Dong-Qing Ye

Genome-Wide Association Study in Asian Populations Identifies Variants in ETS1 and WDFY4 Associated with Systemic Lupus Erythematosus

Systemic lupus erythematosus is a complex and potentially fatal autoimmune disease, characterized by autoantibody production and multi-organ damage. By a genome-wide association study (320 patients and 1,500 controls) and subsequent replication altogether involving a total of 3,300 Asian SLE patients from Hong Kong, Mainland China, and Thailand, as well as 4,200 ethnically and geographically matched controls, genetic variants in ETS1 and WDFY4 were found to be associated with SLE (ETS1: rs1128334, P = 2.33×10−11, OR = 1.29; WDFY4: rs7097397, P = 8.15×10−12, OR = 1.30). ETS1 encodes for a transcription factor known to be involved in a wide range of immune functions, including Th17 cell development and terminal differentiation of B lymphocytes. SNP rs1128334 is located in the 3′-UTR of ETS1, and allelic expression analysis from peripheral blood mononuclear cells showed significantly lower expression level from the risk allele. WDFY4 is a conserved protein with unknown function, but is predominantly expressed in primary and secondary immune tissues, and rs7097397 in WDFY4 changes an arginine residue to glutamine (R1816Q) in this protein. Our study also confirmed association of the HLA locus, STAT4, TNFSF4, BLK, BANK1, IRF5, and TNFAIP3 with SLE in Asians. These new genetic findings may help us to gain a better understanding of the disease and the functions of the genes involved.

A Functional Variant in MicroRNA-146a Promoter Modulates Its Expression and Confers Disease Risk for Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with a strong genetic predisposition, characterized by an upregulated type I interferon pathway. MicroRNAs are important regulators of immune homeostasis, and aberrant microRNA expression has been demonstrated in patients with autoimmune diseases. We recently identified miR-146a as a negative regulator of the interferon pathway and linked the abnormal activation of this pathway to the underexpression of miR-146a in SLE patients. To explore why the expression of miR-146a is reduced in SLE patients, we conducted short parallel sequencing of potentially regulatory regions of miR-146a and identified a novel genetic variant (rs57095329) in the promoter region exhibiting evidence for association with SLE that was replicated independently in 7,182 Asians (P meta = 2.74×10−8, odds ratio = 1.29 [1.18–1.40]). The risk-associated G allele was linked to reduced expression of miR-146a in the peripheral blood leukocytes of the controls. Combined functional assays showed that the risk-associated G allele reduced the protein-binding affinity and activity of the promoter compared with those of the promoter containing the protective A allele. Transcription factor Ets-1, encoded by the lupus-susceptibility gene ETS1, identified in recent genome-wide association studies, binds near this variant. The manipulation of Ets-1 levels strongly affected miR-146a promoter activity in vitro; and the knockdown of Ets-1, mimicking its reduced expression in SLE, directly impaired the induction of miR-146a. We also observed additive effects of the risk alleles of miR-146a and ETS1. Our data identified and confirmed an association between a functional promoter variant of miR-146a and SLE. This risk allele had decreased binding to transcription factor Ets-1, contributing to reduced levels of miR-146a in SLE patients.

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.

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.

Emerging role of interleukin-22 in autoimmune diseases

Interleukin-22 (IL-22) is an IL-10 family cytokine member that was recently discovered to be mainly produced by Th17 cells. Previous studies have indicated the importance of IL-22 in host defense against Gram-negative bacterial organisms (in gut and lung). Recently, there is emerging evidence that IL-22 is involved in the development and pathogenesis of several autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), Sjögrens syndrome (SS) and psoriasis. Therapeutics targeting IL-22 therefore may have promise for treating various autoimmune diseases. In this review, we discuss the recent progression of the involvement of IL-22 in the development and pathogenesis of autoimmune diseases, as well as its clinical implications and therapeutic potential.

