Systemic Lupus Erythematosus Lymphocytes Research Articles

Integration of multi-omics analysis reveals metabolic alterations of B lymphocytes in systemic lupus erythematosus

ObjectiveTo link changes in the B-cell transcriptome from systemic lupus erythematosus (SLE) patients with those in their macroenvironment, including cellular and fluidic components. MethodsAnalysis was performed on 363 patients and 508 controls, encompassing transcriptomics, metabolomics, and clinical data. B-cell and whole-blood transcriptomes were analysed using DESeq and GSEA. Plasma and urine metabolomics peak changes were quantified and annotated using Ceu Mass Mediator database. Common sources of variation were identified using MOFA integration analysis. ResultsCellular macroenvironment was enriched in cytokines, stress responses, lipidic synthesis/mobility pathways and nucleotide degradation. B cells shared these pathways, except nucleotide degradation diverted to nucleotide salvage pathway, and distinct glycosylation, LPA receptors and Schlafen proteins. ConclusionsB cells showed metabolic changes shared with their macroenvironment and unique changes directly or indirectly induced by IFN-α signalling. This study underscores the importance of understanding the interplay between B cells and their macroenvironment in SLE pathology.

Assessment of hematologic indices for diagnosis in juvenile systemic lupus erythematosus.

The aim was to present effective approaches utilizing novel hematological parameters for early diagnosis of juvenile-onset systemic lupus erythematosus (jSLE). Our study at Umraniye Training and Research Hospital involved a jSLE patient cohort from 2016 to 2022 and matched healthy controls aligning with sex and age. We use the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) for disease activity. Our approach was to analyze leukocyte, neutrophil, lymphocyte, monocyte, and platelet counts, along with ratios such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), and monocyte-to-platelet ratio (MPR). We also explored novel indices: the systemic inflammatory index (SII), systemic inflammation response index (SIRI), and aggregate index of systemic inflammation (AISI) to identify relationships between systemic indices and jSLE activity. Upon comparative analysis with the healthy control group, systemic lupus erythematosus (SLE) patients exhibited significantly elevated levels of the hematological parameters NLR, SII, and SIRI (p-values: 0.010, 0.048, 0.025, respectively). Among SLE patients, neutrophil, lymphocyte, and platelet distribution width (PDW) values were notably higher, while hemoglobin, red blood cell distribution width (RDW), and procalcitonin (PCT) values were significantly lower. In comparison, C-reactive protein (CRP) and sedimentation values were markedly elevated in the SLE group in contrast to the healthy control cohort. Patients with significantly elevated disease activity had notably higher values of NLR (p = 0.010) and SII (p = 0.048). Among patients with positive antinuclear antibodies (ANA), elevated levels of NLR, SII, and SIRI were noted (p-values: 0.018, 0.021, 0.035). In this study, the novel hematological markers SII, SIRI, and AISI were found to effectively reflect inflammation in SLE patients, exhibit associations with high disease activity, and demonstrate heightened sensitivity in detecting cases with high disease activity.

Olanzapine’s Cytogenetic Effect on T Lymphocytes in Systemic Lupus Erythematosus and Rheumatoid Arthritis Patients: In Vitro Study

This study will investigate olanzapine's cytogenetic behavior in cultured human T lymphocytes in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Three olanzapine solutions were added in cultures of peripheral blood lymphocytes of healthy individuals, SLE, and RA patients. After 72 hours of incubation, the cultured lymphocytes were plated on glass slides and stained with the fluorescence plus Giemsa method. Sister chromatid exchanges (SCEs), proliferation rate index (PRI), and mitotic index (MI) were measured with the optical microscope. There was a statistically significant (p=0.001) dose-dependent increase of SCEs in SLE and RA patients compared to healthy individuals and a statistically significant (p=0.001) reduction of PRI and MI in the highest concentration in the SLE group. Moreover, Spearman's rank correlation coefficient was applied to calculate the correlation between SCEs, PRI, and MI. Negative significant correlations were noticed for both patient groups concerning SCEs-PRI alterations and SCEs-MI alterations. Conversely, positive correlations were noticed for both patient groups for PRI-MI alterations. Conclusions: Olanzapine affects T lymphocytes from SLE and RA patients by modifying DNA replication procedures and DNA damage response. Considering the use of olanzapine in neuropsychiatric symptoms of SLE, further in vivo studies are necessary to evaluate its effect on human DNA.

