白细胞介素-21 对 B 细胞信号调节及与系统性红斑狼疮发病机制的研究_West China Medical Journal

Authors：

何瑶 , 曾玉萍 , 孟妍明 ,  武永康

四川大学华西医院实验医学科（成都 610041）;

Corresponding author：

武永康, Email: vipwyk@163.com

Keywords：

白细胞介素-21; B 细胞; 系统性红斑狼疮; 信号通路; 靶向治疗

DOI：

10.7507/1002-0179.201710146

Video：

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系统性红斑狼疮（systemic lupus erythematosus，SLE）是一种女性多发、累及多器官的慢性难治性自身免疫性疾病。白细胞介素（interleukin，IL）-21 是一种具有多种生物学功能的细胞因子，主要由活化 T 细胞合成与分泌，其受体分布广泛，与 B 细胞表面的 IL-21 受体结合可调控 B 细胞，包含正向促进 B 细胞向浆细胞分化，调节免疫球蛋白产生；反向条件性诱导 B 细胞凋亡及 B10 细胞产生两方面作用。正向作用在于促使 SLE 患者产生自身抗体，而反向作用是促使产生自身抗体的 B 细胞数量减少，而且使 B10 细胞产生更多的具有免疫抑制作用的 IL-10。正反向平衡精准调控有助于对 SLE 病情进行条件性干预，对于疾病的治疗具有重要潜在价值。该文探讨了 IL-21 调控 B 细胞的分化及其与 SLE 之间的关系，对探索 IL-21 对 B 细胞的信号通路在 SLE 发病机制和靶向治疗提供新的思路。

Citation： 何瑶, 曾玉萍, 孟妍明, 武永康. 白细胞介素-21 对 B 细胞信号调节及与系统性红斑狼疮发病机制的研究. West China Medical Journal, 2017, 32(12): 1972-1976. doi: 10.7507/1002-0179.201710146 Copy

