Please wait a minute...
浙江大学学报（医学版）
浙江大学学报（医学版）  2021, Vol. 50 Issue (6): 783-794    DOI: 10.3724/zdxbyxb-2021-0072
综述     
原发性干燥综合征患者颌下腺炎症反应机制研究进展
任渊,崔戈丹,高永翔()
成都中医药大学临床医学院，四川 成都 610075
Research progress on inflammatory mechanism of primary Sj?gren syndrome
REN Yuan,CUI Gedan,GAO Yongxiang()
School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
 全文: PDF(2191 KB)   HTML( 13 )
摘要：

原发性干燥综合征是一种由大量淋巴细胞浸润外分泌腺并导致腺体功能障碍的自身免疫性疾病，其发病机制与遗传、免疫缺陷和病毒感染等导致外分泌腺慢性炎症反应有关。长期炎症使颌下腺上皮细胞凋亡加快，腺体结构紊乱，趋化因子CXC亚家族配体（CXCL）12和CXCL13、B细胞活化因子（BAF）、白介素-6、γ干扰素和肿瘤坏死因子α等炎症因子表达增加，在树突状细胞、巨噬细胞等抗原呈递细胞的作用下，诱导以B淋巴细胞为主的淋巴细胞在次级淋巴器官中成熟并迁徙至颌下腺，促进生发中心的形成和自身抗体的合成。同时，先天淋巴细胞、血管内皮细胞及黏膜相关恒定T细胞作为重要的免疫细胞，也通过不同作用机制参与了原发性干燥综合征患者颌下腺的炎症反应。这个过程涉及JAK激酶/信号转导及转录激活蛋白、丝裂原激活蛋白激酶/胞外信号调节激酶、磷酸酰肌醇3激酶/蛋白激酶B/哺乳动物雷帕霉素靶蛋白、程序性死亡蛋白1/程序性死亡蛋白配体1、Toll样受体/髓样分化因子88/核因子κB、BAF/BAF受体以及干扰素等多条信号通路的激活，这些信号通路相互影响，错综复杂，导致淋巴细胞不断活化并侵袭颌下腺。本文对国内外最新研究进行了综述，以期阐明原发性干燥综合征患者颌下腺炎症反应的机制，为下一步研究提供思路。
关键词： 原发性干燥综合征;  颌下腺;  免疫细胞;  炎症机制;  信号通路;  综述    
Abstract:

Primary Sj?gren syndrome is an autoimmune disease, in which a large number of lymphocytes infiltrate the exocrine glands and cause gland dysfunction. Its pathogenesis is related to the chronic inflammation of the exocrine glands caused by genetic factors, immunodeficiency or viral infection. Long-term inflammation leads to accelerated apoptosis of epithelial cells, disordered gland structure, increased expression of proinflammatory cytokine such as CXC subfamily ligand (CXCL) 12, CXCL13, B cell-activating factor (BAF), interleukin (IL)-6, interferon (IFN)-γ and tumor necrosis factor (TNF)-α in submandibular gland. With the action of antigen-presenting cells such as dendritic cells and macrophages, lymphocytes (mainly B cells) are induced to mature in secondary lymphoid organs and migrate to the submandibular gland to promotes the formation of germinal centers and the synthesis of autoantibodies. Meanwhile, innate lymphocytes, vascular endothelial cells and mucosa-associated constant T cells as important immune cells, also participated in the inflammatory response of the submandibular gland in primary Sj?gren syndrome through different mechanisms. This process involves the activation of multiple signal pathways such as JAK/STAT, MAPK/ERK, PI3K/AKT/mTOR, PD-1/PD-L1, TLR/MyD88/NF-κB, BAF/BAF-R and IFN. These signaling pathways interact with each other and are intricately complex, causing lymphocytes to continuously activate and invade the submandibular glands. This article reviews the latest literature to clarify the mechanism of submandibular gland inflammation in primary Sj?gren syndrome, and to provide insights for further research.