UCTD and SLE patients show increased levels of oxidative and DNA damage together with an altered kinetics of DSB repair.

Immunological tolerance is a critical feature of the immune system; its loss might lead to an abnormal response of lymphocytes causing autoimmune diseases. One of the most important groups belonging to autoimmune disorders is the connective tissue diseases (CTD). CTD are classified among systemic rheumatic diseases and include pathologies such as systemic lupus erythematosus (SLE), and undifferentiated CTD (UCTD). In this study, we evaluated oxidative and genome damage in peripheral blood lymphocytes from patients with SLE and UCTD, further classified on the basis of disease activity and the presence/absence of a serological profile. Oxidative damage was evaluated in cell membrane using the fluorescent fatty acid analogue BODIPY581/591 C11. The percentage of oxidised lymphocytes in both SLE and UCTD patients was higher than in the control group, and the oxidative stress correlated positively with both disease activity and autoantibody profile. The γH2AX focus assay was used to quantify the presence of spontaneous double strand breaks (DSBs), and to assess the abilities of DSBs repair system after T cells were treated with mitomycin C (MMC). Subjects with these autoimmune disorders showed a higher number of γH2AX foci than healthy controls, but no correlation with diseases activity and presence of serological profile was observed. In addition, patients displayed an altered response to MMC-induced DSBs, which led their peripheral cells to greatly increase apoptosis. Taken together our results confirmed an interplay among oxidative stress, DNA damage and impaired DNA repair, which are directly correlated to the aggressiveness and clinical progression of the diseases. We propose the evaluation of these molecular markers to better characterise SLE and UCTD, aiming to improve the treatment plan and the quality of the patients' life.

Skewed allelic expression on X chromosome associated with aberrant expression of XIST on systemic lupus erythematosus lymphocytes.

A common feature of autoimmune diseases, including systemic lupus erythematosus (SLE), is an increased prevalence in women. However, the molecular basis for sex disparity in SLE remains poorly understood. To examine the role of X-linked transcription in SLE adaptive immune cells, we performed RNA-seq in T cell and B cell subsets from either healthy donors or patients with SLE. Analyses of allelic expression (AE) profiles identified a pattern of increased allelic imbalance across the entire X chromosome in SLE lymphocytes. X-linked genes exhibiting AE in SLE had an extensive overlap with genes known to escape X chromosome inactivation (XCI). XIST RNA was overexpressed in SLE patients. Differential XIST expression correlated with AE profiles more positively at X-linked genes than the genome-wide background. Analysis of three independent RNA-seq data verified the XIST-associated skewed AE on X chromosome in SLE. Integrative analyses of DNA methylation profiles showed an increased variability of DNA methylation levels at these AE-related X-linked genes. In cultured lymphoblastic cells, knockdown of XIST specifically altered allelic imbalance patterns between X chromosomes. Our study provides genetic evidence that upregulation of XIST accompanied with more skewed allelic expression on X chromosome is associated with the pathogenesis of SLE and may provide mechanistic insights into the increased incidence of SLE in females.

Peripheral blood brain-derived neurotrophic factor level and tyrosine kinase B expression on T lymphocytes in systemic lupus erythematosus: Implications for systemic involvement

