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.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/toll-like-receptor-3-plays-a-role-in-loss-of-tolerance-to-the-rossa-auto-antigen-in-systemic-lupus-erythematosus/