目的 分析T细胞活化免疫球蛋白抑制V型结构域（V-domain Ig suppressor of T cell activation，VISTA）在幼年特发性关节炎（juvenile idiopathic arthritis，JIA）患儿外周血的表达情况，探讨其在发病中的作用。 方法 前瞻性收集不同亚型JIA患儿（47例）及健康儿童（10例）的外周血，利用流式细胞术检测CD14+单核细胞、CD4+T淋巴细胞、CD8+T淋巴细胞上VISTA、干扰素-γ（interfern-γ，IFN-γ）、肿瘤坏死因子-α（tumor necrosis factor-α，TNF-α）的表达情况。 结果 VISTA在JIA患儿中的表达水平比健康儿童低（P<0.05）；不同亚型JIA患儿VISTA表达差异有统计学意义，以全身型表达水平最低（P<0.05）；不同免疫细胞表达VISTA差异有统计学意义，单核细胞表面VISTA表达水平更高（P<0.05）。相关性分析发现CD4+T细胞上VISTA与IFN-γ（r=-0.436，P<0.05）、TNF-α（r=-0.382，P<0.05）表达呈负相关，CD8+T细胞上VISTA与IFN-γ（r=-0.348，P<0.05）、TNF-α（r=-0.487，P<0.05）表达呈负相关；CD14+单核细胞上VISTA与IFN-γ（r=-0.582，P<0.05）、TNF-α（r=-0.603，P<0.05）表达呈负相关。 结论 VISTA表达不足可能与JIA发病相关，增强VISTA的免疫调节作用可能是未来治疗JIA的途径之一。
Abstract
Objective To study the expression of V-domain Ig suppressor of T cell activation (VISTA) in peripheral blood of children with juvenile idiopathic arthritis (JIA) and its role in the pathogenesis of JIA. Methods In this prospective study, peripheral blood was collected from 47 children with different subtypes of JIA and 10 healthy children. Flow cytometry was used to measure the expression levels of VISTA, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) on CD14+ mononuclear cells, CD4+ T lymphocytes, and CD8+ T lymphocytes. Results The children with JIA had a significantly lower expression level of VISTA than the healthy children (P<0.05). There was a significant difference in the expression of VISTA between the children with different subtypes of JIA, with the lowest expression level in those with systemic JIA (P<0.05). There was also a significant difference in the expression of VISTA between different immune cells, with a significantly higher expression level on the surface of monocytes (P<0.05). Correlation analysis showed that VISTA was negatively correlated with the expression of IFN-γ and TNF-α on CD4+ T cells (r=-0.436 and -0.382 respectively, P<0.05), CD8+ T cells (r=-0.348 and -0.487 respectively, P<0.05), and CD14+ mononuclear cells (r=-0.582 and -0.603 respectively, P<0.05). Conclusions The insufficient expression of VISTA may be associated with the pathogenesis of JIA, and enhancing the immunomodulatory effect of VISTA might be one option for the treatment of JIA in the future.
关键词
幼年特发性关节炎 /
T细胞活化免疫球蛋白抑制V型结构域 /
单核细胞 /
淋巴细胞 /
儿童
Key words
Juvenile idiopathic arthritis /
V-domain Ig suppressor of T cell activation /
Monocyte /
Lymphocyte /
Child
{{custom_sec.title}}
{{custom_sec.title}}
{{custom_sec.content}}
参考文献
1 李彩凤, 黄新翔, 王永福, 等. 幼年特发性关节炎诊疗规范[J]. 中华内科杂志, 2022, 61(2): 142-156. PMID: 35090249. DOI: 10.3760/cma.j.cn112138-20210929-00666.
2 曾华松. 幼年特发性关节炎国际分类标准及治疗[J]. 实用儿科临床杂志, 2011, 26(9): 721-724. DOI: 10.3969/j.issn.1003-515X.2011.09.032.
3 Lin YT, Wang CT, Gershwin ME, et al. The pathogenesis of oligoarticular/polyarticular vs systemic juvenile idiopathic arthritis[J]. Autoimmun Rev, 2011, 10(8): 482-489. PMID: 21320644. DOI: 10.1016/j.autrev.2011.02.001.
4 Huang X, Zhang X, Li E, et al. VISTA: an immune regulatory protein checking tumor and immune cells in cancer immunotherapy[J]. J Hematol Oncol, 2020, 13(1): 83. PMID: 32600443. PMCID: PMC7325042. DOI: 10.1186/s13045-020-00917-y.
5 Wu C, Cao X, Zhang X. VISTA inhibitors in cancer immunotherapy: a short perspective on recent progresses[J]. RSC Med Chem, 2021, 12(10): 1672-1679. PMID: 34778768. PMCID: PMC8528208. DOI: 10.1039/d1md00185j.
6 ElTanbouly MA, Zhao Y, Nowak E, et al. VISTA is a checkpoint regulator for na?ve T cell quiescence and peripheral tolerance[J]. Science, 2020, 367(6475): eaay0524. PMID: 31949051. PMCID: PMC7391053. DOI: 10.1126/science.aay0524.
