Association between interleukin-18 polymorphisms and systemic lupus erythematosus: a meta-analysis

The aim of this study was to determine whether the three functional interleukin-18 (IL-18) promoter ?607 C/A (rs1946518), ?137 G/C (rs187238), and ?1297 C/T (rs360719) polymorphisms confer susceptibility to systemic lupus erythematosus (SLE) in ethnically different populations. Meta-analysis was conducted on the associations between these IL-18 polymorphisms and SLE using; (1) allele contrast, (2) the recessive model, (3) the dominant model, and (4) the additive model. A total of 11 comparisons (nine studies) involving 8,453 subjects (2,928 SLE patients and 5,525 controls) were included in the meta-analysis. In all study subjects, meta-analysis showed no association between SLE and the IL-18 ?607 C allele (odds ratio [OR] = 1.065, 95 % confidence interval [CI] = 0.870–1.303, p = 0.541). However, stratification by ethnicity indicated a significant association between this allele and SLE in Europeans (OR = 0.864, 95 % CI = 0.757–0.986, p = 0.031), but not in Asians (OR = 1.230, 95 % CI = 0.902–1.676, p = 0.190). Meta-analyses showed the same pattern for the IL-18 ?607 C allele using the dominant and additive models. Meta-analysis of the IL-18 ?137 G/C polymorphism showed no association between SLE and the IL-18 ?137 G allele in all study subjects (OR = 0.916, 95 % CI = 0.836–1.003, p = 0.057), but stratification by ethnicity indicated a significant association between this allele and SLE in Asians (OR = 0.792, 95 % CI = 0.629–0.997, p = 0.047), but not in Europeans (OR = 0.930, 95 % CI = 0.839–1.032, p = 0.171). Furthermore, meta-analysis showed that the IL-18 ?1297 C allele was significantly associated with SLE in all study subjects and in Europeans (OR = 1.240, 95 % CI = 1.052–1.482, p = 0.010 and OR = 1.303, 95 % CI = 1.050–1.617, p = 0.016). This meta-analysis shows that the IL-18 ?607 C/A and ?1297 C/T polymorphism are associated with the development of SLE in Europeans, and the IL-18 ?137 G/C polymorphism is associated with SLE in Asians.     

Decrease in HLA-DR-positive monocytes in patients with systemic lupus erythematosus (SLE)

Monocyte populations expressing HLA-DR antigens were studied in SLE patients by flow cytofluorometry with indirect immunofluorescence. Both the number of HLA-DR-positive monocytes and the expression of HLA-DR antigens on monocytes were markedly decreased in active SLE patients and were recovered to the normal level in inactive SLE patients. Because Ia-positive monocytes play a regulatory role for several immune responses, the decrease in HLA-DR-positive monocytes will result in abnormal regulations of immune responses and will play some critical role in the pathogenesis and the process of SLE.     

Interleukin-6, interleukin-1 gene cluster and interleukin-1 receptor polymorphisms in Iranian patients with juvenile systemic lupus erythematosus

Background

Juvenile systemic lupus erythematosus (JSLE) is a polygenic, autoimmune disorder of unknown origin. As proinflammatory cytokines, including interleukin-6 (IL-6) and the interleukin-1 (IL-1) family, seem to contribute to the pathogenesis of JSLE, this investigation was performed to assess the associations of particular single nucleotide polymorphisms (SNPs) of IL-6 and IL-1 genes in a case-control study.

Methods

Fifty nine JSLE cases were recruited for this study as the patient group, and were compared against 140 healthy, unrelated, control subjects. Using the polymerase chain reaction with the sequence-specific primer method, genotyping was carried out for the IL-6 gene at positions ?174 and nt565, as well as the IL-1α gene at position ?889, the IL-1β gene at positions ?511 and +3962, the interleukin-1 receptor (IL-1R) gene at position Pst-I 1970, and the interleukin-1 receptor antagonist (IL-1Ra) gene at position Mspa-I 11100.

Results

Results of the analyzed data revealed a remarkable, positive association for the promoter sequence of the IL-1β gene at position ?511 for T/T in the patient group compared with healthy controls (P value, 0.03). Furthermore, a significant negative association was found between the T/C genotype at the same position on the IL-1β gene in juvenile SLE (P value, 0.03).

Conclusions

cytokine gene polymorphisms might play a role in the pathophysiology of JSLE. Particular IL-1 gene variants could affect individual susceptibility to JSLE.

     

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.     

