Dysregulated balance of Th17 and Th1 cells in systemic lupus erythematosus

Introduction  

Interleukin (IL)-17 is a proinflammatory cytokine that is produced largely by a unique CD4⁺ T-helper (Th) subset called Th17 cells. The development of Th17 cells is suppressed by interferon (IFN)-γ produced by Th1 cells, suggesting cross-regulation between Th17 and Th1 cells. Thus, this study analyzed the balance of CD4⁺ Th17 and Th1 cell responses in peripheral blood from patients with systemic lupus erythematosus (SLE) and healthy subjects.     

Imbalance between Th17 and regulatory T-cells in systemic lupus erythematosus

Impaired function of regulatory T-cells (Treg) leads to a failure in immune tolerance and triggers autoimmunity. We analyzed whether the deficiency in Treg in systemic lupus erythematosus (SLE) is accompanied by an increase in effector T-cell responses. We studied the frequencies of IL-17A (Th17) and IFNg (Th1) producing CD4(+) T-cells by flow cytometric detection of intracellular cytokines in PMA/ionomycin stimulated blood lymphocytes from seven patients with active SLE, eight with SLE in remission, and 11 healthy controls. Circulating Treg were evaluated as CD4(+)CD25(+) lymphocytes expressing FoxP3. There was no difference in the percentage of Treg cells between the groups, but their absolute counts were decreased in active SLE (5 [1-7] cells/μL) compared to inactive SLE (11 [6-15]; p = 0.05) and healthy controls (16 [10-20]; p 〈 0.01). Both the frequency and numbers of Th1 cells were decreased in SLE compared to controls. No difference was observed in the number of Th17 cells, which resulted in a decreased Th1/Th17 ratio. In parallel, a higher Treg/Th17 ratio in healthy controls (2.2 [1.8-3.6]) compared to active SLE (1.1 [1.0-2.1]; p 〈 0.05) was observed. There was a correlation between the number of Treg cells and disease activity status (SLEDAI, r = -0.59). SLE patients in the active phase of the disease are characterized by a deficiency in Treg cells and decreased Treg/Th17 ratio. This suggests that the imbalance between major T-cells subsets might be responsible for an increased proinflammatory response in the exacerbation of SLE.     

Increased caspase-3 expression and activity contribute to reduced CD3zeta expression in systemic lupus erythematosus T cells

T cells isolated from patients with systemic lupus erythematosus (SLE) express low levels of CD3zeta-chain, a critical molecule involved in TCR-mediated signaling, but the involved mechanisms are not fully understood. In this study we examined caspase-3 as a candidate for cleaving CD3zeta in SLE T cells. We demonstrate that SLE T cells display increased expression and activity of caspase-3. Treatment of SLE T cells with the caspase-3 inhibitor Z-Asp-Glu-Val-Asp-FMK reduced proteolysis of CD3zeta and enhanced its expression. In addition, Z-Asp-Glu-Val-Asp-FMK treatment increased the association of CD3zeta with lipid rafts and simultaneously reversed the abnormal lipid raft preclustering, heightened TCR-induced calcium responses, and reduced the expression of FcRgamma-chain exclusively in SLE T cells. We conclude that caspase-3 inhibitors can normalize SLE T cell function by limiting the excessive digestion of CD3zeta-chain and suggest that such molecules can be considered in the treatment of this disease.     

