Stevens-Johnson综合征/中毒性表皮坏死松解综合征的发病机制研究进展
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摘要
Stevens-Johnson综合征/中毒性表皮坏死松解综合征(SJS/TEN)是一类少见的,由药物引起的以广泛皮肤松解坏死为特征的重症皮肤不良反应,临床主要表现为皮肤黏膜疼痛、红斑、水疱、表皮剥脱等。虽然本病发病率很低,但死亡率高。大量研究表明其主要是由遗传、药理、免疫等多方面共同作用的结果,但发病机制目前尚未完全明确,目前,已发现多种人类白细胞抗原(HLA)风险等位基因与特定药物引起的SJS/TEN相关。近年来,除了更为精准的认识到HLA在抗原的识别、提呈过程中的作用,免疫细胞(T细胞、NKT细胞等)及细胞因子(穿孔素/颗粒酶B、颗粒溶素、Fas-FasL、TNF-α、IL-15等)在发病机制中的作用也得到了更为广泛的研究,本文主要对近年来SJS/TEN发病机制方面的研究进展进行综述。
Stevens-Johnson syndrome/toxic epidermal necrolysis syndrome(SJS/TEN) is a rare,mostly drug-induced severe cutaneous adverse reaction which is characterized by widespread epidermal necrosis.The main clinical manifestations are mucocutaneous pain,erythema,blisters,epidermal exfoliation,etc.In severe cases,multiple organs are involved.Although the incidence is low,the mortality is high.Numerous studies have shown that it is mainly the result of a combination of genetics,pharmacology,and immunity.However,the exact pathogenesis is still unclear.In recent years,in addition to a more accurate recognition of the role of HLA in antigen recognition and presentation,the role of immune cells(T cells,NKT cells,etc),and cytokines(Perforin/granzyme B,Granuiysin,Fas-FasL,TNF-α,IL-15,etc.) in the pathogenesis of SJS/TEN have also been studied more extensively.This article mainly reviews recent advances in the pathogenesis of SJS/TEN.
Stevens-Johnson syndrome/toxic epidermal necrolysis syndrome(SJS/TEN) is a rare,mostly drug-induced severe cutaneous adverse reaction which is characterized by widespread epidermal necrosis.The main clinical manifestations are mucocutaneous pain,erythema,blisters,epidermal exfoliation,etc.In severe cases,multiple organs are involved.Although the incidence is low,the mortality is high.Numerous studies have shown that it is mainly the result of a combination of genetics,pharmacology,and immunity.However,the exact pathogenesis is still unclear.In recent years,in addition to a more accurate recognition of the role of HLA in antigen recognition and presentation,the role of immune cells(T cells,NKT cells,etc),and cytokines(Perforin/granzyme B,Granuiysin,Fas-FasL,TNF-α,IL-15,etc.) in the pathogenesis of SJS/TEN have also been studied more extensively.This article mainly reviews recent advances in the pathogenesis of SJS/TEN.
引文
[1] Estrella-Alonso A,Aramburu JA,Gonzalez-Ruiz MY,et al.Toxic epidermal necrolysis:a paradigm of critical illness [J].Rev Bras Ter Intensiva,2017,29(4):499-508.
[2] Wang YH,Chen CB,Tassaneeyakul W,et al.The medication risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in Asians:the major drug causality and comparison to the USA FDA label [J].Clin Pharmacol Ther,2019,105(1):112-120.
[3] Abe R.Immunological response in Stevens-Johnson syndrome and toxic epidermal necrolysis [J].J Dermatol,2015,42(1):42-48.
[4] Redwood AJ,Pavlos RK,White KD,et al.HLAs:Key regulators of T-cell-mediated drug hypersensitivity [J].PMC,2018,91(1):3-16.
[5] Sousa-Pinto B,Correia C,Gomes L,et al.HLA and delayed drug-induced hypersensitivity [J].Int Arch Allergy Immunol,2016,170(3):163-179.
[6] Cheng CY,Su SC.HLA associations and clinical implications in T-cell mediated drug hypersensitivity reactions:an updated review [J].J Immunol Res,2014,2014:565320.
[7] Zhang FR,Liu H,Irwanto A,et al.HLA-B*13:01 and the dapsone hypersensitivity syndrome [J].N Engl J Med,2013,369(17):1620-1628.
[8] Tangamornsuksan W,Lohitnavy M.Association between HLA-B*1301 and dapsone-induced cutaneous adverse drug reactions:a systematic review and meta-analysis [J].JAMA Dermatol,2018,154(4):441-446.
[9] Cheng L,Xiong Y,Qin CZ,et al.HLA-B*58:01 is strongly associated with allopurinol-induced severe cutaneous adverse reactions in Han Chinese patients:a multicentre retrospective case-control clinical study [J].Br J Dermatol,2015,173(2):555-558.
[10] Illing PT,Mifsud NA,Purcell AW.Allotype specific interactions of drugs and HLA molecules in hypersensitivity reactions [J].Curr Opin Immunol,2016,42:31-40.
