干扰素调节因子8抑制辅助性T淋巴细胞17分化在白塞病发病机制中的作用
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摘要
白塞病是一种主要表现为复发性口腔溃疡、生殖器溃疡、眼炎和皮肤损害的慢性系统性血管炎。白塞病发病机制尚不明确,可能是遗传易感个体在感染或环境等因素触发下发生的自身免疫性疾病,辅助性T淋巴细胞17(Th17)在白塞病发病过程中有重要作用。干扰素调节因子8(IRF8)可抑制Th17分化,从而抑制Th17及白细胞介素17产生的炎性反应。基因组学研究提示,IRF8相关单核苷酸多态性位点是白塞病的风险基因位点。近年来,IRF8抑制Th17分化在白塞病发病机制中的作用已经成为研究热点。
Beh?et's disease(BD) is a chronic systemic vasculitis that mainly characterized by recurrent oral ulcers, genital ulcers, uveitis and skin lesions. The pathogenesis of BD is still unknown. BD is considered to be an autoimmune disease triggered by infection or environmental factors in genetically susceptible individuals. Helper T cell 17(Th17) play an important role in the pathogenesis of BD. Interferon regulatory factor 8(IRF8) inhibits Th17 differentiation, thereby inhibiting the inflammation induced by Th17 and interleukin 17. Genomic studies suggest that IRF8-associated single nucleotide polymorphisms(SNPs) are risk loci of BD. In recent years, role of IRF8 inhibiting Th17 differentiation in the pathogenesis of BD has become a research focus.
Beh?et's disease(BD) is a chronic systemic vasculitis that mainly characterized by recurrent oral ulcers, genital ulcers, uveitis and skin lesions. The pathogenesis of BD is still unknown. BD is considered to be an autoimmune disease triggered by infection or environmental factors in genetically susceptible individuals. Helper T cell 17(Th17) play an important role in the pathogenesis of BD. Interferon regulatory factor 8(IRF8) inhibits Th17 differentiation, thereby inhibiting the inflammation induced by Th17 and interleukin 17. Genomic studies suggest that IRF8-associated single nucleotide polymorphisms(SNPs) are risk loci of BD. In recent years, role of IRF8 inhibiting Th17 differentiation in the pathogenesis of BD has become a research focus.
引文
[1]管剑龙. 白塞病临床诊治现状与几点认识[J]. 内科理论与实践,2016,11:347-351.
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[3]MARWAHA A K, LEUNG N J, McMURCHY A N, LEVINGS M K. Th17 cells in autoimmunity and immunodeficiency: protective or pathogenic?[J/OL]. Front Immunol, 2012, 3: 129. doi: 10.3389/fimmu.2012.00129.
[4]ZHENG S G. Regulatory T cells vs Th17: differentiation of Th17 versus Treg, are the mutually exclusive?[J]. Am J Clin Exp Immunol, 2013, 2: 94-106.
[5]YADAV M, STEPHAN S, BLUESTONE J A.Peripherally induced Tregs－role in immune homeostasis and autoimmunity[J/OL]. Front Immunol, 2013, 4: 232.doi: 10.3389/fimmu.2013.00232.
[6]HAMZAOUI K, BOUALI E, GHORBEL I, KHANFIR M, HOUMAN H, HAMZAOUI A. Expression of Th-17 and RORγt mRNA in Beh?et’s disease[J]. Med Sci Monit, 2011, 17: CR227-CR234.
[7]GERI G, TERRIER B, ROSENZWAJG M, WECHSLER B, TOUZOT M, SEILHEAN D, et al. Critical role of IL-21 in modulating Th17 and regulatory T cells in Beh?et disease[J]. J Allergy Clin Immunol, 2011, 128: 655-664.
[8]SUGITA S, KAWAZOE Y, IMAI A, YAMADA Y, HORIE S, MOCHIZUKI M. Inhibition of Th17 differentiation by anti-TNF-α therapy in uveitis patients with Beh?et’s disease[J/OL]. Arthritis Res Ther, 2012, 14: R99. doi:10.1186/ar3824.
