嗜酸性粒细胞在大疱性类天疱疮发病机制中的作用

doi:10.3760/cma.j.issn.0412-4030.2019.08.017

摘要/Abstract

摘要： 【摘要】大疱性类天疱疮（BP）是最常见的自身免疫性表皮下水疱病，皮损真皮内有大量嗜酸性粒细胞（EOS）浸润。此外，在BP患者的水疱和外周血中，也发现有大量EOS及其活化的细胞因子和趋化因子，而且EOS被证实可导致真表皮分离。BP 患者的血清及疱液中白细胞介素 5 水平明显增高，该因子由 Th2 细胞及 EOS 分泌，具有调节 EOS 分化、活化和存活的作用。以上证据均表明 EOS 与 BP 发病有一定的相关性。针对EOS及其细胞因子的研究，将开启BP靶向治疗的新领域。

关键词: 类天疱疮, 大疱性；嗜酸性粒细胞；发病机制；真表皮分离

Abstract: 【Abstract】 Bullous pemphigoid （BP） is the most common autoimmune subepidermal blistering skin disease, and a large number of eosinophils （EOS） obviously infiltrate the dermis of BP lesions. Additionally, EOS and their activated cytokines and chemokines are abundantly present in blisters and peripheral blood of BP patients. It is also proved that EOS can induce the dermal-epidermal separation. The level of interleukin （IL）-5 is markedly increased in the sera and blister fluids of BP patients, and IL-5 secreted by Th2 cells and EOS can regulate the differentiation, activation and survival of EOS. All the above evidence indicates that EOS are associated with the occurrence of BP. Researches on EOS and their cytokines will develop a new field of targeted therapy for BP.

Key words: Pemphigoid, bullous, Eosinophil, Pathogenesis, Dermal?epidermal separation

沈佳元慧杰潘萌. 嗜酸性粒细胞在大疱性类天疱疮发病机制中的作用[J]. 中华皮肤科杂志, 2019, 52(8): 579-581.

Shen Jia, Yuan Huijie, Pan Meng. Role of eosinophils in the pathogenesis of bullous pemphigoid[J]. Chinese Journal of Dermatology, 2019, 52(8): 579-581.