ObjectiveBrain-derived neurotrophic factor (BDNF) has been reported to be involved in the pathogenesis of autoimmune diseases and tyrosine kinase B (TrkB) is the specific receptor for BDNF. Our aim in this study was to investigate serum BDNF level and TrkB expression on peripheral blood T cell surface in patients with systemic lupus erythematosus (SLE) and explore potential relationship between serum BDNF and SLE. MethodsSamples from fifty SLE patients and thirty healthy controls were evaluated. Serum BDNF level was measured by enzyme-linked immunosorbent assay (ELISA) and the percentages of TrkB expression on the surface of CD3 + CD4 + and CD3 + CD8 + T lymphocytes were measured by flow cytometry. The SLE patients were divided into subgroups according to whether they exhibited brain, kidney or lung involvement, and whether the disease was active or inactive. ResultsSerum BDNF levels in SLE patients were decreased when compared to the controls (p < 0.001). Comparing with the SLE individuals without systemic involvement, the BDNF levels were decreased in SLE patients with lupus nephritis (p = 0.042) and in SLE patients with neuropsychiatric manifestations (p = 0.04). On the other hand, the BDNF level was significantly increased in the inactive SLE group (p < 0.001) compared to the active SLE group. In addition, the percentages of TrkB expression on CD3 + CD4 + and CD3 + CD8 + T cell surface in SLE were significantly higher (p < 0.001; p < 0.001, respectively) than that in the controls. ConclusionsSerum BDNF level combined with TrkB expression on T cell surface can reflect SLE activity. It is possible that BDNF may be used as a potential serological biomarker for disease activity of SLE. In addition, the significant decrease in serum BDNF level may imply systemic involvement of SLE, as well as, possibly, differentiate neuropsychiatric SLE from hormone-induced mental disorders.

Relationship between endothelial dysfunction, videocapillaroscopy and circulating CD3+CD31+CXCR4+ lymphocytes in systemic lupus erythematosus without cardiovascular risk factors.

The objective of this paper is to analyse whether digital capillary morphology, analysed by nailfold videocapillaroscopy (NVC), and the number of circulating CD3 + CD31 + CXCR4 + lymphocytes (angiogenic T cells) could be markers of endothelial dysfunction (ED) in systemic lupus erythematosus (SLE) without cardiovascular disease (CVD) and CV risk factors. Nineteen consecutive SLE patients, according to Systemic Lupus International Collaborating Clinics Classification Criteria, with a disease duration less than five years, low disease activity, without CVD and CV risk factors (diabetes, chronic renal disease, uncontrolled systemic arterial hypertension, smoking, hypercholesterolemia, obesity), statin or beta-blocker use were enrolled. Each patient and sex- and age-matched healthy control (HC) underwent Doppler echocardiogram, an endothelial function study by peripheral arterial tonometry technique, NVC and peripheral blood immunophenotyping. SLE ED+ more frequently showed NVC abnormalities compared with HCs ( p < 0.0001) in terms of minor alterations ( p = 0.017), lower capillary numbers ( p = 0.0035) and major alterations. SLE ED + showed a higher rate of CD3 + CD31 + CXCR4 + lymphocytes compared with SLE ED- and with HCs. NVC + SLE showed a significantly reduced rate of total CD3 + cells, but a higher rate and absolute number of CD3 + CD31 + CXCR4 + , compared with NVC- SLE. NVC alterations are frequent in SLE without any CV risk factors and CVD. They are associated with ED and increased circulating CD3 + CD31 + CXCR4 + lymphocytes. These findings demonstrate a clear microvascular perturbation in patients with short disease duration, low disease activity and no CV risk factors.

Role of P-glycoprotein on CD69+CD4+ cells in the pathogenesis of proliferative lupus nephritis and non-responsiveness to immunosuppressive therapy

IntroductionP-glycoprotein (P-gp) expression on activated lymphocytes in systemic lupus erythematosus (SLE) plays a role in active efflux of intracellular drugs, resulting in drug resistance. The role of P-gp-expressing lymphocytes in...

Effects of 1,25(OH)2 D3 and vitamin D receptor on peripheral CD4+ /CD8+ double-positive T lymphocytes in a mouse model of systemic lupus erythematosus.

