immune disease (60 subjects) including (30 patients with systemic lupus erythematosus, 30 patients with rheumatoid arthritis) who received two doses of COVID-19 vaccine. Group B: age-matched healthy controls who received two doses of COVID-19 vaccine (30 Subjects). All patients were recruited from the outpatient clinic of department of Internal Medicine – Rheumatology division at Ain Shams University Hospital. Control group were recruited from medical and non-medical staff working at Ain Shams University Hospital. Results There was no statistically significant difference in the titre of anti-spikes antibodies with the use of different immune suppressive drugs in RA group such as methotrexate and leflunomide with p- value = 0.935,0.257, respectively,also in SLE patients there was no statistically significant difference in the titre of anti-spikes antibodies with the use of different immune suppressive drugs in SLE group such as azathioprine, mycophenolate mofetil and cyclophosphamide with p-value = 0.317, 1.000 and 0.513 respectively,(all patients in our study were on corticosteroids and hydroxychloroquine). There was statistically significant difference as regarding disease activity in RA patients before and after covid-19 vaccine with p-value = 0.001,with a total percentage of 26.70% of patients developed mild disease activity,13.30% developed moderate disease activity while 3.3% of patients developed severe activity and as regarding SLE patients there was statistically significant difference as regarding disease activity in SLE patients before and after covid-19 vaccine with p-value = 0.002,with a total percentage of 23.3% of patients developed mild disease activity, 6.7% developed moderate disease activity while 10% of patients developed severe activity. Conclusion Comparable side effects in both control and patients group with only minor side effects were reported. The Sinopharm BIBP COVID-19 vaccine was immunogenic in the majority of patients in comparison to control group, with an acceptable safety profile. The use of different immune suppressive therapies (methotrexate, azathioprine, mycophenolate mofetil, cyclophosphamide) didn’t affect humoral response after two doses of the vaccine. Apparent impact on disease activity of both SLE and RA patients but mainly in the form of mild disease activity.

#5689 ASSOCIATION BETWEEN INTERLEUKIN-37 RS3811047 POLYMORPHISM AND LUPUS NEPHRITIS IN AN EGYPTIAN POPULATION

Abstract Background and Aims Systemic lupus erythematosus (SLE) is a chronic, clinically heterogenous, autoimmune disorder with unpredictable course and features ranging from mild skin affection to life-threatening involvement of major organs. Interleukin 37 (IL-37) is a cytokine with anti-inflammatory and immune-suppressive effects; it suppresses both innate and adaptive immune responses, thus protecting against excessive inflammation-induced tissue damage. Aim investigate the association of IL-37 (rs3811047) polymorphism with lupus nephritis in Egyptian population. Method This case-control study comprised 3 groups: 109 SLE patients without nephritis, 97 SLE patients with LN, and 240 healthy controls. History taking, clinical examination, disease activity in SLE patients was assessed and routine laboratory tests were done. Genotyping of the IL-37 rs3811047 polymorphism was done using real time polymerase chain reaction (PCR). Results The AA genotype was more frequently represented in LN patients (21.6%) compared to SLE patients without LN (7.3%) (p = 0.007), and carriers of the AA genotype had four times increased susceptibility to acquire LN compared to GG and GA genotype carriers (OR: 4.1). Likewise, the A allele was more represented in LN patients (43%) than in SLE patients without LN (30%) (p = 0.004), and the carriers of the A allele had nearly two times more risk of developing LN compared to carriers of the G allele (OR: 1.79). Moreover, the AA genotype was associated with LN susceptibility under the recessive genetic model (OR = 3.49, CI: 1.47-8.30) (p = 0.002), but not under other genetic models. Conclusion The AA genotype of the IL-37 rs3811047 polymorphism contributes to the development of SLE in Egyptian patients with doubled risk of acquiring LN in carriers of the allele A.

An immunomodulatory antibody-drug conjugate targeting BDCA2 strongly suppresses plasmacytoid dendritic cell function and glucocorticoid responsive genes.

