2016, Vol. 43扩展功能
文章信息
- 尹西, 蒲传强
- 白细胞介素在多发性肌炎和皮肌炎发病中的作用
- 国际神经病学神经外科学杂志, 2016, 43(2): 168-171
-
文章历史
收稿日期: 2016-02-20
修回日期: 2016-04-20
多发性肌炎(polymyositis,PM)和皮肌炎(dermatomyositis,DM)是临床上较为常见的特发性炎性肌病，其主要的临床表现为急性或亚急性进行性肌无力、肌痛，同时伴有肺脏、皮肤等的病变[1]。DM/PM发病机制仍未十分明确，目前的研究多认为其为免疫失调引起的一类自身免疫性疾病，包括细胞免疫和体液免疫的异常。需要注意的是，PM和DM患者炎细胞(CD4+T细胞、CD8+T细胞、巨噬细胞、树突状细胞、B细胞等)、肌细胞及内皮细胞等均可产生大量的细胞因子[2]，促进炎细胞分化活化，相互作用产生免疫瀑布效应，进一步参与致病。细胞因子参与特发性炎性肌病发病是各型肌炎共同机制[3]。细胞因子是一种分泌性的低分子可溶性蛋白，参与炎细胞分化与活化过程，调节免疫反应。白细胞介素(interleukin,IL)是一大类常见的细胞因子，最初发现于白细胞而命名。白细胞介素参与免疫细胞的成熟、分化和增殖过程，在一系列免疫调节中起重要作用。近年来的研究发现多种白细胞介素参与多发性肌炎和皮肌炎发病，过表达的白细胞介素刺激、活化炎细胞，导致肌纤维炎细胞浸润，也可促使炎细胞合成新的细胞因子，产生持续的过强免疫反应，对肌肉组织造成持续损害[4]。本文拟对白细胞介素在多发性肌炎和皮肌炎发病中作用研究进展进行介绍，以提高对其发病机制的认识。
1 白细胞介素1白细胞介素1(interleukin-1,IL-1)是包含有11种细胞因子的超家族，其中IL-1α和IL-1β的研究最为深入，二者通过与I型IL-1受体结合，而后募集IL-1受体相关蛋白(IL-1 receptor accessory protein,IL-1RAcP)，通过激活Toll样受体(Toll-like receptor,TLR)信号通路中的关键转导蛋白髓样分化因子(myeloid differentiation factor 88,MyD88)参与信号传导过程[5]，提高血管内皮细胞黏附分子表达，趋化白细胞，并且促进抗体生成。Lundberg等[6]发现在激素治疗的多肌炎和皮肌炎病例中肌肉组织中IL-1α/β的表达较治疗前有明显减低，且肌肉功能恢复与IL-1α/β的表达降低相关。通过免疫分析方法，与对照相比，IL-1α在特发性炎性肌病患者肌肉组织中高表达，且主要表达于血管内皮细胞[7">7]。定量PCR研究表明，IL-1β RNA水平在多发性肌炎及皮肌炎中均有明显升高，与对照组相比，其表达提高6～8倍[8]，肌肉组织中浸润的炎细胞染色多呈现IL-1β阳性，IL-1β通路在炎性肌病中被激活[9]。Takahiko等[10]采用重组人类骨骼肌C蛋白成功诱导多发性肌炎小鼠模型，而后通过单抗拮抗IL-1受体，有效减轻肌炎动物模型肌肉组织中炎细胞浸润，提示拮抗IL-1阻断相关的细胞通路，可作为多发性肌炎新的治疗靶点。
2 白细胞介素15白细胞介素15(interleukin-15,IL-15)是多能促炎因子，参与巨噬细胞、CD8+T细胞等的活化。皮肌炎患者分离出的成肌细胞可分泌过量的IL-15[11]，多发性肌炎和皮肌炎患者血清中IL-15水平随病情加重而升高[12]。免疫组化研究提示，经过免疫抑制的多发性肌炎和皮肌炎患者，与治疗相比肌肉组织中IL-15阳性率减低，且与肌肉功能恢复相关[13]，免疫双染提示IL-15与CD3+T细胞共表达，在炎性肌病患者中，IL-15的表达受到肿瘤坏死因子α(tumor necrosis factor α,TNF-α)和干扰素γ(interferon γ,IFN-γ)的激活，IL-15高表达可起到对T细胞的激活作用[14]。Notarnicola等[15]通过对14例多发性肌炎和10例皮肌炎患者血清细胞因子研究中发现，皮肌炎患者IL-15表达升高明显，同时IL-15的表达与IL-17高度相关，且不受患者病程和治疗的影响，考虑IL-15参与激活Th17细胞相关，IL-17主要由Th17细胞产生。
3 白细胞介素17、22和23Th17辅助细胞是最近研究热点，皮肌炎患者中Th17细胞的比例与肌酸激酶CK值成正相关，与骨骼肌特异性表达相关小RNA miR-206呈负相关[16]，白细胞介素17 (interleukin-17,IL-17)及其相关的细胞因子白细胞介素22(interleukin-22,IL-22)是潜在的治疗靶点。研究者在多发性肌炎、皮肌炎患者发现IL-22与IL-17共表达，与疾病活动程度成正相关，免疫球蛋白治疗有效的皮肌炎患者肌肉组织中IL-22 RNA表达减低[17, 18]。IL-17和IL-1α可以通过激活细胞核因子Kappa B(NF-κB)信号通路直接作用于肌纤维，导致肌纤维表面的MHC-I表达上调，并产生更多的细胞因子和黏附分子。此外，与对照组相比，分离自多发性肌炎和皮肌炎患者的外周血单核细胞分泌大量的白细胞介素23(interleukin-23,IL-23)，后者参与Th17细胞的成熟分化过程[19]，成熟Th17细胞产生大量的IL-17，参与致病。Moran等[20]研究发现，多发性肌炎、皮肌炎患者肌肉组织中IL-17的RNA和蛋白水平升高，且患者血清IL-17水平与干扰素IFN表达相关。