This study aims to explore effects of 1,25(OH)2D3 and vitamin D receptor (VDR) on peripheral CD4+/CD8+ double‐positive (DP) T lymphocytes in systemic lupus erythematosus (SLE). MRL‐LPr/LPr mice with SLE (n = 20) and normal MRL mice (n = 20) were assigned into the control group (normal mice, without feeding with 1,25(OH)2D3), the 1,25(OH)2D3 group (SLE mice, feeding with 1,25(OH)2D3), the VDR‐knock‐in + 1,25(OH)2D3 group (SLE mice, VDR‐knock‐in, feeding with 1,25(OH)2D3) and the VDR‐knockout group (normal mice, VDR‐knockout, without feeding with 1,25(OH)2D3) (n = 10 per group). Levels of T lymphocytes were measured by flow cytometry. The mRNA and proteins expressions of inflammatory factors were measured by qRT‐PCR and ELISA. Extracellular signal‐regulated kinase‐1/2 (ERK1/2) expression was measured by Western blotting. Compared with normal mice, SLE mice showed reduced levels of CD4+, CD4+/CD8+ ratio, and DP lymphocytes. The levels of SLE‐related indicators all increased significantly, followed with severe skin ulcers and urinary system infection. With the increase in time, skin ulcers and urinary system infection were significantly improved, levels of CD4+, CD4+/CD8+ ratio, and DP lymphocytes increased, and levels of SLE‐related indicators all decreased in the 1,25(OH)2D3 group. There were no significant changes in bioindicators in the control and the VDR‐knock‐in + 1,25(OH)2D3 groups. The symptoms of SLE gradually occurred in the VDR‐knockout group. This study demonstrates that VDR and 1,25(OH)2D3 could elevate CD4+/CD8+ DP T lymphocytes and reduce expressions of inflammatory factors, thus inhibiting the development and progression of SLE.

The role of microRNA-31 and microRNA-21 as regulatory biomarkers in the activation of T lymphocytes of Egyptian lupus patients.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by familial aggregation and genetic predisposition. MicroRNAs (MiRNAs) serve as critical biomarkers in lupus patients because of their aberrant expression in different SLE stages. The study aimed to investigate the correlation of miR-31 and miR-21 with IL-2 in SLE patients as regulatory biomarkers in the activation of T lymphocytes of Egyptian lupus patients. Quantitative RT-PCR is carried out to estimate the expressions of miR-31 and miR-21, and IL-2 levels were determined using ELISA in plasma of 40 patients with SLE, 20 of their first-degree relatives and 20 healthy controls. The study also determined the systemic lupus erythematosus disease activity index (SLEDAI) score and proteinuria in SLE patients. The results revealed that miR-31 was lower expressed, while miR-21 was high expressed in SLE patients compared to their first-degree relatives and controls. MiR-31 was negatively correlated with SLEDAI and proteinuria in lupus patients, while miR-21 showed positive correlation with them. Also we found that there is a significant positive correlation between miR-31 and IL-2 in SLE patients, while miR-21 was negatively correlated with IL-2 level in patients. In conclusion, the study disclosed a significant association between miR-31 and miR-21 expression with IL-2 level in SLE patients. The regulatory biomarkers of miR-31 and miR-21 might have an impact on regulating IL-2 pathway expression and in turn on the activation of T lymphocytes in SLE.

Autophagic behavior of T lymphocytes in systemic lupus erythematosus

Elena Ortona1, Walter Malorni2* and Marina Pierdominici1 1Department of Cell Biology and Neurosciences, Istituto Superiore di Sanita, Rome, Italy 2Department of Therapeutic Research and Medicine Evaluation, Istituto Superiore di Sanita, Rome, Italy *Corresponding author: Walter Malorni, Department of Therapeutic Research and Medicine Evaluation, Section of Cell Aging and Degeneration, Istituto Superiore di Sanita', Rome, Italy, Tel: 00390649902905; Fax: 00390649903691; E-mail: malorni@iss.it

The effects of freeze/thawing on the function and phenotype of CD4+ lymphocyte subsets in normal individuals and patients with systemic lupus erythematosus

