诊断学理论与实践

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2024 , Vol. 23 >Issue 03: 278 - 284

DOI: https://doi.org/10.16150/j.1671-2870.2024.03.005

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干燥综合征发病免疫机制研究现状及靶向治疗策略进展

  • 袁祥 ,
  • 厉小梅
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  • 中国科学技术大学附属第一医院风湿免疫科，安徽 合肥 230001
厉小梅 E-mail：lixiaomei@ustc.edu.cn

收稿日期: 2024-05-13

  录用日期: 2024-05-28

  网络出版日期: 2024-06-25

基金资助

国家自然科学基金(U2120365);“科大新医学“联合基金(WK9110000148)

收起

Advances in current research on the immunopathogenesis of Sjögren’s syndrome and targeted therapeutic strategies

  • YUAN Xiang ,
  • LI Xiaomei
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  • The Department of Rheumatology and Immunology, The First Affiliated Hospital of University of Science and Technology of China, Anhui Hefei 230001, China

Received date: 2024-05-13

  Accepted date: 2024-05-28

  Online published: 2024-06-25

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摘要

干燥综合征（Sjögren's syndrome， SS）是一种常见的全身性自身免疫性疾病，主要累及外分泌腺体，病理特征为淋巴细胞和浆细胞浸润。SS患者的主要临床表现为口干、眼干，还可出现脏器（如消化道、肺、肾脏等）受累。我国SS患病率为0.29%~0.77%，其中老年人的SS患病率为3.00%~4.00%。欧洲地区SS患病率约为0.23%。SS发病涉及多种细胞和细胞因子的相互作用，包括唾液腺上皮细胞、T细胞、B细胞、树突状细胞、干扰素（interferon， IFN）、白细胞介素（interleukin， IL）、肿瘤坏死因子（tumor necrosis factor， TNF）和炎症小体等。目前，SS的腺体治疗以局部治疗为主，系统性受累的治疗方案主要借鉴其他自身免疫性疾病，尚无获批的针对性药物。SS的靶向治疗药物中，B细胞靶向治疗药物中，研究最多的是利妥昔单抗，其对存在冷球蛋白血管炎的SS患者显示出改善唾液的疗效；BAFF抑制剂、靶向CD40和间充质干细胞等也显示了一定疗效。对于大多数存在系统损害的SS患者，糖皮质激素（glucocorticoids， GCs）是一线治疗用药。免疫抑制剂和生物制剂作为二线用药，用于GCs耐受或抵抗的SS患者。在SS的发病机制中已经确定了许多潜在的治疗靶点，但只有少部分药物可转化为临床应用。当前，需要在全面评估患者病情、借助多学科协助的基础上，联合应用现有药物，制定出相对安全、有效、不良反应较小的治疗方案。靶向治疗、低不良反应以及多药物联合仍是未来SS药物研究的重点。

关键词： 干燥综合征; 免疫机制; 靶向药物

本文引用格式

袁祥 , 厉小梅 . 干燥综合征发病免疫机制研究现状及靶向治疗策略进展[J]. 诊断学理论与实践, 2024 , 23(03) : 278 -284 . DOI: 10.16150/j.1671-2870.2024.03.005

Abstract

Sjögren's syndrome (SS) is a prevalent systemic autoimmune disease, primarily affecting exocrine glands, characterized by lymphocyte and plasma cell infiltration. Patients typically exhibit dry mouth and eyes, with potential involvement of the digestive tract, lungs, and kidneys. In China, SS prevalence ranges from 0.29% to 0.77%, rising to 3.00%-4.00% among the elderly. In Europe, the prevalence is approximately 0.23%. The pathogenesis of SS involves interactions of multiple cells and cytokines, including salivary gland epithelial cells, T-cells, B-cells, dendritic cells, interferon (IFN), interleukin (IL), tumour necrosis factor (TNF) and inflammasomes. Currently, glandular therapy for SS is primarily localised, while treatment for systemic involvement is mainly borrowed from other autoimmune diseases, with no approved targeted drugs yet. Among the targeted therapeutic agents for SS, rituximab, a B-cell targeted therapy, is the most studied and has shown improved salivary efficacy in SS patients with cryoglobulin vasculitis. BAFF inhibitors, CD40 targeting agents, and mesenchymal stem cells have also demonstrated cartain therapeutic effects. For most systemic involvement, glucocorticoids (GCs) are the first-line treatment, while immunosuppressants and biologics serve as second-line options for GCs-tolerant or resistant patients. Although many potential therapeutic targets have been identified, few drugs have been clinically translated. Currently, there is a need to develop relatively safe and effective treatment regimens with minimal adverse effects through comprehensive patient assessment and multidisciplinary collaboration. Future SS drug research will focus on targeted therapies, adverse effects reduction, and multi-drug combinations.

