FRI0017 ACTIVATION OF TOLL-LIKE RECEPTORS IN PERIPHERAL BLOOD MONONUCLEAR CELLS OF TAKAYASU ARTERITIS PATIENTS
Authors: Y. Tian, J. Li, X. Tian, X. Zeng
Journal: Annals of the Rheumatic Diseases (2020)

Background: The activation of self-specific T cells is essential in pathogenesis of Takayasu arteritis (TAK). Dendritic cell (DC) plays an indispensable role as the only antigen presenting cell for initial T cell, and Toll-like receptors (TLRs) are common source of activation signals for DCs. Then we speculate that there are activation of TLRs in TAK patients. Objectives: To investigate the activation of TLRs in TAK patients. Methods: Twenty-seven TAK patients were enrolled during April to October in 2019, with diagnosis met the 1990 criteria of American College of Rheumatology. Patient were divided into groups by the disease activity and medication history. Disease activity was assessed by the 1994 NIH criteria. Quantitative Real-time Polymerase Chain Reaction (RT-qPCR) was used to analyze the mRNA relative abundance of 28 target genes in peripheral blood mononuclear cells (PBMCs). Differences between groups and correlation between any two genes were analyzed. Results: The demographic data and clinical features of TAK patients were shown in Table 1. (1) Compared with health control (HC) group, mRNA abundance of TLR2, TLR4, P50, P65, IκBα, CTLA4, CD3, and BCL6 in untreated TAK group was upregulated (&lt;0.05), whereas mRNA abundance of CD40 was downregulated (p &lt;0.05). (2) Compared with HC group, mRNA abundance of TLR2, TLR4, IκBα, PD-1 and BCL6 in treated TAK group was upregulated (p &lt;0.05), whereas mRNA abundance of LAG3, CD40 and TCR was downregulated (p &lt;0.05). (3) Compared with untreated TAK group, mRNA abundance of P50, P65, CD28, CTLA4, TLR2, TLR4, IκBα, PD-1 and RORC was upregulated in treated TAK group (p &lt;0.05). (4) Compared with non-active treated TAK group, mRNA abundance of p50, CD28, TCR, GATA3, RORC and FOXP3 was upregulated in nonactive treated TAK group (p &lt;0.05). BCL6 showed correlation with the TLRs-NFκB pathway. (Figure 1~2, Table 2) Table 1. Demographic data and clinical features of patients with TAK Age (year) Gender (male/ female) Disease duration* (months) ESR (mm/h) hs-CRP* (mg/L) Interleukin 6 (pg/mL) TNFα(pg/mL) Prednisone used/ non-used Dosage (mg/d) Treated ( n =20) 39.37±9.27 1/19 43 (12, 103) 14.60±8.94 1 (0.55, 5.625) 2.1 (2, 3.95) 7.56±4.39 18/2 10 (10, 32.5) Active ( n =11) 39.30±7.889 1/10 118 (16, 166.5) 16.82±10.81 5.63 (1.49, 8.33) 3.15 (2.025, 5.775) 8.42±5.57 10/1 10 (10, 15) Nonactive ( n =9) 39.44±10.59 0/9 40 (12, 44) 11.89±4.61 0.84 (0.31, 1) 2 (2, 2.4) 6.60±2.11 8/1 8.75 (6.875, 16.25) P value 0.89 — 0.16 0.34 0.02 0.08 0.65 — 0.37 Untreated ( n =7) Active ( n =4) 1 31 M — 91 140.72 — — — 0 2 25 F — 19 11.28 6.3 5.2 — 0 3 23 M — 71 77.36 6.3 6.2 — 0 4 29 F — 127 113.62 22.2 8.4 — 0 Nonactive ( n =3) 5 34 F — 7 0.34 2 4.3 — 0 6 27 F — 14 0.16 25.7 4 — 0 7 38 F — 5 0.32 3 4 — 0 * median (min, max) Table 2. Genes expressed abnormally in PBMCs of TAK patients Abnormally expressed in untreated TAK Abnormally expressed in treated TAK Influenced by treatment Associated with the TAK activity upregulated downregulated upregulated downregulated upregulated downregulated Upregulated downregulated Genes associated with the TLRs-NFκB pathway TLR2, TLR4, p50, p65, IκBα — TLR2, TLR4, IκBα — — p50, p65 p50 — Positive and negative costimulatory molecules and their ligands CTLA4 CD40 PD-1 CD40, LAG3 — CD28, CTLA4 CD28 — Genes associated with the activation or differentiation of T cell or B cell CD3, BCL6 — BCL6 TCR — CD3, TCR, RORC TCR, GATA3, RORC, FOXP3 — Conclusion: TLRs-NFκB pathway may be activated in TAK patients, with upregulation of BCL6 , and there may be deficiency of CD40 . TLR2, TLR4, PD-1, LAG3, CD40 and BCL6 may play roles in the pathogenesis of TAK. p50, CD28, TCR, GATA3, RCRC and FOXP3 may be related to the disease activity of TAK. Disclosure of Interests: Yixiao Tian: None declared, Jing Li: None declared, Xinping Tian: None declared, Xiaofeng Zeng Consultant of: MSD Pharmaceuticals