Hai-Feng Pan

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.

Meta-analysis Followed by Replication Identifies Loci in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as Associated with Systemic Lupus Erythematosus in Asians

Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with a strong genetic involvement and ethnic differences. Susceptibility genes identified so far only explain a small portion of the genetic heritability of SLE, suggesting that many more loci are yet to be uncovered for this disease. In this study, we performed a meta-analysis of genome-wide association studies on SLE in Chinese Han populations and followed up the findings by replication in four additional Asian cohorts with a total of 5,365 cases and 10,054 corresponding controls. We identified genetic variants in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as associated with the disease. These findings point to potential roles of cell-cycle regulation, autophagy, and DNA demethylation in SLE pathogenesis. For the region involving TET3 and that involving CDKN1B, multiple independent SNPs were identified, highlighting a phenomenon that might partially explain the missing heritability of complex diseases.

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.

Type 17 T-helper cells might be a promising therapeutic target for systemic lupus erythematosus.

Emerging data implicate a novel subset of CD4+ T cells, termed TH17 cells, in the pathogenesis of several autoimmune diseases. In this Viewpoint article, the authors discuss the role of TH17 cells in systemic lupus erythematosus and discuss their potential as a therapeutic target.

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.

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