Table 1.
Recommended Studies on T cell Pathogenesis in GO.
| Reference | Study subjects | Main findings | |
|---|---|---|---|
| T cell immunity and TCR repertoires | |||
| Heufelder et al. (12) | Biopsies of thyroid glands, orbital connective tissues, pretibial skins, and PBMCs from two GD patients with both orbitopathy and dermopathy and two non-GO controls | Both orbital connective tissues and pretibial connective tissues were infiltrated by CD3+ T cells; Marked similarities of intrathyroidal, orbital, and pretibial TCR gene repertoires were found, which indicate apparent TCR restriction and T cell oligoclonality. | |
| Pappa et al. (13) | Biopsies of EOMs from five early active GO patients, nine late stable GO patients, and 14 non-GO patients | CD4+ and CD8+ T cells and macrophages were significantly present in EOMs of active GO compared with both stable GO and controls; Increased HLA-DR expression on OFs, but not EOM fibres, was observed in both active and stable GO. | |
| Rotondo Dottore et al. (14) | Biopsies of orbital connective tissues from 20 consecutive GO patients | A positive correlation was found between CD3+ T and CD20+ B cells infiltrating orbital connective tissues with GO clinical activity. | |
| Wang et al. (15) | Biopsies of thyroid glands and PBMCs from six GD patients; PBMCs from 43 GO patients and 57 stable GD patients | A model for prediction of GO progression in GD cohort with high sensitivity and specificity. | |
| Aniszewski et al. (16) | 117 CD4+ T cell clones expanded from orbital connective tissues of 6 GO patients | Th1 immune response predominated in early active GO and Th2 immune response predominated in late stable GO. | |
| Effector T cell, OF, and fibrocyte interaction | |||
| Feldon et al. (17) | GO and control OFs; autologous T cells from PBMCs | Autologous T cells promoted the proliferation of GO OFs dependent on MHC class II and CD40-CD40L pathways. | |
| Hwang et al. (18) | GO and control OFs | GO OFs expressed elevated levels of CD40 that could be further up-regulated by IFN-γ; CD40-CD40L combination led to IL-6, IL-8, and MCP-1 production in GO OFs; CD90+ GO OFs expressed more CD40 than CD90- GO OFs. | |
| van Steensel et al. (19) | Biopsies of orbital connective tissues from GO patients and controls; GO OFs | Mast cells, monocytes, and macrophages expressed increased levels of PDGF-A and PDGF-B in GO orbital connective tissues; PDGF-AB and PDGF-BB promoted proliferation and hyaluronan and IL-6 production by GO OFs. | |
| Tsui et al. (20) | Biopsies of thyroid glands and orbital connective tissues; GO and control OFs; thyrocytes | TSHR levels were higher on thyrocytes than GO and control OFs; Differentiation of GO OFs, but not control OFs, into adipocytes led to increased TSHR expression; IGF-1R levels were higher on GO OFs than control OFs; TSHR and IGF-1R colocalized to the perinuclear and cytoplasmic areas of both GO OFs and thyrocytes. | |
| Cao et al. (21) | GO and control OFs | CD40-CD40L combination led to the synthesis of hyaluronan and PGE2 in GO OFs; PGE2 production in GO OFs was caused by increased expression of PGSH-2 at both transcriptional and translational levels regulated by IL-1α expression | |
| Koumas et al. (22) | GO OFs; myometrial fibroblasts | CD90+ myometrial fibroblasts and GO OFs were capable of myofibroblast differentiation by TGF-β or platelet concentrate supernatant treatment; CD90- myometrial fibroblasts and GO OFs were capable of lipofibroblast differentiation by 15-deoxy-Δ12,14-PGJ2 or ciglitazone treatment. | |
| Antonelli et al. (23) | Sera from consecutive subjects including 60 GD patients, 60 GO patients, and 60 controls; GO thyrocytes, OFs, and induced preadipocytes; Control fibroblasts and induced preadipocytes from dermal tissues of the same patients | CXCL10 was higher in GD and GO patients than controls; CXCL10 was significantly higher in active GO patients than inactive GO patients; IFN-γ and TNF-α synergistically induced CXCL10 production in GO thyrocytes, OFs, and preadipocytes, which was suppressed by PPAR-γ agonist. | |
| Antonelli et al. (24) | GO thyrocytes, OFs, and induced preadipocytes; Control fibroblasts and induced preadipocytes from dermal tissues of the same patients | IFN-γ and TNF-α synergistically induced CXCL9 and CXCL11 production in GO thyrocytes, OFs, and preadipocytes, which was suppressed by PPAR-γ agonist. | |
| Han et al. (25) | GO and control OFs | IFN-γ and IL-4 attenuated IL-1β-provoked PGE2 production by suppressing PGHS-2 gene promoter activity but enhanced IL-1β-initiated hyaluronan production by up-regulating hyaluronan synthase-2 gene expression in GO OFs. | |
