Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Arthritis Research & Therapy
Published in: Arthritis Research & Therapy 1/2010

Open Access 01-02-2010 | Research article

Functional consequences of DECTIN-1early stop codon polymorphism Y238X in rheumatoid arthritis

Authors: Theo S Plantinga, Jaap Fransen, Nozomi Takahashi, Rinke Stienstra, Piet L van Riel, Wim B van den Berg, Mihai G Netea, Leo AB Joosten

Published in: Arthritis Research & Therapy | Issue 1/2010

Login to get access

Abstract

Introduction

Dectin-1, a pattern recognition receptor expressed by the innate immune system, is known to be a major receptor inducing Th17-type adaptive immune responses that have been demonstrated to mediate autoimmunity. In this study, dectin-1 mRNA and protein expression, as well as the recently characterized DECTIN-1 Y238X early stop codon polymorphism, were studied in relation to rheumatoid arthritis (RA) susceptibility and severity.

Methods

Dectin-1 mRNA expression was measured in synovial tissue specimens of RA, osteoarthritis (OA), and nonrheumatic patients. Dectin-1 protein expression and localization were assessed in RA synovial tissue specimens. Macrophages from individuals with different DECTIN-1 genotypes were examined for differences in cytokine responses on dectin-1 stimulation. Furthermore, clinical parameters of inflammation and bone destruction of 262 RA patients were correlated with the presence of the DECTIN-1 Y238X polymorphism.

Results

Evaluation of dectin-1 mRNA expression in synovial tissue biopsies revealed an increased expression in RA specimens, compared with biopsies from OA and nonrheumatic patients. Accordingly, dectin-1 protein expression in RA synovial tissue biopsies was moderate to high, especially on macrophage-like cells. Cytokine production capacity of macrophages bearing the DECTIN-1 Y238X polymorphism was demonstrated to be impaired on dectin-1 stimulation. However, the presence of the DECTIN-1 Y238X polymorphism was not associated with RA susceptibility or disease severity.