4 白细胞介素18白细胞介素18(interleukin-18,IL-18)是与Th1细胞相关的白细胞介素，可与IL-12协同作用促进IFN-γ的表达，诱导幼稚T细胞活化，同时其与巨噬细胞的激活密切相关，IL-18过度高表达引起机体免疫调控异常，参与多发性肌炎和皮肌炎的致病[21]。此外，IL-18还可激活β趋化因子2(CCL2)的表达，通过募集巨噬细胞、记忆性T细胞、树突状细胞引起局部的免疫反应，造成肌细胞损坏[22]。Tucci等[23]的研究表明，多发性肌炎和皮肌炎患者肌肉组织中血管周或肌内膜下巨噬细胞和树突状细胞产生大量的IL-18，释放到血液中，产生免疫级联反应，募集免疫细胞，进一步损伤肌纤维，血清中IL-18浓度升高与肌酸激酶CK浓度呈正相关。血清IL-18浓度在伴有间质性肺病(interstitial lung disease,ILD)的皮肌炎患者比不伴有ILD的皮肌炎患者更高[24]，且与血清铁蛋白浓度呈正相关[25]，后者与ILD密切相关，表明IL-18可能是ILD发生的重要因素，肺泡中激活的巨噬细胞可产生过量的白三烯和IL-18，从而介导肺部纤维化。肌肉组织和血清中过表达的IL-18提示，IL-18/IL-18R通路的调控异常是肌炎发病机制之一，经治疗症状改善的皮肌炎患者血清IL-18浓度降低，可作为其病情严重程度的风向标之一[26]。
5 其他白细胞介素6(interleukin-6,IL-6)是一种多能细胞因子，多种炎细胞均可产生，主要参与免疫反应的急性期。除炎细胞，DM和PM患者中激活的成肌细胞也可产生IL-6，此外，在IL-17过量的情况下，IL-6产生也增多[27]。Hidenaga等[28]最近的研究提示，IL-6与IL-8、IL-10可能共同引起多发性肌炎和皮肌炎患者的高铁蛋白血症，进而引起急性进行性间质性肺病(ILD)。此外，IL-6的表达还与干扰素(IFN)相关[29]。白细胞介素10(interleukin-10,IL-10)传统上认为是一种抑炎因子，但在特定的环境和其他细胞因子的作用下，在DM/PM中起到促炎作用。DM/PM患者肌肉组织中IL-10表达升高，在免疫球蛋白治疗的患者中，表达降低[30]。白细胞介素8(interleukin-8,IL-8)与IL-6发挥协同作用，与I型干扰素的表达成正相关[31]，且在患有ILD的DM/PM患者中高表达，提示其不仅参与肌肉组织发病，也参与肌肉外其他器官的发病。需要注意的是，Th2相关白细胞介素4(interleukin-4,IL-4)对DM患者肌肉组织起到保护作用，IL-4的高表达与CK和LDH的浓度呈负相关，提示病情减轻[32]。考虑是IL-4激活M2型巨噬细胞，后者起到组织修复作用[2]。
6 总结白细胞介素是参与多发性肌炎和皮肌炎发病的重要因素，白细胞介素相互作用，募集并活化炎细胞，也能刺激肌纤维产生更多的细胞因子，引起免疫瀑布效应，持续对肌纤维造成破坏。IL-1、IL-15、IL-17和IL-18是其中的关键因子，通过对其参与DM/PM发病机制的研究，探讨关键的作用点，为治疗提供新的靶点。
| [1] |
Dalakas MC. Inflammatory muscle diseases. N Eng J Med, 2015, 372(18): 1734–1747. |
| [2] |
Rayavarapu S, Coley W, Kinder TB, et al. Idiopathic inflammatory myopathies: pathogenic mechanisms of muscle weakness. Skelet Muscle, 2013, 3(1): 13. |
| [3] |
Loell I, Lundberg IE. Can muscle regeneration fail in chronic inflammation: a weakness in inflammatory myopathies? J Intern Med, 2011, 269(3): 243-257. J Intern Med, 2011, 269(3): 243–257. |
| [4] |
Dalakas MC. Mechanisms of disease: signaling pathways and immunobiology of inflammatory myopathies. Nat Clin Pract Rheumatol, 2006, 2(4): 219–227. |
| [5] |
Schett G, Dayer JM, Manger B. Interleukin-1 function and role in rheumatic disease. Nat Rev Rheumatol, 2016, 12(1): 14–24. |
| [6] |
Lundberg I, Kratz AK, Alexanderson H, et al. Decreased expression of interleukin-1alpha, interleukin-1beta, and cell adhesion molecules in muscle tissue following corticosteroid treatment in patients with polymyositis and dermatomyositis. Arthritis Rheum, 2000, 43(2): 336–348. |
| [7] |
Baird GS, Montine TJ. Multiplex immunoassay analysis of cytokines in idiopathic inflammatory myopathy. Arch Pathol Lab Med, 2008, 132(2): 232–238. |
| [8] |
Schmidt J, Barthel K, Wrede A, et al. Interrelation of inflammation and APP in sIBM: IL-1 beta induces accumulation of beta-amyloid in skeletal muscle. Brain, 2008, 131(Pt 5): 1228–1240. |
| [9] |