Increased serum interleukin 17 in patients with systemic lupus erythematosus

Interleukin 17 (IL-17) is a Th17 cytokine associated with inflammation, autoimmunity and defense against some bacteria, it has been implicated in many chronic autoimmune diseases including psoriasis, multiple sclerosis and systemic sclerosis. However, whether IL-17 plays a role in the pathogenesis of systemic lupus erythematosus (SLE) remains unclear. In the present study, we aimed to investigate the serum IL-17 level in patients with SLE and it’s associations with disease manifestations and activity. Fifty-seven patients with SLE and 30 healthy volunteers were recruited. Serum IL-17 levels were examined by enzyme linked immunosorbent assay (ELISA). Statistic analyzes were performed by SPSS 10.01. Results show that serum IL-17 levels were significantly elevated in SLE patients as compared with normal controls. Nevertheless, no associations of serum IL-17 level with clinical and laboratory parameters were found; no significant difference regarding serum IL-17 level between SLE patients with nephritis and those without nephritis was found; no significant difference was found between Less active SLE and More active SLE; Correlation analysis between serum IL-17 levels and SLEDAI showed no association. Taken together, our results indicate increased serum IL-17 levels in SLE patients, suggesting that this cytokine may trigger the inflammatory process in SLE. However, no associations of serum IL-17 level with disease manifestations were found. Therefore, further studies are required to confirm this preliminary data.     

Increased level of B cell differentiation factor in systemic lupus erythematosus patients

Most autoimmune disease are driven by a dysfunction in T and B cells, but B cells are still an interesting area of research, perturbations in their development are implicated in autoimmune diseases. B cell differentiating factor (BCDF) plays a part in the differentiation of B cells. The aim was To assess the levels of BCDF, IgM and IgG in SLE patients and whether they have any peculiarity in the clinical context of SLE. Thirty six patients with SLE and 24 healthy volunteers as control were enrolled in the study. BCDF was measured using Sandwich ELISA, total human IgM and IgG were measured by calorimetric methods. The mean concentrations of BCDF and IgM were significantly higher in patients with SLE as compared with controls (P?<?0.001 and P?<?0.0001 respectively). No significant difference was observed as regard IgG. We observed positive correlation between BCDF and IgM (r?=?0.281, P?=?0.03), and between IgG and IgM, duration of the disease (r?=?0.468, P?=?0.004, r?=?0.337, P?=?0.008 respectively). Moreover we observed lower IgM level in patients with discoid lesion (P?=?0.009) and lower IgG level in those with hematologic manifestations (P?=?0.02). ROC analysis revealed area under curve (AUC) 0.861 for BCDF and 0.902 for IgM, they can delineate SLE from controls at a cut-off value of 98.5?pg/ml, and 18?mg/dl IgM respectively.

Increased expression of costimulatory markers CD134 and CD80 on interleukin-17 producing T cells in patients with systemic lupus erythematosus

Introduction  

There is growing evidence that interleukin 17 (IL-17) producing T cells are involved in the pathogenesis of systemic lupus erythematosus (SLE). Previous studies showed that increased percentages of T-cell subsets expressing the costimulatory molecules CD80 and CD134 are associated with disease activity and renal involvement in SLE. The aim of this study was to investigate the distribution and phenotypical characteristics of IL-17 producing T-cells in SLE, in particular in patients with lupus nephritis, with emphasis on the expression of CD80 and CD134.     

SCE frequencies in lymphocytes of systemic lupus erythematosus patients

The frequency of sister-chromatid exchanges (SCEs) was investigated in peripheral lymphocytes of lupus erythematosus patients and compared with values obtained for healthy controls. Irrespective of the kind of medical treatment, an increased level of spontaneously occurring SCEs could be demonstrated in lupus patients. In addition to spontaneously occurring SCEs, mitomycin C (MMC)-induced SCEs were evaluated. No difference between patients and controls was found with respect to MMC-induced SCEs.     

