Gui-Mei Chen

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.

Low Level of Serum Interleukin 27 in Patients With Systemic Lupus Erythematosus

T helper 17 (TH17) cells are beginning to be implicated in the pathogenesis of systemic lupus erythematosus (SLE). Recent studies have shown that interleukin 27 (IL-27) controls the development of TH17. However, whether IL-27 plays a role in the development of SLE is still unclear. In the present work, we investigated the serum IL-27 level in SLE and its relations to disease activity. Fifty-six patients with SLE and 30 healthy volunteers were recruited. Serum IL-27 levels were detected by enzyme-linked immunosorbent assay. The clinical and laboratory parameters were collected from medical records or by questionnaire. The serum IL-27 level in SLE patients was significantly lower than that in healthy controls (P < 0.001). Compared with SLE patients without nephritis, patients with nephritis had a significantly decreased serum IL-27 level (P < 0.05). However, there was no significant difference between less active and more active SLE (P > 0.05). Correlation analysis between serum IL-27 levels and SLE disease activity index showed no association (P > 0.05). In summary, a decrease in serum IL-27 level in patients with SLE suggested that this cytokine might be implicated in the pathomechanism of this disease.

Gene-gene and gene-sex epistatic interactions of MiR146a, IRF5, IKZF1, ETS1 and IL21 in systemic lupus erythematosus.

Several confirmed genetic susceptibility loci involved in the interferon signaling and Th17/B cell response for SLE in Chinese Han populations have been described. Available data also indicate that sex-specific genetic differences contribute to SLE susceptibility. The aim of this study was to test for gene–gene/gene-sex epistasis (interactions) in these known lupus susceptibility loci. Six single-nucleotide polymorphisms (SNPs) in MiR146a, IRF5, IKZF1, ETS1 and IL21 were genotyped by Sequenom MassArray system. A total of 1,825 subjects (858 SLE patients and 967 controls) were included in the final analysis. Epistasis was tested by additive model, multiplicative model and multifactor dimensionality reduction (MDR) method. Additive interaction analysis revealed interactions between IRF5 and IKZF1 (OR 2.26, 95% CI 1.48–3.44 [P = 1.21×104]). A similar tendency was also observed between IL21 and ETS1 by parametric methods. In addition, multiple high dimensional gene-gene or gene-sex interactions (three-and four-way) were identified by MDR analysis. Our study identified novel gene–gene/gene-sex interactions in lupus. Furthermore, these findings highlight sex, interferon pathway, and Th17/B cells as important contributors to the pathogenesis of SLE.

The dual nature of Ets-1: focus to the pathogenesis of systemic lupus erythematosus.

E26 transformation-specific-1 (Ets-1) belongs to the Ets family of transcription factors which share a common 85-amino-acid DNA-binding domain. Ets-1 is essential to regulation of the immune system including immune cell proliferation and differentiation. Past data demonstrated Ets-1 play a role in negative regulation of Th17 cells and B cells differentiation. Recently, association of genetic variation in Ets-1 with susceptibility to systemic lupus erythematosus (SLE) have been independently identified by two Genome-wide association studies (GWAS), and decreased Ets-1mRNA level in peripheral blood mononuclear cells (PBMCs) of SLE patients has been reported. All these findings suggest that the transcription factor is broadly linked to the pathogenesis of this disease. However, aberrant control of other immune cells and effector molecules illuminated the complexities of Ets-1 biology. In this review article, we will focus on the dual nature of Ets-1 and discuss its regulatory capability. Hopefully the information obtained will lead to a better understanding of the pathogenesis and development of novel therapeutic strategies for SLE.

Expression profiles of Th17 pathway related genes in human systemic lupus erythematosus.

Recently, evidence is emerging that inappropriate regulation of type 17 T helper cells (Th17) plays a fundamental role in the development of many autoimmune diseases including systemic lupus erythematosus (SLE). However, the role of Th17-related cytokines in SLE remains elusive. To further investigate the role and imbalance of Th17-related cytokines in the pathogenesis of SLE. A Quantitative RT-PCR Array (Human Th17 for Autoimmunity & Inflammation PCR Array) analyses were performed to study Th17-related genes expression in peripheral white blood cells of 25 new-onset patients with SLE and 15 healthy subjects. When gene expression for SLE patients was compared to the mean of normal controls, among the 84 target genes related to Th17 pathway, 7 (CXCL1, ICAM1, IL10, IL5, IL8, ISG20, JAK2,) were upregulated and 6 (CD28, CD40LG, S1PR1, IL17RE, IL23R, RORC) downregulated. However, comparisons of mRNA expression of Th17 related cytokines between lupus nephritis (LN) patients and SLE patients without nephritis (SLE non LN) showed no significant difference. In conclusion, SLE patients and normal controls showed different expression of a few genes in Th17 pathway, indicating that the pathway may be involved in the pathogenesis of 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.

Increased serum RANTES in patients with systemic lupus erythematosus

The aim of this study was to investigate the serum RANTES (regulated on activation, normal T-cell expressed and secreted) level in patients with systemic lupus erythematosus (SLE), and the associations with disease activity and clinical laboratory indexes. Twenty-seven SLE patients and 27 normal controls were enrolled in this study. Serum RANTES was measured by enzyme-linked immunosorbent assay (ELISA). The clinical and laboratory parameters of the patients were also recorded. Results showed that serum RANTES level was significantly elevated in SLE patients when compared with normal controls. Serum RANTES level was correlated with C3, ANA, anti-dsDNA antibodies, anti-Sm antibodies, and anti-SSB antibodies. Nevertheless, no association of serum RANTES level with SLEDAI was found. Taken together, serum RANTES level was significantly higher in SLE patients, suggesting that RANTES might be involved in the pathogenesis of SLE.

