PD-1/PD-L1 affects Graves progression through lymphocytes on the proliferation, apoptosis and inflammatory cytokine secretion of thyroid follicular epithelial cells

Han, Hongwei; Fu, Xiaodan; Huang, Jiao; Zhang, Xianfeng; Yu, Jianyi

doi:10.2131/jts.45.701

Cited by 6 publications

(5 citation statements)

References 26 publications

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“…Our data shows that PD-L1 also inhibits the expression of CD40L in T cells, which is in line with the finding in an inflammatory model ( 37 ). Recent studies suggested that PD-1/PD-L1 could partially inhibit the pathogenesis of GD ( 22 – 25 ). Moreover, the application of a PD-1 inhibitor resulted in some symptoms similar to TAO ( 21 ).…”

Section: Discussionmentioning

confidence: 99%

“…More importantly, the application of a PD-1 inhibitor presented clinical symptoms of TAO, including exophthalmos and enlargement of extraocular muscles ( 21 ). Interestingly, the PD-1/PD-L1 pathway is also operative in the pathogenesis of GD and may be a compensatory mechanism to restrain the autoimmune system but probably not to the extent of hindering the progression of GD ( 22 – 25 ). Due to the absence of research about the PD-1/PD-L1 pathway in TAO, however, the role of the PD-1/PD-L1 pathway in the pathogenesis of TAO remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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PD-L1 Inhibits T Cell-Induced Cytokines and Hyaluronan Expression via the CD40-CD40L Pathway in Orbital Fibroblasts From Patients With Thyroid Associated Ophthalmopathy

Liu

Mingming

et al. 2022

Front. Immunol.

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Thyroid associated ophthalmopathy (TAO), characterized by T cell infiltration and orbital fibroblast activation, is an organ-specific autoimmune disease which is still short of effective and safety therapeutic drugs. The PD-1/PD-L1 pathway has been reported hindering the progression of Graves’ disease to some extent by inhibiting T cell activity, and tumor therapy with a PD-1 inhibitor caused some adverse effects similar to the symptoms of TAO. These findings suggest that the PD-1/PD-L1 pathway may be associated with the pathogenesis of TAO. However, it remains unknown whether the PD-1/PD-L1 pathway is involved in orbital fibroblast activation. Here, we show that orbital fibroblasts from patients with TAO do not express PD-L1. Based on in vitro OF-T cell co-culture system, exogenous PD-L1 weakens T cell-induced orbital fibroblast activation by inhibiting T cell activity, resulting in reduced production of sICAM-1, IL-6, IL-8, and hyaluronan. Additionally, exogenous PD-L1 treatment also inhibits the expression of CD40 and the phosphorylation levels of MAPK and NF-κB pathways in orbital fibroblasts of the OF-T cell co-culture system. Knocking down CD40 with CD40 siRNA or down-regulating the phosphorylation levels of MAPK and NF-κB pathways with SB203580, PD98059, SP600125, and PDTC can both reduce the expression of these cytokines and hyaluronan. Our study demonstrates that the orbital immune tolerance deficiency caused by the lack of PD-L1 in orbital fibroblasts may be one of the causes for the active orbital inflammation in TAO patients, and the utilization of exogenous PD-L1 to reconstruct the orbital immune tolerance microenvironment may be a potential treatment strategy for TAO.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PD-L1 Inhibits T Cell-Induced Cytokines and Hyaluronan Expression via the CD40-CD40L Pathway in Orbital Fibroblasts From Patients With Thyroid Associated Ophthalmopathy

Liu

Mingming

et al. 2022

Front. Immunol.

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“…One possible explanation is that there may be a counter‐regulatory or compensatory transient increase in circulating PD‐1 + CD4 + T cells in response to excessive activation of autoreactive T cells during the initial phase of Graves' disease. Another explanation is that secondary increases in PD‐1 + CD4 + T lymphocytes may accelerate development of Graves' disease by promoting the growth of thyroid follicular epithelial cells and inhibiting their apoptosis because a previous study demonstrated that in mouse thyroid follicular epithelial cells cocultured with PD‐1 + CD4 + and PD‐1 + CD8 + T lymphocytes, the cell viability, thyroid hormones, and TRAb titre were increased, whereas the cell apoptosis and TSH levels were decreased 21 . To control the activation level of autoreactive T cells in such a situation and to prevent further increases in the levels of these cells, PD‐1 may be increasingly expressed in the membrane of T lymphocytes, which may induce a vicious cycle, thus leading to the further development of Graves' disease.…”

Section: Discussionmentioning

confidence: 99%

Effects of treatment with methimazole on circulating CD4⁺ and CD8⁺ T cells positive for programed cell death protein‐1 and on subsets of CD4⁺ T cells in untreated hyperthyroid patients with Graves' disease

Hirao

Iijima

Tanuma

et al. 2022

Clinical Endocrinology

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Objective: We investigated longitudinal changes in circulating CD4 + and CD8 + T cells positive for programed cell death protein-1 (PD-1) and in other subsets of CD4 + T cells in untreated hyperthyroid patients with Graves' disease after treatment with methimazole (MMI).Design and Patients: The study included 18 untreated hyperthyroid patients with Graves' disease and 18 age-matched controls. Before and after 12-week treatment with MMI, we used flow cytometry to measure circulating PD-1 + D4 + and PD-1 + CD8+ T cells and subsets of CD4 + T cells in peripheral blood, as well as serum levels of chemokines related to T-helper type 1 (Th-1) and Th-2 cells.Results: At baseline, the percentage of CD4 + and CD8 + T cells expressing PD-1 was significantly higher in patients than in age-matched controls. Serum levels of chemokines related to Th-1 and Th-2 also were higher in patients. Twelve weeks after initiation of MMI, the percentage of CD4 + T cells expressing PD-1 was significantly lower than at baseline, but no such change was seen in CD8 + T cells.Furthermore, the percentage of Th-1 cells among CD4 + T cells and the serum levels of soluble CD26/dipeptidyl peptidase-4, a surface marker of Th-1 cells, also were significantly lower than at baseline. Conclusions:The expression of PD-1 on circulating CD4 + and CD8 + T cells is increased in hyperthyroid patients with active Graves' disease. MMI significantly decreases levels of circulating PD-1 + CD4 + T cells, suggesting that PD-1 + T lymphocytes may be associated with the pathogenesis of Graves' disease.

