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系统性红斑狼疮患者外周血滤泡辅助性T细胞和滤泡调节性T细胞表达变化及意义
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Abstract:
目的：检测系统性红斑狼疮(SLE)患者外周血中滤泡辅助性T细胞(Tfh)细胞亚型和效应记忆Tfh细胞(Tfh-EM)以及滤泡调节性T细胞(Tfr)的表达，并探讨其在SLE患者发病中的临床意义。方法：流式细胞术分别检测30例SLE患者和26例健康对照的外周血中Tfh (CD4 CXCR5 )细胞亚型Tfh1 (CD4 CXCR5 CXCR3 CCR6？)、Tfh2 (CD4 CXCR5 CXCR3？CCR6？)、Tfh17 (CD4 CXCR5 CXCR3？CCR6 )、Tfh-EM (CD4 CXCR5 ICOS PD-1 )和Tfr (CD4 CD25 CXCR5 CD127low)的水平。收集入组SLE患者的临床资料及实验室指标，采用酶联免疫吸附试验(ELISA)法检测各组受试者外周血中白细胞介素21 (IL-21)。结果：SLE组与健康对照组相比，外周血中Tfh-EM细胞、Tfh17细胞、总Tfh细胞的表达和外周血中IL-21水平较健康对照组表达升高(P均 < 0.05)。SLE组Tfh/Tfr高于健康对照组(P = 0.020)。外周血Tfh-EM细胞在SLE组中高病情活动度的表达高于低疾病活动度的患者(P = 0.024)。Tfh-EM细胞与抗ds-DNA抗体存在正相关(ρ = 0.444, P = 0.018)，Tfr细胞的比率与疾病活动度SLEDAI-2K评分呈负相关(ρ = ？0.392, P = 0.039)。结论：SLE组Tfh表达升高致Tfh/Tfr比值失衡，Tfh-EM细胞、Tfh17表达异常可能参与了SLE的发生和发展。
Objective: To investigate the expression of follicular helper T cell (Tfh) subtypes and effector memory Tfh cells (Tfh-EM) in the peripheral blood of patients with systemic lupus erythematosus (SLE), as well as the expression of follicular regulatory T cells (Tfr), and to explore their clinical significance in the onset of SLE. Methods: Flow cytometry was utilized to analyze the levels of Tfh (CD4 CXCR5 ) cell subtypes, including Tfh1 (CD4 CXCR5 CXCR3 CCR6？), Tfh2 (CD4 CXCR5 CXCR3？ CCR6？), Tfh17 (CD4 CXCR5 CXCR3？CCR6 ), Tfh-EM (CD4 CXCR5 ICOS PD-1 ), and Tfr (CD4 CD25 CXCR5 CD127low) in the peripheral blood of 30 SLE patients and 26 healthy controls. Clinical data and laboratory parameters of the SLE patients were collected, and enzyme-linked immunosorbent assay (ELISA) was employed to measure the levels of interleukin-21 (IL-21) in the peripheral blood of each participant. Results: The expression of Tfh-EM cells, Tfh17 cells, total Tfh cells in peripheral blood and the level of IL-21 in peripheral blood were elevated in the SLE group compared to healthy controls (P all < 0.05). Tfh/Tfr was higher in the SLE group than in healthy controls (P = 0.020), Peripheral blood Tfh-EM cells were expressed higher in the SLE group with high disease activity than in patients with low disease activity (P = 0.024).