Key words: Primary Sj?gren syndrome    Submandibular gland    Immunocytes    Inflammatory response mechanisms    Signaling pathway    Review
收稿日期: 2021-03-16 出版日期: 2022-03-22
CLC:  R593.2  
基金资助: 国家自然科学基金（82004242）；国家“重大新药创制”科技重大专项（2018ZX09721004-009）；中华中医药学会青年人才托举工程项目（QNRC2-C01）；中国博士后科学基金（2018M633333）；四川省科技计划（18MZGC0038）；成都市哲学社会科学规划项目（2018Z02）
通讯作者: 高永翔     E-mail: drgaoyx@cdutcm.edu.cn
服务　　
把本文推荐给朋友
加入引用管理器
E-mail Alert
RSS
作者相关文章　　
任渊
崔戈丹
高永翔

引用本文:

任渊,崔戈丹,高永翔. 原发性干燥综合征患者颌下腺炎症反应机制研究进展[J]. 浙江大学学报（医学版）, 2021, 50(6): 783-794.

REN Yuan,CUI Gedan,GAO Yongxiang. Research progress on inflammatory mechanism of primary Sj?gren syndrome. J Zhejiang Univ (Med Sci), 2021, 50(6): 783-794.

链接本文:

https://www.zjujournals.com/med/CN/10.3724/zdxbyxb-2021-0072    或    https://www.zjujournals.com/med/CN/Y2021/V50/I6/783

1 SJ?GREN H. Zur kenntnis der keratoconjunctivitis sicca. Ⅲ[J]Acta Ophthalmologica, 2009, 13( 1-2): 40-45.
doi: 10.1111/j.1755-3768.1935.tb04187.x
2 QIN B, WANG J, YANG Z, et al.Epidemiology of primary Sj?gren’s syndrome: a systematic review and meta-analysis[J]Ann Rheum Dis, 2015, 74( 11): 1983-1989.
doi: 10.1136/annrheumdis-2014-205375
3 AKPEK E K, BUNYA V Y, SALDANHA I J. Sj?gren’s syndrome: more than just dry eye[J]Cornea, 2019, 38( 5): 658-661.
doi: 10.1097/ICO.0000000000001865
4 ALAM J, LEE A, LEE J, et al.Dysbiotic oral microbiota and infected salivary glands in Sj?gren’s syndrome[J/OL]PLoS One, 2020, 15( 3): e0230667.
doi: 10.1371/journal.pone.0230667
5 GONGY Z, NITITHAMJ, TAYLORK, et al.Differentiation of follicular helper T cells by salivary gland epithelial cells in primary Sj?gren’s syndrome[J]J Autoimmunity, 2014, 57-66.
doi: 10.1016/j.jaut.2013.11.003
6 MANOUSSAKIS M N, SPACHIDOU M P, MARATHEFTIS C I. Salivary epithelial cells from Sjogren’s syndrome patients are highly sensitive to anoikis induced by TLR-3 ligation[J]J Autoimmunity, 2010, 35( 3): 212-218.
doi: 10.1016/j.jaut.2010.06.010
7 CROW M K. Long interspersed nuclear elements (LINE-1): potential triggers of systemic autoimmune disease[J]Autoimmunity, 2010, 43( 1): 7-16.
doi: 10.3109/08916930903374865
8 SENFT D, RONAI Z’ A. UPR, autophagy, and mitochondria crosstalk underlies the ER stress response[J]Trends Biochem Sci, 2015, 40( 3): 141-148.
doi: 10.1016/j.tibs.2015.01.002
9 HILLEN M R, VERVERS F A, KRUIZE A A, et al.Dendritic cells, T-cells and epithelial cells: a crucial interplay in immunopathology of primary Sj?gren’s syndrome[J]Expert Rev Clin Immunol, 2014, 10( 4): 521-531.
doi: 10.1586/1744666X.2014.878650
10 DU B, ZHU M, LI Y, et al.The prostaglandin E2 increases the production of IL‐17 and the expression of costimulatory molecules on γδ T cells in rheumatoid arthritis[J/OL]Scand J Immunol, 2020, 91( 5): e12872.
doi: 10.1111/sji.12872
11 REIZIS B. Plasmacytoid dendritic cells: development, regulation, and function[J]Immunity, 2019, 50( 1): 37-50.
doi: 10.1016/j.immuni.2018.12.027
12 SHEN L, SURESH L, MALYAVANTHAM K, et al.Different stages of primary Sj?gren’s syndrome involving lymphotoxin and type 1 IFN[J]J Immunol, 2013, 191( 2): 608-613.