[11] Usui T,Naisbitt DJ.Human leukocyte antigen and idiosyncratic adverse drug reactions [J].Drug Metab Pharmacokinet,2017,32(1):21-30.
[12] Pichler WJ,Naisbitt DJ,Park BK.Immune pathomechanism of drug hypersensitivity reactions [J].J Allergy Clin Immunol,2011,127(3 Suppl):S74-81.
[13] Chung WH,Hung SI.Recent advances in the genetics and immunology of Stevens-Johnson syndrome and toxic epidermal necrosis [J].J Dermatol Sci,2012,66(3):190-196.
[14] Ostrov DA,Grant BJ,Pompeu YA,et al.Drug hypersensitivity caused by alteration of the MHC-presented self-peptide repertoire [J].Proc Natl Acad Sci USA,2012,109(25):9959-9964.
[15] Tohyama M,Watanabe H,Murakami S,et al.Possible involvement of CD14+ CD16+ monocyte lineage cells in the epidermal damage of Stevens-Johnson syndrome and toxic epidermal necrolysis [J].Br J Dermatol,2012,166(2):322-330.
[16] Nassif A,Bensussan A,Boumsell L,et al.Toxic epidermal necrolysis:effector cells are drug-specific cytotoxic T cells [J].J Allergy Clin Immunol,2004,114(5):1209-1215.
[17] Yang Y,Li F,Du J,et al.Variable levels of apoptotic signal-associated cytokines in the disease course of patients with Stevens-Johnson syndrome and toxic epidermal necrolysis [J].Australas J Dermatol,2017,58(3):e61-e67.
[18] 朱启星,张澄,刘坡.细胞毒性T淋巴细胞在药疹发病机制中的作用 [J].国际皮肤性病学杂志,2015,41(6):392-397.
[19] Viard-Leveugle I,Gaide O,Jankovic D,et al.TNF-α and IFN-γ are potential inducers of Fas-mediated keratinocyte apoptosis through activation of inducible nitric oxide synthase in toxic epidermal necrolysis [J].J Invest Dermatol,2013,133(2):489.
[20] Suda G,Yamamoto Y,Nagasaka A,et al.Serum granulysin levels as a predictor of serious telaprevir-induced dermatological reactions [J].Hepatol Res,2014,45(8):837-845.
[21] Takahashi R,Kano Y,Yamazaki Y,et al.Defective regulatory T cells in patients with severe drug eruptions:timing of the dysfunction is associated with the pathological phenotype and outcome [J].J Immunol,2009,182(12):8071-8079.
[22] Teraki Y,Kawabe M,Izaki S.Possible role of TH17 cells in the pathogenesis of Stevens-Johnson syndrome and toxic epidermal necrolysis [J].J Allergy Clin Immunol,2013,131(3):907-909.
[23] Patidar M,Yadav N,Dalai SK.Interleukin 15:A key cytokine for immunotherapy [J].Cytokine Growth Factor Rev,2016,31:49-59.
[24] Su SC,Mockenhaupt M,Wolkenstein P,et al.Interleukin-15 is associated with severity and mortality in stevens-Johnson syndrome/toxic epidermal necrolysis [J].J Invest Dermatol,2017,137(5):1065-1073.
[25] Stern RS,Divito SJ.Stevens-Johnson syndrome and toxic epidermal necrolysis:associations,outcomes,and pathobiology-thirty years of progress but still much to be done [J].J Invest Dermatol,2017,137(5):1004-1008.
[26] Kinoshita Y,Saeki H.A review of the pathogenesis of toxic epidermal necrolysis [J].J Nippon Med Sch,2016,83(6):216-222.
[27] Kinoshita Y,Saeki H.A review of the active treatments for toxic epidermal necrolysis [J].J Nippon Med Sch,2017,84(3):110-117.
[28] Wang CW,Yang LY,Chen CB.Randomized,controlled trial of TNF-α antagonist in CTL-mediated severe cutaneous adverse reactions [J].J Clin Invest,2018,128(3):985-996.
[2] Wang YH,Chen CB,Tassaneeyakul W,et al.The medication risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in Asians:the major drug causality and comparison to the USA FDA label [J].Clin Pharmacol Ther,2019,105(1):112-120.
[3] Abe R.Immunological response in Stevens-Johnson syndrome and toxic epidermal necrolysis [J].J Dermatol,2015,42(1):42-48.
[4] Redwood AJ,Pavlos RK,White KD,et al.HLAs:Key regulators of T-cell-mediated drug hypersensitivity [J].PMC,2018,91(1):3-16.
[5] Sousa-Pinto B,Correia C,Gomes L,et al.HLA and delayed drug-induced hypersensitivity [J].Int Arch Allergy Immunol,2016,170(3):163-179.
[6] Cheng CY,Su SC.HLA associations and clinical implications in T-cell mediated drug hypersensitivity reactions:an updated review [J].J Immunol Res,2014,2014:565320.