1.	Hamming OJ, Kang L, Svensson A, et al. Crystal structure of interleukin-21 receptor (IL-21R) bound to IL-21 reveals that sugar chain interacting with WSXWS motif is integral part of IL-21R. J Biol Chem, 2012, 287(12): 9454-9460.
2.	Ettinger R, Kuchen S, Lipsky PE. The role of IL-21 in regulating B-cell function in health and disease. Immunol Rev, 2008, 223: 60-86.
3.	Li J, Nara H, Rahman M, et al. Impaired IL-7 signaling may explain a case of atypical JAK3-SCID. Cytokine, 2010, 49(2): 221-228.
4.	Wu Y, van Besouw NM, Shi Y, et al. The biological effects of IL-21 signaling on B-cell-mediated responses in organ transplantation. Front Immunol, 2016, 7: 319.
5.	Jin H, Malek TR. Redundant and unique regulation of activated mouse B lymphocytes by IL-4 and IL-21. J Leukoc biol, 2006, 80(6): 1416-1423.
6.	Spolski R, Leonard WJ. Interleukin-21: basic biology and implications for cancer and autoimmunity. Annu Rev Immunol, 2008, 26: 57-79.
7.	Shaffer AL, Yu X, He YS, et al. BCL-6 represses genes that function in lymphocyte differentiation, inflammation, and cell cycle control. Immunity, 2000, 13(2): 199-212.
8.	Rincon-Arevalo H, Sanchez-Parra CC, Castano D, et al. Regulatory B cells and mechanisms. Int Rev Immunol, 2016, 35(2): 156-176.
9.	Wang JH, New JS, Xie S, et al. Extension of the germinal center stage of B cell development promotes autoantibodies in BXD2 mice. Arthritis Rheum, 2013, 65(10): 2703-2712.
10.	Lal G, Kulkarni N, Nakayama Y, et al. IL-10 from marginal zone precursor B cells controls the differentiation of Th17, Tfh and Tfr cells in transplantation tolerance. Immunol Lett, 2016, 170: 52-63.
11.	Iwata Y, Matsushita T, Horikawa M, et al. Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells. Blood, 2011, 117(2): 530-541.
12.	Tedder TF. B10 cells: a functionally defined regulatory B cell subset. J Immunol, 2015, 194(4): 1395-1401.
13.	赵楠, 赵明峰, Rajbhandary S, 等. 人源 IL-21 增强细胞因子诱导杀伤细胞抗白血病作用及其机制研究. 中华血液学杂志, 2012, 33(10): 823-828.
14.	Mackay M, Stanevsky A, Wang T, et al. Selective dysregulation of the FcgammaⅡB receptor on memory B cells in SLE. J Exp Med, 2006, 203(9): 2157-2164.
15.	Zharkova O, Celhar T, Cravens PD, et al. Pathways leading to an immunological disease: systemic lupus erythematosus. Rheumatology, 2017, 56(1): 55-66.
16.	Bubier JA, Sproule TJ, Foreman O, et al. A critical role for IL-21 receptor signaling in the pathogenesis of systemic lupus erythematosus in BXSB-Yaa mice. Proc Natl Acad Sci USA, 2009, 106(5): 1518-1523.
17.	Bubier JA, Bennett SM, Sproule TJ, et al. Treatment of BXSB-Yaa mice with IL-21R-Fc fusion protein minimally attenuates systemic lupus erythematosus. Ann N Y Acad Sci, 2007, 1110: 590-601.
18.	Zotos D, Coquet JM, Zhang Y, et al. IL-21 regulates germinal center B cell differentiation and proliferation through a B cell-intrinsic mechanism. J Exp Med, 2010, 207(2): 365-378.
19.	Han JH, Umiker BR, Kazimirova AA, et al. Expression of an anti-RNA autoantibody in a mouse model of SLE increases neutrophil and monocyte numbers as well as IFN-I expression. Eur J Immunol, 2014, 44(1): 215-226.
20.	Wang L, Zhao P, Ma L, et al. Increased interleukin 21 and follicular helper T-like cells and reduced interleukin 10⁺B cells in patients with new-onset systemic lupus erythematosus. J Rheumatol, 2014, 41(9): 1781-1792.
21.	Asokan R, Banda NK, Szakonyi G, et al. Human complement receptor 2 (CR2/CD21) as a receptor for DNA: implications for its roles in the immune response and the pathogenesis of systemic lupus erythematosus (SLE). Mol Immunol, 2013, 53(1/2): 99-110.
22.	Looney RJ, Anolik J, Sanz I. A perspective on B-cell-targeting therapy for SLE. Mod Rheumatol, 2010, 20(1): 1-10.
23.	Gensous N, Schmitt N, Richez C, et al. T follicular helper cells, interleukin-21 and systemic lupus erythematosus. Rheumatology, 2017, 56(4): 516-523.