Th1/Th2 cytokine profile in childhood-onset systemic lupus erythematosus

ObjectiveTo determine the serum levels of Th1 (IL-12, IFN-γ,TNF-α) and Th2 (IL-5, IL-6 and IL-10) cytokines in childhood-onset SLE, first-degree relatives and healthy controls. To elucidate their association with disease activity, laboratory and treatment features.MethodsWe included 60 consecutive childhood-onset SLE patients [median age 18 years (range 10–37)], 64 first-degree relatives [median 40 (range 28–52)] and 57 healthy [median age 19 years (range 6–30 years)] controls. Controls were age and sex-matched to SLE patients. SLE patients were assessed for clinical and laboratory SLE manifestations, disease activity (SLEDAI), damage (SDI) and current drug exposures. Mood and anxiety disorders were determined through Becks Depression (BDI) and Anxiety Inventory (BAI). Th1 (IL-12, IFN-γ,TNF-α) and Th2 (IL-5, IL-6 and IL-10) cytokines levels were measured by ELISA and compared by non-parametric tests.ResultsSerum TNF-α (p = 0.004), IL-6 (p = 0.007) and IL-10 (p = 0.03) levels were increased in childhood-onset SLE patients when compared to first-degree relatives and healthy controls. TNF-α levels were significantly increased in patients with active disease (p = 0.014) and correlated directly with SLEDAI scores (r = 0.39; p = 0.002). IL-12 (p = 0.042) and TNF-α (p = 0.009) levels were significantly increased in patients with nephritis and TNF-α in patients with depression (p = 0.001). No association between cytokine levels and SDI scores or medication was observed.ConclusionTh1 cytokines may play a role in the pathogenesis of neuropsychiatric and renal manifestations in childhood-onset SLE. The correlation with SLEDAI suggests that TNF-α may be a useful biomarker for disease activity in childhood-onset SLE, however longitudinal studies are necessary to determine if increase of this cytokine may predict flares in childhood-onset SLE.     

Toll-like receptors and innate immune responses in systemic lupus erythematosus

A series of discoveries over the past several years has provided a new paradigm for understanding autoimmunity in systemic lupus erythematosus. The discoveries of pattern recognition receptors and of how these receptors can be recruited into autoimmune responses underpin this paradigm. The implications of these observations continue to unfold with ongoing investigation into the range and specificity of pattern recognition receptors, into how immune complexes containing nucleic acids trigger these receptors, into how endogenous macromolecular 'danger signals' stimulate innate immune responses, and into the effect of pattern recognition receptor activation on various cell types in initiating and perpetuating autoimmunity. The development of clinical trials using therapeutic agents that target components of the innate immune system suggests that these advances may soon culminate in new medications for treating patients with systemic lupus erythematosus.     

Roles of CD147 on T lymphocytes activation and MMP-9 secretion in systemic lupus erythematosus

The cellular and molecular mechanisms involved in many abnormalities described in Systemic Lupus Erythematosus (SLE) are still unclear. Some of these abnormalities referred to the hyperactivation of T lymphocytes and the enhanced secretion of MMP-9 by peripheral blood mononuclear cells (PBMCs). Therefore, in this paper we investigated the potential role of CD147 molecule in these abnormalities. Our results demonstrated that CD147 molecule is overexpressed on CD3+T lymphocytes from SLE patients when compared with CD3+T lymphocytes from healthy donors. Monoclonal anti-CD147 antibodies, MEM-M6/1 clone, were able to inhibit protein tyrosine phosphorylation only in CD3 x CD28 costimulated T lymphocytes from SLE patients. However, this monoclonal antibody was unable to inhibit the enhanced activity of MMP-9 secreted by SLE PBMCs.     

Clinical associations of serum interleukin-17 in systemic lupus erythematosus

Introduction

Serum interleukin (IL)-17 concentrations have been reported to be increased in systemic lupus erythematosus (SLE), but associations with clinical characteristics are not well understood. We characterized clinical associations of serum IL-17 in SLE.

Methods

We quantified IL-17 in serum samples from 98 SLE patients studied cross-sectionally, and in 246 samples from 75 of these patients followed longitudinally over two years. Disease activity was recorded using the SLE Disease Activity Index (SLEDAI)-2k. Serum IL-6, migration inhibitory factor (MIF), and B cell activating factor of the tumour necrosis factor family (BAFF) were also measured in these samples.