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“…The PD-1/PD-L1 pathway is involved in maintaining immune intolerance and restraining autoimmune reactivity in patients with AITD [ 17 , 18 ]. In particular, PD-L1 expression in thyroid follicular cells and intra-thyroidal infiltrating lymphocytes might play a key role in the chronic progressive pattern of AITD [ 3 ].…”

Section: Discussionmentioning

confidence: 99%

Programmed Cell Death-Ligand 1 (PD-L1) gene Single Nucleotide Polymorphism in Graves’ Disease and Hashimoto’s Thyroiditis in Korean Patients

et al. 2021

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Background: Programmed cell death-ligand 1 (PD-L1) has an important role in regulating immune reactions by binding to programmed death 1 (PD-1) on immune cells, which could prevent the exacerbation of autoimmune thyroid disease (AITD). The aim of this study was to evaluate the association of PD-L1 polymorphism with AITD, including Graves' disease (GD) and Hashimoto's thyroiditis (HT). Methods: A total of 189 GD patients, 234 HT patients, and 846 healthy age-and sex-matched controls were enrolled in this study. We analyzed PD-L1 single nucleotide polymorphism (SNP) (rs822339) and investigated the associations with clinical disease course and outcome. Results: Genotype frequency at the PD-L1 marker RS822339 in GD (P=0.219) and HT (P=0.764) patients did not differ from that among healthy controls. In patients with GD, the A/G or G/G genotype group demonstrated higher TBII titer (20.6±20.5 vs. 28.0± 25.8, P=0.044) and longer treatment duration (39.0±40.4 months vs. 62.4±65.0 months, P=0.003) compared to the A/A genotype group. Among patients in whom anti-thyroid peroxidase (TPO) antibody was measured after treatment of GD, post-treatment anti-TPO positivity was higher in the A/G or G/G genotype group compared to the A/A genotype group (48.1% vs. 69.9%, P=0.045). Among patients with HT, there was no significant difference of anti-TPO antibody positivity (79.4% vs. 68.6%, P=0.121), anti-thyroglobulin antibody positivity (80.9% vs. 84.7%, P=0.661), or development to overt hypothyroidism (68.0% vs. 71.1%, P=0.632) between the A/A genotype group and the A/G or G/G genotype group. Conclusion:The genotype frequency of PD-L1 (rs822339) is not different in patients with AITD compared with healthy controls. The intact PD-1/PD-L1 pathway in GD and HT might be important to maintain chronicity of AITD by protecting immune tolerance. However, the PD-L1 SNP could be associated with difficulty in achieving remission in patients with GD, which may be helpful to predict the possibility of longer treatment. Further studies are required to investigate the complex immune tolerance system in patients with AITD.

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PD-1/PD-L1 affects Graves progression through lymphocytes on the proliferation, apoptosis and inflammatory cytokine secretion of thyroid follicular epithelial cells

Cited by 6 publications

References 26 publications

PD-L1 Inhibits T Cell-Induced Cytokines and Hyaluronan Expression via the CD40-CD40L Pathway in Orbital Fibroblasts From Patients With Thyroid Associated Ophthalmopathy

PD-L1 Inhibits T Cell-Induced Cytokines and Hyaluronan Expression via the CD40-CD40L Pathway in Orbital Fibroblasts From Patients With Thyroid Associated Ophthalmopathy

Effects of treatment with methimazole on circulating CD4⁺ and CD8⁺ T cells positive for programed cell death protein‐1 and on subsets of CD4⁺ T cells in untreated hyperthyroid patients with Graves' disease

Programmed Cell Death-Ligand 1 (PD-L1) gene Single Nucleotide Polymorphism in Graves’ Disease and Hashimoto’s Thyroiditis in Korean Patients

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PD-1/PD-L1 affects Graves progression through lymphocytes on the proliferation, apoptosis and inflammatory cytokine secretion of thyroid follicular epithelial cells

Cited by 6 publications

References 26 publications

PD-L1 Inhibits T Cell-Induced Cytokines and Hyaluronan Expression via the CD40-CD40L Pathway in Orbital Fibroblasts From Patients With Thyroid Associated Ophthalmopathy

PD-L1 Inhibits T Cell-Induced Cytokines and Hyaluronan Expression via the CD40-CD40L Pathway in Orbital Fibroblasts From Patients With Thyroid Associated Ophthalmopathy

Effects of treatment with methimazole on circulating CD4+ and CD8+ T cells positive for programed cell death protein‐1 and on subsets of CD4+ T cells in untreated hyperthyroid patients with Graves' disease

Programmed Cell Death-Ligand 1 (PD-L1) gene Single Nucleotide Polymorphism in Graves’ Disease and Hashimoto’s Thyroiditis in Korean Patients

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Effects of treatment with methimazole on circulating CD4⁺ and CD8⁺ T cells positive for programed cell death protein‐1 and on subsets of CD4⁺ T cells in untreated hyperthyroid patients with Graves' disease