Seroprevalence of HIV, syphilis, and hepatitis C virus in the general population of the Liangshan Prefecture, Sichuan Province, China†‡

This study aimed at understanding the HIV prevalence, distribution of HIV risk factors and whether the HIV has spread from high‐risk groups to the general population in the Yanyuan and Muli counties, Liangshan Prefecture, Sichuan Province, China. A multistage probability method was used to select a representative sample of villages in each county, with stratification by risk employed in the sampling for the Yanyuan county. A real‐name registration and confidential method were adopted to collect the information of the participants. Blood specimens were tested for HIV, syphilis, and hepatitis C virus. A total of 4,950 subjects participated in the study. Of the participants aged ≥ 15 years, 0.12% self‐reported being drug users and 40% were injection drug users; 0.46% had multiple sex partners and the condom use rate was only 26.3% during the last sexual intercourse. HIV, syphilis, and HCV prevalence of Yanyuan county were 0.06% (95% CI: 0–0.142), 0.06% (95% CI: 0–0.142), and 0.15% (95% CI: 0.020–0.280), respectively. HCV prevalence of Muli county was 0.06% (95% CI: 0–0.191), and none was found to be HIV or syphilis positive. Therefore, the rate of HIV infection in Yanyuan and Muli counties is at a low level currently. The Yanyuan county HIV infection rate is similar to the average rate in all of China, and the Muli county rate is below Chinas average. The HIV epidemic has not spread from high‐risk groups to the general population in these two counties. J. Med. Virol. 84:1–5, 2011.

Genetic interaction between genes involved in NF-κB signaling pathway in systemic lupus erythematosus.

Recently, multiple genetic associations have been found between genes involved in nuclear factor-kappaB (NF-κB) signaling pathway and systemic lupus erythematosus (SLE) or other autoimmune diseases. This study was undertaken to replicate some of these associations and further test for genetic interactions among these genes in SLE in a Chinese population. Ten single-nucleotide polymorphisms (SNPs) in NFKB1, REL, inhibitor of κB-like (IκBL), IκB kinase β (IKBKB), tumor necrosis factor receptor associated factor 6 (TRAF6), tumor necrosis factor a-induced protein 3 (TNFAIP3), TNFAIP3 interacting protein 1 (TNIP1) were genotyped in 898 Chinese patients with SLE and 988 healthy controls by Sequenom MassArray technology. Single-marker genetic association analysis was performed, and additive and multiplicative interactions were analyzed. Associations of TNFAIP3 rs2230926 (p=1.43 × 10(-3)) and TNIP1 rs10036748 (p=4.33 × 10(-3)) with SLE were replicated in our study. Two other SNPs, NFKB1 rs28362491 and IκBL rs2071592, showed nominal evidence for association (p=4.70 × 10(-2) and p=5.90 × 10(-3), respectively) but these were not significant after applying Bonferroni correction. Additive interaction analysis revealed significant interaction between NFKB1 rs28362491 and TNFAIP3 rs2230926 (RERI=0.98, 95%CI=0.02-1.93; AP=43.2%, 95%CI=0.12-0.74). Significant multiplicative interaction was observed between NFKB1 rs28362491 and TNIP1 rs3792783 (p=0.03). Our results provide evidence for gene-gene interactions, which further support the important role of NF-κB signaling pathway in the genetic basis of SLE and the notion of genetic interactions accounting for missing heritability.

D18S880 microsatellite polymorphism of carnosinase gene and diabetic nephropathy: a meta-analysis.

OBJECTIVE The aim of this study was to determine whether the CNDP1 (carnosinase gene) D18S880 microsatellite polymorphism confers susceptibility to diabetic nephropathy (DN). METHODS The authors conducted meta-analysis on association between the CNDP1 D18S880 microsatellite polymorphism and DN susceptibility, using fixed and random effects models. RESULTS A total of nine comparative studies were included in this meta-analysis, which included 4546 DN, 7994 diabetes mellitus (DM), and 1826 healthy (Heal) subjects. Overall, the analysis revealed that the D18S880 microsatellite polymorphism was significantly associated with DN for the five trinucleotide repeat (5L) allele and five leucines repeat (5L-5L) homozygous in the comparisons of DN versus DM (5L: odds ratio [OR] 0.90, 95% confidence interval [CI] 0.84-0.97, p=0.008; 5L-5L: OR 0.88, 95% CI 0.81-0.97, p=0.006) and DN versus non-DN (DM+Heal) (5L: OR 0.92, 95% CI 0.86-0.98, p=0.009; 5L-5L: OR 0.89, 95% CI 0.82-0.96, p=0.004). The protective effects of the D18S880 polymorphism were similar to those observed in the subgroups of the type 2 DM and the Caucasian population. However, significant association was not found in the type 1 DM population. CONCLUSIONS This meta-analysis confirms that the carnosinase D18S880 microsatellite polymorphism is associated with DN susceptibility, especially in the type 2 DM and the Caucasian population.