doi: 10.4049/jimmunol.1203440
13 HOOPER K M, YEN J H, KONG W, et al.Prostaglandin E2 inhibition of IL-27 production in murine dendritic cells: a novel mechanism that involves IRF1[J]J Immunol, 2017, 198( 4): 1521-1530.
doi: 10.4049/jimmunol.1601073
14 SAITOH S I, ABE F, KANNO A, et al.TLR7 mediated viral recognition results in focal type Ⅰ interferon secretion by dendritic cells[J]Nat Commun, 2017, 8( 1): 1592.
doi: 10.1038/s41467-017-01687-x
15 VERSTAPPEN G M, CORNETH O B J, BOOTSMA H, et al.Th17 cells in primary Sj?gren’s syndrome: pathogenicity and plasticity[J]J Autoimmunity, 2018, 16-25.
doi: 10.1016/j.jaut.2017.11.003
16 CHAUDHARI S, KUMAR M S. Marine sponges Sarcotragus foetidus, Xestospongia carbonaria and Spongia obscura constituents ameliorate IL-1β and IL-6 in lipopolysaccharide-induced RAW 264.7 macrophages and carrageenan-induced oedema in rats[J]Inflammopharmacology, 2020, 28( 4): 1091-1119.
doi: 10.1007/s10787-020-00699-2
17 CHRISTODOULOU M I, KAPSOGEORGOU E K, MOUTSOPOULOS H M. Characteristics of the minor salivary gland infiltrates in Sj?gren’s syndrome[J]J Autoimmunity, 2010, 34( 4): 400-407.
doi: 10.1016/j.jaut.2009.10.004
18 ZHOU D, MCNAMARA N A. Macrophages: important players in primary Sj?gren’s syndrome?[J]Expert Rev Clin Immunol, 2014, 10( 4): 513-520.
doi: 10.1586/1744666X.2014.900441
19 KANG J K, HYUN C G. 4-Hydroxy-7-methoxycoumarin inhibits inflammation in LPS-activated RAW264.7 macrophages by suppressing NF-κB and MAPK activation[J]Molecules, 2020, 25( 19): 4424.
doi: 10.3390/molecules25194424
20 ROVATI L, KANEKO N, PEDICA F, et al.Mer tyrosine kinase as a possible link between resolution of inflammation and tissue fibrosis in IgG4-related disease[J]Rheumatology, 2021, 60( 10): 4929-4941.
doi: 10.1093/rheumatology/keab096
21 WITAS R, PECK A B, AMBRUS J L, et al.Sj?gren’s syndrome and TAM receptors: a possible contribution to disease onset[J]J Immunol Res, 2019, 4813795.
doi: 10.1155/2019/4813795
22 DE VRIES J E. Immunosuppressive and anti-inflammatory properties of interleukin 10[J]Ann Med, 1995, 27( 5): 537-541.
doi: 10.3109/07853899509002465
23 MORETTA L, LOCATELLI F. Innate lymphoid cells in normal and disease: an introductory overview[J]Immunol Lett, 2016, 1.
doi: 10.1016/j.imlet.2016.07.008
24 CHIOSSONE L, DUMAS P Y, VIENNE M, et al.Natural killer cells and other innate lymphoid cells in cancer[J]Nat Rev Immunol, 2018, 18( 11): 671-688.
doi: 10.1038/s41577-018-0061-z
25 BERNINK J H, PETERS C P, MUNNEKE M, et al.Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues[J]Nat Immunol, 2013, 14( 3): 221-229.
doi: 10.1038/ni.2534
26 BRITO-ZERóN P, BALDINI C, BOOTSMA H, et al.Sj?gren syndrome[J]Nat Rev Dis Primers, 2016, 2( 1): 16047.
doi: 10.1038/nrdp.2016.47
27 李鑫, 吴刚, 金向楠, 等. Ⅱ型固有淋巴样细胞（ILC2）通过分泌IL-13减缓类风湿性关节炎患者的发病进程[J]. 细胞与分子免疫学杂志, 2020, 36(9): 815-820
LI Xin, WU Gang, JIN Xiangnan, et al. Group 2 innate lymphoid cells (ILC2) relieves pathogenesis of rheumatoid arthritis by secreting IL-13[J]. Chinese Journal of Cellular and Molecular Immunology, 2020, 36(9): 815-820. (in Chinese)
28 CAI T, QIU J, JI Y, et al.IL-17-producing ST2+ group 2 innate lymphoid cells play a pathogenic role in lung inflammation[J]J Allergy Clin Immunol, 2019, 143( 1): 229-244.e9.