Neuropsychological patterns in systemic lupus erythematosus patients with depression

Thirteen patients with systemic lupus erythematosus and depression (Depressed-SLE), 10 Depressed-Control subjects, and 25 Healthy Control subjects completed cognitive testing and self-report questionnaires of pain, depression, and fatigue. The Depressed-SLE group scored higher on the American College of Rheumatology Neuropsychological Battery for systemic lupus erythematosus cognitive impairment index compared to Depressed-Control and Healthy Control subjects (p < 0.05 and p < 0.02, respectively). No correlations between cognitive impairment and pain, fatigue, or perceived cognitive failures were observed in the Depressed-SLE participants. Moderate agreement (86.4%) was found between a comprehensive neuropsychology battery cognitive impairment index and the ACR-SLE impairment index in the Depressed-SLE patients. Overall, the magnitude and pattern of cognitive impairment in Depressed-SLE patients cannot be explained by depression alone.     

Serum antibodies to human fetal antigens in patients with systemic lupus erythematosus (SLE)

Serum antibodies to human fetal antigens were measured by a radiolabeled anti-immunoglobulin binding assay by using human fetal fibroblasts (Flow cell line No. 1000) as target cells. High titers of IgG antibody to the fetal cells were found in sera of patients with systemic lupus erythematosus (SLE). The antibody reacted with surface membrane antigens shared by various fetal tissues of human and murine origin but not by adult tissues. The reaction of the SLE antibody to the fetal cells was inhibited by heterologous antiserum to the Flow 1000 cells and antiserum to murine embryonic fibroblasts, but not by antiserum to human alpha-fetoprotein or human fibronectin. Absorption of SLE serum with isolated nuclei did not abolish the reaction indicating that these were not anti-nuclear antibodies. The antibody activity was found to reside in the F(ab')2 fragment. The serum titer of the anti-fetal antibody was higher in SLE patients with active disease than those in clinical remission.     

Essential fatty acids in diabetes and systemic lupus erythematosus (SLE) patients

Sera obtained from normal subjects and juvenile-onset diabetes (JD) and systemic lupus erythromatus (SLE) patients were examined for free fatty acid composition and 6-keto-PGF1 alpha content. In addition, prostaglandins in urine samples from normal and diabetic individuals were separated by HPLC, and 6-keto-PGF1 alpha levels were monitored by RIA. Arachidonate (20:4) content in diabetic and SLE individuals were significantly lower than that of controls. Urine from diabetic individuals showed decreased levels of 6-keto-PG F1 alpha. The study also indicated that RIA measurements on crude biological samples may yield erroneous data due to immune cross reactivity with other compounds.     

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.     

The role of interleukin-10 in autoimmune disease: systemic lupus erythematosus (SLE) and multiple sclerosis (MS)

Interleukin-10 (IL-10) is an immunoregulatory cytokine that plays a crucial role in inflammatory and immune reactions. It has potent anti-inflammatory and immunosuppressive activities on myeloid cell functions which forms a solid basis for its use in acute and chronic inflammatory diseases. Here, we discuss the role of IL-10 in autoimmune diseases and examine its beneficial effects in cellular-based autoimmune diseases such as multiple sclerosis (MS) or its involvement in humoral-based autoimmune diseases such as systemic lupus erythematosus (SLE). Inhibition of the immune stimulatory activities of IL-10 may provide novel approaches in the treatment of humoral autoimmune diseases, infectious diseases and cancer.     

Predictors of clinical outcomes in patients with neuropsychiatric systemic lupus erythematosus

IntroductionNeuropsychiatric systemic lupus erythematosus (NPSLE), a serious organ disorder with a variety of symptoms, has diverse therapeutic outcomes because of the variability of NPSLE manifestations. A comprehensive association study of NPSLE among clinical and immunopathogenic aspects and outcomes has not been conducted.MethodsWe analyzed the laboratory data, NPSLE symptoms, and clinical outcomes at 1 yr post-treatment and the profiles of 27 cytokines, chemokines and growth factors in cerebrospinal fluid (CSF) samples using the Bio-Plex Human 27-plex panel from 28 NPSLE patients. Univariate and multivariable competing risks regression analyses were used to determine the predictive factors of clinical response. We also tried to predict the outcome of NPSLE by the 27 cytokines/chemokines/growth factors using a weighted-voting (WV) algorithm.ResultsOf the two males and 26 females (92.9%), 16 were non-responders at 1 yr post-treatment; in the final model, the independent predictors of non-responders were longer disease durations of SLE (odds ratio [OR]: 1.490, 95% confidence interval [CI]: 1.143–2.461, p = 0.0003) and patients with more than one NPSLE symptom types (OR: 15.14, 95% CI: 1.227–452.1, p = 0.0334). The pretreatment CSF interleukin (IL)-6, IL-10, interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) levels were significantly higher in the non-responders (p = 0.0207, p = 0.0054, p = 0.0242 and p = 0.0077, respectively). We identified six “minimum predictive markers:” IL-10, TNF-α, IL-6, IFN-γ, IL-4 and IL-13 by a WV algorithm that showed the highest accuracy (70.83%) and highest Matthews correlation coefficient (54.23%).ConclusionsWe have devised a numerical prediction scoring system that was able to separate the non-responders from responders. The patients with longer disease durations of SLE and those with more than one NPSLE symptom types had poorer outcomes. Our findings may indicate both the importance of making a diagnosis at an earlier phase for better therapeutic response and the usefulness of measuring multiple cytokines to predict NPSLE therapeutic outcomes.     