| [1] | Tsokos, G.C. (2011) Systemic Lupus Erythematosus. The New England Journal of Medicine, 365, 2110-2121. https://doi.org/10.1056/NEJMra1100359 |
| [2] | Comte, D., Karampetsou, M.P. and Tsokos, G.C. (2015) T Cells as a Therapeutic Target in SLE. Lupus, 24, 351-363. https://doi.org/10.1177/0961203314556139 |
| [3] | Deng, J., Wei, Y. and Fonseca, V.R. (2019) T Follicular Helper Cells and T Follicular Regulatory Cells in Rheumatic Diseases. Nature Reviews Rheumatology, 15, 475-490. https://doi.org/10.1038/s41584-019-0254-2 |
| [4] | Nurieva, R.I., Chung, Y. and Martinez, G.J. (2009) Bcl6 Mediates the Development of T Follicular Helper Cells. Science, 325, 1001-1005. https://doi.org/10.1126/science.1176676 |
| [5] | Crotty, S., (2019) T Follicular Helper Cell Biology: A Decade of Discovery and Diseases. Immunity, 50, 1132-1148. https://doi.org/10.1016/j.immuni.2019.04.011 |
| [6] | He, J., Tsai, L.M. and Leong, Y.A. (2013) Circulating Precursor CCR7loPD-1hi CXCR5 CD4 T Cells Indicate Tfh Cell Activity and Promote Antibody Responses upon Antigen Reexposure. Immunity, 39, 770-781. https://doi.org/10.1016/j.immuni.2013.09.007 |
| [7] | Jandl, C., Liu, S.M. and Canete, P.F. (2017) IL-21 Restricts T Follicular Regulatory T Cell Proliferation Through Bcl-6 Mediated Inhibition of Responsiveness to IL-2. Nature Communications, 8, Article No. 14647. https://doi.org/10.1038/ncomms14647 |
| [8] | Locci, M., Havenar-Daughton, C. and Landais, E. (2013) Human Circulating PD-1 CXCR3-CXCR5 Memory Tfh Cells Are Highly Functional and Correlate with Broadly Neutralizing HIV Antibody Responses. Immunity, 39, 758-769. https://doi.org/10.1016/j.immuni.2013.08.031 |
| [9] | Morita, R., Schmitt, N. and Bentebibel, S.E. (2011) Human Blood CXCR5 CD4 T Cells Are Counterparts of T Follicular Cells and Contain Specific Subsets That Differentially Support Antibody Secretion. Immunity, 34, 108-121. https://doi.org/10.1016/j.immuni.2010.12.012 |
| [10] | Gong, Y., Tong, J. and Wang, S. (2017) Are Follicular Regulatory T Cells Involved in Autoimmune Diseases? Frontiers in Immunology, 8, Article 1790. https://doi.org/10.3389/fimmu.2017.01790 |
| [11] | Sage, P.T., Ron-Harel, N. and Juneja, V.R. (2016) Suppression by TFR Cells Leads to Durable and Selective Inhibition of B Cell Effector Function. Nature Immunology, 17, 1436-1446. https://doi.org/10.1038/ni.3578 |
| [12] | Chung, Y., Tanaka, S. and Chu, F. (2011) Follicular Regulatory T Cells Expressing Foxp3 and Bcl-6 Suppress Germinal Center Reactions. Nature Medicine, 17, 983-988. https://doi.org/10.1038/nm.2426 |
| [13] | Dhaeze, T., Stinissen, P. and Liston, A. (2015) Humoral Autoimmunity: A Failure of Regulatory T Cells? Autoimmunity Reviews, 14, 735-741. https://doi.org/10.1016/j.autrev.2015.04.006 |
| [14] | Weckerle, C.E. and Niewold, T.B. (2011) The Unexplained Female Predominance of Systemic Lupus Erythematosus: Clues from Genetic and Cytokine Studies. Clinical Reviews in Allergy & Immunology, 40, 42-49. https://doi.org/10.1007/s12016-009-8192-4 |
| [15] | Blanco, P., Ueno, H. and Schmitt, N. (2016) T Follicular Helper (Tfh) Cells in Lupus: Activation and Involvement in SLE Pathogenesis. European Journal of Immunology, 46, 281-290. https://doi.org/10.1002/eji.201545760 |
