TLR3 plays a role in loss of tolerance to the Ro/SSA auto-antigen in systemic lupus erythematosus
(2013) Annual meeting of the American College of Rheumatology — Location: San Diego (26.October.2013)
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- Abstract
- Background/Purpose: Toll-like Receptor (TLR)3 is an endosomal TLR that binds double-stranded viral RNA and endogenous double-stranded RNA-like structures. Recently, it has been reported that UV irradiation causes changes in self noncoding RNAs, which induce TLR3-dependent inflammatory responses resulting in solar injury. Since the TLR3 gene is located in 4q35, a chromosomic region associated with susceptibility to systemic lupus erythematosus (SLE) in patients with anti-Ro/SSA antibodies (Ab), and since photosensitivity is a major clinical symptom in patients carrying these autoantibodies, we investigated the role of TLR3 in the pathogenesis of SLE. Methods: The variations in the genomic sequence of TLR3 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: Out of the 8 TLR3 Tag SNP, 2 are significantly associated with SLE in Western-European anti-Ro/SSA 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.
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Ducreux, J., Gutierrez-Roelens, I., Galant, C., Marot, L., Bozzolo, E., D’Alfonso, S., Coulie, P., Van den Eynde, B., Houssiau, F., & Lauwerys, B. (2013). TLR3 plays a role in loss of tolerance to the Ro/SSA auto-antigen in systemic lupus erythematosus. Annual meeting of the American College of Rheumatology, San Diego. https://hdl.handle.net/2078.5/234037