Conclusions

Although expression of dectin-1 was high in synovial tissue of RA patients, and reduced cytokine production was observed in macrophages of individuals bearing the DECTIN-1 Y238X polymorphism, loss of one functional allele of DECTIN-1 is not associated with either susceptibility to or severity of RA.
Appendix
Available only for authorised users
Literature
1.
Abdollahi-Roodsaz S, Joosten LA, Roelofs MF, Radstake TR, Matera G, Popa C, Meer van der JW, Netea MG, Berg van den WB: Inhibition of Toll-like receptor 4 breaks the inflammatory loop in autoimmune destructive arthritis. Arthritis Rheum. 2007, 56: 2957-2967. 10.1002/art.22848.CrossRefPubMed
2.
Roelofs MF, Wenink MH, Brentano F, Abdollahi-Roodsaz S, Oppers-Walgreen B, Barrera P, van Riel PL, Joosten LA, Kyburz D, Berg van den WB, Radstake TR: Type I interferons might form the link between Toll-like receptor (TLR) 3/7 and TLR4 mediated synovial inflammation in rheumatoid arthritis (RA). Ann Rheum Dis. 2009, 68: 1486-1493. 10.1136/ard.2007.086421.CrossRefPubMed
3.
Kattah MG, Wong MT, Yocum MD, Utz PJ: Cytokines secreted in response to Toll-like receptor ligand stimulation modulate differentiation of human Th17 cells. Arthritis Rheum. 2008, 58: 1619-1629. 10.1002/art.23497.PubMedCentralCrossRefPubMed
4.
5.
Brown GD, Gordon S: Immune recognition: a new receptor for beta-glucans. Nature. 2001, 413: 36-37. 10.1038/35092620.CrossRefPubMed
6.
Underhill DM, Rossnagle E, Lowell CA, Simmons RM: Dectin-1 activates Syk tyrosine kinase in a dynamic subset of macrophages for reactive oxygen production. Blood. 2005, 106: 2543-2550. 10.1182/blood-2005-03-1239.PubMedCentralCrossRefPubMed
7.
Gringhuis SI, den Dunnen J, Litjens M, Vlist van der M, Wevers B, Bruijns SC, Geijtenbeek TB: Dectin-1 directs T helper cell differentiation by controlling noncanonical NF-kappaB activation through Raf-1 and Syk. Nat Immunol. 2009, 10: 203-213. 10.1038/ni.1692.CrossRefPubMed
8.
Rogers NC, Slack EC, Edwards AD, Nolte MA, Schulz O, Schweighoffer E, Williams DL, Gordon S, Tybulewicz VL, Brown GD, Reis E, Sousa C: Syk-dependent cytokine induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectins. Immunity. 2005, 22: 507-517. 10.1016/j.immuni.2005.03.004.CrossRefPubMed
9.
Gross O, Gewies A, Finger K, Schafer M, Sparwasser T, Peschel C, Forster I, Ruland J: Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity. Nature. 2006, 442: 651-656. 10.1038/nature04926.CrossRefPubMed
10.
Hara H, Ishihara C, Takeuchi A, Imanishi T, Xue L, Morris SW, Inui M, Takai T, Shibuya A, Saijo S, Iwakura Y, Ohno N, Koseki H, Yoshida H, Penninger JM, Saito T: The adaptor protein CARD9 is essential for the activation of myeloid cells through ITAM-associated and Toll-like receptors. Nat Immunol. 2007, 8: 619-629. 10.1038/ni1466.CrossRefPubMed
11.
Ferwerda G, Meyer-Wentrup F, Kullberg BJ, Netea MG, Adema GJ: Dectin-1 synergizes with TLR2 and TLR4 for cytokine production in human primary monocytes and macrophages. Cell Microbiol. 2008, 10: 2058-2066. 10.1111/j.1462-5822.2008.01188.x.CrossRefPubMed
12.
Dennehy KM, Ferwerda G, Faro-Trindade I, Pyz E, Willment JA, Taylor PR, Kerrigan A, Tsoni SV, Gordon S, Meyer-Wentrup F, Adema GJ, Kullberg BJ, Schweighoffer E, Tybulewicz V, Mora-Montes HM, Gow NA, Williams DL, Netea MG, Brown GD: Syk kinase is required for collaborative cytokine production induced through Dectin-1 and Toll-like receptors. Eur J Immunol. 2008, 38: 500-506. 10.1002/eji.200737741.PubMedCentralCrossRefPubMed
13.
Gerosa F, Baldani-Guerra B, Lyakh LA, Batoni G, Esin S, Winkler-Pickett RT, Consolaro MR, De MM, Giachino D, Robbiano A, Astegiano M, Sambataro A, Kastelein RA, Carra G, Trinchieri G: Differential regulation of interleukin 12 and interleukin 23 production in human dendritic cells. J Exp Med. 2008, 205: 1447-1461. 10.1084/jem.20071450.PubMedCentralCrossRefPubMed
14.
Leibundgut-Landmann S, Gross O, Robinson MJ, Osorio F, Slack EC, Tsoni SV, Schweighoffer E, Tybulewicz V, Brown GD, Ruland J, Reis E, Sousa C: Syk- and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17. Nat Immunol. 2007, 8: 630-638. 10.1038/ni1460.CrossRefPubMed
15.
Frasnelli ME, Tarussio D, Chobaz-Peclat V, Busso N, So A: TLR2 modulates inflammation in zymosan-induced arthritis in mice. Arthritis Res Ther. 2005, 7: R370-R379. 10.1186/ar1494.PubMedCentralCrossRefPubMed
16.
Hida S, Miura NN, Adachi Y, Ohno N: Cell wall beta-glucan derived from Candida albicans acts as a trigger for autoimmune arthritis in SKG mice. Biol Pharm Bull. 2007, 30: 1589-1592. 10.1248/bpb.30.1589.CrossRefPubMed
17.
Yordanov M, Danova S, Ivanovska N: Inflammation induced by inoculation of the joint with Candida albicans. Inflammation. 2004, 28: 127-132. 10.1023/B:IFLA.0000039558.03872.52.CrossRefPubMed
18.