1. Hamming OJ, Kang L, Svensson A, et al. Crystal structure of interleukin-21 receptor (IL-21R) bound to IL-21 reveals that sugar chain interacting with WSXWS motif is integral part of IL-21R. J Biol Chem, 2012, 287(12): 9454-9460.
2. Ettinger R, Kuchen S, Lipsky PE. The role of IL-21 in regulating B-cell function in health and disease. Immunol Rev, 2008, 223: 60-86.
3. Li J, Nara H, Rahman M, et al. Impaired IL-7 signaling may explain a case of atypical JAK3-SCID. Cytokine, 2010, 49(2): 221-228.
4. Wu Y, van Besouw NM, Shi Y, et al. The biological effects of IL-21 signaling on B-cell-mediated responses in organ transplantation. Front Immunol, 2016, 7: 319.
5. Jin H, Malek TR. Redundant and unique regulation of activated mouse B lymphocytes by IL-4 and IL-21. J Leukoc biol, 2006, 80(6): 1416-1423.
6. Spolski R, Leonard WJ. Interleukin-21: basic biology and implications for cancer and autoimmunity. Annu Rev Immunol, 2008, 26: 57-79.
7. Shaffer AL, Yu X, He YS, et al. BCL-6 represses genes that function in lymphocyte differentiation, inflammation, and cell cycle control. Immunity, 2000, 13(2): 199-212.
8. Rincon-Arevalo H, Sanchez-Parra CC, Castano D, et al. Regulatory B cells and mechanisms. Int Rev Immunol, 2016, 35(2): 156-176.
9. Wang JH, New JS, Xie S, et al. Extension of the germinal center stage of B cell development promotes autoantibodies in BXD2 mice. Arthritis Rheum, 2013, 65(10): 2703-2712.
10. Lal G, Kulkarni N, Nakayama Y, et al. IL-10 from marginal zone precursor B cells controls the differentiation of Th17, Tfh and Tfr cells in transplantation tolerance. Immunol Lett, 2016, 170: 52-63.
11. Iwata Y, Matsushita T, Horikawa M, et al. Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells. Blood, 2011, 117(2): 530-541.
12. Tedder TF. B10 cells: a functionally defined regulatory B cell subset. J Immunol, 2015, 194(4): 1395-1401.
13. 赵楠, 赵明峰, Rajbhandary S, 等. 人源 IL-21 增强细胞因子诱导杀伤细胞抗白血病作用及其机制研究. 中华血液学杂志, 2012, 33(10): 823-828.
14. Mackay M, Stanevsky A, Wang T, et al. Selective dysregulation of the FcgammaⅡB receptor on memory B cells in SLE. J Exp Med, 2006, 203(9): 2157-2164.
15. Zharkova O, Celhar T, Cravens PD, et al. Pathways leading to an immunological disease: systemic lupus erythematosus. Rheumatology, 2017, 56(1): 55-66.
16. Bubier JA, Sproule TJ, Foreman O, et al. A critical role for IL-21 receptor signaling in the pathogenesis of systemic lupus erythematosus in BXSB-Yaa mice. Proc Natl Acad Sci USA, 2009, 106(5): 1518-1523.
17. Bubier JA, Bennett SM, Sproule TJ, et al. Treatment of BXSB-Yaa mice with IL-21R-Fc fusion protein minimally attenuates systemic lupus erythematosus. Ann N Y Acad Sci, 2007, 1110: 590-601.
18. Zotos D, Coquet JM, Zhang Y, et al. IL-21 regulates germinal center B cell differentiation and proliferation through a B cell-intrinsic mechanism. J Exp Med, 2010, 207(2): 365-378.
19. Han JH, Umiker BR, Kazimirova AA, et al. Expression of an anti-RNA autoantibody in a mouse model of SLE increases neutrophil and monocyte numbers as well as IFN-I expression. Eur J Immunol, 2014, 44(1): 215-226.
20. Wang L, Zhao P, Ma L, et al. Increased interleukin 21 and follicular helper T-like cells and reduced interleukin 10⁺B cells in patients with new-onset systemic lupus erythematosus. J Rheumatol, 2014, 41(9): 1781-1792.
21. Asokan R, Banda NK, Szakonyi G, et al. Human complement receptor 2 (CR2/CD21) as a receptor for DNA: implications for its roles in the immune response and the pathogenesis of systemic lupus erythematosus (SLE). Mol Immunol, 2013, 53(1/2): 99-110.
22. Looney RJ, Anolik J, Sanz I. A perspective on B-cell-targeting therapy for SLE. Mod Rheumatol, 2010, 20(1): 1-10.
23. Gensous N, Schmitt N, Richez C, et al. T follicular helper cells, interleukin-21 and systemic lupus erythematosus. Rheumatology, 2017, 56(4): 516-523.

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白细胞介素-21 对 B 细胞信号调节及与系统性红斑狼疮发病机制的研究

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