Long noncoding RNAs: novel insights into gastric cancer.

Long non-coding RNAs (lncRNAs) are functional RNAs longer than 200 nucleotides. Recent advances in the non-protein coding part of human genome analysis have discovered extensive transcription of large RNA transcripts that lack coding protein function, termed non-coding RNA (ncRNA). It is becoming evident that lncRNAs may be an important class of pervasive genes involved in carcinogenesis and metastasis. However, the biological and molecular mechanisms of lncRNAs in diverse diseases are not yet fully understood. Thus, it is anticipated that more efforts should be made to clarify the lncRNA world. Moreover, accumulating evidence has demonstrated that many lncRNAs are dysregulated in gastric cancer (GC) and closely related to tumorigenesis, metastasis, and prognosis or diagnosis. In this review, we will briefly outline the regulation and functional role of lncRNAs in GC. Finally, we discussed the potential of lncRNAs as prospective novel targets in GC treatment and biomarkers for GC diagnosis.

Emerging role of long noncoding RNAs in autoimmune diseases.

Long noncoding RNA (lncRNA), with size larger than 200 nucleotides, is a new class of noncoding RNA. Emerging evidence has revealed that lncRNAs play a key role in the regulation of immunological functions and autoimmunity. Herein, we review the recent findings of lncRNA regulation in immune functions and in the development of autoimmunity and autoimmune disease. In addition, we focus on the involvement of lncRNA regulation in innate and adaptive immune responses, immune cell development, and differential expression of lncRNAs in autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), type 1 diabetes mellitus (T1DM), multiple sclerosis (MS), autoimmune thyroid disease (AITD), psoriasis, polymyositis/dermatomyositis (PM/DM) and Crohns disease (CD).

Association of MicroRNA-146a with Autoimmune Diseases

MicroRNAs (miRNAs) are a group of approximately 20–22-nucleotide-long non-coding RNAs that repress target gene expression through mRNA degradation and translation inhibition. MiRNA (miR)-146a, located in the second exon of the LOC285628 gene on human chromosome 5, is a negative regulator in immune and inflammatory responses. Studies have indicated that miR-146a is associated with the pathogenesis of several autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and Sjögren’s syndrome. In this review, emphasis will be laid on the recent progress in the functional roles of miR-146a in these autoimmune diseases.

Comparative effectiveness and tolerance of treatments for Helicobacter pylori: systematic review and network meta-analysis.

Objective To determine the most efficacious treatment for eradication of Helicobacter pylori with the lowest likelihood of some common adverse events among pre-recommended and newer treatment regimens. Design Systematic review and network meta-analysis. Data sources Cochrane Library, PubMed, and Embase without language or date restrictions. Study selection Full text reports of randomised controlled trials that compared different eradication treatments for H pylori among adults. Results Of the 15 565 studies identified, 143 were eligible and included. Data on 14 kinds of treatments were available. Of 91 possible comparisons for the efficacy outcome, 34 were compared directly and the following treatments performed better: seven days of concomitant treatment (proton pump inhibitor and three kinds of antibiotics administered together), 10 or 14 days of concomitant treatment, 10 or 14 days of probiotic supplemented triple treatment (standard triple treatment which is probiotic supplemented), 10 or 14 days of levofloxacin based triple treatment (proton pump inhibitor, levofloxacin, and antibiotic administered together), 14 days of hybrid treatment (proton pump inhibitor and amoxicillin used for seven days, followed by a proton pump inhibitor, amoxicillin, clarithromycin, and 5-nitroimidazole for another seven days), and 10 or 14 days of sequential treatment (five or seven days of a proton pump inhibitor plus amoxicillin, followed by five or seven additional days of a proton pump inhibitor plus clarithromycin and 5-nitroimidazole or amoxicillin). In terms of tolerance, all treatments were considered tolerable, but seven days of probiotic supplemented triple treatment and seven days of levofloxacin based triple treatment ranked best in terms of the proportion of adverse events reported. Conclusion Comparison of different eradication treatments for H pylori showed that concomitant treatments, 10 or 14 days of probiotic supplemented triple treatment, 10 or 14 days of levofloxacin based triple treatment, 14 days of hybrid treatment, and 10 or 14 days of sequential treatment might be better alternatives for the eradication of H pylori.

