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10.02.2024 | Original Paper

Characteristics of peripheral blood mononuclear cells and potential related molecular mechanisms in patients with autoimmune hepatitis: a single-cell RNA sequencing analysis

Erschienen in: Medical Molecular Morphology

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Abstract

Autoimmune hepatitis (AIH) is an immune disorder characterized by hypergammaglobulinemia, autoantibodies, and chronic active hepatitis on liver histology. However, immune cell population characteristics in AIH patients remain poorly understood. This study was designed to analyze peripheral blood mononuclear cell (PBMC) characteristics in AIH through single-cell RNA sequencing (scRNA-seq) and explore potential AIH-related molecular mechanisms. We generated 3690 and 3511 single-cell transcriptomes of PBMCs pooled from 4 healthy controls (HCs) and 4 AIH patients, respectively, by scRNA-seq. These pooled PBMC transcriptomes were used for cell cluster identification and differentially expressed gene (DEG) identification. GO functional enrichment analysis was performed on the DEGs to determine the most active AIH immune cell biological functions. Although the PCA-based uniform manifold approximation and projection (UMAP) algorithm was used to cluster cells with similar expression patterns in the two samples, 87 up- and 12 downregulated DEGs were retained in monocytes and 101 up- and 15 downregulated DEGs were retained in NK cells from AIH PBMCs. Moreover, enriched GO terms in the PBMC-derived monocyte and NK cell clusters were related mainly to antigen processing and presentation, IFN-γ-mediated signaling, and neutrophil degranulation and activation. These potential molecular mechanisms may be important targets for AIH treatment.

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Krawitt EL (1996) Autoimmune hepatitis. N Engl J Med 334:897–903PubMedCrossRef

Vergani D, Mieli-Vergani G (2007) The impact of autoimmunity on hepatocytes. Semin Liver Dis 27:140–151PubMedCrossRef

Takahashi A, Ohira H, Abe K, Zeniya M, Abe M, Arinaga-Hino T, Torimura T, Yoshizawa K, Takaki A, Kang JH, Suzuki Y, Nakamoto N, Inui A, Tanaka A, Takikawa H (2020) Increasing incidence of acute autoimmune hepatitis: a nationwide survey in Japan. Sci Rep 10:14250ADSPubMedPubMedCentralCrossRef

Longhi MS, Ma Y, Bogdanos DP, Cheeseman P, Mieli-Vergani G, Vergani D (2004) Impairment of CD4 (+) CD25 (+) regulatory T cells in autoimmune liver disease. J Hepatol 41:31–37PubMedCrossRef

Ohira H, Takahashi A, Zeniya M, Abe M, Arinaga-Hino T, Joshita S, Takaki A, Nakamoto N, Kang JH, Suzuki Y, Sogo T, Inui A, Koike K, Harada K, Nakamoto Y, Kondo Y, Genda T, Tsuneyama K, Matsui T, Tanaka A (2022) Clinical practice guidelines for autoimmune hepatitis. Hepatol Res 52:571–585PubMedCrossRef

Gatselis NK, Zachou K, Koukoulis GK, Dalekos GN (2015) Autoimmune hepatitis, one disease with many faces: etiopathogenetic, clinico-laboratory and histological characteristics. World J Gastroenterol 21:60–83PubMedPubMedCentralCrossRef

Ebadi M, Bhanji RA, Mazurak VC, Lytvyak E, Mason A, Czaja AJ, Montano-Loza AJ (2019) Severe vitamin D deficiency is a prognostic biomarker in autoimmune hepatitis. Aliment Pharmacol Ther 49:173–182PubMedCrossRef

Abe K, Fujita M, Hayashi M, Takahashi A, Ohira H (2020) Association of serum 25-hydroxyvitamin D levels with severe necroinflammatory activity and inflammatory cytokine production in type I autoimmune hepatitis. PLoS One. 15:e0239481PubMedPubMedCentralCrossRef

Bossen L, Gerussi A, Lygoura V, Mells GF, Carbone M, Invernizzi P (2018) Support of precision medicine through risk-stratification in autoimmune liver diseases—histology, scoring systems, and noninvasive markers. Autoimmun Rev 17:854–865PubMedCrossRef

10.

de Boer YS, van Gerven NM, Zwiers A, Verwer BJ, van Hoek B, van Erpecum KJ, Beuers U, van Buuren HR, Drenth JP, den Ouden JW, Verdonk RC, Koek GH, Brouwer JT, Guichelaar MM, Vrolijk JM, Kraal G, Mulder CJ, van Nieuwkerk CM, Fischer J, Berg T, Stickel F, Sarrazin C, Schramm C, Lohse AW, Weiler-Normann C, Lerch MM, Nauck M, Völzke H, Homuth G, Bloemena E, Verspaget HW, Kumar V, Zhernakova A, Wijmenga C, Franke L, Bouma G, Dutch Autoimmune Hepatitis Study Group, Life Lines Cohort Study, Study of Health in Pomerania (2014) Genome-wide association study identifies variants associated with autoimmune hepatitis type 1. Gastroenterology. 147:443–452PubMedCrossRef

11.