| Han et al. (26) | GO and control OFs | IFN-γ and IL-4 attenuated IL-1β-induced TIMP-1 production by suppressing TIMP-1 gene promoter activity in GO OFs. | |
| Huber et al. (27) | Whole blood from 216 GD patients and 368 healthy controls | rs2201841 was strongly associated with GO development, especially AA and CC genotypes of Il23r. | |
| Douglas et al. (28) | Biopsies of orbital connective tissues; PBMCs from 70 GD patients (including 51 GO patients) and 25 healthy controls; GO and control OFs; thyrocytes; fibrocytes | CD34+CXCR4+Collagen I+TSHR+ fibrocytes were increased in PBMCs of GD patients; TSH induced fibrocytes to produce IL-6 and TNF-α; Increased fibrocytes were found in orbital connective tissues of GO patients. | |
| Gillespie et al. (29) | PBMCs from 31 GO patients and 19 healthy controls; GO OFs; GO and control fibrocytes | Fibrocytes expressed higher levels of TSHR than GO OFs; GO fibrocytes expressed higher levels of TSHR than control fibrocytes; TSH or M22 greatly stimulated the production of various cytokines and chemokines such as IL-8, RANTES, and MCP-1 in both GO and control fibrocytes. | |
| Fang et al. (30) | Biopsies of orbital connective tissues; PBMCs from 34 GO patients and 36 healthy controls; GO and control OFs; in vitro-differentiated Th17 cells | GO peripheral Th17 cells produced IFN-γ and IL-22 and were related to clinical activity score; IL-17A enhanced TGF-β–induced fibrosis in CD90+ OFs but inhibited 15-deoxy-Δ12,14-PGJ2–induced adipogenesis in CD90- OFs; Th17 cells stimulated proinflammatory cytokine expression of GO OFs and GO OFs promoted Th17 cell differentiation by PGE2 production. | |
| Fang et al. (31) | 21 GO orbital connective tissues and 38 control orbital connective tissues; CD34+ GO OFs; in vitro-differentiated Th17 cells | GO orbital microenvironment was composed of T cells, B cells, natural killer cells, dendritic cells, macrophages, plasma cells, and CD34+ OFs; Orbit-infiltrating Th17 cells displayed a Th1-like phenotype and expressed high levels of IL-1R and IL-23R; CD34+ OFs enhanced IL-1R and IL-23R expression on Th17 cells by PGE2-EP2/EP4-cAMP signaling. | |
| Fang et al. (32) | PBMCs from 16 active and 14 stable GO patients and 20 healthy controls; GO and control fibrocytes; in vitro-differentiated Th17 cells | IL-17A stimulated cytokine production in both GO and control fibrocytes; Autologous Th17 cells promoted inflammatory and antigen-presenting functions of GO fibrocytes; GO fibrocytes enhanced Th17 cell phenotype and recruited Th17 cells by MIP-3 and CCR6 combination. | |
| Fang et al. (33) | Biopsies of orbital connective tissues; Sera and PBMCs from consecutive subjects including 37 GO patients, 38 GD patients, and 32 healthy controls | Increased CXCR3+ IFN-γ–producing Th17.1 cells were positively correlated with GO activity and associated with the development of very severe GO; In GC-resistant, very severe GO patients, CXCR3+ IFN-γ–producing Th17.1 cells remained at high levels in blood and orbital connective tissues, which were positively correlated with elevated triglycerides. | |
| Fernando et al. (34) | GO OFs; GO and control fibrocytes | TSH and M22 induced IL-23, but not IL-12, expression in fibrocytes, while they induced IL-12 production in GO OFs; The shift from IL-23 expression in fibrocytes to that of IL-12 in CD34+ GO OFs was regulated by Slit2. | |
| GO animal model | |||
| Moshkelgosha et al. (35) | hTSHR-A subunit plasmid-immunized BALB/c mice | TSHR was the pathogenic antigen in GO; Interstitial inflammation of extraocular muscles with CD3+ T cells, F4/80+ macrophages, and mast cells, accompanied by glycosaminoglycan deposition was observed in murine orbits. | |
| Zhang et al. (36) | hTSHR-A subunit-expressing adenovirus-immunized BALB/c mice | Fibrosis and adipogenesis accompanied by CD4+ T cell infiltration were seen in murine periorbital fat tissues; Increased frequencies of Th1 cells and decreased frequencies of Th2 cells and regulatory T cells were shown in the splenocytes of GO mice. | |
| Masetti et al. (37) | hTSHR-A subunit plasmid-immunized BALB/c mice | Bacteroides and Bifidobacterium counts were more abundant in mice in Center 1, while Lactobacillus counts were more abundant in mice in Center 2; Significantly higher yeast counts were found in Center 1 TSHR-immunized mice; A significant positive correlation was found between the presence of Firmicutes and orbital adipogenesis in Center 2 TSHR-immunized mice. | |