Blood dendritic cell antigen 2 (BDCA2) is exclusively expressed on plasmacytoid dendritic cells (pDCs) whose uncontrolled production of type I IFN (IFN-I) is crucial in pathogenesis of SLE and other autoimmune diseases. Although anti-BDCA2 antibody therapy reduced disease activity in SLE patients, its clinical efficacy needs further improvement. We developed a novel glucocorticoid receptor agonist and used it as a payload to conjugate with an anti-BDCA2 antibody to form an BDCA2 antibody-drug conjugate (BDCA2-ADC). The activation of BDCA2-ADC was evaluated in vitro. Inhibitory activity of BDCA2-ADC was evaluated in peripheral blood mononuclear cells or in purified pDCs under ex vivo toll-like receptor agonistic stimulation. The global gene regulation in purified pDCs was analysed by RNA-seq. The antigen-dependent payload delivery was measured by reporter assay. The BDCA2-ADC molecule causes total suppression of IFNα production and broader inhibition of inflammatory cytokine production compared with the parental antibody in human pDCs. Global gene expression analysis confirmed that the payload and antibody acted synergistically to regulate both type I IFN signature genes and glucocorticoid responsive genes in pDCs. Taken together, these data suggest dual mechanisms of BDCA2-ADC on pDCs and the potential for BDCA2-ADC to be the first ADC treatment for SLE in the world and a better treatment option than anti-BDCA2 antibody for SLE patients.

Plasma soluble tumor necrosis factor receptor I as a biomarker of lupus nephritis and disease activity in systemic lupus erythematosus patients

Objectives The goal of our study was to evaluate the potential role of sTNF-RI as a biomarker of renal involvement in SLE patients and active SLE. Methods The study sample consisted of two cohorts. The discovery cohort included 16 SLE patients without renal involvement (non-LN), 60 lupus nephritis (LN) patients and 21 healthy controls (HCs) and the replication cohort included 18 SLE non-LN patients, 116 LN patients and 36 HCs. Results The sTNF-RI levels differed significantly in the discovery cohort. The plasma sTNF-RI levels were higher in LN patients than in non-LN patients (p = .009) and HCs (p = 4 × 10−6). Plasma sTNF-RI levels were significantly higher in non-LN patients than in HCs (p = .03). The finding was confirmed in independent replication cohort (LNs vs. non-LN, p = 4.053 × 10−7; LNs vs. HCs, p = 2.395 × 10−18; non-LN vs. HCs, p = 2.51 × 10−4). The plasma sTNF-RI levels were associated with disease activity, renal function in SLE patients and urine protein in LN patients. The multivariate analysis revealed that high sTNF-RI was an independent risk factor for renal involvement. The multivariate logistic regression results suggested that high TNF-RI, high systolic blood pressure, high serum creatinine, low C4 and positive anti-dsDNA were independent risks of active SLE patients. A nomogram was constructed based on the results of multivariate logistic regression analysis and it was practical in predicting the risk of the active SLE patients. Immunohistochemistry suggested that the expression of TNF-RI in the kidney was increased. Conclusions Plasma sTNF-RI might be a good biomarker of renal involvement and disease activity in SLE patients.

Association of the STAT4 Gene rs7574865 Polymorphism with IFN-γ Levels in Patients with Systemic Lupus Erythematosus.

STAT4 plays an important role in disease activity in SLE patients. STAT4 particles have the capacity to activate the transcription of genes associated with the production of TH1 and Th17 lymphocytes, with a greater predominance on the production of IFN-γ and IL-17A. The presence of variants in STAT4 genes has a major impact on the generation of autoimmunity. However, there are few studies evaluating the impact of these variants on the production of proinflammatory cytokines such as IFN-γ and IL-17A. Methods-A case-control study was carried out with 206 Mexican mestizo patients residing in Western Mexico with a diagnosis of SLE and a group of 80 patients without autoimmune diseases was captured to determine the cut-off point for high IFN-γ levels. In this study, SLE patients with high IFN-γ levels were considered as cases (cut-off > 15.6 pg/mL), and SLE patients with normal IFN-γ levels were considered as controls (cut-off ≤ 15.6 pg/mL). Disease activity was identified from the systemic lupus erythematosus disease activity index (SLEDAI). For the determination of levels of cytokines IFN-γ, IL-12, and IL17A, commercial ELISA kits were used. Genotyping of STAT4 rs7574865 (G > T) was performed by quantitative polymerase chain reaction (qPCR) using TaqMan probes. Results-The patients with SLE had a median age of 45 years with a range of disease duration from 4 years to 18 years; 45.6% were identified as having disease activity. In this sample, we identified a high IFN-γ prevalence of 35.4%. The levels of IFN-γ were higher in the patients with genotype TT than GG. We found that TT genotype conferred a higher risk of high IFN-γ when compared to the GG and GT genotypes. Conclusions-In this study, we identified that the polymorphic genotype TT of the STAT4 gene rs7574865 polymorphism is associated with increased levels of IFN-γ. However, its strength of association was weak, so complementary studies are needed to evaluate its impact on SLE patients.

