原发性硬化性胆管炎的免疫生物学机制与研究进展

摘要/Abstract

摘要： 原发性硬化性胆管炎(PSC)是一种慢性进行性胆汁淤积性肝病,其病理特征为肝内和(或)肝外胆管的进行性炎症和纤维化,最终可发展为肝硬化。遗传易感性、免疫相关基因变异、自身抗体的存在、与炎症性肠病的高度临床相关性以及与其他免疫介导性疾病共存,均提示免疫系统在PSC发病机制中发挥重要作用。近年来,单细胞RNA测序和空间转录组学等新技术的应用加深了对PSC免疫病理的认识。然而,其关键致病机制仍未完全阐明。本综述从固有免疫和适应性免疫两方面总结PSC中主要免疫细胞的功能改变,重点讨论Th17/Treg轴的潜在失衡、免疫细胞与胆管上皮细胞的相互作用、肠-肝轴在PSC中的免疫学意义,以及免疫靶向治疗的研究现状与挑战,为深入了解PSC的免疫发病机制和探索新的治疗策略提供参考。

关键词: 原发性硬化性胆管炎, 免疫生物学, 免疫细胞, 肠-肝轴, 免疫靶向治疗

蔡凝, 李斌, 戴雪喻, 冯波. 原发性硬化性胆管炎的免疫生物学机制与研究进展[J]. 肝脏, 2026, 31(2): 151-155.

/ 推荐

参考文献

[1] Karlsen T H, Folseraas T, Thorburn D, et al. Primary sclerosing cholangitis-a comprehensive review[J]. J Hepatol, 2017, 67(6): 1298-1323.
[2] Ricciuto A, Kamath B M, Hirschfield G M, et al. Primary sclerosing cholangitis and overlap features of autoimmune hepatitis: a coming of age or an age-ist problem?[J]. J Hepatol, 2023, 79(2): 567-575.
[3] Jiang X, Karlsen T H. Genetics of primary sclerosing cholangitis and pathophysiological implications[J]. Nat Rev Gastroenterol Hepatol, 2017, 14(5): 279-295.
[4] Sebode M, Weiler-Normann C, Liwinski T, et al. Autoantibodies in autoimmune liver disease-clinical and diagnostic relevance[J]. Front Immunol, 2018, 9: 609.
[5] Björkström N K. Immunobiology of the biliary tract system[J]. J Hepatol, 2022, 77(6): 1657-1669.
[6] Björkström N K, Ljunggren H G, Michaëlsson J. Emerging insights into natural killer cells in human peripheral tissues[J]. Nat Rev Immunol, 2016, 16(5): 310-320.
[7] Andrews T S, Nakib D, Perciani C T, et al. Single-cell, single-nucleus, and spatial transcriptomics characterization of the immunological landscape in the healthy and PSC human liver[J]. J Hepatol, 2024, 80(5): 730-743.
[8] Poch T, Krause J, Casar C, et al. Single-cell atlas of hepatic T cells reveals expansion of liver-resident naive-like CD4+ T cells in primary sclerosing cholangitis[J]. J Hepatol, 2021, 75(2): 414-423.
[9] Zimmer C L, von Seth E, Buggert M, et al. A biliary immune landscape map of primary sclerosing cholangitis reveals a dominant network of neutrophils and tissue-resident T cells[J]. Sci Transl Med, 2021, 13(599): eabb3107.
[10] Hintermann E, Tondello C, Fuchs S, et al. Blockade of neutrophil extracellular trap components ameliorates cholestatic liver disease in Mdr2 (Abcb4) knockout mice[J]. J Autoimmun, 2024, 146: 103229.
[11] Greenman R, Segal-Salto M, Barashi N, et al. CCL24 regulates biliary inflammation and fibrosis in primary sclerosing cholangitis[J]. JCI Insight, 2023, 8(10): e162270.
[12] Zweers S J, Shiryaev A, Komuta M, et al. Elevated interleukin-8 in bile of patients with primary sclerosing cholangitis[J]. Liver Int, 2016, 36(9): 1370-1377.
[13] Zwicker C, Bujko A, Scott C L. Hepatic macrophage responses in inflammation, a function of plasticity, heterogeneity or both?[J]. Front Immunol, 2021, 12: 690813.
[14] Kunzmann L K, Schoknecht T, Poch T, et al. Monocytes as potential mediators of pathogen-induced T-helper 17 differentiation in patients with primary sclerosing cholangitis (PSC)[J]. Hepatology, 2020, 72(4): 1310-1326.
[15] Chung B K, Jøgaard J, Reims H M, et al. Spatial transcriptomics identifies enriched gene expression and cell types in human liver fibrosis[J]. Hepatol Commun, 2022, 6(9): 2538-2550.
[16] Henriksen E K, Jørgensen K K, Kaveh F, et al. Gut and liver T-cells of common clonal origin in primary sclerosing cholangitis-inflammatory bowel disease[J]. J Hepatol, 2017, 66(1): 116-122.
[17] Sebode M, Peiseler M, Franke B, et al. Reduced FOXP3+ regulatory T cells in patients with primary sclerosing cholangitis are associated with IL2RA gene polymorphisms[J]. J Hepatol, 2014, 60(5): 1010-1016.
[18] Chung B K, Henriksen E K K, Jørgensen K K, et al. Gut and liver B cells of common clonal origin in primary sclerosing cholangitis-inflammatory bowel disease[J]. Hepatol Commun, 2018, 2(8): 956-967.
[19] Thapa M, Tedesco D, Gumber S, et al. Blockade of BAFF reshapes the hepatic B cell receptor repertoire and attenuates autoantibody production in cholestatic liver disease[J]. J Immunol, 2020, 204(12): 3117-3128.
[20] Zhang L, Lewis J T, Abraham S C, et al. IgG4+ plasma cell infiltrates in liver explants with primary sclerosing cholangitis[J]. Am J Surg Pathol, 2010, 34(1): 88-94.
[21] Pinto C, Giordano D M, Maroni L, et al. Role of inflammation and proinflammatory cytokines in cholangiocyte pathophysiology[J]. Biochim Biophys Acta Mol Basis Dis, 2018, 1864(4 Pt B): 1270-1278.
[22] Valestrand L, Zheng F, Hansen S H, et al. Bile from patients with primary sclerosing cholangitis contains mucosal-associated invariant T-cell antigens[J]. Am J Pathol, 2022, 192(4): 629-641.
[23] Valestrand L, Berntsen N L, Zheng F, et al. Lipid antigens in bile from patients with chronic liver diseases activate natural killer T cells[J]. Clin Exp Immunol, 2021, 203(2): 304-314.
[24] Jiang X, Otterdal K, Chung B K, et al. Cholangiocytes modulate CD100 expression in the liver and facilitate pathogenic T-helper 17 cell differentiation[J]. Gastroenterology, 2024, 166(4): 667-679.
[25] Kellerer M, Javed S, Casar C, et al. Antagonistic effects of the cytotoxic molecules granzyme B and TRAIL in the immunopathogenesis of sclerosing cholangitis[J]. Hepatology, 2024, 80(4): 782-796.
[26] Kummen M, Holm K, Anmarkrud J A, et al. The gut microbial profile in patients with primary sclerosing cholangitis is distinct from patients with ulcerative colitis without biliary disease and healthy controls[J]. Gut, 2017, 66(4): 611-619.
[27] Nakamoto N, Sasaki N, Aoki R, et al. Gut pathobionts underlie intestinal barrier dysfunction and liver T helper 17 cell immune response in primary sclerosing cholangitis[J]. Nat Microbiol, 2019, 4(3): 492-503.
[28] European Association for the Study of the Liver. EASL Clinical Practice Guidelines on sclerosing cholangitis[J]. J Hepatol, 2022, 77(3): 761-806.
[29] Shah A, Jones M P, Callaghan G, et al. Efficacy and safety of biologics in primary sclerosing cholangitis with inflammatory bowel disease: a systematic review and meta-analysis[J]. Hepatol Commun, 2024, 8(2): e0347.
[30] Voskens C, Stoica D, Rosenberg M, et al. Autologous regulatory T-cell transfer in refractory ulcerative colitis with concomitant primary sclerosing cholangitis[J]. Gut, 2023, 72(1): 49-53.