Results

Serum IL-17 levels were significantly higher in SLE patients compared to healthy donors (P <0.0001). No correlation was observed between serum IL-17 and SLEDAI-2k, at baseline or during longitudinal follow-up. However, we observed that SLEDAI-2k was positively correlated with IL-17/IL-6 ratio. Serum IL-17 was significantly increased in SLE patients with central nervous system (CNS) disease (P = 0.0298). A strong correlation was observed between serum IL-17 and IL-6 (r = 0.62, P <0.0001), and this relationship was observed regardless of disease activity and persisted when integrating cytokine levels over the period observed (r = 0.66, P <0.0001). A strong correlation of serum IL-17 was also observed with serum BAFF (r = 0.64, P <0.0001), and MIF (r = 0.36, P = 0.0016).

Conclusions

Serum IL-17 concentration correlates poorly with SLE disease activity but is significantly elevated in patients with CNS disease. IL-17/IL-6 ratio may be more useful than IL-17 or IL-6 alone to characterize Th17-driven disease, such as SLE. The association of other cytokines with serum IL-17 suggests that IL-17 may drive activation of diverse immune pathways in SLE.     

Cytokine regulation of apoptosis and Bcl-2 expression in lymphocytes of patients with systemic lupus erythematosus

Both faulty regulation of apoptosis and the inappropriate expression of several interleukins have been considered important defects of lymphocytes in the human autoimmune disease systemic lupus erythematosus (SLE). We therefore tested the in vitro effect of recombinant interleukin (IL-)-2, 4, 7, and 15 on peripheral blood mononuclear cells from patients with SLE and from healthy volunteers. Intracellular Bcl-2 and Bax expression was measured by fluorocytometry and the rate of apoptosis was determined by the TUNEL technique and propidium iodide staining. IL-2, IL-4, IL-7 and IL-15 led to a significant increase in Bcl-2 and a reduction in cell death rates, which was even more pronounced in SLE. Bax levels remained unchanged. Interestingly, the high ex vivo Bcl-2 content of lymphocytes from some SLE patients was maintained after growth factor withdrawal. Anti-apoptotic cytokine signaling may significantly influence the deregulation of cell death in SLE lymphocytes.     

Increased frequency of circulating Th22 in addition to Th17 and Th2 lymphocytes in systemic sclerosis: association with interstitial lung disease

Introduction  

T cell abnormalities have been associated with the pathogenesis of systemic sclerosis (SSc). Recently, besides T helper (Th)17 cells, the Th22 subset has been identified in humans. Our purpose was to investigate the pattern of cytokines produced and chemokine-receptors expressed by peripheral blood (PB) Th cells in SSc and healthy donors (HD) focusing on cells producing interleukin (IL)-17 and IL-22 and to identify specific clinical associations.     

Fcgamma receptors in the initiation and progression of systemic lupus erythematosus

Systemic lupus erythematosus, a systemic autoimmune disorder, is characterized by the production of autoantibodies to nuclear constituents and inflammatory lesions in multiple organ systems. Although the pathogenesis of the disease is largely unknown, recent studies have suggested that disturbances in apoptosis and/or clearance of apoptotic cells may play an important role in the induction and perpetuation of autoantibody production. When autoantibodies subsequently complex to autoantigens present on apoptotic cells, ligation of Fcgamma receptor will result in inflammation and disease development. Indeed, mice deficient in activating Fcgamma receptors were protected against inflammation in models of immune complex-mediated autoimmune disease, whereas deletion of the inhibitory Fcgamma receptors increased autoantibody production and susceptibility to immune complex-induced inflammation. Additionally, functional polymorphisms in Fcgamma receptors were shown to be associated with development of human systemic lupus erythematosus. This review focuses on the role of Fcgamma receptors in the initiation of autoantibody production, inflammatory handling of immune complexes, and disease development in systemic lupus erythematosus.     