[9]TAMURA T, KUROTAKI D, KOIZUMI S. Regulation of myelopoiesis by the transcription factor IRF8[J]. Int J Hematol, 2015, 101: 342-351.
[10]MANCINO A, NATOLI G. Specificity and function of IRF family transcription factors: insights from genomics[J]. J Interferon Cytokine Res, 2016, 36: 462-469.
[11]PELKA K, LATZ E. IRF5, IRF8, and IRF7 in human pDCs－the good, the bad, and the insignificant?[J]. Eur J Immunol, 2013, 43: 1693-1697.
[12]SINGH H, GLASMACHER E, CHANG A B, VANDER LUGT B. The molecular choreography of IRF4 and IRF8 with immune system partners[J]. Cold Spring Harb Symp Quant Biol, 2013, 78: 101-104.
[13]OUYANG X, ZHANG R, YANG J, LI Q, QIN L, ZHU C, et al. Transcription factor IRF8 directs a silencing programme for TH17 cell differentiation[J/OL]. Nat Commun, 2011, 2: 314. doi: 10.1038/ncomms1311.
[14]YOSHIDA Y, YOSHIMI R, YOSHII H, KIM D, DEY A,XIONG H, et al. The transcription factor IRF8 activates integrin-mediated TGF-β signaling and promotes neuroinflammation[J]. Immunity, 2014, 40: 187-198.
[15]KIM S H, BURTON J, YU C R, SUN L, HE C, WANG H, et al. Dual function of the IRF8 transcription factor in autoimmune uveitis: loss of IRF8 in T cells exacerbates uveitis, whereas IRF8 deletion in the retina confers protection[J]. J Immunol, 2015, 195: 1480-1488.
[16]TAKEUCHI M, MIZUKI N, MEGURO A, OMBRELLO M J, KIRINO Y, SATORIUS C, et al. Dense genotyping of immune-related loci implicates host responses to microbial exposure in Beh?et’s disease susceptibility[J].Nat Genet, 2017, 49: 438-443.
[17]JIANG Y, WANG H, YU H, LI L, XU D, HOU S, et al.Two genetic variations in the IRF8 region are associated with Beh?et’s disease in Han Chinese[J/OL]. Sci Rep,2016, 6: 19651. doi: 10.1038/srep19651.
[18]TIAN Y, WANG C, YE Z, XIAO X, KIJLSTRA A,YANG P. Effect of 1,25-dihydroxyvitamin D3 on Th17 and Th1 response in patients with Beh?et’s disease[J].Invest Ophthalmol Vis Sci, 2012, 53: 6434-6441.
[19]QIU Y, ZHU Y, YU H, YI S, SU W, CAO Q, et al. Ocular Beh?et’s disease is associated with aberrant methylation of interferon regulatory factor 8 (IRF8) in monocyte-derived dendritic cells[J]. Oncotarget, 2017, 8: 51277-51287.
[2]ZEIDAN M J, SAADOUN D, GARRIDO M, KLATZMANN D, SIX A, CACOUB P. Beh?et’s disease physiopathology:a contemporary review [J/OL]. Auto Immun Highlights,2016, 7: 4. doi: 10.1007/s13317-016-0074-1.
[3]MARWAHA A K, LEUNG N J, McMURCHY A N, LEVINGS M K. Th17 cells in autoimmunity and immunodeficiency: protective or pathogenic?[J/OL]. Front Immunol, 2012, 3: 129. doi: 10.3389/fimmu.2012.00129.
[4]ZHENG S G. Regulatory T cells vs Th17: differentiation of Th17 versus Treg, are the mutually exclusive?[J]. Am J Clin Exp Immunol, 2013, 2: 94-106.
