Fig 2: Proposed model for the pathogenicity of AECAs in Takayasu arteritis.a APC and HDL, the ligand of EPCR and SR-BI, respectively, suppress expression of adhesion molecules in activated endothelial cells. APC also negatively regulates the differentiation of CD4+ T cells expressing EPCR into Th17 cells, and thus inhibits the production of Th17-related cytokines, including IL-17A, IL-17F, IL-21, and IL-22. These mechanisms contribute to the resolution of vascular inflammation in normal condition. b Autoantibodies against EPCR or SR-BI block bindings of corresponding ligands to their receptors, which promote expression of adhesion molecules in endothelial cells. In addition, anti-EPCR autoantibodies disrupt the negative regulation of Th17 differentiation by APC and thus amplify Th17-mediated immune response. As a result, autoantibodies in TAK inhibit the spontaneous resolution of activated immune responses in the vessel wall and thus lead to the chronic vascular inflammation.

Fig 3: Effects of iron on PQS activity. Inhibition of the release of IFN-γ (A) and IL-17A (B) in murine T cells by PQS was prevented by FeSO4, which alone did not affect cytokine release. Iron reversed the inhibition by PQS of the in vitro differentiation of (C) CD4+FoxP3+ Tregs, (D) CD4+IFN-γ+ Th1 cells, and (E) CD4+IL-17+ Th17 cells; *P<0.05, **P<0.01, ****P<0.001 relative to DMSO; +P<0.05, ++P<0.1 for PQS and iron relative to PQS alone (n = 3). (F) GABA and 2,5-dimethyl-furanone had no effect on IL-17A production, and did not prevent the effect of PQS. (G) In HEK293 cells over-expressing IDO1, PQS reduced kynurenine in the culture medium with no loss of viability using the MTT assay (H).

Fig 4: Differentiation phenotype of CD39+?d Tregs in RSCRC/LSCRC.(A) Representative histogram plot of the expression of IL-17A/IFN-?/PD-1/Tim-3 in/on CD39+ Tregs derived from LSCRC/RSCRC. (B–E) The percentages of IL-17A (B), IFN-? (C), PD-1 (D), and Tim-3 (E) in CD39+?d T cells was calculated. Data are shown as mean ± SEM, using 2-way ANOVA followed by Sidak’s multiple-comparisons test. RSCRC, n = 5; LSCRC, n = 6. Each dot represents 1 patient. N, normal; T, tumor; RSCRC, right-sided colorectal cancer; LSCRC, left-sided colorectal cancer. *P < 0.05, **P < 0.01, ****P < 0.0001.

Fig 5: The expansion of γδT17 cells and upregulation of interleukin (IL)-1β and IL-23 in mucosa-associated lymphoid tissue (MALT) lymphoma patients. (A) Representative immunofluorescence images showing γδT17 (TCRγδ+IL-17+) cells in gastric MALT lymphoma tissues and paired normal tissue. IL-17 in red, TCRγδ in green, and 4′ ,6-diamidino-2-phenylindole (DAPI) in blue; original magnification, 400×. (B) Percentage of γδT17 (TCRγδ+IL-17+) cells in the above groups. (C) Representative immunohistochemistry (IHC) images showing in situ IL-1β and IL-23 in gastric MALT lymphoma tissues and paired normal gastric tissues. (D) Histoscores of IL-1β and IL-23 were statistically higher in gastric MALT lymphoma tissues than control. Original magnification, 400×; **P < 0.01, *P < 0.05.