Evidence for associations between Th1/Th17 "hybrid" phenotype and altered lipometabolism in very severe Graves' orbitopathy.

PURPOSE: To investigate the characteristics of Th1 and Th17 cell lineages for very severe Graves' orbitopathy (GO) development. METHODS: Flow cytometry was performed with blood samples from GO and Graves' disease (GD) patients and healthy controls, to explore effector T cell phenotypes. Lipidomics was conducted with sera from very severe GO patients before and after glucocorticoids (GCs) therapy. Immunohistochemistry and western blotting were used to examine orbital-infiltrating Th17 cells or in vitro models of Th17 polarization. RESULTS: In GD, Th1 cells predominated in peripheral effector T cell subsets while in GO, Th17 lineages predominated. In moderate-to-severe GO, Th17.1 cells expressed RORgammat independently and produced IL-17A while in very severe GO, Th17.1 cells co-expressed RORgammat and Tbet and produced IFN-gamma. Increased IFN-gamma-producing Th17.1 cells positively correlated with GO activity and were associated with the development of very severe GO. Additionally, GCs therapy inhibited both Th1 and Th17 lineages and modulated a lipid panel consisting of 79 serum metabolites. However, in GCs resistant very severe GO, IFN-gamma-producing Th17.1 cells were still at a high level, correlating with increased serum triglycerides. Further, retroorbital tissues from GCs resistant very severe GO were shown to be infiltrated by CXCR3+ Th17 cells expressing Tbet and STAT4 and rich in triglycerides that promoted Th1 phenotype in Th17 cells in vitro. CONCLUSIONS: Our findings address the importance of Th17.1 cells in GO pathogenesis, possibly promoting our understanding of the association between Th17 cell plasticity and disease severity of GO.