FRI0017 ACTIVATION OF TOLL-LIKE RECEPTORS IN PERIPHERAL BLOOD MONONUCLEAR CELLS OF TAKAYASU ARTERITIS PATIENTS

Abstract

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 ofTLR2, TLR4, P50, P65, IκBα, CTLA4, CD3,andBCL6in untreated TAK group was upregulated (<0.05), whereas mRNA abundance ofCD40was downregulated (p <0.05). (2) Compared with HC group, mRNA abundance ofTLR2, TLR4, IκBα, PD-1 and BCL6in treated TAK group was upregulated (p <0.05), whereas mRNA abundance ofLAG3, CD40andTCRwas downregulated (p <0.05). (3) Compared with untreated TAK group, mRNA abundance ofP50, P65, CD28, CTLA4, TLR2, TLR4, IκBα, PD-1 and RORCwas upregulated in treated TAK group (p <0.05). (4) Compared with non-active treated TAK group, mRNA abundance ofp50, CD28, TCR, GATA3, RORC and FOXP3was upregulated in nonactive treated TAK group (p <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 TAKAge (year)Gender (male/ female)Disease duration* (months)ESR (mm/h)hs-CRP* (mg/L)Interleukin 6 (pg/mL)TNFα(pg/mL)Prednisoneused/ non-usedDosage (mg/d)Treated (n=20)39.37±9.271/1943 (12, 103)14.60±8.941 (0.55, 5.625)2.1 (2, 3.95)7.56±4.3918/210 (10, 32.5) Active (n=11)39.30±7.8891/10118 (16, 166.5)16.82±10.815.63 (1.49, 8.33)3.15 (2.025, 5.775)8.42±5.5710/110 (10, 15) Nonactive (n=9)39.44±10.590/940 (12, 44)11.89±4.610.84 (0.31, 1)2 (2, 2.4)6.60±2.118/18.75 (6.875, 16.25) Pvalue0.89—0.160.340.020.080.65—0.37Untreated (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 patientsAbnormally expressed in untreated TAKAbnormally expressed in treated TAKInfluenced by treatmentAssociated with the TAK activityupregulateddownregulatedupregulateddownregulatedupregulateddownregulatedUpregulateddownregulatedGenes associated with the TLRs-NFκB pathwayTLR2, TLR4, p50, p65, IκBα—TLR2, TLR4, IκBα——p50, p65p50—Positive and negative costimulatory molecules and their ligandsCTLA4CD40PD-1CD40, LAG3—CD28, CTLA4CD28—Genes associated with the activation or differentiation of T cell or B cellCD3, BCL6—BCL6TCR—CD3, TCR, RORCTCR, GATA3, RORC, FOXP3—Conclusion:TLRs-NFκB pathway may be activated in TAK patients, with upregulation ofBCL6, and there may be deficiency ofCD40.TLR2, TLR4, PD-1, LAG3, CD40andBCL6may play roles in the pathogenesis of TAK.p50, CD28, TCR, GATA3, RCRCandFOXP3may 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