High serum leptin and adiponectin levels as biomarkers of disease progression in Egyptian patients with active systemic lupus erythematosus.

Objectives: Leptin and adiponectin are adipose-derived immune modulators (adipokines) that may contribute to SLE pathology and symptoms. This study aimed to evaluate the associations of serum adiponectin and leptin with clinical manifestations and disease activity in SLE patients. Methods: This is a case control study, where 70 SLE patients and 50 age- and sex-matched healthy controls were enrolled from the Rheumatology and Rehabilitation Department of Beni-Suef University Hospital from June 2020 till April 2022. The SLE disease activity index (SLEDAI) and Systemic Lupus International Collaborative clinics/America Collage of Rheumatology damage index were used to assess disease severity. Laboratory parameters including erythrocyte sedimentation rate (ESR) and serum concentrations of antinuclear antibody (ANA), anti-double stranded DNA, complement 3 and 4, lipids, and C-reactive protein (CRP) were measured and compared between SLE and control groups. Serum adiponectin and leptin were also measured by enzyme-linked immunosorbent assays (ELISA). Results: Compared to healthy controls, SLE patients exhibited significantly greater serum leptin (21.1 vs 3.9ng/mL, p < 0.001) and adiponectin (18.1 vs 4.8ng/mL, p < 0.001), and both values were positively correlated with SLEDAI scores (p = 0.048 and 0.042). Higher serum leptin was significantly associated with lupus nephritis (LN) (p = 0.048) as well as greater body mass index (p = 0.010), ESR (p = 0.002), serum CRP (p = 0.003), total cholesterol (p = 0.013), and uric acid (p = 0.002), while higher adiponectin was significantly associated with LN (p = 0.046). Conclusion: Serum leptin and adiponectin levels are associated with the clinical and pathological manifestations of SLE, suggesting direct involvement in disease progression and utility as diagnostic biomarkers and therapeutic targets.

Implication of plasma gelsolin in systemic lupus erythematosus patients

BackgroundSystemic lupus erythematosus (SLE) is a chronic autoimmune disorder with more than one organ involvement. Kidney is the foremost commonly affected one. Gelsolin is a protein that induces depolymerization of actin filaments thus preventing downstream stimulation of inflammatory reactions. The aim of this work was to detect the relation of plasma gelsolin to SLE disease activity and severity indices in order to find out if plasma gelsolin could be used as a biomarker of the disease. This study was conducted on 50 SLE female patients and 30 matched control. SLE disease activity Index (SLEDAI) and SLE damage index (SDI) were assessed. All lupus nephritis (LN) patients were subjected to an ultrasound-guided kidney biopsy. Plasma gelsolin level was measured.ResultsThe mean age of the patients was 38.5 ± 6.3 years (26–51 years) with median disease duration of 5 (3–9.3) years. Eighteen patients had LN, 11 had cardiac manifestations and 12 had chest manifestations. The mean SLEDAI was 13.1 ± 4.5 (4–22) and the median SDI was 2 (1–3). Plasma gelsolin level was significantly lower in SLE patients (74.9 mg/l; 57.5–98.8 mg/l) compared to control (801.5 mg/l; 225–1008.3 mg/l) (p < 0.001). There were significant negative correlations of gelsolin levels with anti-ds DNA (r = − 0.63, p < 0.001), SLEDAI (r = − 0.79, p < 0.001), and SDI (r = − 0.74, p = 0.001). Plasma gelsolin level was significantly lower in SLE patients with high/very high activity grades compared to those with low and moderate (p = 0.007 and p < 0.001 respectively). A gelsolin level of ≤ 78.95 mg/l significantly predicted renal affection (p < 0.001), with a sensitivity of 100%, specificity 71.9%, and a positive predictive value 66.7%.ConclusionA decreased gelsolin level is associated with disease activity in SLE patients. Plasma gelsolin was well related to disease activity and severity with a high predictive value for renal affection comparable to anti-ds DNA titre. Plasma gelsolin is a potentially important predictive biomarker for SLE and LN.

