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Circulating TNF-like protein 1A (TL1A) is elevated early in rheumatoid arthritis and depends on TNF.

ABSTRACT: BACKGROUND:The tumor necrosis factor (TNF) superfamily cytokine TNF-like protein 1A (TL1A) and its receptor DR3 are essential for diverse animal models of autoimmune disease and may be pathogenic in rheumatoid arthritis (RA). However, the relationship of TL1A to disease duration, activity, and response to anti-TNF and other therapies in RA is not clear. METHODS:We measured soluble TL1A in synovial fluid (SF), serum, or plasma from RA first-degree relatives (FDRs) and in early RA and established disease. We measured the effects of anti-TNF and methotrexate (MTX) therapy on circulating TL1A from multiple independent RA treatment trials. We also determined the ability of a blocking anti-TL1A antibody to inhibit clinical disease and articular bone destruction in the murine collagen-induced arthritis (CIA) model of human RA. RESULTS:Soluble TL1A was specifically elevated in the blood and SF of patients with RA compared to patients with other diseases and was elevated early in disease and in at-risk anti-cyclic citrullinated peptide (CCP) (+) first-degree relatives (FDRs). Therapeutic TNF inhibition reduced serum TL1A in both responders and non-responders, whereas TL1A declined following MTX treatment only in responders. In murine CIA, TL1A blockade was clinically efficacious and reduced bone erosions. CONCLUSIONS:TL1A is specifically elevated in RA from early in the disease course and in at-risk FDRs. The decline in TL1A after TNF blockade suggests that TL1A levels may be a useful biomarker for TNF activity in RA. These results support the further investigation of the relationship between TL1A and TNF and TL1A blockade as a potential therapeutic strategy in RA.

SUBMITTER: Song YJ

PROVIDER: S-EPMC7204024 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Circulating TNF-like protein 1A (TL1A) is elevated early in rheumatoid arthritis and depends on TNF.

Song Yun-Jeong YJ Choi In Ah IA Meylan Françoise F Demoruelle M Kristen MK Farley Taylor T Richard Arianne C AC Hawley Eric E Botson John J Hong Yoo Jin YJ Lee Eun Young EY Mian Sabina R SR Hamilton Bartlett C BC Thiele Geoffrey M GM Mikuls Ted R TR Gara Naveen N Ward Chris D CD Lamberth Sarah S Deane Kevin D KD Heller Theo T Ward Michael M MM Lee David M DM Migone Thi-Sau TS Stohl William W O'Dell James R JR Norris Jill M JM Holers V Michael VM Gregersen Peter P Song Yeong-Wook YW Siegel Richard M RM

Arthritis research & therapy 20200507 1

<h4>Background</h4>The tumor necrosis factor (TNF) superfamily cytokine TNF-like protein 1A (TL1A) and its receptor DR3 are essential for diverse animal models of autoimmune disease and may be pathogenic in rheumatoid arthritis (RA). However, the relationship of TL1A to disease duration, activity, and response to anti-TNF and other therapies in RA is not clear.<h4>Methods</h4>We measured soluble TL1A in synovial fluid (SF), serum, or plasma from RA first-degree relatives (FDRs) and in early RA a ...[more]

PMID: 32381123

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Project description:In 15 patients with rheumatoid arthritis the baseline expression (t=0) of type I IFN-regulated genes was determined in peripheral blood cells (PAXgene) using cDNA-microarrays and compared to levels one month after (t=1) anti-TNF treatment (infliximab). Therefore, we used 43K cDNA microarrays from the Stanford Functional Genomics Facility (http://microarray.org/sfgf/) printed on aminosilane-coated slides containing ~20.000 unique genes. Only one batch of arrays was used for all experiments. First DNA spots were UV-cross linked to the slide using 150-300 mJoules. Sample preparation and microarray hybridization were performed as described previously (1,2). Data storage and filtering was performed using the Stanford Microarray Database (http://genome-www5.stanford.edu//) as described previously. 1. van der Pouw Kraan TC, Wijbrandts CA, van Baarsen LG, Voskuyl AE, Rustenburg F, Baggen JM et al.: Rheumatoid arthritis subtypes identified by genomic profiling of peripheral blood cells: assignment of a type I interferon signature in a subpopulation of patients. Ann Rheum Dis 2007, 66: 1008-1014. 2. van der Pouw Kraan TC, van Baarsen LG, Rustenburg F, Baltus B, Fero M, Verweij CL: Gene expression profiling in rheumatology. Methods Mol Med 2007, 136: 305-327. Abbreviations: - Bnrs are the different patients analyzed - PAX or Paxgene indicates the total RNA was isolated from peripheral blood obtained in PAXgene tubes - CRS: common reference sample: We made a common reference that consisted of a mixture of mRNAs isolated from 11 different cell lines (Perou CM, Jeffrey SS, van de RM et al. Distinctive gene expression patterns in human mammary epithelial cells and breast cancers. Proc Natl Acad Sci U S A. 1999; 96:9212-9217) supplemented with RNA from rheumatoid synovial tissue, fibroblasts, and activated peripheral blood mononuclear cells (PBMCs). - PMT: photomultiplier tube: the sensitivity/intensity of the scanner can be adjusted to prevent spot saturation. Compound Based Treatment: anti-TNF (infliximab)