Several studies report on lymphocyte phenotypic and functional abnormalities in Systemic Lupus Erythematosus (SLE). Freezing and thawing may alter functional and phenotypic properties of cells. We assessed the effect of the freezing/thawing process (F/T) on Th1 (CD3+CD4+CCR4−CXCR3+CCR5+), Th2 (CD3+CD4+CCR5−CXCR3−CCR4+), Th17 (CD3+CD4+CCR6+CD161+), and Treg (CD3+CD4+CD25highCD127-) cell cultures in healthy controls and SLE patients. F/T was associated with decreased frequency of Th2 and Th17 cells in cultures from SLE patients but not from controls. F/T was also associated with increased frequency of apoptotic cells, as measured by annexin V labeling, in all T cell subtypes analyzed, as well as increased cell proliferation, as measured by Ki-67 labeling, in all cells except Th1 from SLE patients. Thus, F/T can have differentiated effects on T lymphocyte subtypes from SLE patients and controls, and can have significant effects on cell death and proliferation. These findings should be carefully considered when designing and interpreting studies on functional and phenotypic aspects of T lymphocytes in SLE.

Expansion of regulatory GITR+CD25 low/-CD4+ T cells in systemic lupus erythematosus patients.

IntroductionCD4+CD25low/-GITR+ T lymphocytes expressing forkhead box protein P3 (FoxP3) and showing regulatory activity have been recently described in healthy donors. The objective of the study was to evaluate the proportion of CD4+CD25low/-GITR+ T lymphocytes within CD4+ T cells and compare their phenotypic and functional profile with that of CD4+CD25highGITR− T lymphocytes in systemic lupus erythematosus (SLE) patients.MethodsThe percentage of CD4+CD25low/-GITR+ cells circulating in the peripheral blood (PB) of 32 patients with SLE and 25 healthy controls was evaluated with flow cytometry. CD4+CD25low/-GITR+ cells were isolated with magnetic separation, and their phenotype was compared with that of CD4+CD25highGITR− cells. Regulatory activity of both cell subsets was tested in autologous and heterologous co-cultures after purification through a negative sorting strategy.ResultsResults indicated that CD4+CD25low/-GITR+ cells are expanded in the PB of 50% of SLE patients. Expansion was observed only in patients with inactive disease. Phenotypic analysis demonstrated that CD4+CD25low/-GITR+ cells display regulatory T-cell (Treg) markers, including FoxP3, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), transforming growth factor-beta (TGF-β), and interleukin (IL)-10. In contrast, CD4+CD25highGITR− cells appear to be activated and express low levels of Treg markers. Functional experiments demonstrated that CD4+CD25low/-GITR+ cells exert a higher inhibitory activity against both autologous and heterologous cells as compared with CD4+CD25highGITR− cells. Suppression is independent of cell contact and is mediated by IL-10 and TGF-β.ConclusionsPhenotypic and functional data demonstrate that in SLE patients, CD4+CD25low/-GITR+ cells are fully active Treg cells, possibly representing peripheral Treg (pTreg) that are expanded in patients with inactive disease. These data may suggest a key role of this T-cell subset in the modulation of the abnormal immune response in SLE. Strategies aimed at expanding this Treg subset for therapeutic purpose deserve to be investigated.

Aberrant B Cell Selection and Activation in Systemic Lupus Erythematosus

The detrimental role of B lymphocytes in systemic lupus erythematosus (SLE) is evident from the high levels of pathogenic antinuclear autoantibodies (ANAs) found in SLE patients. Affirming this causative role, additional antibody-independent roles of B cells in SLE were appreciated. In recent years, many defects in B cell selection and activation have been identified in murine lupus models and SLE patients that explain the increased emergence and persistence of autoreactive B cells and their lowered activation threshold. Therefore, clinical trials with B cell depletion regimens in SLE patients were initiated but disappointingly the efficacy of B cell depleting agents proved to be limited. Remarkably however, a major breakthrough in SLE therapy was accomplished by blocking B cell survival factors rather then eliminating B cells. This surprising finding indicates that although SLE is a B cell-driven disease, the amplifying crosstalk between B cells and other cells of the immune system likely evokes the observed tolerance breakdown in B cells. Moreover, this implies that intelligent interception of pro-inflammatory loops rather then selectively silencing B cells will be key to the development of new SLE therapies. In this review, we will not only highlight the intrinsic B cell defects that facilitate the persistence of autoreactive B cells and their activation, but in addition we will focus on B cell extrinsic signals derived from T cells and innate immune cells that lower the activation threshold for B cells.