Serum level of fetuin-A in systemic lupus erythematosus patients: association with atherosclerosis and disease activity.

We aimed in this study to determine the level of serum fetuin-A level in systemic lupus erythematosus patients, assess the correlation between serum fetuin-A level and the activity of disease and the frequency of musculoskeletal manifestations, and detect the frequency of atherosclerosis among these patients by using carotid ultrasonography. This case-control study was carried out on 31 SLE patients attending the inpatient and outpatient clinics of Rheumatology and Rehabilitation Department, Faculty of Medicine, Zagazig university hospitals and 31 apparently healthy age- and sex-matched controls between January 1,2017, and December 31, 2018. There is a highly significant difference between the two studied groups as regard fetuin-A and carotid intima-media thickness. There is a strong positive significant correlation between fetuin-A with C3 and a negative significant correlation between fetuin-A with Anti-dsDNA, SLEDAI, and carotid intima-media thickness in case group. Fetuin-A levels were decreased in SLE patients, and these levels were inversely correlated with carotid intima-media thickness. Key Points • Fetuin-A level is a biomarker of atherosclerosis and asses disease activity in SLE patients.

Altered oxidative stress markers in relation to T cells, NK cells & killer immunoglobulin receptors that are associated with disease activity in SLE patients.

Systemic Lupus Erythematosus is an autoimmune disease with symptoms pervasive to all organ systems. It affects more females as compared to males (in the ratio 9:1). Oxidative stress plays a major role in the pathogenesis of SLE and other autoimmune diseases. In order to understand the relationship between cell specific oxidative stress and the severity of SLE, this research study involving the estimation of intracellular ROS accumulation in T and NK cell was conducted on SLE patients of North Indian Population. At the same time, to estimate anti-oxidant defense, Keap1 and Nrf2 levels were estimated in these cell types. The relationship between the expression of Killer immunoglobulin receptors i.e., KIR2DL4 & KIR3DL1 and oxidative stress was also evaluated as these receptors are imperative for the function and self-tolerance of NK cells.Oxidative stress was raised along with Keap1 and Nrf2 in T and NK cell subsets in SLE patients. The expression of KIR2DL4 was raised and that of KIR3DL1 was reduced in the NK cells of patients. The intensity of change in expression and its significance varied among the subsets. Nrf2 expression was raised in these species against oxidative stress as the antioxidant defense mechanism pertaining to Keap1-Nrf2 pathway, but the adequacy of response needs to be understood in further studies. The expression of KIR2DL4 and KIR3DL1 varied among the patient and healthy controls and the expression of the latter was found to have a significant positive relationship with plasma Glutathione(reduced) concentration.

Follicular helper T cells express a metabolic and cell signaling gene signature in a lupus-prone murine model

Abstract Systemic lupus erythematosus (SLE) is an autoimmune disease in which autoreactive follicular helper T (Tfh) cells license high-affinity autoantibody production. Strikingly, the frequency of circulating Tfh is correlated with disease activity in SLE patients. As such, understanding the molecular mechanisms responsible for the aberrant Tfh cell generation and activation in lupus is of fundamental significance. We previously demonstrated that expanded Tfh cells in the B6.Sle1.Sle2.Sle3 (TC for triple congenic) lupus model exhibit high glycolysis and oxidative metabolism, which can be constrained by inhibiting glycolysis with 2-deoxyglucose (2DG). We performed RNA-seq analyses of splenic Tfh and naïve CD4+ T cells (Tn) comparing between TC and B6 mice. First, data revealed a large number of shared gene signatures in Tfh and Tn comparing between TC and B6 group, implicating that the aberrant development of Tfh initiates as early as Tn state. Further alignment of the Tfh transcriptome obtained from RNA-seq and earlier microarray assays demonstrated concerted alterations in numerous gene signatures of overactivation of T cells including dysregulated tyrosine kinase signaling and MAPK signaling pathways. Gene set enrichment analyses (GSEA) further revealed altered metabolic pathways (e.g., oxidative phosphorylation and pyruvate metabolism) among splenic TC Tfh cells. Finally, we demonstrated that 2-DG partially correct the aberrant expression patterns in TC splenic Tfh cells, restoring oxidative phosphorylation and the MAPK pathways. Since 2DG eliminates the expansion of autoreactive TFh cells, these results suggest that these two pathways may be critical to lupus Tfh cell function.