Defective production of interleukin 1 and interleukin 2 in patients with systemic lupus erythematosus (SLE)

The effects of local antigenic exposure on the responsiveness of systemic T cells were evaluated after C3H mice were given drinking water containing 6% bovine serum albumin (BSA) for 10 days and challenged sc with 1.0 mg BSA in adjuvant 28 days after the initiation of antigen feeding. During the first 28 days, no evidence of in vitro antigen-induced proliferation [( 3H]thymidine incorporation) was detected in whole lymphocyte populations from the peripheral lymph nodes (PLN), spleen, or mesenteric nodes. In contrast, PLN cells treated with anti-Lyt-1 plus complement (C) had a significant proliferative response only if the cells were obtained during the first 6 days of antigen ingestion. Lymphoid cells from the same animals, treated with anti-Lyt-2 and C, did not respond to antigen. Two or 4 days after the injection, given on day 28, whole PLN cell populations from antigen-fed mice showed proliferation. No response was observed with PLN cells obtained 8 days after injection. Shortening the interval between the initiation of feeding and parenteral challenge partially restored proliferative responses detected 8 days after injection. Cultures prepared 4 days after simultaneous oral and parenteral antigenic exposure showed proliferation equal to or greater than cultures from mice that received only the injection. These data show that systemic T cell responsiveness is not eliminated by ingestion of soluble antigen, but rather is modulated in a manner previously detected in the humoral immune system.     

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.     

Circulating TCR gammadelta cells in the patients with systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a disorder with a wide range of immunological abnormalities. The results of the studies undertaken in the last decade indicated that SLE pathogenesis was mainly connected with the breakdown of the activation control of B and T cells, generating humoral or cell-mediated responses against several self-antigens of affected cells. The last studies demonstrate that the role of gammadelta T lymphocytes in autoimmune diseases can be especially important. Flow cytometry techniques were used to investigate the number and percentage of TCR gammadelta T cells and their most frequent subtypes in peripheral blood of 32 patients with SLE and 16 healthy volunteers. We also correlated TCR gammadelta cells number with the level of T CD3+, T CD4+, T CD8+, and NK (CD16) cells (cytometric measurements) and SLE activity (on the basis of clinical investigations). Our studies were preliminary attempts to evaluate the role of that minor T cell subpopulation in SLE. Absolute numbers of cells expressing gammadelta TCR in most SLE blood specimens were significantly lower than in the control group (P<0.006). However, since the level of total T cell population was also decreased in the case of SLE, the mean values of the percentage gammadelta T cells of pan T lymphocytes were almost the same in both analysed populations (7.1% vs 6.3%, respectively). In contrast to Vdelta2+ and Vgamma9+ subtypes of pan gammadelta T cells, Vdelta3+ T cells number was higher in SLE patients (20 x 10 cells/microl) than in healthy control group (2 x 2 cells/microl) (P=0.001). However, we found no differences between the numbers of pan gammadelta T lymphocytes and studied their subtypes in the patients with active and inactive disease. These cell subpopulations were doubled in the treated patients with immunosuppressive agents in comparison with untreated ones; however, data were not statistically significant. Our study indicated that Vdelta3+ subtype of gammadelta T cells seems to be involved in SLE pathogenesis; however, we accept the idea that the autoimmunity does not develop from a single abnormality, but rather from a number of different events.     

Autoimmunity induced by human cytomegalovirus in patients with systemic lupus erythematosus

Human cytomegalovirus is a common herpesvirus that is linked to autoimmunity, especially in genetically predisposed persons. The article by Hsieh and colleagues in a previous issue of Arthritis Research & Therapy suggests that a C-terminal peptide of the human cytomegalovirus protein pp65 is highly immunogenic in patients with systemic lupus erythematosus and that antibodies against this peptide cross-react with nuclear proteins and double-stranded DNA, which are highly frequent autoantibodies in systemic lupus erythematosus patients. These observations highlight the fact that immunization with one small cytomegalovirus-specific peptide results in multiple autoreactive antibodies, probably through molecular mimicry and epitope spreading, in genetically predisposed persons.     

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.