7 ElTanbouly MA, Croteau W, Noelle RJ, et al. VISTA: a novel immunotherapy target for normalizing innate and adaptive immunity[J]. Semin Immunol, 2019, 42: 101308. PMID: 31604531. PMCID: PMC7233310. DOI: 10.1016/j.smim.2019.101308.
8 Rogers BM, Smith L, Dezso Z, et al. VISTA is an activating receptor in human monocytes[J]. J Exp Med, 2021, 218(8): e20201601. PMID: 34106206. PMCID: PMC8193568. DOI: 10.1084/jem.20201601.
9 Petty RE, Southwood TR, Manners P, et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001[J]. J Rheumatol, 2004, 31(2): 390-392. PMID: 14760812.
10 Zaripova LN, Midgley A, Christmas SE, et al. Juvenile idiopathic arthritis: from aetiopathogenesis to therapeutic approaches[J]. Pediatr Rheumatol Online J, 2021, 19(1): 135. PMID: 34425842. PMCID: PMC8383464. DOI: 10.1186/s12969-021-00629-8.
11 ElTanbouly MA, Schaafsma E, Noelle RJ, et al. VISTA: coming of age as a multi-lineage immune checkpoint[J]. Clin Exp Immunol, 2020, 200(2): 120-130. PMID: 31930484. PMCID: PMC7160665. DOI: 10.1111/cei.13415.
12 ElTanbouly MA, Zhao Y, Schaafsma E, et al. VISTA: a target to manage the innate cytokine storm[J]. Front Immunol, 2020, 11: 595950. PMID: 33643285. PMCID: PMC7905033. DOI: 10.3389/fimmu.2020.595950.
13 Lines JL, Pantazi E, Mak J, et al. VISTA is an immune checkpoint molecule for human T cells[J]. Cancer Res, 2014, 74(7): 1924-1932. PMID: 24691993. PMCID: PMC3979527. DOI: 10.1158/0008-5472.CAN-13-1504.
14 Lee JJY, Schneider R. Systemic juvenile idiopathic arthritis[J]. Pediatr Clin North Am, 2018, 65(4): 691-709. PMID: 30031494. DOI: 10.1016/j.pcl.2018.04.005.
15 唐雪梅. 全身型幼年特发性关节炎免疫发病机制研究进展[J]. 中华实用儿科临床杂志, 2013, 28(9): 644-646. DOI: 10.3760/cma.j.issn.2095-428X.2013.09.002.
16 Mezouar S, Mege JL. Changing the paradigm of IFN-γ at the interface between innate and adaptive immunity: macrophage-derived IFN-γ[J]. J Leukoc Biol, 2020, 108(1): 419-426. PMID: 32531848. DOI: 10.1002/JLB.4MIR0420-619RR.
17 Jang DI, Lee AH, Shin HY, et al. The role of tumor necrosis factor alpha (TNF-α) in autoimmune disease and current TNF-α inhibitors in therapeutics[J]. Int J Mol Sci, 2021, 22(5): 2719. PMID: 33800290. PMCID: PMC7962638. DOI: 10.3390/ijms22052719.
18 Wang L, Rubinstein R, Lines JL, et al. VISTA, a novel mouse Ig superfamily ligand that negatively regulates T cell responses[J]. J Exp Med, 2011, 208(3): 577-592. PMID: 21383057. PMCID: PMC3058578. DOI: 10.1084/jem.20100619.
19 王亚军, 万健. 幼年特发性关节炎生物制剂临床应用进展[J]. 中华实用儿科临床杂志, 2018, 33(9): 646-650. DOI: 10.3760/cma.j.issn.2095-428X.2018.09.002.
20 Tagliamento M, Agostinetto E, Borea R, et al. VISTA: a promising target for cancer immunotherapy?[J]. Immunotargets Ther, 2021, 10: 185-200. PMID: 34189130. PMCID: PMC8235942. DOI: 10.2147/ITT.S260429.
21 Yuan L, Tatineni J, Mahoney KM, et al. VISTA: a mediator of quiescence and a promising target in cancer immunotherapy[J]. Trends Immunol, 2021, 42(3): 209-227. PMID: 33495077. PMCID: PMC8088836. DOI: 10.1016/j.it.2020.12.008.
22 Xu W, Dong J, Zheng Y, et al. Immune-checkpoint protein VISTA regulates antitumor immunity by controlling myeloid cell-mediated inflammation and immunosuppression[J]. Cancer Immunol Res, 2019, 7(9): 1497-1510. PMID: 31340983. PMCID: PMC6726548. DOI: 10.1158/2326-6066.CIR-18-0489.
基金
国家重点研发计划项目（2021YFC2702003）；重庆医科大学未来医学青年创新团队支持计划（W0114）；重庆渝中区科技局科研项目（20210136）。
PDF(606 KB)
