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  • Open Access

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

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Journal of Translational Medicine20119 (Suppl 2) :O4

  • Published:


  • Dendritic Cell
  • Toll
  • Toll Like Receptor
  • Pulmonary Arterial Hypertension
  • Systemic Sclerosis


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.

Authors’ Affiliations

Dept. of Rheumatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
Instituto de Parasitología y Biomedicina, CSIC, Granada, Spain
Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico and University of Milan, Italy
Dept. of Rheumatology, Lund University, Lund, Sweden
Rheumatic Diseases Centre, University of Manchester, Salford Royal NHS Foundation Trust, UK
Dept. of Dermatology, University of Cologne, Germany
Centre for Rheumatology, Royal Free and University College Medical School, London, UK
Dept. of Rheumatology and Clinical Immunology, Charité University Hospital and German Rheumatism Research Centre, a Leibniz institute, Berlin, Germany
Dept. of Internal Medicine, Division of Rheumatology, University of Vienna, Austria
Servicio de Medicina Interna, Hospital Valle de Hebron, Barcelona, Spain
For the Spanish Systemic Sclerosis group; Servicio de Medicina Interna, Hospital Universitario Central de Asturias, Oviedo, Spain
Servicio de Medicina Interna, Hospital Clinico Universitario, Granada, Spain
Servizio di Reumatologia ed Immunologia Clinica, Spedali Civili, Brescia, Italy
Dept. of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands


© Broen et al; licensee BioMed Central Ltd. 2011

This article is published under license to 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.