紅斑性狼瘡病人週邊血液單核細胞與多形核嗜中性白血球終端體長度及其影響因子的研究

紅斑性狼瘡的主要免疫異常為T淋巴球及B淋巴球的持續活化與增殖,產生各種不同的自體抗體及自我反應性的T淋巴球.其結果導致這些細胞早發性免疫衰老(premature immunosenescence),造成淋巴細胞不再分裂,對外界的刺激呈現低反應甚或引起細胞的死亡.由於真核細胞的線狀染色體在細胞分裂時有末端的複製問題(end-replication problem),在沒有代償機制,如終端體酵素(telomerase)的作用下時,其終端體(telomere)長度會隨著每次細胞分裂而逐漸減少,其喪失速度估計約在50-200鹼基對(base pairs, bp)之間.在哺乳類細胞,當終端體長度小到一臨界點時(<=5kb),便會停止細胞分裂與開始進入複製衰老(replicative senescence)的階段.最小臨界點的終端體長度與染色體的完整性及細胞的存活有關.終端體的長度不僅可當做細胞複製歷史的指標,也可做為細胞對新刺激的殘餘複製潛能.細胞老化己被證實跟終端體長度的加速縮短有關.有些自體免疫疾病,如類風濕性關節炎及全身性硬化症等,其CD4陽性T淋巴球也有早發性免疫衰老的現象與終端體長度的加速縮短.分化成熟的多形核嗜中性白血球雖然不會再複製與分裂,但其終端體長度的確會隨年齡增加而縮短.目前並沒有紅斑性狼瘡病人多形核嗜中性白血球終端體長度的報告.我們的研究首度發現紅斑性狼瘡病人的週邊血液單核細胞或多形核嗜中性白血球都有較同年齡正常人加速縮短的現象,並和疾病的活動度有關.紅斑性狼瘡疾病本身對這些血液細胞終端體長度的影響至少是年齡對終端體長度影響的13.4倍以上.不論是紅斑性狼瘡病人或正常人,其週邊血液單核細胞終端體長度都跟多形核嗜中性白血球終端體長度有高度相關,但兩者長度並沒有統計學上的差異.然而在白血球減少的紅斑性狼瘡病人,其週邊血液單核細胞終端體長度的確較多形核嗜中性白血球終端體長度顯著地短.除了淋巴球的持續活化與增殖會加速終端體的縮短外,紅斑性狼瘡病人淋巴球或多形核嗜中性白血球的加速破壞或氧化壓力的增加也可能是造成終端體長度加速縮短的原因.以終端體縮短造成細胞衰老與免疫衰竭的角度而言,我們的研究指出紅斑性狼瘡病人的週邊血液單核細胞與多形核嗜中性白血球較同年齡的正常人加速早衰老了16.5年與13.4年.我們計劃未來經由不同的自體抗體,抗淋巴球抗體,各細胞激素與氧合代謝物的相互作用之下,來觀察對週邊血液單核細胞與多形核嗜中性白血球弁

關鍵字

週邊血液單核細胞；嗜中性白血球；終端體；紅斑性狼瘡

並列摘要

Systemic lupus erythematosus (SLE) is characterized with aberrant immune regulation and defective function of various leukocytes. CD4+ T cell is the central role of the pathogenesis of SLE, and excessive production of high-affinity pathogenic autoantibodies is T cell driven. The chronic activation/proliferation could lead to premature immune senescence, such as exit from mitotic cycle, low responsiveness to new antigen stimuli and/or cell death. One of the SLE lymphocytes abnormalities is premature immunosenescence and may be associated with the shortening of telomere. Due to the end-replication problem of the linear chromosome during cell division, the telomere length of eukaryotic cell shortens at a rate of 50-200 base pairs per year if no compensatory mechanism, for example, telomerase exists. When telomere shortens to a critical size (<=5kb in mammalian cells), it signals the exit from the mitotic cycle and the onset of cellular senescence. The minimum size of telomere length has an important role in the chromosome integrity and the viability of cell. Telomere length can be an indicator of the cell’s replicative history and their residual replicative potential. Cellular aging has been proved related to the accelerated shortening of the telomere. In autoimmune condition of rheumatoid arthritis, CD4+ T cell presented with features of premature immunosenescence and accelerated telomere shortening. Polymorphonuclear cells (PMN) are terminally differentiated cell without expression of telomerase activity and do not undergo cell division. However, the PMN also have attrition of telomere length. Our study showed accelerated telomere shortening was noted not only in peripheral blood mononuclear cells (MNC), but also in PMN. SLE per se and disease activity had marked effect on the rapid loss of telomere length of these cells. There was a high positive correlation of the telomere length of MNC with that of PMN in normal controls as well as in SLE patients, but the telomere length between these cells in the same subjects was not significant. However, in SLE patients with leucopenia, the telomere length of MNC was significantly shorter than that of PMN. Persistent activation and proliferation of MNC, increased apoptosis or accelerated destruction of MNC as well as PMN, and elevated oxidative stress might contribute to the rapid loss of telomere length in these cells. Telomere shortening of lymphocytes had been linked to the immunosenescence of the immune system. From our study, it might be to say MNC and PMN in SLE patients had premature aging for 16.5 year and 13.4 year, respectively. In the future, we plan to study the effect of various autoantibodies, cytokines, or antioxidants on the function, telomere length, telomerase activity, and immunosenescence markers of MNC and PMN in patients with SLE and try to delay or treat the premature immunosenescence in these patients.

並列關鍵字

telomere length ； polymorphonuclear cells ； SLE ； lupus ； peripheral blood mononuclear cells

參考文獻

1. Ahmed A, Tollefsbol T. Telomeres and telomerase: basic science implications for aging. J Am Geriatr Soc. 2001;49:1105-9.

2. Allsopp RC, Vaziri H, Patterson C, Goldstein S, Younglai EV, Futcher AB, et.al. Telomere length predicts replicative capacity of human fibroblasts. Proc Natl Acad Sci USA.1992;89:10114-10118.

3. Alves JD, Grima B. Oxidative stress in systemic lupus erythematosus and antiphospholipid syndrome: a gateway to atherosclerosis. Curr Rheumatol Rep. 2003;5:383-90.

4. Artlett CM, Black CM, Briggs DC, Stevens CO, Welsh KI. Telomere reduction in scleroderma patients: a possible cause for chromosomal instability. Br J Rheumatol. 1996;35:732-7.

5. Barr SG, Zonana NA, Magder LS, Petri M. Patterns of disease activity in systemic lupus erythematosus. Arthritis Rheum. 1999;42:2682-2688

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紅斑性狼瘡病人週邊血液單核細胞與多形核嗜中性白血球終端體長度及其影響因子的研究

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