Role of CD4+NKG2D+ T cells in the disease activity of juvenile idiopathic arthritis
WANG Jun-Yan, ZHU Xiao-Ping, ZHANG Yu, LUO Chong, TANG Xue-Mei, ZHOU Juan
Department of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University/National Clinical Research Center for Child Health and Disorders/China International Science and Technology Cooperation Base of Child Development and Critical Disorders/Chongqing Key Laboratory of Child Infection and Immunity/Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing 400014, China
Abstract Objective To study the expression levels of CD4+NKG2D+ T cells and NKG2D soluble ligands, the soluble MHC class I chain-related molecules A and B (sMICA/sMICB) in the active stage and stable stage of juvenile idiopathic arthritis (JIA) and their role in the disease activity of JIA. Methods Nineteen children with systemic JIA and 20 children with articular JIA who were diagnosed in Children's Hospital of Chongqing Medical University from November 2019 to December 2021 were enrolled in this prospective study. Six healthy children were enrolled as the control group. After peripheral blood samples were collected, ELISA was used to measure the levels of sMICA and sMICB, and flow cytometry was used to measure the percentage of CD4+NKG2D+ T cells. Systemic Juvenile Arthritis Disease Activity Score-27 (sJADAS-27)/Juvenile Arthritis Disease Activity Score-27 (JADAS-27) was used to evaluate the disease activity in children with JIA. The Pearson correlation analysis and the receiver operating characteristic (ROC) curve were used to assess the role of CD4+NKG2D+ T cells, sMICA and sMICB in the disease activity of JIA. Results The active systemic JIA and active articular JIA groups had a significant increase in the percentage of CD4+NKG2D+ T cells compared with the control group and their corresponding inactive JIA group (P<0.05). The JIA groups had significantly higher levels of sMICA and sMICB than the control group (P<0.05), and the active articular JIA group had a significantly higher level of sMICB than the stable articular JIA group (P<0.05). In the children with JIA, the percentage of CD4+NKG2D+ T cells and the levels of sMICA and sMICB were positively correlated with sJADAS-27/JADAS-27 disease activity scores (P<0.05). The ROC curve analysis showed that sMICB had an area under the curve of 0.755 in evaluating the disease activity of JIA, with a specificity of 0.90 and a sensitivity of 0.64. Conclusions The percentage of CD4+NKG2D+ T cells and the levels of sMICA and sMICB increase in children with JIA compared with healthy children and are positively correlated with the disease activity of JIA, suggesting that CD4+NKG2D+ T cells and NKG2D ligands can be used as potential biomarkers for evaluating the disease activity of JIA.
WANG Jun-Yan,ZHU Xiao-Ping,ZHANG Yu et al. Role of CD4+NKG2D+ T cells in the disease activity of juvenile idiopathic arthritis[J]. CJCP, 2023, 25(2): 166-171.
WANG Jun-Yan,ZHU Xiao-Ping,ZHANG Yu et al. Role of CD4+NKG2D+ T cells in the disease activity of juvenile idiopathic arthritis[J]. CJCP, 2023, 25(2): 166-171.
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.
Tibaldi J, Pistorio A, Aldera E, et al. Development and initial validation of a composite disease activity score for systemic juvenile idiopathic arthritis[J]. Rheumatology (Oxford), 2020, 59(11): 3505-3514. PMID: 32829413. DOI: 10.1093/rheumatology/keaa240.
Hervier B, Ribon M, Tarantino N, et al. Increased concentrations of circulating soluble MHC class I-related chain A (sMICA) and sMICB and modulation of plasma membrane MICA expression: potential mechanisms and correlation with natural killer cell activity in systemic lupus erythematosus[J]. Front Immunol, 2021, 12: 633658. PMID: 34012432. PMCID: PMC8126610. DOI: 10.3389/fimmu.2021.633658.
Mariotte A, Bernardi L, Macquin C, et al. NKG2D ligands in inflammatory joint diseases: analysis in human samples and mouse models[J]. Clin Exp Rheumatol, 2021, 39(5): 982-987. PMID: 33427619. DOI: 10.55563/clinexprheumatol/klc3h6.
Pedicino D, Liuzzo G, Trotta F, et al. Adaptive immunity, inflammation, and cardiovascular complications in type 1 and type 2 diabetes mellitus[J]. J Diabetes Res, 2013, 2013: 184258. PMID: 23762872. PMCID: PMC3676957. DOI: 10.1155/2013/184258.
Giubilato S, Liuzzo G, Brugaletta S, et al. Expansion of CD4+CD28null T-lymphocytes in diabetic patients: exploring new pathogenetic mechanisms of increased cardiovascular risk in diabetes mellitus[J]. Eur Heart J, 2011, 32(10): 1214-1226. PMID: 21217142. DOI: 10.1093/eurheartj/ehq499.
Pariente B, Mocan I, Camus M, et al. Activation of the receptor NKG2D leads to production of Th17 cytokines in CD4+ T cells of patients with Crohn's disease[J]. Gastroenterology, 2011, 141(1): 217-226. PMID: 21600899. DOI: 10.1053/j.gastro.2011.03.061.
Fasth AE, Bj?rkstr?m NK, Anthoni M, et al. Activating NK-cell receptors co-stimulate CD4+CD28- T cells in patients with rheumatoid arthritis[J]. Eur J Immunol, 2010, 40(2): 378-387. PMID: 19904767. DOI: 10.1002/eji.200939399.
Groh V, Bruhl A, El-Gabalawy H, et al. Stimulation of T cell autoreactivity by anomalous expression of NKG2D and its MIC ligands in rheumatoid arthritis[J]. Proc Natl Acad Sci U S A, 2003, 100(16): 9452-9457. PMID: 12878725. PMCID: PMC170939. DOI: 10.1073/pnas.1632807100.
Hamada S, Caballero-Benitez A, Duran KL, et al. Soluble MICB in plasma and urine explains population expansions of NKG2D+CD4 T cells inpatients with juvenile-onset systemic lupus erythematosus[J]. Open J Immunol, 2017, 7(1): 1-17. PMID: 28944101. PMCID: PMC5604888. DOI: 10.4236/oji.2017.71001.
Dai Z, Turtle CJ, Booth GC, et al. Normally occurring NKG2D+CD4+ T cells are immunosuppressive and inversely correlated with disease activity in juvenile-onset lupus[J]. J Exp Med, 2009, 206(4): 793-805. PMID: 19289577. PMCID: PMC2715116. DOI: 10.1084/jem.20081648.