doi: 10.1016/j.jaci.2018.03.007
29 CICCIA F, GUGGINO G, RIZZO A, et al.Interleukin (IL)-22 receptor 1 is over-expressed in primary Sj?gren’s syndrome and Sj?gren-associated non-Hodgkin lymphomas and is regulated by IL-18[J]Clin Exp Immunol, 2015, 181( 2): 219-229.
doi: 10.1111/cei.12643
30 MAGRI G, MIYAJIMA M, BASCONES S, et al.Innate lymphoid cells integrate stromal and immunological signals to enhance antibody production by splenic marginal zone B cells[J]Nat Immunol, 2014, 15( 4): 354-364.
doi: 10.1038/ni.2830
31 DARIDON C, DEVAUCHELLE V, HUTIN P, et al.Aberrant expression of BAFF by B lymphocytes infiltrating the salivary glands of patients with primary Sj?gren’s syndrome[J]Arthritis Rheum, 2007, 56( 4): 1134-1144.
doi: 10.1002/art.22458
32 POLI A, MICHEL T, THéRéSINE M, et al.CD56 bright natural killer (NK) cells: an important NK cell subset[J]Immunology, 2009, 126( 4): 458-465.
doi: 10.1111/j.1365-2567.2008.03027.x
33 PONTARINI E, SCIACCA E, GRIGORIADOU S, et al.NKp30 receptor upregulation in salivary glands of Sj?gren’s syndrome characterizes ectopic lymphoid structures and is restricted by rituximab treatment[J]Front Immunol, 2021, 706737.
doi: 10.3389/fimmu.2021.706737
34 CAPRIO M, NEWFELL B G, LA SALA A, et al.Functional mineralocorticoid receptors in human vascular endothelial cells regulate intercellular adhesion molecule-1 expression and promote leukocyte adhesion[J]Circ Res, 2008, 102( 11): 1359-1367.
doi: 10.1161/CIRCRESAHA.108.174235
35 B?OCHOWIAK K J, OLEWICZ-GAWLIK A, TRZYBULSKA D, et al.Serum ICAM-1, VCAM-1 and E-selectin levels in patients with primary and secondary Sj?gren’s syndrome[J]Adv Clin Exp Med, 2017, 26( 5): 835-842.
doi: 10.17219/acem/61434
36 OHNO A, MITSUI T, ENDO I, et al. Dermatomyositis associated with Sj?gren’s syndrome: VEGF involvement in vasculitis. Clin Neuropathol. 2004, 23(4): 178-182
37 MEERMEIER E W, HARRIFF M J, KARAMOOZ E, et al.MAIT cells and microbial immunity[J]Immunol Cell Biol, 2018, 96( 6): 607-617.
doi: 10.1111/imcb.12022
38 WANG J J, MACARDLE C, WEEDON H, et al.Mucosal-associated invariant T cells are reduced and functionally immature in the peripheral blood of primary Sj?gren’s syndrome patients[J]Eur J Immunol, 2016, 46( 10): 2444-2453.
doi: 10.1002/eji.201646300
39 GUGGINO G, DI LIBERTO D, LO PIZZO M, et al.IL-17 polarization of MAIT cells is derived from the activation of two different pathways[J]Eur J Immunol, 2017, 47( 11): 2002-2003.
doi: 10.1002/eji.201747140
40 DODINGTON D W, DESAI H R, WOO M. JAK/STAT-emerging players in metabolism[J]Trends Endocrinol Metab, 2018, 29( 1): 55-65.
doi: 10.1016/j.tem.2017.11.001
41 CHARRAS A, ARVANITI P, LE DANTEC C, et al.JAK inhibitors suppress innate epigenetic reprogramming: a promise for patients with Sj?gren’s syndrome[J]Clinic Rev Allerg Immunol, 2020, 58( 2): 182-193.
doi: 10.1007/s12016-019-08743-y
42 PENG Y, LUO X, CHEN Y, et al.LncRNA and mRNA expression profile of peripheral blood mononuclear cells in primary Sj?gren’s syndrome patients[J]Sci Rep, 2020, 10( 1): 19629.