Higgs BW, Zhu W, Richman L, et al. Identification of activated cytokine pathways in the blood of systemic lupus erythematosus, myositis, rheumatoid arthritis, and scleroderma patients. Int J Rheum Dis, 2012, 15(1): 25–35. |
| [10] |
Sugihara T, Okiyama N, Watanabe N, et al. Interleukin-1 and tumor necrosis factor alpha blockade treatment of experimental polymyositis in mice. Arthritis Rheum, 2012, 64(8): 2655–2662. |
| [11] |
Sugiura T, Harigai M, Kawaguchi Y, et al. Increased IL-15 production of muscle cells in polymyositis and dermatomyositis. Int Immunol, 2002, 14(8): 917–924. |
| [12] |
Mielnik P, Chwalinska-Sadowska H, Wiesik-Szewczyk E, et al. Serum concentration of interleukin 15, interleukin 2 receptor and TNF receptor in patients with polymyositis and dermatomyositis: correlation to disease activity. Rheumatol Int, 2012, 32(3): 639–643. |
| [13] |
Zong M, Loell I, Lindroos E, et al. Effects of immunosuppressive treatment on interleukin-15 and interleukin-15 receptor alpha expression in muscle tissue of patients with polymyositis or dermatomyositis. Ann Rheum Dis, 2012, 71(6): 1055–1063. |
| [14] |
Huang PL, Hou MS, Wang SW, et al. Skeletal muscle interleukin 15 promotes CD8(+) T-cell function and autoimmune myositis. Skelet Muscle, 2015, 5: 33. |
| [15] |
Notarnicola A, Lapadula G, Natuzzi D, et al. Correlation between serum levels of IL-15 and IL-17 in patients with idiopathic inflammatory myopathies. Scand J Rheumatol, 2015, 44(3): 224–228. |
| [16] |
Tang X, Tian X, Zhang Y, et al. Correlation between the frequency of Th17 cell and the expression of microRNA-206 in patients with dermatomyositis. Clin Dev Immunol, 2013, 2013: 345347. |
| [17] |
Ciccia F, Rizzo A, Alessandro R, et al. Activated IL-22 pathway occurs in the muscle tissues of patients with polymyositis or dermatomyositis and is correlated with disease activity. Rheumatology, 2014, 53(7): 1307–1312. |
| [18] |
Raju R, Dalakas MC. Gene expression profile in the muscles of patients with inflammatory myopathies: effect of therapy with IVIg and biological validation of clinically relevant genes. Brain, 2005, 128(Pt 8): 1887–1896. |
| [19] |
Shen H, Xia L, Lu J, et al. Interleukin-17 and interleukin-23 in patients with polymyositis and dermatomyositis. Scand J Rheumatol, 2011, 40(3): 217–220. |
| [20] |
Moran EM, Mastaglia FL. The role of interleukin-17 in immune-mediated inflammatory myopathies and possible therapeutic implications. Neuromuscul disord, 2014, 24(11): 943–952. |
| [21] |
