Identification of the Association Between Toll-Like Receptors and T-Cell Activation in Takayasu’s Arteritis

Abstract

To explore the relationships between Toll-like receptors (TLRs) and the activation and differentiation of T-cells in Takayasu’s arteritis (TAK), using real-time fluorescence quantitative polymerase chain reaction, mRNA abundance of 29 target genes in peripheral blood mononuclear cells (PBMCs) were detected from 27 TAK patients and 10 healthy controls. Compared with the healthy control group, the untreated TAK group and the treated TAK group had an increased mRNA level of TLR2 and TLR4. A sample-to-sample matrix revealed that 80% of healthy controls could be separated from the TAK patients. Correlation analysis showed that the inactive-treated TAK group exhibited a unique pattern of inverse correlations between the TLRs gene clusters (including TLR1/2/4/6/8, BCL6, TIGIT, NR4A1, etc) and the gene cluster associated with T-cell activation and differentiation (including TCR, CD28, T-bet, GATA3, FOXP3, CCL5, etc). The dynamic gene co-expression network indicated the TAK groups had more active communication between TLRs and T-cell activation than healthy controls. BCL6, CCL5, FOXP3, GATA3, CD28, T-bet, TIGIT, IκBα, and NR4A1 were likely to have a close functional relation with TLRs at the inactive stage. The co-expression of TLR4 and TLR6 could serve as a biomarker of disease activity in treated TAK (the area under curve/sensitivity/specificity, 0.919/100%/90.9%). The largest gene co-expression cluster of the inactive-treated TAK group was associated with TLR signaling pathways, while the largest gene co-expression cluster of the active-treated TAK group was associated with the activation and differentiation of T-cells. The miRNA sequencing of the plasma exosomes combining miRDB, DIANA-TarBase, and miRTarBase databases suggested that the miR-548 family miR-584, miR-3613, and miR-335 might play an important role in the cross-talk between TLRs and T-cells at the inactive stage. This study found a novel relation between TLRs and T-cell in the pathogenesis of autoimmune diseases, proposed a new concept of TLR-co-expression signature which might distinguish different disease activity of TAK, and highlighted the miRNA of exosomes in TLR signaling pathway in TAK.

Animal models for large vessel vasculitis – The unmet need

“…TLR has been implicated in the pathogenesis of LVV. [ 16 , 17 , 18 , 19 ] In theory, it is possible to activate adventitial DC in segments of large arteries by systemic administration of TLR ligands in genetic susceptible animals, but such genetically susceptible animal models are not yet identified. Alternatively, TLR ligands can be injected via originating arteries feeding vasa vasorum of certain segments of aorta or main aorta branches ( Figure 1 ), so that a high concentration gradient of TLR ligands can be achieved at the vasa vasorum to adventitial DC since vasa vasorum are end-arteries solely responsible for supplying blood to the local tissue.…”

Medium-vessel and large-vessel vasculitis in children

“…The pathogenesis of Takayasu arteritis is still relatively poorly understood. The elucidation of pathogenic role of T lymphocytes as the source of interferon-g (IFN-g) and the specific role of novel TH-17 sub-populations (Th17.1 and PD1þTh17) combined with reduced peripheral regulatory T cells as well as specific gene signatures for follicular helper T cells in the circulation and aortic tissue of patients with Takayasu arteritis offer insights into the pathogenesis of Takayasu arteritis [13][14][15][16][17]. Macrophage subpopulations in the aortic tissues of patients with Takayasu arteritis have also been reported on in two recent studies [18,19].…”