Key words： Dry syndrome; Immune mechanism; Targeted drugs

参考文献

[1] BRITO-ZERóN P, BALDINI C, BOOTSMA H, et al. Sjogren syndrome[J]. Nat Rev Dis Primers, 2016, 2:16047.
[2] OZAKI Y, ITO T, SON Y, et al. Decrease of blood dendritic cells and increase of tissue-infiltrating dendritic cells are involved in the induction of Sj?gren's syndrome but not in the maintenance[J]. Clin Exp Immunol, 2010, 159(3):315-326.
[3] VAN BLOKLAND S C, VAN HELDEN-MEEUWSEN C G, WIERENGA-WOLF A F, et al. Two different types of sialoadenitis in the NOD- and MRL/lpr mouse models for Sjogren's syndrome: a differential role for dendritic cells in the initiation of sialoadenitis?[J]. Lab Invest, 2000, 80(4):575-585.
[4] SAEGUSA K, ISHIMARU N, YANAGI K, et al. Treatment with anti-CD86 costimulatory molecule prevents the autoimmune lesions in murine Sjogren's syndrome (SS) through up-regulated Th2 response[J]. Clin Exp Immunol, 2000, 119(2):354-360.
[5] KAPSOGEORGOU E K, TZIOUFAS A G. Interaction of human salivary gland epithelial cells with B lymphocytes: implications in the pathogenesis of sj?gren's syndrome[J]. Mediterr J Rheumatol, 2020, 31(4):424-426.
[6] VERSTAPPEN G M, KROESE F G M, BOOTSMA H. T cells in primary Sj?gren's syndrome: targets for early intervention[J]. Rheumatology (Oxford), 2021, 60(7):3088-3098.
[7] PONTARINI E, MURRAY-BROWN W J, CROIA C, et al. Unique expansion of IL-21+ Tfh and Tph cells under control of ICOS identifies Sjogren's syndrome with ectopic germinal centres and MALT lymphoma[J]. Ann Rheum Dis, 2020, 79(12):1588-1599.
[8] IVANCHENKO M, AQRAWI L A, BJ?RK A, et al. FoxP3(+) CXCR5(+) CD4(+) T cell frequencies are increased in peripheral blood of patients with primary Sjogren's syndrome[J]. Clin Exp Immunol, 2019, 195(3):305-309.
[9] LI P, YANG Y, JIN Y, et al. B7-H3 participates in human salivary gland epithelial cells apoptosis through NF-kappaB pathway in primary Sjogren's syndrome[J]. J Transl Med, 2019, 17(1):268.
[10] SOYFOO M S, NICAISE C. Pathophysiologic role of Interleukin-33/ST2 in Sjogren's syndrome[J]. Autoimmun Rev, 2021, 20(3):102756.
[11] MIAO M, HAO Z, GUO Y, et al. Short-term and low-dose IL-2 therapy restores the Th17/Treg balance in the peripheral blood of patients with primary Sjogren's syndrome[J]. Ann Rheum Dis, 2018, 77(12):1838-1840.
[12] PETERS A, PITCHER L A, SULLIVAN J M, et al. Th17 cells induce ectopic lymphoid follicles in central nervous system tissue inflammation[J]. Immunity, 2011, 35(6):986-996.
[13] IIZUKA M, TSUBOI H, MATSUO N, et al. A crucial role of RORgammat in the development of spontaneous Sialadenitis-like Sjogren's syndrome[J]. J Immunol, 2015, 194(1):56-67.
[14] LIU D, CAO T, WANG N, et al. IL-25 attenuates rheumatoid arthritis through suppression of Th17 immune responses in an IL-13-dependent manner[J]. Sci Rep, 2016, 6:36002.
[15] CICCIA F, GUGGINO G, RIZZO A, et al. Potential involvement of IL-22 and IL-22-producing cells in the inflamed salivary glands of patients with Sjogren's syndrome[J]. Ann Rheum Dis, 2012, 71(2):295-301.
[16] SHEN L, ZHANG C, WANG T, et al. Development of autoimmunity in IL-14alpha-transgenic mice[J]. J Immunol, 2006, 177(8):5676-5686.
[17] ZANDBELT M M, DE WILDE P, VAN DAMME P, et al. Etanercept in the treatment of patients with primary Sjogren's syndrome: a pilot study[J]. J Rheumatol, 2004, 31(1):96-101.
[18] SANKAR V, BRENNAN M T, KOK M R, et al. Etanercept in Sjogren's syndrome: a twelve-week randomized, double-blind, placebo-controlled pilot clinical trial[J]. Arthritis Rheum, 2004, 50(7):2240-2245.
[19] GROOM J, KALLED S L, CUTLER A H, et al. Association of BAFF/BLyS overexpression and altered B cell differentiation with Sjogren's syndrome[J]. J Clin Invest, 2002, 109(1):59-68.
[20] VAKALOGLOU K M, MAVRAGANI C P. Activation of the type I interferon pathway in primary Sjogren's syndrome: an update[J]. Curr Opin Rheumatol, 2011, 23(5):459-464.
[21] LEE J, LEE J, KWOK S K, et al. JAK-1 inhibition suppresses interferon-induced BAFF production in human salivary gland: potential therapeutic strategy for primary Sjogren's syndrome[J]. Arthritis Rheumatol, 2018, 70(12):2057-2066.