AB0138 Altered er stress-induced autophagic reactions are associated with increased apoptosis of t lymphocytes in systemic lupus erythematosus

BackgroundThe autophagic responses to ER stress are involved in the regulation of the maintenance of lymphocyte homeostasis and has been implicated in the pathogenesis of autoimmunity. However, there were no...

High occurrence ofin vitroapoptosis of lymphocytes induced by serum from systemic lupus erythematosus patients is associated with increased serum levels of anti-C1q autoantibodies

The ethiopathogenesis of increased apoptosis of lymphocytes in systemic lupus erythematosus (SLE) is still incompletely understood but anti-C1q autoantibodies have been shown to induce apoptosis in lymphocytes from healthy donors and certain cell lines. This study was undertaken to investigate the relationship between peripheral lymphocyte apoptosis and serum levels of anti-C1q autoantibodies in SLE patients. The sera of 124 patients with SLE involving 62 active SLE and 62 inactive SLE, fulfilling America College of Rheumatology (ACR) classification criteria for SLE (1997) were incubated with peripheral blood lymphocytes of healthy donors. The results were compared with 124 sex- and age-matched normal controls. Apoptotic lymphocytes (AL) were detected by flow cytometry using annexin V and propidium iodide binding. Anti-C1q autoantibodies were detected by an enzyme-linked immunoassay kit for all SLE patients. Results demonstrated that the percentage of AL in the peripheral blood of active SLE patients was significantly higher (n=62, 34.95±12.78%) than that of the inactive SLE patients (n=62, 30.69±10.13%, P=0.042, 95%CI=0.16-8.36) and normal controls (n=124, 27.92±10.22%, P=0.001, 95%CI=3.33-10.73). The percentage of AL significantly correlated with serum levels of anti-C1q autoantibodies in the active SLE patients (r=0.263, P=0.039) but not in the inactive SLE patients (r=0.170, P=0.185). The results of this study suggest that increased serum levels of anti-C1q autoantibodies are responsible for apoptosis and may play a pathogenic role in SLE patients, especially in active disease.

Hydrogen Sulfide Inhibits Abnormal Proliferation of Lymphocytes via AKT/GSK3β Signal Pathway in Systemic Lupus Erythematosus Patients

Background/Aim: The abnormal activation of the AKT/GSK3β signal pathway in lymphocytes from systemic lupus erythematosus (SLE) patients plays an important role in the pathogenesis of the disease. Recently Hydrogen sulfide (H₂S) has been recognized as a crucial gaseous signaling molecule, involved in regulation of cell proliferation. However, the role of H₂S in regulating the abnormal activation of lymphocytes from SLE patients has not been established. This study was conducted to investigate the effect of H₂S on lymphocytes and to explore the mechanisms involved. Methods: The lymphocytes were isolated from SLE patients with or without renal disease and healthy controls. The cells were treated as indicated in each experiment. Cell viability was analyzed by CCK-8. Cell cycle distribution was determined by flow cytometry. Western blot was used to detect the expression of phosphorylated AKT (ser473), GSK3β (ser9) and CDK2, p27^Kip1 and p21^WAF1/CIP1. Results: Our findings showed that proliferation of lymphocytes was stimulated following treatment with NaHS (a H₂S donor) at low NaHS concentrations (<1mM) but inhibited at high NaHS concentrations (>2mM). Similar results were observed using GYY4137, which is a slow-releasing H₂S donor. Pretreatment of lymphocytes from SLE patients with NaHS at high concentrations prior to exposure to phytohemagglutinin (PHA) significantly attenuated proliferation, evidenced by decrease in cell viability and S phase distribution of cell cycle. Pretreatment with NaHS decreased PHA-induced expression of CDK2, phosphorylation levels of AKT (ser473) and GSK3β (ser9) and increased the expression of p27^Kip1 and p21^WAF1/CIP1. Moreover, pretreatment with NaHS blunted the stimulation of SLE lymphocyte proliferation by GSK3β inhibitor lithium chloride. Conclusion: These results demonstrate that H₂S inhibits the abnormal activation of lymphocytes from SLE patients throuqh the AKT/GSK3β signal pathway.