doi: 10.1038/s41598-020-76701-2
43 PERTOVAARA M, SILVENNOINEN O, ISOM?KI P. Cytokine-induced STAT1 activation is increased in patients with primary Sj?gren’s syndrome[J]Clin Immunol, 2016, 60-67.
doi: 10.1016/j.clim.2016.03.010
44 CHARRAS A, ARVANITI P, LE DANTEC C, et al.JAK inhibitors and oxidative stress control[J]Front Immunol, 2019, 2814.
doi: 10.3389/fimmu.2019.02814
45 PONTARINI E, MURRAY-BROWN W J, CROIA C, et al.Unique expansion of IL-21+ Tfh and Tph cells under control of ICOS identifies Sj?gren’s syndrome with ectopic germinal centres and MALT lymphoma[J]Ann Rheum Dis, 2020, 79( 12): 1588-1599.
doi: 10.1136/annrheumdis-2020-217646
46 LONG D, CHEN Y J, WU H J, et al.Clinical significance and immunobiology of IL-21 in autoimmunity[J]J Autoimmunity, 2019, 1-14.
doi: 10.1016/j.jaut.2019.01.013
47 BARRERA M J, AGUILERA S, CASTRO I, et al.Tofacitinib counteracts IL-6 overexpression induced by deficient autophagy: implications in Sj?gren’s syndrome[J]Rheumatology, 2021, 60( 4): 1951-1962.
doi: 10.1093/rheumatology/keaa670
48 LEE J, LEE J, KWOK S K, et al.JAK‐1 inhibition suppresses interferon‐induced BAFF production in human salivary gland[J]Arthritis Rheumatol, 2018, 70( 12): 2057-2066.
doi: 10.1002/art.40589
49 AQRAWI L A, IVANCHENKO M, BJ?RK A, et al.Diminished CXCR5 expression in peripheral blood of patients with Sj?gren’s syndrome may relate to both genotype and salivary gland homing[J]Clin Exp Immunol, 2018, 192( 3): 259-270.
doi: 10.1111/cei.13118
50 IKAI K, SAKAI M, MINAGI H O, et al.ΔNp63 is upregulated during salivary gland regeneration following duct ligation and irradiation in mice[J]FEBS Lett, 2020, 594( 19): 3216-3226.
doi: 10.1002/1873-3468.13896
51 CHEN X, ZHANG P, LIU Q, et al.Alleviating effect of paeoniflorin-6′-O-benzene sulfonate in antigen-induced experimental Sj?gren’s syndrome by modulating B lymphocyte migration via CXCR5-GRK2-ERK/p38 signaling pathway[J]Int Immunopharmacol, 2020, 106199.
doi: 10.1016/j.intimp.2020.106199
52 FU J, SHI H, CAO N, et al.Toll-like receptor 9 signaling promotes autophagy and apoptosis via divergent functions of the p38/JNK pathway in human salivary gland cells[J]Exp Cell Res, 2019, 375( 2): 51-59.
doi: 10.1016/j.yexcr.2018.12.027
53 PARK E, KIM D, LEE S M, et al.Inhibition of lysophosphatidic acid receptor ameliorates Sj?gren’s syndrome in NOD mice[J]Oncotarget, 2017, 8( 16): 27240-27251.
doi: 10.18632/oncotarget.15916
54 SISTO M, LORUSSO L, INGRAVALLO G, et al.TGFβ1-Smad canonical and -Erk noncanonical pathways participate in interleukin-17-induced epithelial-mesenchymal transition in Sj?gren’s syndrome[J]Lab Invest, 2020, 100( 6): 824-836.
doi: 10.1038/s41374-020-0373-z
55 WILLIAMS A E G, CHOI K, CHAN A L, et al.Sj?gren’s syndrome-associated microRNAs in CD14+ monocytes unveils targeted TGFβ signaling[J]Arthritis Res Ther, 2016, 18( 1): 95.
doi: 10.1186/s13075-016-0987-0
56 FRUMAN D A, CHIU H, HOPKINS B D, et al.The PI3K pathway in human disease[J]Cell, 2017, 170( 4): 605-635.
doi: 10.1016/j.cell.2017.07.029
57 CAI Y, SUN R, WANG R, et al.The activation of Akt/mTOR pathway by bleomycin in epithelial-to-mesenchymal transition of human submandibular gland cells: a treatment mechanism of bleomycin for mucoceles of the salivary glands[J]Biomed Pharmacother, 2017, 109-115.