Gelsolin: a new biomarker of disease activity in SLE patients associated with HDL-c.

To identify potential biomarkers of disease activity analysing the proteome of high-density lipoprotein (HDL) particles from SLE patients in clinical remission and when they develop a flare compared with a healthy control group. Quantitative proteomic analyses of purified HDL were performed using Tandem Mass Tag isobaric tag-labelling and nanoLC-Orbitrap (nLC-MS/MS) from nine SLE patients in clinical remission when they developed a flare and from nine healthy controls (9-9-9). We verified the identified proteins by Western blot and ELISA in a cohort of 104 SLE women patients, 46 healthy women and 14 SLE patients when a flare developed. We found 17 proteins with a significant fold-change (>1.1) compared with the control group. In lupus patients experiencing a flare compared with those in remission, we identified four proteins with a significant fold-change (C4, Indian Hedgehog protein, S100A8 and gelsolin). Plasma gelsolin (pGSN) levels were decreased in the 104 SLE patients (176.02(74.9) mcg/l) compared with the control group (217.13(86.7) mcg/l); P=0.005 and when they developed a clinical flare (104.84(41.7) mcg/l); P=0.002). pGSN levels were associated with HDL cholesterol levels (r = 0.316, P<0.001). Antimalarial treated patients showed significant higher levels of pGSN (214.56(88.94) mcg/l regarding 170.35(66.36) mcg/l); P = 0.017. Decreased pGSN are associated with clinical disease activity in SLE patients. Antimalarial treatment and HDL cholesterol are associated with higher levels of pGSN.

NovelmiRNA-25 inhibits AMPD2 in peripheral blood mononuclear cells of patients with systemic lupus erythematosus and represents a promising novel biomarker

BackgroundSystemic lupus erythematosus (SLE) is a multisystemic autoimmune disease with various clinical manifestations. MicroRNAs (miRNAs) and immunometabolism are recognized as key elements in SLE pathogenesis; however, the relationship between miRNAs in peripheral blood mononuclear cells (PBMCs) and metabolism in SLE remains unclear.MethodsWe detected PBMC miRNA and mRNA profiles from 3 pooled SLE patients and 3 healthy controls (HCs) using next-generation sequencing, predicted miRNA targets in dysregulated mRNAs, predicted functions and interactions of differentially expressed genes using bioinformatics analysis, validated candidate miRNAs using qRT-PCR, and investigated the association between the expression of candidate miRNAs and SLE clinical characteristics. Moreover, we validated the direct and transcriptional regulatory effect of NovelmiRNA-25 on adenosine monophosphate deaminase 2 (AMPD2) using a dual-luciferase reporter assay and western blot and confirmed AMPD2 mRNA and protein expression in PBMCs using qRT-PCR and western blot, respectively.ResultsMultilayer integrative analysis of microRNA and mRNA regulation showed that 10 miRNAs were down-regulated and 19 miRNAs were up-regulated in SLE patient PBMCs compared with HCs. Bioinformatics analysis of regulatory networks between miRNAs and mRNAs showed that 19 miRNAs were related to metabolic processes. Two candidate miRNAs, NovelmiRNA-25 and miR-1273h-5p, which were significantly increased in the PBMCs of SLE patients (P < 0.05), represented diagnostic biomarkers with sensitivities of 94.74% and 89.47%, respectively (area under the curve = 0.574 and 0.788, respectively). NovelmiRNA-25 expression in PBMCs was associated with disease activity in SLE patients, in both active and stable groups (P < 0.05). NovelmiRNA-25 overexpression downregulated AMPD2 expression in HEK293T cells through direct targeting of the AMPD2 3ʹUTR (P < 0.01), while inhibition of NovelmiRNA-25 activity led to increased AMPD2 expression (P < 0.01). NovelmiRNA-25 overexpression also downregulated AMPD2 protein expression in HEK293T cells; AMPD2 protein expression in SLE patient PBMCs was decreased. Our results show that differentially expressed miRNAs play an important role in SLE.ConclusionsOur data demonstrate a novel mechanism in SLE development that involves the targeting of AMPD2 expression by NovelmiRNA-25. miRNAs may serve as novel biomarkers for the diagnosis and evaluation of disease activity of SLE and represent potential therapeutic targets for this disease.

