The Role of TL1A and DR3 in Autoimmune and Inflammatory Diseases

Aiba, Yoshihiro; Nakamura, Minoru

doi:10.1155/2013/258164

Cited by 59 publications

(52 citation statements)

References 95 publications

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“…This locus has been implicated in several autoimmune diseases10. Two previous studies have reported that two functional SNPs, rs6478108 and rs4979462, in the TNFSF15 promoter region are associated with TNFSF15 expression1112.…”

Section: Resultsmentioning

confidence: 99%

A genome-wide association study identifies six novel risk loci for primary biliary cholangitis

Qiu¹,

Tang²,

Zuo³

et al. 2017

Nat Commun

108

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Primary biliary cholangitis (PBC) is an autoimmune liver disease with a strong hereditary component. Here, we report a genome-wide association study that included 1,122 PBC cases and 4,036 controls of Han Chinese descent, with subsequent replication in a separate cohort of 907 PBC cases and 2,127 controls. Our results show genome-wide association of 14 PBC risk loci including previously identified 6p21 (HLA-DRA and DPB1), 17q12 (ORMDL3), 3q13.33 (CD80), 2q32.3 (STAT1/STAT4), 3q25.33 (IL12A), 4q24 (NF-κB) and 22q13.1 (RPL3/SYNGR1). We also identified variants in IL21, IL21R, CD28/CTLA4/ICOS, CD58, ARID3A and IL16 as novel PBC risk loci. These new findings and histochemical studies showing enhanced expression of IL21 and IL21R in PBC livers (particularly in the hepatic portal tracks) support a disease mechanism in which the deregulation of the IL21 signalling pathway, in addition to CD4 T-cell activation and T-cell co-stimulation are critical components in the development of PBC.

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Section: Resultsmentioning

confidence: 99%

A genome-wide association study identifies six novel risk loci for primary biliary cholangitis

Qiu¹,

Tang²,

Zuo³

et al. 2017

Nat Commun

108

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“…4,7 Since TL1A encoded by TNFSF15 is involved in apoptosis and immune responses leading to Th1 and Th17 differentiation, it is likely that TL1A has an important role in the development of both diseases through these mechanisms. 9 Although the age of onset and gender distribution of these two diseases are different and the concomitance of PBC and CD is very rare, these two diseases have several shared clinical characteristics such as epithelial cell destruction with inflammation and granuloma formation at locations involved in the enterohepatic circulation of bile salts. In addition, many disease susceptibility genes are shared among various autoimmune diseases, indicating the presence of shared pathogenic pathways among autoimmune disease.…”

Section: Introductionmentioning

confidence: 99%

Disease susceptibility genes shared by primary biliary cirrhosis and Crohn’s disease in the Japanese population

et al. 2015

Self Cite

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We previously identified TNFSF15 as the most significant susceptibility gene at non-HLA loci for both primary biliary cirrhosis (PBC) and Crohn's diseases (CD) in the Japanese population. The aim of this study is to identify further disease susceptibility genes shared by PBC and CD. We selected 15 and 33 genetic variants that were significantly associated with PBC and CD, respectively, based on previously reported genome-wide association studies of the Japanese population. Next, an association study was independently performed for these genetic variants in CD (1312 CD patients and 3331 healthy controls) and PBC (1279 PBC patients and 1015 healthy controls) cohorts. Two CD susceptibility genes, ICOSLG rs2838519 and IL12B rs6556412, were also nominally associated with susceptibility to PBC (P=3.85 × 10(-2) and P=8.40 × 10(-3), respectively). Three PBC susceptibility genes, CXCR5 rs6421571, STAT4 rs7574865 and NFKB1 rs230534, were nominally associated with susceptibility to CD (P=2.82 × 10(-2), P=3.88 × 10(-2) and P=2.04 × 10(-2), respectively). The effect of ICOSLG and CXCR5 variants were concordant but the effect of STAT4, NFKB1 and IL12B variants were discordant for PBC and CD. TNFSF15 and ICOSLG-CXCR5 might constitute a shared pathogenic pathway in the development of PBC and CD in the Japanese population, whereas IL12B-STAT4-NFKB1 might constitute an opposite pathogenic pathway, reflecting the different balance between Th1 and Th17 in the two diseases.

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“…DR3 is the primary activating receptor of TL1A and is predominantly expressed on leucocytes 5. DR3 expression is significantly upregulated on various activated cells in the immune system, including T lymphocytes, B lymphocytes, natural killer T (NKT) cells, dendritic cells and macrophages 15. Previous studies have indicated that DR3 is a very powerful lymphocyte costimulatory, and DR3 signalling amplifies a series of immune responses, culminating in the activation of T lymphocytes, and initiates the secretion of proinflammatory cytokines 16 17.…”

Section: Discussionmentioning

confidence: 99%

Expression of death receptor 3 (DR3) on peripheral blood mononuclear cells of patients with psoriasis vulgaris

Lin

et al. 2018

Postgraduate Medical Journal

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BackgroundA series of previous reports indicated that tumour necrosis factor-like ligand 1A (TL1A) and its receptor death receptor 3 (DR3) are involved in the pathogenesis of psoriasis vulgaris (PV), which is a common chronic skin disease accompanied by a number of comorbidities, although their exact roles remain unclear. Our previous studies demonstrated that serum TL1A levels were substantially elevated in patients with PV, but the detection of DR3 expression in peripheral blood mononuclear cells (PBMCs) of patients with PV had not been reported. Therefore, we detected DR3 expression on CD4+, CD8+, CD14+ and CD19+ PBMCs of patients with PV, atopic dermatitis (AD) and healthy volunteers.MethodsBlood samples were collected from participants with PV before and after treatment. Then, PBMCs from patients with PV were isolated. The Psoriasis Area Severity Index (PASI) was used to assess severity in patients with PV. The DR3 on CD4+, CD8+, CD14+ and CD19+ PBMCs were detected by flow cytometry analysis. Pearson’s correlation analysis was then used to investigate the relationship between DR3 expression and PASI scores in patients with PV.ResultsComparing with the healthy volunteers and patients with AD, the percentage of DR3-expressing on CD8+ and CD14+ PBMCs in patients with PV was elevated, but the percentage of DR3-expressing on CD8+ and CD14+ cells decreased after anti-inflammatory treatment, which was correlated with PASI scores.ConclusionsTaken together, these findings suggest that DR3 may play a key role in the pathogenesis of PV.

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The Role of TL1A and DR3 in Autoimmune and Inflammatory Diseases

Cited by 59 publications

References 95 publications

A genome-wide association study identifies six novel risk loci for primary biliary cholangitis

A genome-wide association study identifies six novel risk loci for primary biliary cholangitis

Disease susceptibility genes shared by primary biliary cirrhosis and Crohn’s disease in the Japanese population

Expression of death receptor 3 (DR3) on peripheral blood mononuclear cells of patients with psoriasis vulgaris

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