Higuchi T, Oka S, Furukawa H, Tohma S, Yatsuhashi H, Migita K (2021) Genetic risk factors for autoimmune hepatitis: implications for phenotypic heterogeneity and biomarkers for drug response. Hum Genomics 15:6PubMedPubMedCentralCrossRef

12.

Umemura T, Katsuyama Y, Yoshizawa K, Kimura T, Joshita S, Komatsu M, Matsumoto A, Tanaka E, Ota M (2014) Human leukocyte antigen class II haplotypes affect clinical characteristics and progression of type 1 autoimmune hepatitis in Japan. PLoS ONE 9:e100565ADSPubMedPubMedCentralCrossRef

13.

Furumoto Y, Asano T, Sugita T, Abe H, Chuganji Y, Fujiki K, Sakata A, Aizawa Y (2015) Evaluation of the role of HLA-DR antigens in Japanese type 1 autoimmune hepatitis. BMC Gastroenterol 15:144PubMedPubMedCentralCrossRef

14.

Maeda Y, Migita K, Higuchi O, Mukaino A, Furukawa H, Komori A, Nakamura M, Hashimoto S, Nagaoka S, Abiru S, Yatsuhashi H, Matsuo H, Kawakami A, Yasunami M, Nakane S (2016) Association between anti-ganglionic nicotinic acetylcholine receptor (gAChR) antibodies and HLA-DRB1 alleles in the Japanese population. PLoS ONE 11:e0146048PubMedPubMedCentralCrossRef

15.

Oka S, Furukawa H, Yasunami M, Kawasaki A, Nakamura H, Nakamura M, Komori A, Abiru S, Nagaoka S, Hashimoto S, Naganuma A, Naeshiro N, Yoshizawa K, Yamashita H, Ario K, Ohta H, Sakai H, Yabuuchi I, Takahashi A, Abe K, Yatsuhashi H, Tohma S, Ohira H, Tsuchiya N, Migita K (2017) HLA-DRB1 and DQB1 alleles in Japanese type 1 autoimmune hepatitis: the predisposing role of the DR4/DR8 heterozygous genotype. PLoS ONE 12:e0187325PubMedPubMedCentralCrossRef

16.

Umemura T, Joshita S, Hamano H, Yoshizawa K, Kawa S, Tanaka E, Ota M (2017) Association of autoimmune hepatitis with Src homology 2 adaptor protein 3 gene polymorphisms in Japanese patients. J Hum Genet 62:963–967PubMedCrossRef

17.

Tang F, Barbacioru C, Wang Y, Nordman E, Lee C, Xu N, Wang X, Bodeau J, Tuch BB, Siddiqui A, Lao K, Surani MA (2009) mRNA-Seq whole-transcriptome analysis of a single cell. Nat Methods 6:377–382PubMedCrossRef

18.

Renand A, Cervera-Marzal I, Gil L, Dong C, Garcia A, Kervagoret E, Aublé H, Habes S, Chevalier C, Vavasseur F, Clémenceau B, Cardon A, Judor JP, Mosnier JF, Tanné F, Laplaud DA, Brouard S, Gournay J, Milpied P, Conchon S (2020) Integrative molecular profiling of autoreactive CD4 T cells in autoimmune hepatitis. J Hepatol 73:1379–1390PubMedCrossRef

19.

Johnson PJ, McFarlane IG (1993) Meeting report: international autoimmune hepatitis group. Hepatology 18:998–1005PubMedCrossRef

20.

Alvarez F, Berg PA, Bianchi FB, Bianchi L, Burroughs AK, Cancado EL (1999) International autoimmune hepatitis group report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol 31:929–938PubMedCrossRef

21.

Hennes EM, Zeniya M, Czaja AJ, Parés A, Dalekos GN, Krawitt EL, Bittencourt PL, Porta G, Boberg KM, Hofer H, Bianchi FB, Shibata M, Schramm C, Eisenmann de Torres B, Galle PR, McFarlane I, Dienes HP, Lohse AW, International Autoimmune Hepatitis Group (2008) Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology 48:169–176PubMedCrossRef

22.

European Association for the Study of the Liver (2015) EASL clinical practice guidelines: autoimmune hepatitis. J Hepatol 63:971–1004CrossRef

23.

Abe K, Takahashi A, Fujita M, Hayashi M, Okai K, Nozawa Y, Ohira H (2019) Interleukin-33/ST2-mediated inflammation plays a critical role in the pathogenesis and severity of type I autoimmune hepatitis. Hepatol Commun 3:670–684PubMedPubMedCentralCrossRef

24.