| [16] | Eivazi, S., Bagheri, S. and Hashemzadeh, M.S. (2016) Development of T Follicular Helper Cells and Their Role in Disease and Immune System. Biomed Pharmacother, 84, 1668-1678. https://doi.org/10.1016/j.biopha.2016.10.083 |
| [17] | Romme Christensen, J., Bornsen, L. and Ratzer, R. (2013) Systemic Inflammation in Progressive Multiple Sclerosis Involves Follicular T-Helper, Th17-and Activated B-Cells and Correlates with Progression. PLOS ONE, 8, e57820. https://doi.org/10.1371/journal.pone.0057820 |
| [18] | Szabo, K., Papp, G. and Szanto, A. (2016) A Comprehensive Investigation on the Distribution of Circulating Follicular T Helper Cells and B Cell Subsets in Primary Sjogren’s Syndrome and Systemic Lupus Erythematosus. Clinical and Experimental Immunology, 183, 76-89. https://doi.org/10.1111/cei.12703 |
| [19] | Zhu, C., Ma, J. and Liu, Y. (2012) Increased Frequency of Follicular Helper T Cells in Patients with Autoimmune Thyroid Disease. The Journal of Clinical Endocrinology & Metabolism, 97, 943-950. https://doi.org/10.1210/jc.2011-2003 |
| [20] | Brokstad, K.A., Fredriksen, M. and Zhou, F. (2018) T Follicular-Like Helper Cells in the Peripheral Blood of Patients with Primary Sjogren’s Syndrome. Scandinavian Journal of Immunology, 88, e12679. https://doi.org/10.1111/sji.12679 |
| [21] | Yu, M., Cavero, V. and Lu, Q. (2015) Follicular Helper T Cells in Rheumatoid Arthritis. Clinical Rheumatology, 34, 1489-1493. https://doi.org/10.1007/s10067-015-3028-5 |
| [22] | Choi, J.Y., Ho, J.H. and Pasoto, S.G. (2015) Circulating Follicular Helper-Like T Cells in Systemic Lupus Erythematosus: Association with Disease Activity. Arthritis & Rheumatology, 67, 988-999. https://doi.org/10.1002/art.39020 |
| [23] | Zhu, Y., Zou, L. and Liu, Y.C. (2016) T Follicular Helper Cells, T Follicular Regulatory Cells and Autoimmunity. International Immunology, 28, 173-179. https://doi.org/10.1093/intimm/dxv079 |
| [24] | Sage, P.T. and Sharpe, A.H. (2015) T Follicular Regulatory Cells in the Regulation of B Cell Responses. Trends in Immunology, 36, 410-418. https://doi.org/10.1016/j.it.2015.05.005 |
| [25] | Sage, P.T., Francisco, L.M. and Carman, C.V. (2013) the Receptor PD-1 Controls Follicular Regulatory T Cells in the Lymph Nodes and Blood. Nature Immunology, 14, 152-161. https://doi.org/10.1038/ni.2496 |
| [26] | Feng, X., Wang, D. and Chen, J. (2012) Inhibition of Aberrant Circulating Tfh Cell Proportions by Corticosteroids in Patients with Systemic Lupus Erythematosus. PLOS ONE, 7, e51982. https://doi.org/10.1371/journal.pone.0051982 |
| [27] | Kawamoto, S., et al. (2012) the Inhibitory Receptor PD-1 Regulates IgA Selection and Bacterial Composition in the Gut. Science, 336, 485-489. https://doi.org/10.1126/science.1217718 |
| [28] | Xu, H., Liu, J. and Cui, X. (2015) Increased Frequency of Circulating Follicular Helper T Cells in Lupus Patients Is Associated with Autoantibody Production in a CD40L-Dependent Manner. Cellular Immunology, 295, 46-51. https://doi.org/10.1016/j.cellimm.2015.01.014 |
| [29] | Mao, M., Xu, S. and Lin, L. (2022) Impact of Corticosteroids on the Proportions of Circulating Tfh Cell Subsets in Patients with Systemic Lupus Erythematous. Frontiers in Medicine, 9, Article 949334. https://doi.org/10.3389/fmed.2022.949334 |