[22] AOTA K, YAMANOI T, KANI K, et al. Inhibition of JAK-STAT Signaling by Baricitinib Reduces Interferon-γ-Induced CXCL10 Production in Human Salivary Gland Ductal Cells[J]. Inflammation, 2021, 44(1):206-216.
[23] CUMMINS M J, PAPAS A, KAMMER G M, et al. Treatment of primary Sjogren's syndrome with low-dose human interferon alfa administered by the oromucosal route: combined phase Ⅲ results[J]. Arthritis Rheum, 2003, 49(4):585-593.
[24] MANOUSSAKIS M N, BOIU S, KORKOLOPOULOU P, et al. Rates of infiltration by macrophages and dendritic cells and expression of interleukin-18 and interleukin-12 in the chronic inflammatory lesions of Sjogren's syndrome: correlation with certain features of immune hyperactivity and factors associated with high risk of lymphoma development[J]. Arthritis Rheum, 2007, 56(12):3977-3988.
[25] BALDINI C, ROSSI C, FERRO F, et al. The P2X7 receptor-inflammasome complex has a role in modulating the inflammatory response in primary Sjogren's syndrome[J]. J Intern Med, 2013, 274(5):480-489.
[26] HUSAIN-KRAUTTER S, KRAMER J M, LI W, et al. The osteopontin transgenic mouse is a new model for Sjogren's syndrome[J]. Clin Immunol, 2015, 157(1):30-42.
[27] RAMOS-CASALS M, BRITO-ZERóN P, BOMBARDIERI S, et al. EULAR recommendations for the management of Sj?gren's syndrome with topical and systemic therapies[J]. Ann Rheum Dis, 2020, 79(1):3-18.
[28] CHU L L, CUI K, POPE J E. Meta-Analysis of Treatment for Primary Sj?gren's Syndrome[J]. Arthritis Care Res (Hoboken), 2020, 72(7):1011-1021.
[29] BOWMAN S J, EVERETT C C, O'DWYER J L, et al. Randomized Controlled Trial of Rituximab and Cost-Effectiveness Analysis in Treating Fatigue and Oral Dryness in Primary Sjogren's Syndrome[J]. Arthritis Rheumatol, 2017, 69(7):1440-1450.
[30] MARIETTE X, SEROR R, QUARTUCCIO L, et al. Efficacy and safety of belimumab in primary Sjogren's syndrome: results of the BELISS open-label phase II study[J]. Ann Rheum Dis, 2015, 74(3):526-531.
[31] MARIETTE X, BARONE F, BALDINI C, et al. A randomized, phase Ⅱ study of sequential belimumab and rituximab in primary Sjogren's syndrome[J]. JCI Insight, 2022, 7(23):e163030.
[32] BOWMAN S J, FOX R, D?RNER T, et al. Safety and efficacy of subcutaneous ianalumab (VAY736) in patients with primary Sjogren's syndrome: a randomised, double-blind, placebo-controlled, phase 2b dose-finding trial[J]. Lancet, 2022, 399(10320):161-171.
[33] XU D, FANG J, ZHANG S, et al. Efficacy and safety of telitacicept in primary Sjogren's syndrome: a randomi-zed, double-blind, placebo-controlled, phase 2 trial[J]. Rheumatology (Oxford), 2024, 63(3):698-705.
[34] FISHER B A, SZANTO A, NG W F, et al. Assessment of the anti-CD40 antibody iscalimab in patients with primary Sjogren's syndrome: a multicentre, randomised, double-blind, placebo-controlled, proof-of-concept study[J]. Lancet Rheumatol, 2020, 2(3):e142-e152.
[35] XU J, WANG D, LIU D, et al. Allogeneic mesenchymal stem cell treatment alleviates experimental and clinical Sjogren syndrome[J]. Blood, 2012, 120(15):3142-3151.
[36] ALURI H S, SAMIZADEH M, EDMAN M C, et al. Delivery of bone marrow-derived mesenchymal stem cells improves tear production in a mouse model of Sjogren's syndrome[J]. Stem Cells Int, 2017, 2017:3134543.
[37] LI B, XING Y, GAN Y, et al. Labial gland-derived mesenchymal stem cells and their exosomes ameliorate murine Sjogren's syndrome by modulating the balance of Treg and Th17 cells[J]. Stem Cell Res Ther, 2021, 12(1):478.
[38] ZHANG X, MIAO M, ZHANG R, et al. Efficacy and safety of low-dose interleukin-2 in combination with methotrexate in patients with active rheumatoid arthritis: a randomized, double-blind, placebo-controlled phase 2 trial[J]. Signal Transduct Target Ther, 2022, 7(1):67.
[39] XU J, LIU O, WANG D, et al. In vivo generation of SSA/Ro antigen-specific regulatory T cells improves experimental Sjogren's syndrome in mice[J]. Arthritis Rheumatol, 2022, 74(10):1699-1705.
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