Project description:BackgroundTNF-like cytokine 1A (TL1A) is a subgroup of the tumor necrosis factor superfamily that exerts pleiotropic effects on cell proliferation, inflammation, activation, and differentiation of immune cells. The purpose of the current study is to investigate the clinical significance of TL1A expression in coronary and peripheral blood of patients with acute coronary syndrome (ACS) to determine if TL1A levels can serve as an accurate prognostic indicator.MethodsA total of 141 patients undergoing coronary angiography were divided into 4 groups: Control (n = 35), Unstable Angina (UA) (n = 35), acute non-ST segment elevation myocardial infarction (NSTEMI) (n = 37), and acute ST segment elevation myocardial infarction (STEMI) (n = 34). The levels of TL1A, MPO, hs-CRP, and IL-10 were detected in coronary and peripheral blood using enzyme linked immunosorbent assay (ELISA), and the MACE incidence rates were compared during 26.3 months of follow-up.ResultsTL1A levels were not significantly different between the UA group and control group. In the UA group, TL1A levels were not significantly different between coronary blood and peripheral blood. However, TL1A levels were higher in the STEMI and NSTEMI groups than in the control group (P < .05). Moreover, TL1A levels in the coronary blood of the STEMI and NSTEMI groups were higher than in the peripheral blood (P < .05). The expression of TL1A in the coronary blood was the highest in the STEMI group. In addition, TL1A level in the coronary blood was highly correlated with levels in the peripheral blood (correlation coefficient: 0.899, P < .001). The hs-CRP and MPO levels in the coronary and peripheral blood of all the UA, NSTEMI, and STEMI groups were higher than the control group. Plasma IL-10 levels in all the UA, NSTEMI and STEMI groups were lower than those in the control group. Plasma TL1A level was positively correlated with the cTnI level, degree of coronary thrombus burden, occurrence of slow coronary flow / no coronary reflow and MACE, but negatively correlated with the IL-10 level or non-correlated with the Syntax score.ConclusionPlasma TL1A concentration levels can be used as a predictor of inflammatory response and prognosis in patients with ACS.Trial registrationClinicalTrials.gov, number: NCT02430025; Unique Protocol ID: FJPH20150101; Brief Title: Fujian Province Cardiovascular Diseases Study (FJCVD).

Project description:IntroductionSurfactant protein D (SP-D) is a collectin with immuno-regulatory functions, which may depend on oligomerization. Anti-microbial and anti-inflammatory properties have been attributed to multimeric SP-D variants, while trimeric subunits per se have been suggested to enhance inflammation. Previously, we reported low circulating SP-D in early rheumatoid arthritis (RA), and the present investigation aims to extend these data by serial SP-D serum measurements, studies on synovial fluid, SP-D size distribution and genotyping in patients with early RA.MethodsOne-hundred-and-sixty disease-modifying antirheumatic drug (DMARD) naïve RA patients with disease duration less than six months were studied prospectively for four years (CIMESTRA (Ciclosporine, Methotrexate, Steroid in RA) trial) including disease activity measures (C-reactive protein, joint counts and Health Assessment Questionnaire (HAQ) score), autoantibodies, x-ray findings and SP-D. SP-D was quantified by enzyme-linked immunosorbent assay (ELISA) and molecular size distribution was assessed by gel filtration chromatography. Further, SP-D Met11Thr single nucleotide polymorphism (SNP) analysis was performed.ResultsSerum SP-D was significantly lower in RA patients at baseline compared with healthy controls (P < 0.001). SP-D increased slightly during follow-up (P < 0.001), but was still subnormal at four years after adjustment for confounders (P < 0.001). SP-D in synovial fluid was up to 2.5-fold lower than in serum. While multimeric variants were detected in serum, SP-D in synovial fluid comprised trimeric subunits only. There were no significant associations between genotype distribution and SP-D. Baseline SP-D was inversely associated to CRP and HAQ score. A similar relationship was observed regarding temporal changes in SP-D and CRP (zero to four years). SP-D was not associated to x-ray findings.ConclusionsThis study confirms that circulating SP-D is persistently subnormal in early and untreated RA despite a favourable therapeutic response obtained during four years of follow-up. SP-D correlated negatively to disease activity measures, but was not correlated with x-ray progression or SP-D genotype. These observations suggest that SP-D is implicated in RA pathogenesis at the protein level. The exclusive presence of trimeric SP-D in affected joints may contribute to the maintenance of joint inflammation.Trial registration(j.nr NCT00209859).

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Circulating TNF-like protein 1A (TL1A) is elevated early in rheumatoid arthritis and depends on TNF.

Publications

Circulating TNF-like protein 1A (TL1A) is elevated early in rheumatoid arthritis and depends on TNF.

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