Genes associated with ARID3a expression in B Lymphocytes from Systemic Lupus Erythematosus patients

Abstract Systemic Lupus Erythematosus (SLE) is a complex autoimmune disease characterized by overproduction of autoantibodies by B cells and the loss of tolerance to nucleic acids. Our previous studies demonstrated that AT-rich interacting domain 3a (ARID3a), a DNA-binding protein associated with immunoglobulin transcription, is more abundant in SLE B lymphocytes than in healthy control B cells. ARID3a expression in SLE patient blood occurred in naïve B cell subsets which do not express ARID3a in healthy controls. Importantly, increased numbers of ARID3a+ B cells in SLE correlated with increased disease activity in patients. Our recent data indicated that ARID3a is critical for the expression of the key inflammatory cytokine, interferon-alpha (IFNa), in B cells and other blood cells. ARID3a+ B cells appear to denote a new kind of B effector cell that can induce IFNa expression in other cell types. We hypothesize that ARID3a is an important contributor to increased disease activity in SLE patients. Therefore, it is important to better define the characteristics of these cells. ARID3a is bimodally expressed, such that only a fraction of the cells within any B cell subset express ARID3a at a given time. Our current studies took advantage of this bimodal expression using single-cell technology to perform RNA-seq analyses of ARID3a+ and ARID3a− SLE B cells to identify differentially expressed genes associated with ARID3a. To date, ARID3a expression is correlated with innate immune response genes and epigenetic regulators. We predict these studies will be informative regarding how ARID3a expression contributes to disease pathogenesis in patients with SLE, and will provide novel information defining a new subset of effector B cells.

Immune complexes containing serum B-cell activating factor and immunoglobulin G correlate with disease activity in systemic lupus erythematosus

Levels of serum BAFF, IgG anti-BAFF and BAFF-IgG complexes were quantified by enzyme-linked immunosorbent assay. IgG anti-BAFF and BAFF-IgG complexes were further characterized using serum fractions obtained by fast protein liquid chromatography. To study the association of serum BAFF, IgG anti-BAFF and BAFF-IgG complex levels with SLE manifestations, 373 visits from 178 patients prospectively included in the Swiss SLE Cohort Study were analysed. While IgG anti-BAFF levels were not associated with clinical manifestations of SLE, serum BAFF levels correlated with disease activity and were higher in patients with renal involvement. Interestingly, we could also demonstrate the occurrence of BAFF-IgG complexes of different sizes in the sera of SLE patients, which were not due to treatment with belimumab and differed from complexes constructed in vitro. Most strikingly, the levels of these BAFF-IgG complexes were found to strongly correlate with overall disease activity, low complement levels and a history of lupus nephritis. BAFF-IgG complexes strongly correlate with disease activity in SLE patients, suggesting a pathogenic role in SLE.

Pentraxin 3 Plasma Levels and Disease Activity in Systemic Lupus Erythematosus.