doi: 10.1016/j.biopha.2017.02.098
58 BLOKLAND S L M, HILLEN M R, WICHERS C G K, et al.Increased mTORC1 activation in salivary gland B cells and T cells from patients with Sj?gren’s syndrome: mTOR inhibition as a novel therapeutic strategy to halt immunopathology?[J/OL]RMD Open, 2019, 5( 1): e000701.
doi: 10.1136/rmdopen-2018-000701
59 WANG J, WANG X, WANG L, et al.MiR-let-7d-3p regulates IL-17 expression through targeting AKT1/mTOR signaling in CD4+T cells[J]In Vitro Cell Dev Biol Anim, 2020, 56( 1): 67-74.
doi: 10.1007/s11626-019-00409-5
60 SOYPA?AC? Z, GüMü? Z Z, ?AKALO?LU F, et al.Role of the mTOR pathway in minor salivary gland changes in Sjogren’s syndrome and systemic sclerosis[J]Arthritis Res Ther, 2018, 20( 1): 170.
doi: 10.1186/s13075-018-1662-4
61 SILVER N, PROCTOR G B, ARNO M, et al.Activation of mTOR coincides with autophagy during ligation-induced atrophy in the rat submandibular gland[J/OL]Cell Death Dis, 2010, 1( 1): e14.
doi: 10.1038/cddis.2009.12
62 LU X, LI N, ZHAO L, et al.Human umbilical cord mesenchymal stem cells alleviate ongoing autoimmune dacryoadenitis in rabbits via polarizing macrophages into an anti-inflammatory phenotype[J]Exp Eye Res, 2020, 107905.
doi: 10.1016/j.exer.2019.107905
63 KYTHREOTOU A, SIDDIQUE A, MAURI F A, et al.PD-L1[J]J Clin Pathol, 2018, 71( 3): 189-194.
doi: 10.1136/jclinpath-2017-204853
64 CHEMNITZ J M, PARRY R V, NICHOLS K E, et al.SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation[J]J Immunol, 2004, 173( 2): 945-954.
doi: 10.4049/jimmunol.173.2.945
65 LITAK J, MAZUREK M, GROCHOWSKI C, et al.PD-L1/PD-1 axis in glioblastoma multiforme[J]Int J Mol Sci, 2019, 20( 21): 5347.
doi: 10.3390/ijms20215347
66 KOBAYASHI M, KAWANO S, HATACHI S, et al. Enhanced expression of programmed death-1 (PD-1)/PD-L1 in salivary glands of patients with Sj?gren’s syndrome[J]. J Rheumatol. 2005, 32(11): 2156-2163
67 CHEN Y, WANG Y, XU L, et al.Influence of total glucosides of paeony on PD-1/PD-L1 expression in primary Sj?gren’s syndrome[J]Int J Rheum Dis, 2019, 22( 2): 200-206.
doi: 10.1111/1756-185X.13391
68 XIA L, LIU Y, WANG Y. PD-1/PD-L1 blockade therapy in advanced non-small-cell lung cancer: current status and future directions[J]Oncol, 2019, 24( S1): 31.
doi: 10.1634/theoncologist.2019-IO-S1-s05
69 AKIRA S, UEMATSU S, TAKEUCHI O. Pathogen recognition and innate immunity[J]Cell, 2006, 124( 4): 783-801.
doi: 10.1016/j.cell.2006.02.015
70 KIRIPOLSKY J, ROMANO R A, KASPEREK E M, et al.Activation of myd88-dependent TLRs mediates local and systemic inflammation in a mouse model of primary Sj?gren’s syndrome[J]Front Immunol, 2020, 2963.
doi: 10.3389/fimmu.2019.02963
71 KIRIPOLSKY J, MCCABE L G, GAILE D P, et al.Myd88 is required for disease development in a primary Sj?gren’s syndrome mouse model[J]J Leukoc Biol, 2017, 102( 6): 1411-1420.
doi: 10.1189/jlb.3A0717-311R
72 KARLSEN M, JONSSON R, BRUN J G, et al.TLR-7 and -9 stimulation of peripheral blood B cells indicate altered TLR signalling in primary Sj?gren’s syndrome patients by increased secretion of cytokines[J]Scand J Immunol, 2015, 82( 6): 523-531.