参考文献 35

［1］	della TR, Combescure C, Cortés B, et al. Clinical presentation and diagnostic delay in bullous pemphigoid: a prospective nationwide cohort［J］. Br J Dermatol, 2012,167（5）:1111⁃1117. doi: 10.1111/j.1365⁃2133.2012.11108.x.
［2］	Amber KT, Valdebran M, Kridin K, et al. The role of eosinophils in bullous pemphigoid: a developing model of eosinophil pathogenicity in mucocutaneous disease［J/OL］. Front Med （Lausanne）, 2018,5:201. ［2018⁃08⁃02］. https://www. frontiersin.org/articles/10.3389/fmed.2018.00201/full. doi: 10.3389/ fmed.2018.00201.
［3］	Messingham KN, Wang JW, Holahan HM, et al. Eosinophil localization to the basement membrane zone is autoantibody⁃ and complement⁃dependent in a humancryosection model of bullous pemphigoid［J］. Exp Dermatol, 2016,25（1）:50⁃55. doi: 10.1111/exd.12883.
［4］	Tedeschi A, Marzano AV, Lorini M, et al. Eosinophil cationic protein levels parallel coagulation activation in the blister fluid of patients with bullous pemphigoid［J］. J Eur Acad Dermatol Venereol, 2015,29（4）:813⁃817. doi: 10.1111/jdv.12464.
［5］	van Beek N, Schulze FS, Zillikens D, et al. IgE⁃mediated mechanisms in bullous pemphigoid and other autoimmune bullous diseases［J］. Expert Rev Clin Immunol, 2016,12（3）:267⁃277. doi: 10.1586/1744666X.2016.1123092.
［6］	Diny NL, Rose NR, Čiháková D. Eosinophils in autoimmune diseases［J/OL］. Front Immunol, 2017,8:484. ［2017⁃06⁃22］. https://www.frontiersin.org/articles/10.3389/fimmu.2017.00484/full. doi: 10.3389/fimmu. 2017.00484.
［7］	Morshed M, Yousefi S, Stöckle C, et al. Thymic stromal lymphopoietin stimulates the formation of eosinophil extracellular traps［J］. Allergy, 2012,67（9）:1127⁃1137. doi: 10.1111/j.1398⁃9995.2012.02868.x.
［8］	Yousefi S, Gold JA, Andina N, et al. Catapult⁃like release of mitochondrial DNA by eosinophils contributes to antibacterial defense［J］. Nat Med, 2008,14（9）:949⁃953. doi: 10.1038/nm. 1855.
［9］	Choi Y, Le PD, Lee DH, et al. Biological function of eosinophil extracellular traps in patients with severe eosinophilic asthma［J］. Exp Mol Med, 2018,50（8）:104. doi: 10.1038/s12276⁃018⁃0136⁃8.
［10］	Lin L, Hwang BJ, Culton DA, et al. Eosinophils mediate tissue injury in the autoimmune skin disease bullous pemphigoid［J］. J Invest Dermatol, 2018,138（5）:1032⁃1043. doi: 10.1016/j.jid. 2017.11.031.
［11］	Januskevicius A, Gosens R, Sakalauskas R, et al. Suppression of eosinophil integrins prevents remodeling of airway smooth muscle in asthma［J/OL］. Front Physiol, 2016,7:680. ［2017⁃12⁃28］. https://www.frontiersin.org/articles/10.3389. doi: 10.3389/fphys.2016.00680.
［12］	Lampinen M, Carlson M, Håkansson LD, et al. Cytokine⁃regulated accumulation of eosinophils in inflammatory disease［J］. Allergy, 2004,59（8）:793⁃805. doi: 10.1111/j.1398⁃9995. 2004.00469.x.
［13］	Foley SC, Préfontaine D, Hamid Q. Images in allergy and immunology: role of eosinophils in airway remodeling［J］. J Allergy Clin Immunol, 2007,119（6）:1563⁃1566. doi: 10.1016/j.jaci.2007. 03.040.
［14］	Lamkhioued B, Gounni AS, Aldebert D, et al. Synthesis of type 1 （IFN gamma） and type 2 （IL⁃4, IL⁃5, and IL⁃10） cytokines by human eosinophils［J］. Ann N Y Acad Sci, 1996,796:203⁃208.
［15］	Ohno I, Nitta Y, Yamauchi K, et al. Transforming growth factor beta 1 （TGF beta 1） gene by eosinophils in asthmatic airway inflammation［J］. Am J Respir Cell Mol Biol, 1996,15（3）:404⁃409. doi: 10.1165/ajrcmb.15.3.8810646.
［16］	Wang YH, Liu YJ. Thymic stromal lymphopoietin, OX40⁃ligand, and interleukin⁃25 in allergic responses［J］. Clin Exp Allergy, 2009,39（6）:798⁃806. doi: 10.1111/j.1365⁃2222.2009.03241.x.
［17］	Peters MS, Rodriguez M, Gleich GJ. Localization of human eosinophil granule major basic protein, eosinophil cationic protein, and eosinophil⁃derived neurotoxin by immunoelectron microscopy［J］. Lab Invest, 1986,54（6）:656⁃662.
［18］	Gleich GJ, Frigas E, Loegering DA, et al. Cytotoxic properties of the eosinophil major basic protein［J］. J Immunol, 1979,123（6）:2925⁃2927.
［19］	Young JD, Peterson CG, Venge P, et al. Mechanism of membrane damage mediated by human eosinophil cationic protein［J］. Nature, 1986,321（6070）:613⁃616. doi: 10.1038/321613a0.
［20］	Ramirez GA, Yacoub MR, Ripa M, et al. Eosinophils from physiology to disease: a comprehensive review［J］. Biomed Res Int, 2018,2018:9095275. doi: 10.1155/2018/9095275.
［21］	Watanabe H, Sueki H, Kitami A, et al. Flame figures associated with bullous pemphigoid［J］. J Dermatol, 1998,25（10）:632⁃636.
［22］	de Graauw E, Sitaru C, Horn M, et al. Evidence for a role of eosinophils in blister formation in bullous pemphigoid［J］. Allergy, 2017,72（7）:1105⁃1113. doi: 10.1111/all.13131.
［23］	Kridin K. Peripheral eosinophilia in bullous pemphigoid: prevalence and influence on the clinical manifestation［J］. Br J Dermatol, 2018,179（5）:1141⁃1147. doi: 10.1111/bjd.16679.
［24］	Moriuchi R, Nishie W, Ujiie H, et al. In vivo analysis of IgE autoantibodies in bullous pemphigoid: a study of 100 cases［J］. J Dermatol Sci, 2015,78（1）:21⁃25. doi: 10.1016/j.jdermsci.2015. 01.013.
［25］	Kinet JP. The high⁃affinity IgE receptor （Fc epsilon RI）: from physiology to pathology［J］. Annu Rev Immunol, 1999,17:931⁃972. doi: 10.1146/annurev.immunol.17.1.931.
［26］	Wakugawa M, Nakamura K, Hino H, et al. Elevated levels of eotaxin and interleukin⁃5 in blister fluid of bullous pemphigoid: correlation with tissue eosinophilia［J］. Br J Dermatol, 2000,143（1）:112⁃116.
［27］	Engmann J, Rüdrich U, Behrens G, et al. Increased activity and apoptosis of eosinophils in blister fluids, skin and peripheral blood of patients with bullous pemphigoid［J］. Acta Derm Venereol, 2017,97（4）:464⁃471. doi: 10.2340/00015555⁃2581.
［28］	Ståhle⁃Bäckdahl M, Inoue M, Guidice GJ, et al. 92⁃kD gelatinase is produced by eosinophils at the site of blister formation in bullous pemphigoid and cleaves the extracellular domain of recombinant 180⁃kD bullous pemphigoid autoantigen［J］. J Clin Invest, 1994,93（5）:2022⁃2030. doi: 10.1172/JCI117196.
［29］	Bushkell LL, Jordon RE. Bullous pemphigoid: a cause of peripheral blood eosinophilia［J］. J Am Acad Dermatol, 1983,8（5）:648⁃651.
［30］	Nakashima H, Fujimoto M, Asashima N, et al. Serum chemokine profile in patients with bullous pemphigoid［J］. Br J Dermatol, 2007,156（3）:454⁃459. doi: 10.1111/j.1365⁃2133.2006.07601.x.
［31］	Lamberts A, Euverman HI, Terra JB, et al. Effectiveness and safety of rituximab in recalcitrant pemphigoid diseases［J/OL］. Front Immunol, 2018,9:248. ［2018⁃05⁃22］. https://www.frontiersin.org/articles/10.3389/fimmu.2018.00248/full. doi: 10. 3389/fimmu.2018.00248.
［32］	Menzinger S, Kaya G, Schmidt E, et al. Biological and clinical response to omalizumab in a patient with bullous pemphigoid［J］. Acta Derm Venereol, 2018,98（2）:284⁃286. doi: 10.2340/000 15555⁃2845.
［33］	Roufosse F. Targeting the interleukin⁃5 pathway for treatment of eosinophilic conditions other than asthma［J/OL］. Front Med （Lausanne）, 2018,5:49. ［2018⁃06⁃03］. https://www.frontiersin.org/articles/10.3389/fmed.2018.00049/full. doi: 10.3389/fmed. 2018.00049.
［34］	Radonjic⁃Hoesli S, Valent P, Klion AD, et al. Novel targeted therapies for eosinophil⁃associated diseases and allergy［J］. Annu Rev Pharmacol Toxicol, 2015,55:633⁃656. doi: 10.1146/annurev⁃pharmtox⁃010814⁃124407.
［35］	Gounni AS, Wellemans V, Agouli M, et al. Increased of Th2⁃associated chemokines in bullous pemphigoid disease. Role of eosinophils in the production and release of these chemokines［J］. Clin Immunol, 2006,120（2）:220⁃231. doi: 10. 1016/j.clim.2006.03.014.