Hida S, Miura NN, Adachi Y, Ohno N: Effect of Candida albicans cell wall glucan as adjuvant for induction of autoimmune arthritis in mice. J Autoimmun. 2005, 25: 93-101. 10.1016/j.jaut.2005.06.002.CrossRefPubMed
19.
Yordanov M, Tchorbanov A, Ivanovska N: Candida albicans cell-wall fraction exacerbates collagen-induced arthritis in mice. Scand J Immunol. 2005, 61: 301-308. 10.1111/j.1365-3083.2005.01575.x.CrossRefPubMed
20.
Yoshitomi H, Sakaguchi N, Kobayashi K, Brown GD, Tagami T, Sakihama T, Hirota K, Tanaka S, Nomura T, Miki I, Gordon S, Akira S, Nakamura T, Sakaguchi S: A role for fungal {beta}-glucans and their receptor Dectin-1 in the induction of autoimmune arthritis in genetically susceptible mice. J Exp Med. 2005, 201: 949-960. 10.1084/jem.20041758.PubMedCentralCrossRefPubMed
21.
Veerdonk van de FL, Marijnissen RJ, Kullberg BJ, Koenen HJ, Cheng SC, Joosten I, Berg van den WB, Williams DL, Meer van der JW, Joosten LA, Netea MG: The macrophage mannose receptor induces IL-17 in response to Candida albicans. Cell Host Microbe. 2009, 5: 329-340. 10.1016/j.chom.2009.02.006.CrossRefPubMed
22.
Ferwerda B, Ferwerda G, Plantinga TS, Willment JA, van Spriel AB, Venselaar H, Elbers CC, Johnson MD, Cambi A, Huysamen C, Jacobs L, Jansen T, Verheijen K, Masthoff L, Morre SA, Vriend G, Williams DL, Perfect JR, Joosten LA, Wijmenga C, Meer van der JW, Adema GJ, Kullberg BJ, Brown GD, Netea MG: Human dectin-1 deficiency and mucocutaneous fungal infections. N Engl J Med. 2009, 361: 1760-1767. 10.1056/NEJMoa0901053.PubMedCentralCrossRefPubMed
23.
Welsing PM, van Riel PL: The Nijmegen inception cohort of early rheumatoid arthritis. J Rheumatol Suppl. 2004, 69: 14-21.PubMed
24.
Prevoo ML, van 't Hof MA, Kuper HH, van Leeuwen MA, Putte van de LB, van Riel PL: Modified disease activity scores that include twenty-eight-joint counts: development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum. 1995, 38: 44-48. 10.1002/art.1780380107.CrossRefPubMed
25.
Rau R, Wassenberg S, Herborn G, Stucki G, Gebler A: A new method of scoring radiographic change in rheumatoid arthritis. J Rheumatol. 1998, 25: 2094-2107.PubMed
26.
Lockhart DJ, Dong H, Byrne MC, Follettie MT, Gallo MV, Chee MS, Mittmann M, Wang C, Kobayashi M, Horton H, Brown EL: Expression monitoring by hybridization to high-density oligonucleotide arrays. Nat Biotechnol. 1996, 14: 1675-1680. 10.1038/nbt1296-1675.CrossRefPubMed
27.
28.
Li C, Wong WH: Model-based analysis of oligonucleotide arrays: expression index computation and outlier detection. Proc Natl Acad Sci USA. 2001, 98: 31-36. 10.1073/pnas.011404098.PubMedCentralCrossRefPubMed
29.
Osorio F, Leibundgut-Landmann S, Lochner M, Lahl K, Sparwasser T, Eberl G, Reis E, Sousa C: DC activated via dectin-1 convert Treg into IL-17 producers. Eur J Immunol. 2008, 38: 3274-3281. 10.1002/eji.200838950.PubMedCentralCrossRefPubMed
30.
Joosten LA, Helsen MM, Saxne T, Loo van De FA, Heinegard D, Berg van den WB: IL-1 alpha beta blockade prevents cartilage and bone destruction in murine type II collagen-induced arthritis, whereas TNF-alpha blockade only ameliorates joint inflammation. J Immunol. 1999, 163: 5049-5055.PubMed
31.
Zwerina J, Redlich K, Polzer K, Joosten L, Kronke G, Distler J, Hess A, Pundt N, Pap T, Hoffmann O, Gasser J, Scheinecker C, Smolen JS, van den BW, Schett G: TNF-induced structural joint damage is mediated by IL-1. Proc Natl Acad Sci USA. 2007, 104: 11742-11747. 10.1073/pnas.0610812104.PubMedCentralCrossRefPubMed
Metadata
Title
Functional consequences of DECTIN-1early stop codon polymorphism Y238X in rheumatoid arthritis
Authors
Theo S Plantinga
Jaap Fransen
Nozomi Takahashi
Rinke Stienstra
Piet L van Riel
Wim B van den Berg
Mihai G Netea
Leo AB Joosten
Publication date
01-02-2010
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 1/2010
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/ar2933

Other articles of this Issue 1/2010

Arthritis Research & Therapy 1/2010 Go to the issue

Research article

Regulation of microsomal prostaglandin E2synthase-1 and 5-lipoxygenase-activating protein/5-lipoxygenase by 4-hydroxynonenal in human osteoarthritic chondrocytes

Editorial

'Rac'-ing upstream to treat rheumatoid arthritis

Review

A role for age-related changes in TGFβ signaling in aberrant chondrocyte differentiation and osteoarthritis

Research article

Pentosan polysulfate promotes proliferation and chondrogenic differentiation of adult human bone marrow-derived mesenchymal precursor cells

Research article

Transcriptional profiling of bovine intervertebral disc cells: implications for identification of normal and degenerate human intervertebral disc cell phenotypes

Research article

The effect of the pro-inflammatory cytokine tumor necrosis factor-alpha on human joint capsule myofibroblasts
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits