The expression and clinicopathological significance of macrophage-associated protein and TIM-3 in IgG4-related sialadenitis

doi:10.19438/j.cjoms.2026.04.007

Abstract

Abstract: PURPOSE: To investigate the expression characteristics of macrophage-associated proteins (CD68, CD80, CD163) and TIM-3 protein in IgG4-related sialadenitis (IgG4-RS) and their correlation with clinicopathological parameters of patients. METHODS: Salivary gland tissue samples from 33 patients with IgG4-RS, 8 patients with Sjögren syndrome (SS) and 8 healthy controls were selected. The expression levels of CD68, CD80, CD163 and TIM-3 proteins in the three groups were detected by HE staining, Masson staining and immunohistochemical staining. The correlations between the expression of these proteins and patients' age, number of involved organs, ratio of IgG4/IgG positive plasma cells, and fibrosis area were analyzed. RESULTS: The expression levels of CD68, CD163 and TIM-3 in the salivary gland tissues of patients with IgG4-RS were significantly higher than those in the SS group (P<0.05). CD68 expression was correlated with patients' age and number of involved organs (P<0.05), CD80 expression was correlated with the number of involved organs (P<0.05), CD163 expression was correlated with the ratio of IgG4/IgG positive plasma cells and age (P<0.05), and TIM-3 expression was correlated with age (P<0.05). Spearman correlation analysis showed that the expression levels of CD68, CD163 and TIM-3 in the glandular tissues of IgG4-RS patients were positively correlated with the relative area of fibrosis (P<0.05). CONCLUSIONS: CD68, CD163 and TIM-3 proteins are highly expressed in the salivary gland tissues of IgG4-RS, and their expression levels are closely related to patients' age, number of involved organs, and degree of tissue fibrosis. This study provides a new theoretical basis for revealing the immune pathogenesis of IgG4-RS and optimizing clinical diagnosis and treatment strategies.

Key words: Macrophages, TIM-3, Fibrosis, IgG4-related diseases, IgG4-related sialadenitis, Clinicopathological features, Immunohistochemistry

CLC Number:

Yue Rongrong, Li Chenxi, Zhou Yuchuan, Hu Lulu, Gong Zhongcheng. The expression and clinicopathological significance of macrophage-associated protein and TIM-3 in IgG4-related sialadenitis[J]. China Journal of Oral and Maxillofacial Surgery, 2026, 24(4): 361-367.

References

[1] Umehara H, Okazaki K, Masaki Y, et al.A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details[J]. Mod Rheumatol, 2012, 22(1): 1-14.
[2] Zhou W, Li Y, Yan C, et al.The prevalence of extra-salivary gland complications in immunoglobulin G4-related sialadenitis[J]. Oral Dis, 2022, 28(6):1468-1483.
[3] Pu J, Jia M, Shi W, et al.Immunohistochemical analysis of pyroptosis-related protein expression in IgG4-related sialadenitis[J]. J Oral Pathol Med, 2022, 51(4): 388-394.
[4] Balint G, Watson Buchanan W, Kean CA, et al.Sjögren's syndrome[J]. Inflammopharmacology, 2024, 32(1): 37-43.
[5] 俞光岩, 洪霞, 李巍, 等. IgG4 相关唾液腺炎的临床病理特点及诊断[J]. 北京大学学报(医学版), 2019, 51(1): 1-3.
Yu GY, Hong X, Li W, et al.Clinicopathological characteristics and diagnosis of IgG4-related sialadenitis[J]. Journal of Peking University: Health Sciences, 2019, 51(1): 1-3.
[6] Liu C, Zhang P, Zhang W.Immunological mechanism of IgG4-related disease[J]. J Transl Autoimmun, 2020, 3: 100047.
[7] 李晨曦, 龚忠诚, 郑佞波. 肿瘤源性外泌体对巨噬细胞极化的调控作用的研究进展[J]. 中华微生物学和免疫学杂志, 2023, 43(1): 76-83.
Li CX, Gong ZC, Zheng NB.Progress in the regulatory effects of tumor-derived exosomes on macrophage polarization[J]. Chinese Journal of Microbiology and Immunology, 2023, 43(1): 76-83.
[8] Cutolo M, Campitiello R, Gotelli E, et al.The role of M1/M2 macrophage polarization in rheumatoid arthritis synovitis[J]. Front Immunol, 2022, 13: 867260.
[9] Wang C, Ma C, Gong L, et al.Macrophage polarization and its role in liver disease[J]. Front Immunol, 2021, 12: 803037.
[10] Lasch M, Sudan K, Paul C, et al.Isolation of decidual macrophages and hofbauer cells from term placenta-comparison of the expression of CD163 and CD80[J]. Int J Mol Sci, 2022, 23(11): 6113.
[11] Cao Y, Li Q, Liu H, et al.Role of Tim-3 in regulating tumorigenesis, inflammation, and antitumor immunity therapy[J]. Cancer Biomark, 2021, 32(2): 237-248.
[12] Zhang W, Zhang Y, He Y, et al.Lipopolysaccharide mediates time-dependent macrophage M1/M2 polarization through the Tim-3/Galectin-9 signalling pathway[J]. Exp Cell Res, 2019, 376(2): 124-132.
[13] 钱嘉航, 任军, 贾凌云, 等. 自身免疫性疾病与自身抗体概述[J]. 中国免疫学杂志, 2022, 38(17): 2152-2158.
Qian JH, Ren J, Jia LY, et al.An overview of autoimmune diseases and autoantibodies[J]. Chinese Journal of Immunology, 2022, 38(17): 2152-2158.
[14] 蒲娇, 胡露露, 牛雅琪, 等. 31例IgG4 相关性疾病的临床分析[J]. 口腔医学研究, 2021, 37(2): 173-178.
Pu J, Hu LL, Niu QY, et al.Clinical analysis of thirty-one cases of IgG4-related disease[J]. Journal of Oral Science Research, 2021, 37(2): 173-178.
[15] 张盼盼, 赵继志, 王木, 等. IgG4 相关性疾病346例临床特征分析[J]. 中华内科杂志, 2017, 56(9): 644-649.
Zhang PP, Zhao JZ, Wang M, et al.The clinical characteristics of 346 patients with IgG4-related disease[J]. Chinese Journal of Internal Medicine, 2017, 56(9): 644-649.
[16] 夏荣辉, 胡宇华, 钱佳骏, 等. IgG4相关唾液腺炎临床病理特征分析[J]. 中华口腔医学杂志, 2023, 58(8): 815-820.
Xia RH, Hu YH, Qian JJ, et al.Analysis of clinicopathological characteristics of IgG4-related sialadenitis[J]. Chinese Journal of Stomatology, 2023, 58(8): 815-820.
[17] Fragoulis GE, Zampeli E, Moutsopoulos HM.IgG4-related sialadenitis and Sjögren's syndrome[J]. Oral Dis, 2017, 23(2): 152-156.
[18] Zhang YY, Hong X, Wang Z, et al.Diagnostic utility of submandibular and labial salivary gland biopsy in IgG4-related sialadenitis[J]. Clin Rheumatol, 2020, 39(12): 3715-3721.
[19] Cheng D, Chai J, Wang H, et al.Hepatic macrophages: key players in the development and progression of liver fibrosis[J]. Liver Int, 2021, 41(10): 2279-2294.
[20] Wu N, Xu XF, Xin JQ, et al.The effects of nuclear factor-kappa B in pancreatic stellate cells on inflammation and fibrosis of chronic pancreatitis[J]. J Cell Mol Med, 2021, 25(4): 2213-2227.
[21] Tsuboi H, Honda F, Takahashi H, et al.Pathogenesis of IgG4-related disease. comparison with Sjögren's syndrome[J]. Mod Rheumatol, 2020, 30(1): 7-16.
[22] Chinju A, Moriyama M, Kakizoe-Ishiguro N, et al.CD163+ M2 macrophages promote fibrosis in IgG4-related disease via Toll-like receptor 7/interleukin-1 receptor-associated kinase 4/NF-κB signaling[J]. Arthritis Rheumatol, 2022, 74(5): 892-901.
[23] 罗璇, 彭钰, 费允云. IgG4 相关性疾病复发的危险因素[J]. 中华临床免疫和变态反应杂志, 2019, 13(6): 480-482.
Luo X, Peng Y, Fei YY.Risk factors for relapse of IgG4-related diseases[J]. Chinese Journal of Allergy & Clinical Immunology, 2019, 13(6): 480-482.
[24] Yunyun F, Yu P, Panpan Z, et al.Efficacy and safety of low dose mycophenolate mofetil treatment for immunoglobulin G4-related disease: a randomized clinical trial[J]. Rheumatology (Oxford), 2019, 58(1): 52-60.
[25] Hesketh M, Sahin KB, West ZE, et al.Macrophage phenotypes regulate scar formation and chronic wound healing[J]. Int J Mol Sci, 2017, 18(7): 1545.
[26] Kung CC, Dai SP, Chiang H, et al.Temporal expression patterns of distinct cytokines and M1/M2 macrophage polarization regulate rheumatoid arthritis progression[J]. Mol Biol Rep, 2020, 47(5): 3423-3437.
[27] Feng Y, Ren J, Gui Y, et al.Wnt/β-catenin-promoted macrophage alternative activation contributes to kidney fibrosis[J]. J Am Soc Nephrol, 2018, 29(1): 182-193.
[28] He Y, Gao Y, Zhang Q, et al.IL-4 switches microglia/macrophage M1/M2 polarization and alleviates neurological damage by modulating the JAK1/STAT6 pathway following ICH[J]. Neuroscience, 2020, 437: 161-171.
[29] Dhar D, Baglieri J, Kisseleva T, et al.Mechanisms of liver fibrosis and its role in liver cancer[J]. Exp Biol Med (Maywood), 2020, 245(2): 96-108.
[30] Moar P, Tandon R.Galectin-9 as a biomarker of disease severity[J]. Cell Immunol, 2021, 361: 104287.
[31] 林道泼, 邵晓晓, 胡定元, 等. Tim-3调控巨噬细胞极化在克罗恩病发生发展中的作用[J]. 温州医科大学学报, 2022, 52(12): 947-955.
Lin DP, Shao XX, Hu DY, et al.The role of Tim-3 in regulating macrophage polarization in the occurrence and development of Crohn's disease[J]. Journal of Wenzhou Medical University, 2022, 52(12): 947-955.
[32] Kang J, Wei ZF, Li MX, et al.Modulatory effect of Tim-3/Galectin-9 axis on T-cell-mediated immunity in pulmonary tuberculosis[J]. J Biosci, 2020, 45: 60.
[33] Wang Y, Kuai Q, Gao F, et al.Overexpression of TIM-3 in macrophages aggravates pathogenesis of pulmonary fibrosis in mice[J]. Am J Respir Cell Mol Biol, 2019, 61(6): 727-736.