[7] Zhang FR,Liu H,Irwanto A,et al.HLA-B*13:01 and the dapsone hypersensitivity syndrome [J].N Engl J Med,2013,369(17):1620-1628.
[8] Tangamornsuksan W,Lohitnavy M.Association between HLA-B*1301 and dapsone-induced cutaneous adverse drug reactions:a systematic review and meta-analysis [J].JAMA Dermatol,2018,154(4):441-446.
[9] Cheng L,Xiong Y,Qin CZ,et al.HLA-B*58:01 is strongly associated with allopurinol-induced severe cutaneous adverse reactions in Han Chinese patients:a multicentre retrospective case-control clinical study [J].Br J Dermatol,2015,173(2):555-558.
[10] Illing PT,Mifsud NA,Purcell AW.Allotype specific interactions of drugs and HLA molecules in hypersensitivity reactions [J].Curr Opin Immunol,2016,42:31-40.
[11] Usui T,Naisbitt DJ.Human leukocyte antigen and idiosyncratic adverse drug reactions [J].Drug Metab Pharmacokinet,2017,32(1):21-30.
[12] Pichler WJ,Naisbitt DJ,Park BK.Immune pathomechanism of drug hypersensitivity reactions [J].J Allergy Clin Immunol,2011,127(3 Suppl):S74-81.
[13] Chung WH,Hung SI.Recent advances in the genetics and immunology of Stevens-Johnson syndrome and toxic epidermal necrosis [J].J Dermatol Sci,2012,66(3):190-196.
[14] Ostrov DA,Grant BJ,Pompeu YA,et al.Drug hypersensitivity caused by alteration of the MHC-presented self-peptide repertoire [J].Proc Natl Acad Sci USA,2012,109(25):9959-9964.
[15] Tohyama M,Watanabe H,Murakami S,et al.Possible involvement of CD14+ CD16+ monocyte lineage cells in the epidermal damage of Stevens-Johnson syndrome and toxic epidermal necrolysis [J].Br J Dermatol,2012,166(2):322-330.
[16] Nassif A,Bensussan A,Boumsell L,et al.Toxic epidermal necrolysis:effector cells are drug-specific cytotoxic T cells [J].J Allergy Clin Immunol,2004,114(5):1209-1215.
[17] Yang Y,Li F,Du J,et al.Variable levels of apoptotic signal-associated cytokines in the disease course of patients with Stevens-Johnson syndrome and toxic epidermal necrolysis [J].Australas J Dermatol,2017,58(3):e61-e67.
[18] 朱启星,张澄,刘坡.细胞毒性T淋巴细胞在药疹发病机制中的作用 [J].国际皮肤性病学杂志,2015,41(6):392-397.
[19] Viard-Leveugle I,Gaide O,Jankovic D,et al.TNF-α and IFN-γ are potential inducers of Fas-mediated keratinocyte apoptosis through activation of inducible nitric oxide synthase in toxic epidermal necrolysis [J].J Invest Dermatol,2013,133(2):489.
[20] Suda G,Yamamoto Y,Nagasaka A,et al.Serum granulysin levels as a predictor of serious telaprevir-induced dermatological reactions [J].Hepatol Res,2014,45(8):837-845.
[21] Takahashi R,Kano Y,Yamazaki Y,et al.Defective regulatory T cells in patients with severe drug eruptions:timing of the dysfunction is associated with the pathological phenotype and outcome [J].J Immunol,2009,182(12):8071-8079.
[22] Teraki Y,Kawabe M,Izaki S.Possible role of TH17 cells in the pathogenesis of Stevens-Johnson syndrome and toxic epidermal necrolysis [J].J Allergy Clin Immunol,2013,131(3):907-909.
[23] Patidar M,Yadav N,Dalai SK.Interleukin 15:A key cytokine for immunotherapy [J].Cytokine Growth Factor Rev,2016,31:49-59.
[24] Su SC,Mockenhaupt M,Wolkenstein P,et al.Interleukin-15 is associated with severity and mortality in stevens-Johnson syndrome/toxic epidermal necrolysis [J].J Invest Dermatol,2017,137(5):1065-1073.
[25] Stern RS,Divito SJ.Stevens-Johnson syndrome and toxic epidermal necrolysis:associations,outcomes,and pathobiology-thirty years of progress but still much to be done [J].J Invest Dermatol,2017,137(5):1004-1008.
[26] Kinoshita Y,Saeki H.A review of the pathogenesis of toxic epidermal necrolysis [J].J Nippon Med Sch,2016,83(6):216-222.
[27] Kinoshita Y,Saeki H.A review of the active treatments for toxic epidermal necrolysis [J].J Nippon Med Sch,2017,84(3):110-117.
[28] Wang CW,Yang LY,Chen CB.Randomized,controlled trial of TNF-α antagonist in CTL-mediated severe cutaneous adverse reactions [J].J Clin Invest,2018,128(3):985-996.
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