Wawrocki S, Druszczynska M, Kowalewicz-Kulbat M, et al. Interleukin 18 (IL-18) as a target for immune intervention. Acta Biochim Pol, 2016, 63(1): 59–63. |
| [22] |
Kaser A, Kaser S, Kaneider NC, et al. Interleukin-18 attracts plasmacytoid dendritic cells (DC2s) and promotes Th1 induction by DC2s through IL-18 receptor expression. Blood, 2004, 103(2): 648–655. |
| [23] |
Tucci M, Quatraro C, Dammacco F, et al. Interleukin-18 overexpression as a hallmark of the activity of autoimmune inflammatory myopathies. Clin Exp Immunol, 2006, 146(1): 21–31. |
| [24] |
Gono T, Kawaguchi Y, Sugiura T, et al. Interleukin-18 is a key mediator in dermatomyositis: potential contribution to development of interstitial lung disease. Rheumatology, 2010, 49(10): 1878–1881. |
| [25] |
Gono T, Kawaguchi Y, Hara M, et al. Increased ferritin predicts development and severity of acute interstitial lung disease as a complication of dermatomyositis. Rheumatology, 2010, 49(7): 1354–1360. |
| [26] |
Tucci M, Quatraro C, Dammacco F, et al. Increased IL-18 production by dendritic cells in active inflammatory myopathies. Ann N Y Acad Sci, 2007, 1107: 184–192. |
| [27] |
Tournadre A, Lenief V, Miossec P. Expression of Toll-like receptor 3 and Toll-like receptor 7 in muscle is characteristic of inflammatory myopathy and is differentially regulated by Th1 and Th17 cytokines. Arthrit Rheum, 2010, 62(7): 2144–2151. |
| [28] |
Kawasumi H, Gono T, Kawaguchi Y, et al. IL-6, IL-8, and IL-10 are associated with hyperferritinemia in rapidly progressive interstitial lung disease with polymyositis/dermatomyositis. Biomed Res Int, 2014, 2014: 815245. |
| [29] |
Bilgic H, Ytterberg SR, Amin S, et al. Interleukin-6 and type I interferon-regulated genes and chemokines mark disease activity in dermatomyositis. Arthri Rheum, 2009, 60(11): 3436–3446. |
| [30] |
Zschuntzsch J, Voss J, Creus K, et al. Provision of an explanation for the inefficacy of immunotherapy in sporadic inclusion body myositis: quantitative assessment of inflammation and beta-amyloid in the muscle. Arthrit Rheum, 2012, 64(12): 4094–4103. |
| [31] |
Reed AM, Peterson E, Bilgic H, et al. Changes in novel biomarkers of disease activity in juvenile and adult dermatomyositis are sensitive biomarkers of disease course. Arthriti Rheum, 2012, 64(12): 4078–4086. |
| [32] |
Fujiyama T, Ito T, Ogawa N, et al. Preferential infiltration of interleukin-4-producing CXCR4+ T cells in the lesional muscle but not skin of patients with dermatomyositis. Clin Exp Immunol, 2014, 177(1): 110–120. |