Decreased serum IL-22 levels in patients with systemic lupus erythematosus

Normal controls 30 340.19 (212.45–586.62) SLE 57 36.00 (26.69–54.85) b0.001 SLE without nephritis 30 39.75 (28.33–56.55) SLE with nephritis 27 31.41 (21.50–51.47) NS Less active SLE 16 36.85 (26.33–52.38) More active SLE 41 36.00 (26.69–55.82) NS a vs normal controls. b vs SLE without nephritis. c vs less active SLE. Systemic lupus erythematosus (SLE) is a systemic autoimmune disease, characterized by a multitude of autoantibody production, complement activation and immune-complex deposition, which causes tissue and organ damage. The etiology and pathogenetic mechanisms of SLE have not been clearly elucidated. Cytokines produced by abnormal T-helper (Th) cells have been shown to be involved in the pathogenesis of SLE [1]. Activated T cells have been indicated to differentiate into memory/effector T cells that are classified into T helper 1 (Th1) and Th2 subsets based on their cytokine production profiles [2]. Until recently, Th1 dominant immune responses have been generally considered to be pathological in autoimmune disease via the induction of inflammatory reaction, and large amounts of Th1 cytokines such as interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and IL-12 have been found in SLE [3,4]. However, there are growing evidences that a recently recognized subset of Tcells, named Th17 cells have been implicated in the etiology of autoimmune disease including SLE and systemic scleroderma [1,5]. Th17 cells are a novel subset of Th cells that selectively secrete several proinflammatory cytokines, including IL-17, IL23 and IL-22 [6]. It has been shown that IL-17 is involved in tissue pathology in autoimmune models, and anti-IL-17 reduced joint inflammation and bone erosion in an experimental arthritis model. In addition, previous studies have shown that the increased production of IL-17 exerts a synergistic effect on the inflammatory reactions to induce increased production of a panel of proinflammatory cytokines including IFN-[gamma], IL-2 and granulocyte monocyte-colony stimulating factor in SLE [7]. Dong et al. found that IL-17might play an important role in the pathogenesis of lupus nephritis through the induction of IgG, anti-dsDNA overproduction and IL-6 overexpression of PBMC in patients with lupus nephritis [8]. A recent study also indicated hyperproduction of IL-23 and IL-17 in patients with SLE [9]. Nevertheless, whether IL-22 plays a role in the pathogenesis of SLE is still unclear and remains to be established. The assessment of a cytokine at the serum level would certainly simplify clinical evaluation [10]. Therefore, in the present study, we investigated serum IL-22 levels in SLE, in comparison with normal controls, and relations to disease activity. Fifty-sevenpatientswith SLE (55 females, 2males;mean age 36±13 y, range 16–60 y) were recruited from the Departments of Rheumatology at Anhui Provincial Hospital. The diagnosis of SLE was established by the presence of four or more American College of Rheumatology (ACR) diagnostic criteria [11]. Renal involvementof SLEwasdefinedaccording to the ACR criteria, i.e., any one of the following: 1) persistent proteinuria ≥0.5g/day; 2) thepresenceof active cellular casts; or 3) biopsyevidenceof lupus nephritis [12]. Individual disease activity was quantified using the SLEdisease activity index (SLEDAI) score [13].More active SLEwasdefined as a SLEDAI score ≥10, those patientswith SLEDAIb10were classed as less active. 30 healthy volunteers (29 females, 1 male; mean age 44±12 y, range from 15 to 66 y) were included as normal controls, all of them did