Relationship between FOXP3 positive populations and cytokine production in systemic lupus erythematosus

In this work we studied CD4+FOXP3+ populations in systemic lupus erythematosus (SLE) and the relationship with Th cytokine production. We found an increment in CD25−FOXP3+ population in SLE associated with CD4+ downregulation and disease progression. CD25low cells were also upregulated and showed increased percentages of FOXP3+ and CD127−/low cells, supporting the activated status of SLE lymphocytes. Despite the normal levels of CD25highFOXP3+ cells, the negative correlations observed in controls with the frequency of IFNγ, TNFα and IL-10 secreting cells were disrupted in patients, supporting a defective Treg function. Also, CD25high cells showed an altered balance in the production of these cytokines. In addition, CD25highFOXP3+ cells correlated directly with IL-17A and IL-8 but not with TGFβ in SLE. The increased proportion of IL-17+ cells among the CD25high subset and the positive correlation between IL-17 levels and Treg cells suggest a trans-differentiation of Treg into Th17 cells in SLE.

Different Effects of Bortezomib on the Expressions of Various Protein Kinase C Isoenzymes in T Cells of Patients with Systemic Lupus Erythematosus and in Jurkat Cells

The effects of proteosome inhibitor Bortezomib (BZ) were studied in vitro for 24 h on the protein kinase C (PKC) profiles, rates of proliferation and apoptosis in Jurkat cells and lymphocytes of 10 patients with systemic lupus erythematosus (SLE) and nine healthy subjects. The expressions of PKC proteins, the rates of proliferation and apoptosis were determined. The effects of BZ were different in the Jurkat and lupus T cells. Whereas BZ elevated the expression of PKC θ, δ and ξ isoenzymes in the Jurkat cells, it was unable to do that in the lupus T cells. BZ induced a dose-dependent increase in the apoptosis of Jurkat cells, while decreased the proliferation. The same effect of BZ was observed on the apoptosis of lymphocytes both in SLE and healthy subjects at concentrations higher than the therapeutic dose. We conclude that BZ treatment in vitro was not able to restore the SLE-specific defect (decrease) in the expression of PKC isoenzymes in the T cells as it was expected. This can be a limiting factor in the positive clinical effects of BZ in lupus.

Expressions of estrogen receptor-α and related cytokines and their clinical correlation in patients with systemic lupus erythematosus (SLE)

Objective To study the mechanism of effects of estrogen receptor (ER) on T and B lymphocytes in patients with SLE and synergistic effect of T and B lymphocytes in the pathogenesis of SLE.Methods Real-time fluorescence quantitative PCR was performed to detect the mRNA expressions of ER-α,interleukin 10 (IL-10) and B lymphocyte stimulator (BLyS) in peripheral blood mononuclear cells (PBMCs)from 40 SLE patients and 40 normal human controls. The clinical and laboratory correlation with the levels of these parameters was analyzed. Results A significant increase was observed in the relative expression levels of ER-α, IL-10 and BLyS mRNA in SLE patients compared with the normal human controls (P ＜ 0.05 or 0.01 ), in active SLE patients compared with inactive SLE patients (P ＜ 0.05 or 0.01 ). Additionally, the mRNA expression levels of the 3 parameters were significantly correlated with the presence of renal damage, proteinuria, arthritis, etc. No statistical difference was observed in the mRNA expression levels of these parameters between female and male patients or between female and male normal controls. Conclusions IL-10 and BLyS appear to be correlated with the disease activity and severity of SLE, and ER-α may play an important role in the action mechanism of T and B lymphocytes in SLE.