[5]YADAV M, STEPHAN S, BLUESTONE J A.Peripherally induced Tregs－role in immune homeostasis and autoimmunity[J/OL]. Front Immunol, 2013, 4: 232.doi: 10.3389/fimmu.2013.00232.
[6]HAMZAOUI K, BOUALI E, GHORBEL I, KHANFIR M, HOUMAN H, HAMZAOUI A. Expression of Th-17 and RORγt mRNA in Beh?et’s disease[J]. Med Sci Monit, 2011, 17: CR227-CR234.
[7]GERI G, TERRIER B, ROSENZWAJG M, WECHSLER B, TOUZOT M, SEILHEAN D, et al. Critical role of IL-21 in modulating Th17 and regulatory T cells in Beh?et disease[J]. J Allergy Clin Immunol, 2011, 128: 655-664.
[8]SUGITA S, KAWAZOE Y, IMAI A, YAMADA Y, HORIE S, MOCHIZUKI M. Inhibition of Th17 differentiation by anti-TNF-α therapy in uveitis patients with Beh?et’s disease[J/OL]. Arthritis Res Ther, 2012, 14: R99. doi:10.1186/ar3824.
[9]TAMURA T, KUROTAKI D, KOIZUMI S. Regulation of myelopoiesis by the transcription factor IRF8[J]. Int J Hematol, 2015, 101: 342-351.
[10]MANCINO A, NATOLI G. Specificity and function of IRF family transcription factors: insights from genomics[J]. J Interferon Cytokine Res, 2016, 36: 462-469.
[11]PELKA K, LATZ E. IRF5, IRF8, and IRF7 in human pDCs－the good, the bad, and the insignificant?[J]. Eur J Immunol, 2013, 43: 1693-1697.
[12]SINGH H, GLASMACHER E, CHANG A B, VANDER LUGT B. The molecular choreography of IRF4 and IRF8 with immune system partners[J]. Cold Spring Harb Symp Quant Biol, 2013, 78: 101-104.
[13]OUYANG X, ZHANG R, YANG J, LI Q, QIN L, ZHU C, et al. Transcription factor IRF8 directs a silencing programme for TH17 cell differentiation[J/OL]. Nat Commun, 2011, 2: 314. doi: 10.1038/ncomms1311.
[14]YOSHIDA Y, YOSHIMI R, YOSHII H, KIM D, DEY A,XIONG H, et al. The transcription factor IRF8 activates integrin-mediated TGF-β signaling and promotes neuroinflammation[J]. Immunity, 2014, 40: 187-198.
[15]KIM S H, BURTON J, YU C R, SUN L, HE C, WANG H, et al. Dual function of the IRF8 transcription factor in autoimmune uveitis: loss of IRF8 in T cells exacerbates uveitis, whereas IRF8 deletion in the retina confers protection[J]. J Immunol, 2015, 195: 1480-1488.
[16]TAKEUCHI M, MIZUKI N, MEGURO A, OMBRELLO M J, KIRINO Y, SATORIUS C, et al. Dense genotyping of immune-related loci implicates host responses to microbial exposure in Beh?et’s disease susceptibility[J].Nat Genet, 2017, 49: 438-443.
[17]JIANG Y, WANG H, YU H, LI L, XU D, HOU S, et al.Two genetic variations in the IRF8 region are associated with Beh?et’s disease in Han Chinese[J/OL]. Sci Rep,2016, 6: 19651. doi: 10.1038/srep19651.
[18]TIAN Y, WANG C, YE Z, XIAO X, KIJLSTRA A,YANG P. Effect of 1,25-dihydroxyvitamin D3 on Th17 and Th1 response in patients with Beh?et’s disease[J].Invest Ophthalmol Vis Sci, 2012, 53: 6434-6441.
[19]QIU Y, ZHU Y, YU H, YI S, SU W, CAO Q, et al. Ocular Beh?et’s disease is associated with aberrant methylation of interferon regulatory factor 8 (IRF8) in monocyte-derived dendritic cells[J]. Oncotarget, 2017, 8: 51277-51287.