doi: 10.1111/sji.12368
73 BAUMANN C L, ASPALTER I M, SHARIF O, et al.CD14 is a coreceptor of Toll-like receptors 7 and 9[J]J Exp Med, 2010, 207( 12): 2689-2701.
doi: 10.1084/jem.20101111
74 CHEN L, CHEN P, LIU J, et al.Sargassum fusiforme polysaccharide SFP-F2 activates the NF-κB signaling pathway via CD14/IKK and P38 axes in RAW264.7 cells[J]Mar Drugs, 2018, 16( 8): 264.
doi: 10.3390/md16080264
75 YOSHIMOTO K, SUZUKI K, TAKEI E, et al.Elevated expression of BAFF receptor, BR3, on monocytes correlates with B cell activation and clinical features of patients with primary Sj?gren’s syndrome[J]Arthritis Res Ther, 2020, 22( 1): 157.
doi: 10.1186/s13075-020-02249-1
76 CARRILLO-BALLESTEROS F J, PALAFOX-SáNCHEZ C A, FRANCO-TOPETE R A, et al.Expression of BAFF and BAFF receptors in primary Sj?gren’s syndrome patients with ectopic germinal center-like structures[J]Clin Exp Med, 2020, 20( 4): 615-626.
doi: 10.1007/s10238-020-00637-0
77 SALAZAR-CAMARENA D C, ORTíZ-LAZARENO P, MARíN-ROSALES M, et al.BAFF-R and TACI expression on CD3+ T cells: interplay among BAFF, APRIL and T helper cytokines profile in systemic lupus erythematosus[J]Cytokine, 2019, 115-127.
doi: 10.1016/j.cyto.2018.11.008
78 FU J, SHI H, ZHAN T, et al.BST-2/Tetherin is involved in BAFF-enhanced proliferation and survival via canonical NF-κB signaling in neoplastic B-lymphoid cells[J]Exp Cell Res, 2021, 398( 1): 112399.
doi: 10.1016/j.yexcr.2020.112399
79 DERUDDER E, HERZOG S, LABI V, et al.Canonical NF-κB signaling is uniquely required for the long-term persistence of functional mature B cells[J]Proc Natl Acad Sci U S A, 2016, 113( 18): 5065-5070.
doi: 10.1073/pnas.1604529113
80 GANDOLFO S, DE VITA S. Double anti-B cell and anti-BAFF targeting for the treatment of primary Sj?gren’s syndrome[J]. Clin Exp Rheumatol. 2019, 37 Suppl 118(3): 199-208
81 DECKER T, MüLLER M, STOCKINGER S. The yin and yang of type Ⅰ interferon activity in bacterial infection[J]Nat Rev Immunol, 2005, 5( 9): 675-687.
doi: 10.1038/nri1684
82 BODEWES I L A, HUIJSER E, VAN HELDEN-MEEUWSEN C G, et al.TBK1: a key regulator and potential treatment target for interferon positive Sj?gren’s syndrome, systemic lupus erythematosus and systemic sclerosis[J]J Autoimmunity, 2018, 97-102.
doi: 10.1016/j.jaut.2018.02.001
83 BODEWES I L A, BJ?RK A, VERSNEL M A, et al.Innate immunity and interferons in the pathogenesis of Sj?gren’s syndrome[J]Rheumatology, 2021, 60( 6): 2561-2573.
doi: 10.1093/rheumatology/key360
84 MARIA N I, STEENWIJK E C, IJPMA A S, et al.Contrasting expression pattern of RNA-sensing receptors TLR7, RIG-Ⅰ and MDA5 in interferon-positive and interferon-negative patients with primary Sj?gren’s syndrome[J]Ann Rheum Dis, 2017, 76( 4): 721-730.
doi: 10.1136/annrheumdis-2016-209589
85 IVASHKIV L B, DONLIN L T. Regulation of type Ⅰ interferon responses[J]Nat Rev Immunol, 2014, 14( 1): 36-49.
doi: 10.1038/nri3581
86 MAVRAGANI C P. Mechanisms and new strategies for primary Sj?gren’s syndrome[J]Annu Rev Med, 2017, 68( 1): 331-343.
doi: 10.1146/annurev-med-043015-123313
87 DAVIES R, HAMMENFORS D, BERGUM B, et al.Aberrant cell signalling in PBMCs upon IFN‐α stimulation in primary Sj?gren’s syndrome patients associates with type Ⅰ interferon signature[J]Eur J Immunol, 2018, 48( 7): 1217-1227.
