Changes and clinical significance of type I innate lymphoid cells and associated cytokines in primary immune thrombocytopenia

doi:10.11958/20251351

Abstract

Abstract:

Objective To investigate the expression levels and clinical significance of type Ⅰ innate lymphoid cells (ILC1s), T-box transcription factor (T-bet), interleukin (IL)-12, IL-18 and interferon-gamma (IFN-γ) in peripheral blood of patients with primary immune thrombocytopenia (ITP). Methods Thirty-five ITP patients with their first episode were selected as the initial treatment group. Thirteen of these patients were followed up after receiving treatment. Additionally, 20 healthy individuals underwent routine physical examinations during the same period were recruited as the control group. Peripheral blood samples were collected for analysis. The proportion of ILC1s was determined by flow cytometry. T-bet mRNA expression was measured using quantitative real-time PCR (qRT-PCR). Serum levels of IL-18, IL-12 and IFN-γ were quantified by enzyme-linked immunosorbent assay (ELISA). The differences in ILC1s proportion, T-bet mRNA expression and cytokine levels were compared between groups. Correlations between ILC1s proportion, T-bet mRNA, cytokine levels and platelet (PLT) counts were also analyzed. Results Compared with the control group, the initial treatment group exhibited significantly elevated levels of peripheral ILC1s, T-bet mRNA and serum IL-18, IL-12 and IFN-γ (P<0.05). Among the 13 patients who were followed up, all these indices decreased significantly after treatment (P<0.05). Correlation analysis revealed that the proportion of ILC1s in the initial treatment group was positively correlated with IL-12, IL-18, IFN-γ and T-bet mRNA levels (r_s = 0.666, 0.647, 0.677, and 0.750, respectively, P<0.01), and negatively correlated with PLT count (r_s= -0.637, P<0.01). Conclusion Innate immunity may play a role in the pathogenesis and progression of ITP by regulating the expression levels of ILC1s, T-bet, IL-12, IL-18 and IFN-γ.

Key words: thrombocytopenia, lymphocytes, T-box domain proteins, interleukin-12, interleukin-18, interferon-gamma, primary immune thrombocytopenia, type Ⅰ innate lymphoid cells

CLC Number:

R558.2

Figures/Tables 4

References 19

[1]	HE X, LI N, LIU D, et al. Regulatory role of ceRNA network in B lymphocytes of patients with immune thrombocytopenia[J]. Autoimmunity, 2023, 56(1):2281225. doi:10.1080/08916934.2023.2281225.
[2]	LIU S Y, QU H T, SUN R J, et al. High-throughput DNA methylation analysis in ITP confirms NOTCH1 hypermethylation through the Th1 and Th2 cell differentiation pathways[J]. Int Immunopharmacol, 2022,111:109105. doi:10.1016/j.intimp.2022.109105.
[3]	王秀娟, 孙明玲, 刘颖, 等. sST2/IL-33与Th17/Treg相关细胞因子在原发免疫性血小板减少症中的作用研究[J]. 天津医药, 2019, 47(7):732-734.
	WANG X J, SUN M L, LIU Y, et al. Study of sST2/IL-33 and Th17/Treg related cytokines on patients with primary immune thrombocytopenia[J]. Tianjin Med J, 2019, 47(7):732-734. doi:10.11958/20182195.
[4]	WANG X, ZHOU Q, YANG W, et al. The role of CD83 in the pathogenesis of immune thrombocytopenia[J]. Hematology, 2024, 29(1):2372482. doi:10.1080/16078454.2024.2372482.
[5]	CAO J, JI L, ZHAN Y, et al. MST4 kinase regulates immune thrombocytopenia by phosphorylating STAT1-mediated M1 polarization of macrophages[J]. Cell Mol Immunol, 2023, 20(12):1413-1427. doi:10.1038/s41423-023-01089-8.
[6]	SRIVASTAVA R K, SAPRA L, BHARDWAJ A, et al. Unravelling the immunobiology of innate lymphoid cells (ILCs):implications in health and disease[J]. Cytokine Growth Factor Rev, 2023, 74:56-75. doi:10.1016/j.cytogfr.2023.09.002.
[7]	KORCHAGINA A A, SHEIN S A, KOROLEVA E, et al. Transcriptional control of ILC identity[J]. Front Immunol, 2023,14:1146077. doi:10.3389/fimmu.2023.1146077.
[8]	CLOTTU A S, HUMBEL M, FLUDER N, et al. Innate lymphoid cells in autoimmune diseases[J]. Front Immunol, 2021,12:789788. doi:10.3389/fimmu.2021.789788.
[9]	KAWKA L, FELTEN R, SCHLEISS C, et al. Alteration of innate lymphoid cell homeostasis mainly concerns salivary glands in primary Sjögren's syndrome[J]. RMD Open, 2023, 9(2):e003051. doi:10.1136/rmdopen-2023-003051.
[10]	YANG F, LUO X, ZHU W, et al. Dysregulation of innate lymphoid cells in patients with active rheumatoid arthritis and mice with collagen-induced arthritis[J]. Mediators Inflamm, 2021,2021:1915068. doi:10.1155/2021/1915068.
[11]	AUDIA S, MOULINET T, CIUDAD-BONTÉ M, et al. Altered distribution and function of splenic innate lymphoid cells in adult chronic immune thrombocytopenia[J]. J Autoimmun, 2018, 93:139-144. doi:10.1016/j.jaut.2018.07.015.
[12]	WANG S C, YANG K D, LIN C Y, et al. Intravenous immunoglobulin therapy enhances suppressive regulatory T cells and decreases innate lymphoid cells in children with immune thrombocytopenia[J]. Pediatr Blood Cancer, 2020, 67(2):e28075. doi:10.1002/pbc.28075.
[13]	ZHONG L, WANG Y H, KAHLFUSS S, et al. STIM1-mediated NFAT signaling synergizes with STAT1 to control T-bet expression and TH1 differentiation[J]. Nat Immunol, 2025, 26(3):484-496. doi:10.1038/s41590-025-02089-8.
[14]	LIAO Z, YANG X, HE L, et al. Cordyceps protein alleviates renal injury by inhibiting T cell infiltration and Th1 cell differentiation in lupus nephritis mice[J]. Int Immunopharmacol, 2024,138:112566. doi:10.1016/j.intimp.2024.112566.
[15]	KANG J, LIGGETT J R, PATIL D, et al. Type 1 innate lymphoid cells are proinflammatory effector cells in ischemia-reperfusion injury of steatotic livers[J]. Front Immunol, 2022,13:899525. doi:10.3389/fimmu.2022.899525.
[16]	KRZYWINSKA E, SOBECKI M, NAGARAJAN S, et al. The transcription factor HIF-1α mediates plasticity of NKp46+ innate lymphoid cells in the gut[J]. J Exp Med, 2022, 219(2):e20210909. doi:10.1084/jem.20210909.
[17]	LI Q, YANG M, XIA R, et al. Elevated expression of IL-12 and IL-23 in patients with primary immune thrombocytopenia[J]. Platelets, 2015, 26(5):453-458. doi:10.3109/09537104.2014.934217.
[18]	LIU L, XU H, WANG J, et al. Trimethylamine-N-oxide (TMAO) and basic fibroblast growth factor(bFGF)are possibly involved in corticosteroid resistance in adult patients with immune thrombocytopenia[J]. Thromb Res, 2024, 233:25-36. doi:10.1016/j.thromres.2023.11.003.
[19]	WANG Z M, ZHANG J, WANG F, et al. The tipped balance of ILC1/ILC2 in peripheral blood of oral lichen planus is related to inflammatory cytokines[J]. Front Cell Dev Biol, 2021,9:725169. doi:10.3389/fcell.2021.725169.