[1]	李锁李志量荆可向睿宇张寒梅冯素英 . 以剥脱性龈炎为表现的皮肤疾病诊疗进展[J]. 中华皮肤科杂志, 2019, 52(6): 440-442.
[2]	于灵冯素英李志量靳培英王宝玺. 不同底物间接免疫荧光对自身免疫性表皮下水疱病诊断的评价[J]. 中华皮肤科杂志, 2019, 52(2): 81-85.
[3]	朱磊李博平巫毅. BP180抗体在大疱性类天疱疮及神经系统疾病患者血清中的表达[J]. 中华皮肤科杂志, 2019, 52(1): 33-35.
[4]	李锁冯素英. BP180相关自身免疫性水疱病的研究进展[J]. 中华皮肤科杂志, 2019, 52(1): 50-52.
[5]	饶诗佳李碧娟李吉谢红付陈明亮赵爽王亚玲施为陆前进. 淋巴血浆置换疗法治疗难治性重症免疫相关性皮肤病疗效观察[J]. 中华皮肤科杂志, 2019, 52(1): 16-19.
[6]	李锁程险峰李新宇李志量荆可向睿宇张寒梅冯素英. 基于热分离法制备的人表皮侧抗原的Western印迹实验对大疱性类天疱疮的诊断价值评估[J]. 中华皮肤科杂志, 2019, 52(1): 6-10.
[7]	李思哲闫天萌李丽晋红中左亚刚. 血清白细胞介素21水平与大疱性类天疱疮无相关性[J]. 中华皮肤科杂志, 2018, 51(8): 595-596.
[8]	张荣鑫赵晔孙令涂彩霞. 原发性皮肤弥漫性大B细胞淋巴瘤腿型合并大疱性类天疱疮一例[J]. 中华皮肤科杂志, 2017, 50(2): 137-137.
[9]	陈柳青黄萌陈金波夏云陈红英马玲姜倩. 结节性类天疱疮七例临床病理分析[J]. 中华皮肤科杂志, 2016, 49(7): 511-513.
[10]	韩宪伟李铁男王珍刘贵军. 类天疱疮样扁平苔藓合并Turner综合征一例[J]. 中华皮肤科杂志, 2015, 48(11): 820-821.
[11]	陈洪晓王婷张建梅刘卫兵. 寻常性银屑病并发大疱性类天疱疮一例[J]. 中华皮肤科杂志, 2013, 46(9): 686-686.
[12]	孙彤邢育华张欣. 白癜风合并大疱性类天疱疮二例[J]. 中华皮肤科杂志, 2011, 44(9): 678-678.
[13]	马蕾黄萍. 大疱性类天疱疮患者血清与疱液中巨噬细胞游走抑制因子的检测[J]. 中华皮肤科杂志, 2010, 43(6): 422-422.
[14]	杜阳张军王云杨勇. 放射性皮炎继发大疱性类天疱疮一例[J]. 中华皮肤科杂志, 2010, 43(6): 433-433.
[15]	俞晨高琳叶瑜张莲王雷高天文王刚. 结节性类天疱疮一例[J]. 中华皮肤科杂志, 2010, 43(12): 888-888.