介白素-15受器體-α次元基因變異於全身性紅斑狼瘡之研究

介白素-15 (IL-15)為一種吸附於細胞膜之細胞激素，主要藉助與IL-15受器體α次元結合而表現於樹突狀細胞(dendritic cells)和單核球(monocytes)細胞表面，功能為促進NK細胞、T細胞和B細胞的增生和分化，並促使細胞產生抗細胞凋亡蛋白Bcl-2。IL-15受器體(IL-15 receptor，IL-15R)為由α、β、γ三個次元所組成的異構三聚體(heterotrimer)，其中IL-15受器體α次元(IL-15Rα)對於IL-15結合具有高親和力。全身性紅斑性狼瘡(Systemic Lupus Erythematosus，SLE)是一種由對抗自體抗原的抗體或是淋巴球 (autoantibodies or autoreactive lymphocytes)所引起全身性慢性發炎的自體免疫性疾病。除了產生多種自體抗體以外，全身性紅斑性狼瘡(SLE)病人在細胞層次上也有多種異常，可能都與SLE病人體內IL-15增加有關。先前的研究指出，大約有40%的SLE病人血清中IL-15的量高於於正常健康人；且血清中IL-15量的增加與其淋巴球Bcl-2表現量增加呈正相關。但於L. Baranda et al. 研究發現，儘管全身性紅斑狼瘡的病人血清中IL-15有增加的現象，來自於全身性紅斑性狼瘡病人的血液中的周邊血液單核球細胞 (PBMCs) 與T淋巴球細胞在受PMA或PHA刺激後，對於IL15的反應卻較健康對照組細胞差，且IL-15受器體的表現並沒有減少的情形，推測SLE病患IL-15受器體功能可能與正常對照組有差異。IL-15受器體α次元為IL-15R複合體中，對IL-15專一性且高親和力的次元，且根據基因剔除的老鼠表現型顯示，IL-15Rα在IL-15的正常生理功能上扮演重要的角色。故若IL-15受器體α次元發生變異，極可能導致細胞對於IL-15反應異常，參與了全身性紅斑性狼瘡的致病機制。故本篇研究以IL-15受器體α次元基因(IL15RA)為研究目標，研究IL15RA在基因單點核苷酸的變異與SLE發生之關聯性。本篇論文主要在探索IL15RA基因之變異與全身性紅斑性狼瘡之相關性，並對全身性紅班性狼瘡的病人與健康對照組進行SNP定型(Typing)，討論IL15RA 基因上單點核苷酸多型性與疾病發生、疾病活性與臨床症狀的關係。在本研究中篩選的13個位於預測之轉錄調節子(regulatory element)與轉錄子(exon)的SNP後，選定了3個在台灣族群中具多型性的SNP (-646G/C、-565C/T、+627A/C)，進行大量檢體的定型。進行統計分析後，發現IL15RA +627A對偶基因型與SLE的發生有顯著的正相關(odds ratio =1.42, 95% confidence interval: 1.01-2.01, p: 0.044)；IL15RA半套体 (-646C/-565C/+627C)則與SLE呈高度負相關。(odds ratio=0.59, 95% CI: 0.40-0.87，p-value: 0.007)。

關鍵字

全身性紅斑性狼瘡；介白素-15 ；介白素-15受器體α次元；單點核苷酸多型性

並列摘要

Interleukin-15, a membrane-bound cytokine, is mainly expressed on the surfaces of dendritic cells and monocytes through binding to the high affinity IL-15 receptor α subunit. IL-15 can stimulate the generation and differentiation of NK cells, T cells and B cells, and induce the production of anti-apoptotic protein, Bcl-2. IL-15 receptor (IL15R) is composed of α, β and γ subunits and IL-15 receptor α subunit (IL-15Rα) is a unique subunit for IL-15 with an extremely high affinity (Ka~1011M-1). Systemic lupus Erythematosus is a systemic autoimmune disease characterized by chronic systemic inflammation disease, which is mediated by autoreactive lymphocytes or autoantibodies. In addition to the production of various antibodies, patients with SLE suffer from many cellular abnormalities, and all the abnormalities could be attributed to the increasing of IL-15 in the sera of patients with SLE. In comparison with healthy control population, IL-15 was found to be elevated in 40% of SLE patients, and the amount of serum IL-15 is correlated with the amount of Bcl-2 in lymphocytes from patients. In spite of elevated serum IL-15 in SLE patients, PBMCs and lymphocytes from SLE patients showed poor responses to recombinant IL-15 and PHA than cells from healthy controls, without diminished expression of IL-15Rα, which suggested an altered function or expression of IL-15 receptor in SLE leukocytes. According to the same phenotypes between IL-15-/- mice and IL-15Rα-/- mice, IL-15Rα is viewed as a critical part in the normal physiological function of IL-15. Variances occur on IL-15Rα or IL15RA gene may result in poor cellular responses to IL-15. Therefore, IL15RA was chosen as candidate gene. Single nucleotide polymorphisms (SNPs) on IL15RA gene were analyzed and investigated if genetic variation of IL15RA gene would correlate to SLE development. Thirteen SNPs in the predicted regulatory elements and exonic regions, and three SNPs (-646G/C, -565C/T, +627A/C) were intensive studied in the SLE patients and the non-lupus control. The results indicated that IL15RA +627A allele was positively associated withSLE (odds ratio=1.42, 95% confidenence interval: 1.01-2.01, p: 0.044), and the haplotype (-646C/-565C/+627C) was significantly negatively correlated to SLE prevalence (odds ratio=0.59, 95% CI: 0.40-0.87, p: 0.007).

並列關鍵字

Systemic lupus erythematosus (SLE) ； interleukin-15 ； interleukin-15 receptor alpha (IL-15Rα) ； Single nucleotide polymorphism (SNP)

參考文獻

2. Janeway, C. A., Travers, P., Walport, M. & Shlomchik, M. Immunobiology : the immune system in health and disease. Janeway, C. A., Travers, P., Walport, M. & Shlomchik, M. (eds.), pp. 501-522 (Garland Pub, New York,2001).

5. Davidson, A. & Diamond, B. Autoimmune Diseases. New Engl J Med 345, 340-350 (2001).

7. Tsokos, G. & Liossis, S.-N. Principles of Molecular Rheumatology. Tsokos, G. C. (ed.), pp. 311-323 (Humana Press, Totowa,2000).

8. Isenberg, D. & Rahman, A. Systemic lupus erythematosus - 2005 annus mirabilis? Nat Clin Prac Rheum 2, 145-152 (2006).

11. Schned, E. S., Glickstein, S. L. & Doyle, M. A. T. Derivation of the Sledai. Arthritis and Rheum 36, 877 (1993).

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介白素-15受器體-α次元基因變異於全身性紅斑狼瘡之研究

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