This article is part of the supplement: 6th European Workshop on Immune-Mediated Inflammatory Diseases

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A rare polymorphism in Toll Like Receptor 2 is associated with systemic sclerosis phenotype and increases production of inflammatory mediators

Jasper CA Broen1*, Lara Bossini-Castillo2, Lenny van Bon1, Madelon C Vonk1, Hanneke Knaapen1, Lorenzo Beretta3, Blanca Rueda2, Roger Hesselstrand4, Ariane Herrick5, Jane Worthington5, Nicholas Hunzelmann6, Christopher Denton7, Carmen Fonseca7, Gabriela Riemekasten8, Hans Kiener9, Raffaella Scorza3, Carmen P Simeon10, Norberto Ortego-Centeno11, Miguel A Gonzalez-Gay12, Paolo Airo’13, Marieke JH Coenen14, Javier Martin2 and Timothy RDJ Radstake1

  • * Corresponding author: Jasper CA Broen

Author Affiliations

1 Dept. of Rheumatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

2 Instituto de Parasitología y Biomedicina, CSIC, Granada, Spain

3 Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico and University of Milan, Italy

4 Dept. of Rheumatology, Lund University, Lund, Sweden

5 Rheumatic Diseases Centre, University of Manchester, Salford Royal NHS Foundation Trust, UK

6 Dept. of Dermatology, University of Cologne, Germany

7 Centre for Rheumatology, Royal Free and University College Medical School, London, UK

8 Dept. of Rheumatology and Clinical Immunology, Charité University Hospital and German Rheumatism Research Centre, a Leibniz institute, Berlin, Germany

9 Dept. of Internal Medicine, Division of Rheumatology, University of Vienna, Austria

10 Servicio de Medicina Interna, Hospital Valle de Hebron, Barcelona, Spain

11 For the Spanish Systemic Sclerosis group; Servicio de Medicina Interna, Hospital Universitario Central de Asturias, Oviedo, Spain

12 Servicio de Medicina Interna, Hospital Clinico Universitario, Granada, Spain

13 Servizio di Reumatologia ed Immunologia Clinica, Spedali Civili, Brescia, Italy

14 Dept. of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

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Journal of Translational Medicine 2011, 9(Suppl 2):O4  doi:10.1186/1479-5876-9-S2-O4

The electronic version of this article is the complete one and can be found online at:

Published:23 November 2011

© 2011 Broen et al; licensee BioMed Central Ltd.

This is an open access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Toll like receptors play an important role in fine-tuning innate immune responses, but genetic variations in TLR genes have been shown previously to augment immune responses and susceptibility to autoimmune disease.


To investigate whether polymorphisms in toll like receptor (TLR) genes, previously reported to be associated with immune mediated diseases are implicated in systemic sclerosis (SSc).


We genotyped 14 polymorphisms in the TLR 2, 4, 7, 8 and 9 genes in a discovery cohort comprising 452 SSc patients and 537 controls and a replication cohort consisting of 1170 SSc patients and 925 controls. Furthermore we analyzed 15 year follow-up data from 964 patients to assess the potential association of TLR variants with the development of disease complications. Next to this, we analyzed the functional impact of the associated polymorphism on monocyte derived and myeloid dendritic cells.


Exploiting the discovery cohort, we observed that a rare functional polymorphism in TLR2 (Pro631His), was associated with anti-topoisomerase positivity (p=0.003 OR 2.24 95%CI:1.24-4.04). This observation was validated in the replication cohort (p=0.0001 OR 2.73 95%CI:1.85-4.04). In addition, the replication cohort also revealed an association between the TLR2 variant with the diffuse subform of the disease and the development of pulmonary arterial hypertension, respectively (p=0.02, Log-Rank p=0.003, Cox proportional hazards ratio: 5.61 ((95%CI 1.53-20.58)). Functional analysis revealed that monocyte derived dendritic cells carrying the Pro63His variant produce more inflammatory mediators (TNFalpha and IL-6) upon TLR2 mediated stimulation (both p<0.0001).


The rare TLR2Pro631His variant is robustly associated with anti-topoisomerase positivity, diffuse SSc and the development of PAH. Besides, this variant influences TLR2 mediated cell responses. Further research is necessary to reveal the precise role of TLR2 in the disease pathogenesis of SSc.