Genetically predicted circulating interleukin-18 levels are associated with risk of systemic lupus erythematosus and type 1 diabetes.

OBJECTIVE: Interleukin-18 (IL-18) is a proinflammatory cytokine. This study aims to determine whether there is a causal relationship between circulating IL-18 concentrations and the risk of inflammatory and autoimmune diseases. METHODS: We collected significant single nucleotide polymorphisms (SNPs) associated with circulating IL-18 levels (p < 5 × 10-8) as instrumental variables (IVs) from a genome-wide association study (GWAS) involving 21,758 individuals of European descent. We mainly employed the inverse-variance weighed (IVW) method of two-sample Mendelian randomization (TSMR) analysis to estimate the causality of circulating IL-18 levels on inflammatory and autoimmune diseases. RESULTS: The IVW method results showed evidence of a causal relationship between IL-18 and the risk of systemic lupus erythematosus (SLE) (OR = 1.32; 95% CI 1.15, 1.50; p < .001) and type 1 diabetes (T1D) (OR = 1.22; 95% CI 1.06, 1.42; p = .007) in individuals of European ancestry. No significant heterogeneity or horizontal pleiotropy for SLE and T1D was detected. The sensitivity analysis, which involved removing confounding SNP, produced similar results for SLE and T1D. The results of sensitivity analysis using leave-one-out method indicated no single SNP significantly influenced the analysis results. However, we did not find any significant findings for multiple sclerosis, psoriasis, asthma, and osteoarthritis. CONCLUSIONS: Our analyses suggest that circulating IL-18 is significantly related to SLE and T1D and may serve as a potential target for the treatment of these diseases.

Association of TNF-α promoter-308 A/G polymorphism with susceptibility to systemic lupus erythematosus: a meta-analysis.

Published data on the association between tumor necrosis factor-alpha (TNF-α) promoter-308 A/G polymorphism and systemic lupus erythematosus (SLE) risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. A total of 28 studies including 2,992 cases and 4,326 controls (5,924 cases and 8,484 controls in A versus G comparison) were involved in this meta-analysis. Meta-analysis was performed for genotypes A/A (recessive effect), A/A+A/G (dominant effect), and A allele in fixed or random effects models. In addition, we also performed a "model-free" analysis by considering the G/G genotype as the reference and estimated the OR for the A/A versus G/G and A/G versus G/G genotype. Overall, an association of TNF-α promoter-308 A/G polymorphism with SLE was found (A versus G: OR = 1.686, 95% CI = 1.400-2.032, P < 0.001; A/A versus A/G+G/G: OR = 3.043, 95% CI = 2.185-4.238, P < 0.001; A/A+A/G versus G/G: OR = 1.822, 95% CI = 1.379-2.407, P < 0.001; A/A versus G/G: OR = 3.686, 95% CI = 2.628-5.172, P < 0.001; A/G versus G/G: OR = 1.691, 95% CI = 1.291-2.215, P < 0.001). However, stratification by ethnicity indicated that the risk A allele was not associated with SLE in Asian (A versus G: OR = 1.207, 95% CI = 0.856-1.702, P = 0.283) and African population (A versus G: OR = 1.225, 95% CI = 0.597-2.516, P = 0.580). In summary, this meta-analysis indicated that TNF-α promoter-308-A/G polymorphism is associated with susceptibility to SLE.

Expression of human tumor necrosis factor-like weak inducer of apoptosis in patients with systemic lupus erythematosus.

The aim of this study was to compare the mRNA and serum expression of tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) in patients with systemic lupus erythematosus (SLE) and healthy controls. Sixty-two SLE patients and 15 healthy controls were recruited in the study. TWEAK messenger RNA (mRNA) expression in peripheral blood mononuclear cells (PBMCs) from 33 of 62 patients was detected by relative quantification RT-PCR. TWEAK concentrations in the sera of all 62 patients were measured by ELISA. TWEAK mRNA expressions in PBMCs were decreased in SLE patients compared with healthy controls. Lower TWEAK mRNA expression was also found in the active SLE patients when compared to inactive ones. However, there was no significant difference between patients with lupus nephritis (LN) and those without. The level of serum TWEAK (sTWEAK) in SLE patients was increased when compared to healthy controls. In addition, the sTWEAK level was higher in SLE patients with vasculitis than those without vasculitis, and so was in comparison between patients with and without headache. Nevertheless, no significant differences were found between active SLE patients and inactive patients, or between LN patients and non-LN SLE patients. In this study, patients with SLE express low levels of TWEAK mRNA but high levels of sTWEAK. Additionally, sTWEAK level was associated with several clinical manifestations of SLE, indicating that TWEAK may play a complex role in SLE.

Role of microRNA-155 in autoimmunity.

MicroRNAs (miRNAs) have recently emerged as a major class of gene expression regulators linked to most biological functions. MiR-155 is encoded within a region known as B cell integration cluster (Bic) gene, identified originally as a frequent integration site for the avian leukosis virus. Disregulation of endogenous miR-155 has been implicated in the pathogenesis of human cancers. Recently, aberrant expression of miR-155 was observed in many autoimmune conditions, including rheumatoid arthritis (RA), multiple sclerosis (MS), and systemic lupus erythematosus (SLE). Moreover, functional analysis demonstrated that miR-155 has powerful regulatory potential in a wide variety of immune cells through targeting specific mRNAs. Since pathogenic immune cells play a pivotal role in pathogenesis of human autoimmune diseases, miR-155 might be a versatile therapeutic target. This review will discuss the current understandings for the role of miR-155 in autoimmunity.

Expressions of IL-22 in circulating CD4+/CD8+ T cells and their correlation with disease activity in SLE patients.

Recently, Th17 cell-associated responses have received growing attention; however, the role of IL-22 (a cytokines also produced by Th17 cells) in the pathogenesis of systemic lupus erythematosus (SLE) has not been widely explored. In this study, we analyze the frequencies of IL-22-positive CD4+/CD8+ T cells in peripheral blood mononuclear cells (PBMCs) from patients with SLE and their correlations with disease activity and clinical data. Five-color flow cytometry (FCM) was used to assess IL-22 production of CD4+/CD8+ T cells in PBMCs from 31 patients with SLE and 22 healthy control subjects, following stimulation ex vivo with phorbol 12-myristate 13-acetate and ionomycin for 4 h. Results showed that the percentages of IL-22-positive CD4+ T cells were increased in the PBMCs of patients with SLE compared with healthy control subjects, whereas there were no significant differences in the percentages of IL-22-positive CD8+ T cells. There was a strong positive correlation between the proportion of CD4+ T cells expressing IL-22 and SLEDAI score (r (s) = 0.65, P < 0.001). Furthermore, the frequencies of IL-22-positive CD4+ T cells were significantly higher in patients with SLE with nephritis than those without nephritis (Z = -2.72, P < 0.01). In conclusion, increased frequencies of IL-22-positive CD4+ T cells in patients with SLE and positive correlation with SLEDAI score and lupus nephritis suggest that this cytokine may be implicated in the pathogenesis of the disease.

TWEAK as a target for therapy in systemic lupus erythematosus.

Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a recently identified proinflammatory cytokine of the TNF superfamily. Through activation of the fibroblast growth factor-inducible 14 (Fn14) receptor, TWEAK regulates cell proliferation, cell death and inflammation. The available evidences have indicated that TWEAK might be a target for therapeutic intervention in renal, vascular injury and neuropathy. Since renal, vascular and neuropsychiatric complications are frequently encountered in systemic lupus erythematosus (SLE)--a systemic autoimmune disease, TWEAK-Fn14 pathway may be implicated in the pathogenesis of SLE. In this review, we will discuss the TWEAK-Fn14 pathway and the therapeutic potential of modulating this pathway in SLE.

IL-23: a promising therapeutic target for systemic lupus erythematosus.

Cytokine-mediated immunity plays a crucial role in the pathogenesis of various autoimmune diseases including systemic lupus erythematosus (SLE). The recent identification of the dimeric interleukin (IL)-12-related cytokine IL-23 now contributes to our understanding of the fine-tuning of cellular immunity. The critical implication of IL-12 p40 in autoimmune inflammation has long been misinterpreted and until recently have studies revealed that it is IL-23, not IL-12, is the crucial factor in this immune dysregulation. Therefore, targeting of IL-23 or the IL-23 receptor is a potential therapeutic approach for autoimmune diseases including SLE. In this opinion article, we will discuss the biological features of IL-23 and summarize recent advances on the role of IL-23 in the pathogenesis and treatment of SLE.