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Abstract Number: 1617

Toll-Like Receptor 3 Plays a Role In Loss Of Tolerance To The Ro/SSA Auto-Antigen In Systemic Lupus Erythematosus

Julie Ducreux1, Christine Galant2, Julie Verbeeck2, Pierre Coulie3, Benoît Van den Eynde3, Frédéric A. Houssiau1 and Bernard Lauwerys2, 1Institut de Recherche Expérimentale et Clinique, Pôle de Maladies Rhumatismales, Université catholique de Louvain, Brussels, Belgium, 2Pôle de Maladies Rhumatismales, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium, 3Institut de Duve, Université catholique de Louvain, Brussels, Belgium

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: systemic lupus erythematosus (SLE) and toll-like receptors

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Session Information

Session Title: Systemic Lupus Erythematosus-Human Etiology and Pathogenesis: Genetics and Genomics

Session Type: Abstract Submissions (ACR)

Background/Purpose: Toll-like Receptor (TLR)7 and TLR9 play a role in the pathogenesis of systemic lupus erythematosus (SLE) by inducing Interferon (IFN)-α and IFN-induced genes expression. However, recent data indicate that other agonists inside the type I IFN system could be involved in the pathogenesis of the disease. In the present study, we described the presence of IFN-β in cutaneous lesions of patients with SLE, an observation that led us to investigate the role of TLR3 in the disease.

Methods: IFN-β evaluation in SLE skin biopsies versus controls was performed by immunohistochemistry. The variations in the genomic sequence of the TLR3 gene were first explored in a population of Western-European SLE patients versus age- and gender-matched healthy controls, using 8 Tag SNP from the HapMap database. In addition, the distribution of TLR3 rs3775291 alleles and genotypes were assessed in two independent populations of Western- and Southern-European SLE patients (n = 197 and 282, respectively) and controls (n = 262 and 291, respectively). Functional experiments were performed on peripheral blood mononuclear cells (PBMC) and monocyte-derived dendritic cells (moDC) generated from PBMC of healthy individuals categorized according to their TLR3 rs3775291 genotype. Anti-Ro/SSA- specific T cells were derived from PBMC of healthy individuals by repeated stimulations with autologous Ro/SSA-pulsed moDC.

Results: We found a positive IFN-β immunostaining in skin lesions of SLE patients, compared to controls. This result prompted us to evaluate the potential role of TLR3 in the pathogenesis of the disease. Out of the 8 TLR3 Tag SNP, 2 are significantly associated with SLE in Western-European anti-Ro/SSA antibody (Ab)-positive patients. None of these intronic SNP have a functional impact. However, one of them is in linkage disequilibrium with rs3775291, a SNP that encodes an amino-acid substitution in the ligand-binding pocket of TLR3. We found a positive association between rs3775291 and susceptibility to SLE in patients with anti-Ro/SSA Ab, in two independent populations of SLE patients and controls. We confirmed that the rs3775291 major allele, which is enriched in anti-Ro/SSA Ab-positive patients, is associated with increased TLR3 responses to stimulation. In addition, moDC from individuals homozygous for the susceptibility TLR3 rs3775291 allele are more susceptible to UV-induced apoptosis, thereby resulting in the release of larger amounts of the Ro/SSA autoantigen in response to UV irradiation. UV exposure of dendritic cells from individuals homozygous for the susceptibility TLR3 rs3775291 allele also results in higher interleukin-6 secretion, and cell surface expression of MHC II molecules and CD86. Finally, we found that UV exposure of Ro/SSA-pulsed moDC from individuals homozygous for the susceptibility TLR3 rs3775291 allele leads to a higher activation of auto-reactive autologous CD4+ T cells.

Conclusion: rs3775291, a functional SNP in the TLR3 gene, is associated with susceptibility to SLE in anti-Ro/SSA Ab-positive patients, and facilitates loss of tolerance to the Ro/SSA auto-antigen through increased maturation of moDC after UV exposure.


Disclosure:

J. Ducreux,
None;

C. Galant,
None;

J. Verbeeck,
None;

P. Coulie,
None;

B. Van den Eynde,
None;

F. A. Houssiau,
None;

B. Lauwerys,
None.

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