Fas expression on peripheral blood lymphocytes in systemic lupus erythematosus: relation to the organ damage and lymphocytes apoptosis

Systemic lupus erythematosus (SLE) is a common autoimmune disease with complex etiology. Recently, a possible role of apoptotic cells in its pathogenesis has been suggested. This study is to evaluate the expression of Fas antigen on peripheral blood lymphocytes (PBLs) in SLE, to determine whether membrane Fas (mFas) has a role in the organ damage in SLE and to explore its relationship with the early apoptosis of the PBLs in SLE. Flow cytometry was used to evaluate the expression of mFas on PBLs in 68 Chinese SLE patients and 37 healthy controls. Systemic lupus international collaborative clinics/american colleges of rheumatology damage index (SDI) scores were calculated to further estimate the relationship of the expression of mFas with disease severity. Results showed that mFas expression levels were significantly higher (P < 0.01) among SLE patients than those in healthy controls. Higher (P = 0.01) expressions of mFas were found in patients with SDI scores ≥ as compared to those with SDI scores <3. Patients with neuropsychiatric or renal disease had a higher expression of mFas than those without neuropsychiatric (P = 0.03) or renal disease (P = 0.01). In addition, the expression levels had a positive (r = 0.381, P < 0.01) correlation with the early apoptosis rate of PBLs in SLE patients. Taken together, our study showed that Fas-expressing PBLs were increased in SLE patients, especially in patients with higher SDI score, and the expression levels of mFas were correlated to the organ damage and lymphocytes apoptosis.     

Complement C4 induces regulatory T cells differentiation through dendritic cell in systemic lupus erythematosus

Background

Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease. Complement component 4 (C4) has be proved to play a role in pathogenesis of SLE. In the present study, we investigated the effect of C4 on T cells differentiation.

Methods

Thirty SLE patients were included in this study. CD4+ T cells were isolated from healthy subjects, and dendritic cells (DCs) were isolated from healthy subjects or SLE patients. C4 was supplemented to co-incubate with T cells and DCs.

Results

Serum C4 concentration was positively correlated with regulatory T cell (Treg) percentage (R² = 0.5907, p < 0.001) and TGFβ concentration (R² = 0.5641, p < 0.001) in SLE patients. Different concentrations of C4 had no effect on T cells differentiation. Co-incubated T cells with DCs and C4 for 7 days, the Treg percentage and TGF-β concentration were significantly elevated. In addition, pre-treated DCs (from healthy subjects or SLE patients) with C4 and then co-incubated with T cells, the increases of Treg percentage and TGF-β concentration were also observed.

Conclusion

C4 takes part in T cells differentiation to Treg cells via DCs.

     

Inflammatory expression profiles in monocyte-to-macrophage differentiation in patients with systemic lupus erythematosus and relationship with atherosclerosis

Introduction

Our objectives were to examine mononuclear cell gene expression profiles in patients with systemic lupus erythematosus (SLE) and healthy controls and to compare subsets with and without atherosclerosis to determine which genes’ expression is related to atherosclerosis in SLE.

Methods

Monocytes were obtained from 20 patients with SLE and 16 healthy controls and were in vitro-differentiated into macrophages. Subjects also underwent laboratory and imaging studies to evaluate for subclinical atherosclerosis. Whole-genome RNA expression microarray was performed, and gene expression was examined.

Results

Gene expression profiling was used to identify gene signatures that differentiated patients from controls and individuals with and without atherosclerosis. In monocytes, 9 out of 20 patients with SLE had an interferon-inducible signature compared with 2 out of 16 controls. By looking at gene expression during monocyte-to-macrophage differentiation, we identified pathways which were differentially regulated between SLE and controls and identified signatures based on relevant intracellular signaling molecules which could differentiate SLE patients with atherosclerosis from controls. Among patients with SLE, we used a previously defined 344-gene atherosclerosis signature in monocyte-to-macrophage differentiation to identify patient subgroups with and without atherosclerosis. Interestingly, this signature further classified patients on the basis of the presence of SLE disease activity and cardiovascular risk factors.

Conclusions

Many genes were differentially regulated during monocyte-to-macrophage differentiation in SLE patients compared with controls. The expression of these genes in mononuclear cells is important in the pathogenesis of SLE, and molecular profiling using gene expression can help stratify SLE patients who may be at risk for development of atherosclerosis.