Session Type: ACR Poster Session C
Session Time: 9:00AM-11:00AM
Toll-like receptor 7 (TLR7) is implicated in the production of type I IFNs and the activation of B cells in systemic lupus erythematosus (SLE). Genetic studies support a link between TLR7 rs3853839 C/G polymorphism, associated with an increase in TLR7 expression and SLE susceptibility. While much has been reported on TLR7 in murine lupus, very little is known about how increased TLR7 signaling may contribute to human B cell function and to SLE pathology. This study was undertaken to determine how variations in TLR7 expression affects peripheral B cell populations, auto-Ab production and cytokine expression levels in SLE patients.
Human peripheral blood mononuclear cells (PBMCs) were collected from SLE patients and healthy controls (HC) and analyzed for the expression of TLR7 and IFN-stimulated genes (ISGs) by real-time PCR. SLEDAI scores were obtained from clinical records. Frequencies of peripheral B cell population were analyzed by multicolor flow cytometry. Autoreactive cells were identified by fluorescently-labeled SmRNP. Autoantibody profiles were quantified by protein microarray and analyzed by Significance Analysis of Microarrays (SAM). Cytokines in the serum were measured by bead-based ELISA.
High TLR7 expression in SLE patients was associated with a more pronounced IFN signature. 75.0% of TLR7hi SLE patients were TLR7 rs3853839 G (risk) allele-carriers, compared to 47.06% in TLR7norm/lo SLE and 33.33% in HC. High TLR7 expression correlated with an increase in IFNα and IFNγ levels in the serum but did not correlate with serum BAFF levels. Analysis of peripheral B cell subsets in TLR7hi SLE patients showed an increase of CD19+ B cells, expansion of transitional B cells and pre-plasma cells as compared to TLR7norm/lo and HCs. TLR7hi B-cells showed an increase in IL-6 and a decrease in IL-10 gene expression. TLR7hi SLE patients displayed increased frequencies of Sm/RNP-specific B cells, which were found mostly within the CD27–IgD+ naïve B cell pool. IgG microarray revealed an increase in auto-Ab titers, enrichment for more autoantibody specificities, and skewing towards Sm/RNP specificities in the TLR7hi SLE group. Importantly, TLR7hi SLE patients had a higher disease activity (mean ± SD SLEDAI 6.56 ± 0.95 versus 3.07 ± 0.6 in TLR7norm/lo, p=0.007) and were more likely to develop lupus nephritis, supporting the clinical significance of our findings.
Our studies provide new insights into the role of TLR7 signaling in human SLE. Variation in TLR7 expression dictated by genetic variation affecting TLR7 RNA turnover appears to “shape” B cell maturation and the auto-Ab repertoire. In addition, high TLR7 is associated with IFN production, possibly linked to immune complex production. TLR7 expression may, therefore, serve as a useful biomarker in SLE. TLR7hi SLE patients, particularly the TLR7 rs3853839 G (risk) allele-carriers, represent a distinct population who could respond well to anti-TLR7 and/or type I and type II IFN – targeted therapies.
To cite this abstract in AMA style:Wang T, Marken J, Tran V, Li M, Cerosaletti K, Elkon KB, Zeng X, Giltiay NV. Increased Toll-like Receptor 7 Expression Promotes B Cell Abnormalities and Skewing of Cytokine and Autoantibody Profiles in SLE Patients [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/increased-toll-like-receptor-7-expression-promotes-b-cell-abnormalities-and-skewing-of-cytokine-and-autoantibody-profiles-in-sle-patients/. Accessed July 3, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/increased-toll-like-receptor-7-expression-promotes-b-cell-abnormalities-and-skewing-of-cytokine-and-autoantibody-profiles-in-sle-patients/