SLE is an autoimmune disorder that involves polyclonal autoimmunity against multiple autoantigens. PTX3, a marker of the acute-phase inflammatory response, plays an important role in innate immunity and in modulation of the adaptive immune response. Our study tried to resolve some rather controversial aspects of the use of PTX3 as a biomarker of disease activity in SLE patients. We demonstrated that plasma PTX3 concentration of the SLE patients was significantly higher than the healthy control groups and reflected disease activity. ROC curve analysis was used to determine best cut-off point (2.8 ng/mL) with a good sensitivity and specificity. In patients with SLE, PTX3 concentrations were correlated with SLEDAI. Trend to remission (TTR) curve was created by plotting PTX3 levels and SLEDAI and we applied the curve as a model for the analysis of two patients with different follow-up. PTX3 plasma levels declined significantly and this decline occurred parallel to the clinical improvement with a complete remission of disease. In patients who experienced a clinical relapse, an increase in PTX3 levels followed the lupus flare. The proposal of PTX3 cut-off associated with TTR and monitoring of PTX3 plasma levels could be an innovative approach to follow-up of SLE patients.

Participation of the neutrophin brain-derived neurotrophic factor in neuropsychiatric systemic lupus erythematosus.

Brain-derived neurotrophic factor (BDNF) is associated with the pathogenesis of several neuropsychiatric (NP) diseases, but there are few studies involving SLE. The aim of this study was to investigate whether plasma BDNF levels are associated with disease activity in SLE patients with severe NPSLE and non-NPSLE manifestations. We assessed 131 SLE patients and 24 randomly selected healthy individuals. SLE patients were evaluated in a cross-sectional study allocated according to the presence or not of NP manifestations and disease activity: (i) active NPSLE (n = 40), (ii) inactive NPSLE (n = 26), (iii) active SLE (n = 29) and (iv) inactive SLE (n = 36). In addition, NPSLE patients (n = 40) were evaluated before and after treatment. Disease activity was assessed according to the SLEDAI score. The plasma BDNF was measured by ELISA. BDNF levels were increased in inactive NPSLE when compared with active SLE and controls (P < 0.0001). We observed similar findings in inactive SLE when compared with active SLE (P < 0.0001). In addition, we found an inverse correlation between plasma BDNF levels and the SLEDAI (r = -0.54, P < 0.0001) and a positive correlation with complement levels. We also observed an increase in BDNF levels in parallel with the improvement in NP symptoms. Plasma BDNF level is increased in SLE patients and this increase is independent of the occurrence of NP manifestations. In addition, plasma BDNF levels increased with control of SLE activity, which points to the potential use of BDNF as a biomarker of response to treatment.

AB0506 Study of Serum Nitric Oxide Level in Patients with Lupus Nephritis and Its Relation to Disease Activity

BackgroundSLE is characterized by the production of a wide range of autoantibodies and immune complexes that may lead to tissue injury. Among patients with Lupus Nephritis; those with proliferative lesions...

Aberant expansion of CXCR5+ memory CD4 T cells in SLE patients (HUM7P.307)

Abstract Autoreactive B cells in SLE undergo autoantigen selection, suggesting a requirement for germinal center follicular helper T (Tfh) cells in their maturation. However, evidence for dysregulation of Tfh cells in SLE and their potential contribution to disease remains unclear. Recently, blood CXCR5+ CD4 T cells, a heterogeneous pool consisting of functionally distinct Th1-, Th2-, and Th17-like subsets, have been proposed to be the circulating (blood) memory Tfh cells. We hypothesized that expanded CXCR5+ memory cells in the blood of human lupus patients promote B cell helper function reflecting the abnormal T-B cell responses in secondary lymphoid organs. We have characterized such cells in SLE patients by flow cytometry and T-B coculture studies. SLE patients had significant expansion of CXCR5+ICOShiPD-1hi CD4 T cells compared to controls. Such cells were Bcl6-, but robustly expressed IL-21 with a portion Ki-67+, indicating their functional activity. The blood cells were capable of providing blood-born memory B cells with survival and differentiation signals to secrete isotype switched Igs, including anti-nuclear antibodies. We speculate that therapies that alter T-B collaboration in lupus will abrogate their expansion, accompanied by reduced autoantibody titers and improved disease activity in SLE patients. Our results suggest that aberrant T-B collaboration in lupus is critical to disease pathogenesis and its blockade is likely to be important therapeutically.

A3.11 Induction of remission by low-dose IL-2-therapy in one SLE patient with increased disease activity refractory to standard therapies: A case report

IL-2 deficiency and associated regulatory T cell (Treg) defects contribute essentially to SLE pathogenesis. In our previous translational work we proved the efficacy and safety of a low-dose IL-2 therapy...