doi: 10.1002/eji.201747213
88 APOSTOLOU E, KAPSOGEORGOU E K, KONSTA O D, et al.Expression of type Ⅲ interferons (IFNλs) and their receptor in Sj?gren’s syndrome[J]Clin Exp Immunol, 2016, 186( 3): 304-312.
doi: 10.1111/cei.12865
89 THOMPSON N, ISENBERG D A, JURY E C, et al.Exploring BAFF: its expression, receptors and contribution to the immunopathogenesis of Sj?gren’s syndrome[J]Rheumatology, 2016, 55( 9): 1548-1555.
doi: 10.1093/rheumatology/kev420
90 DE OLIVEIRA F R, FANTUCCI M Z, ADRIANO L, et al.Neurological and inflammatory manifestations in Sj?gren’s syndrome: the role of the kynurenine metabolic pathway[J]Int J Mol Sci, 2018, 19( 12): 3953.
doi: 10.3390/ijms19123953
[1] 卢茜璇,包黎莎,潘宗富,葛明华. 甲状腺未分化癌免疫治疗的现状及未来[J]. 浙江大学学报（医学版）, 2021, 50(6): 675-684.
[2] 钱晨宏,蒋烈浩,许世莹,王佳峰,谭卓,忻莹,葛明华. 甲状腺未分化癌靶向治疗研究进展[J]. 浙江大学学报（医学版）, 2021, 50(6): 685-693.
[3] 周靖,王艳,徐恩萍. 微单倍型在法医遗传学中的研究进展[J]. 浙江大学学报（医学版）, 2021, 50(6): 777-782.
[4] 马丽娟,吴爽,张凯,田梅,张宏. 大麻素1型受体正电子发射断层显像在神经精神疾病中的应用进展[J]. 浙江大学学报（医学版）, 2021, 50(5): 666-673.
[5] 宣自学,张轶雯,潘宗富,郑小卫,黄萍. 天然药物成分干预铁死亡抑制肿瘤的作用研究进展[J]. 浙江大学学报（医学版）, 2021, 50(5): 601-606.
[6] 曲文政,庄英粮,李学坤. 表观遗传修饰在神经退行性变性疾病中的作用研究进展[J]. 浙江大学学报（医学版）, 2021, 50(5): 642-650.
[7] 孙琦,曹蔚,罗建红. 含GluN3亚基的N-甲基-D-天冬氨酸受体及其在中枢神经系统的功能[J]. 浙江大学学报（医学版）, 2021, 50(5): 651-658.
[8] 史建蓉,马望前,汤慧芳. 磷酸二酯酶抑制剂治疗炎性肠病的研究进展[J]. 浙江大学学报（医学版）, 2021, 50(5): 659-665.
[9] 唐玥,孔元原. 遗传性酪氨酸血症Ⅰ型及其筛查和诊治进展[J]. 浙江大学学报（医学版）, 2021, 50(4): 514-523.
[10] 刘飞,冯春月,毛建华,傅海东. 2019冠状病毒病疫苗接种相关新发及复发肾小球病研究进展[J]. 浙江大学学报（医学版）, 2021, 50(4): 524-528.
[11] 韩连书. 新生儿遗传病基因筛查技术及相关疾病[J]. 浙江大学学报（医学版）, 2021, 50(4): 429-435.
[12] 胡茫莎,韦树丽,周武源,王苹莉. 新生儿Fc受体基础研究和临床应用进展[J]. 浙江大学学报（医学版）, 2021, 50(4): 537-544.
[13] 胡靖依,王青青,刘杨. 蛋白酶体亚基对肝细胞癌发生发展的调控作用研究进展[J]. 浙江大学学报（医学版）, 2021, 50(3): 396-402.
[14] 葛瀛洲,刘欣梅,黄荷凤. 沉默信息调节因子家族参与病理妊娠的研究进展[J]. 浙江大学学报（医学版）, 2021, 50(3): 335-344.
[15] 王锦涛,黄蕾,魏丽丽,陈炜. 重复经颅磁刺激治疗阿尔茨海默病患者的疗效影响因素[J]. 浙江大学学报（医学版）, 2021, 50(3): 383-389.