组别	n	ILC1s/%	T-bet mRNA
对照组	20	23.76（18.72,29.82）	0.85（0.34,1.55）
初治组	35	40.11（28.21,42.74）	1.83（1.28,4.91）
Z		4.086^＊＊	3.692^＊＊
组别	IL-18/（ng/L）	IL-12/（ng/L）	IFN-γ/（ng/L）
对照组	46.45±11.91	1.15±0.33	205.57±40.39
初治组	77.15±25.55	2.14±0.59	400.22±65.46
t	6.048^＊＊	7.862^＊＊	13.628^＊＊

组别	n	ILC1s/%	T-bet mRNA
对照组	20	23.76（18.72,29.82）	0.85（0.34,1.55）
初治组	35	40.11（28.21,42.74）	1.83（1.28,4.91）
Z		4.086^＊＊	3.692^＊＊
组别	IL-18/（ng/L）	IL-12/（ng/L）	IFN-γ/（ng/L）
对照组	46.45±11.91	1.15±0.33	205.57±40.39
初治组	77.15±25.55	2.14±0.59	400.22±65.46
t	6.048^＊＊	7.862^＊＊	13.628^＊＊

时期		ILC1s/%	T-bet mRNA
治疗前		39.13（32.40,42.30）	2.34（1.14，4.27）
治疗后		19.23（15.93，30.99）	0.72（0.51，1.02）
Z		3.180^＊＊	2.900^＊＊
时期	IL-18/（ng/L）	IL-12/（ng/L）	IFN-γ/（ng/L）
治疗前	80.10（71.59,104.63）	2.55（1.96,3.07）	342.92（314.81,382.09）
治疗后	54.42（36.47,65.50）	1.50（1.33,1.50)	233.05（193.86,264.13）
Z	3.110^＊＊	3.180^＊＊	2.970^＊＊

时期		ILC1s/%	T-bet mRNA
治疗前		39.13（32.40,42.30）	2.34（1.14，4.27）
治疗后		19.23（15.93，30.99）	0.72（0.51，1.02）
Z		3.180^＊＊	2.900^＊＊
时期	IL-18/（ng/L）	IL-12/（ng/L）	IFN-γ/（ng/L）
治疗前	80.10（71.59,104.63）	2.55（1.96,3.07）	342.92（314.81,382.09）
治疗后	54.42（36.47,65.50）	1.50（1.33,1.50)	233.05（193.86,264.13）
Z	3.110^＊＊	3.180^＊＊	2.970^＊＊