Scheuer PJ (1991) Classification of chronic viral hepatitis: a need for reassessment. J Hepatol 13:372–374PubMedCrossRef

25.

Desmet VJ, Gerber M, Hoofnagle JH, Manns M, Scheuer PJ (1994) Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology 19:1513–1520PubMedCrossRef

26.

Becht E, McInnes L, Healy J, Dutertre CA, Kwok IWH, Ng LG, Ginhoux F, Newell EW (2018) Dimensionality reduction for visualizing single-cell data using UMAP. Nat Biotechnol. https://doi.org/10.1038/nbt.4314CrossRefPubMed

27.

Goldstein LD, Chen YJ, Dunne J, Mir A, Hubschle H, Guillory J, Yuan W, Zhang J, Stinson J, Jaiswal B, Pahuja KB, Mann I, Schaal T, Chan L, Anandakrishnan S, Lin CW, Espinoza P, Husain S, Shapiro H, Swaminathan K, Wei S, Srinivasan M, Seshagiri S, Modrusan Z (2017) Massively parallel nanowell-based single-cell gene expression profiling. BMC Genomics 18:519PubMedPubMedCentralCrossRef

28.

Treutlein B, Lee QY, Camp JG, Mall M, Koh W, Shariati SA, Sim S, Neff NF, Skotheim JM, Wernig M, Quake SR (2016) Dissecting direct reprogramming from fibroblast to neuron using single-cell RNA-seq. Nature 534:391–395ADSPubMedPubMedCentralCrossRef

29.

Semrau S, Goldmann JE, Soumillon M, Mikkelsen TS, Jaenisch R, van Oudenaarden A (2017) Dynamics of lineage commitment revealed by single-cell transcriptomics of differentiating embryonic stem cells. Nat Commun 8:1096ADSPubMedPubMedCentralCrossRef

30.

Schafflick D, Xu CA, Hartlehnert M, Cole M, Schulte-Mecklenbeck A, Lautwein T, Wolbert J, Heming M, Meuth SG, Kuhlmann T, Gross CC, Wiendl H, Yosef N, Zu M, Horste G (2020) Integrated single cell analysis of blood and cerebrospinal fluid leukocytes in multiple sclerosis. Nat Commun 11:247ADSPubMedPubMedCentralCrossRef

31.

Potter SS (2018) Single-cell RNA sequencing for the study of development, physiology and disease. Nat Rev Nephrol 14:479–492PubMedPubMedCentralCrossRef

32.

Schepis D, Gunnarsson I, Eloranta ML, Lampa J, Jacobson SH, Kärre K, Berg L (2009) Increased proportion of CD56 bright natural killer cells in active and inactive systemic lupus erythematosus. Immunology 126:140–146PubMedPubMedCentralCrossRef

33.

Pridgeon C, Lennon GP, Pazmany L, Thompson RN, Christmas SE, Moots RJ (2003) Natural killer cells in the synovial fluid of rheumatoid arthritis patients exhibit a CD56 bright, CD94 bright, CD158 negative phenotype. Rheumatology (Oxford) 42:870–878PubMedCrossRef

34.

Ajuebor MN, Wondimu Z, Hogaboam CM, Le T, Proudfoot AE, Swain MG (2007) CCR5 deficiency drives enhanced natural killer cell trafficking to and activation within the liver in murine T-cell-mediated hepatitis. Am J Pathol 170:1975–1988PubMedPubMedCentralCrossRef

35.

Christen U, Hintermann E (2016) Immunopathogenic mechanisms of autoimmune hepatitis: how much do we know from animal models? Int J Mol Sci 17:2007PubMedPubMedCentralCrossRef

36.

Ferri S, Longhi MS, De Molo C, Lalanne C, Muratori P, Granito A, Hussain MJ, Ma Y, Lenzi M, Mieli-Vergani G, Bianchi FB, Vergani D, Muratori L (2010) A multifaceted imbalance of T cells with regulatory function characterizes type 1 autoimmune hepatitis. Hepatology 52:999–1007PubMedCrossRef

37.

Zannas AS, Binder EB (2014) Gene–environment interactions at the FKBP5 locus: sensitive periods, mechanisms and pleiotropism. Genes Brain Behav 13:25–37PubMedCrossRef

38.

Lou QY, Li Z, Teng Y, Xie QM, Zhang M, Huang SW, Li WF, Chen YF, Pan FM, Xu SQ, Cai J, Liu S, Tao JH, Liu SX, Huang HL, Wang F, Pan HF, Su H, Xu ZW, Hu WB, Zou YF (2021) Associations of FKBP4 and FKBP5 gene polymorphisms with disease susceptibility, glucocorticoid efficacy, anxiety, depression, and health-related quality of life in systemic lupus erythematosus patients. Clin Rheumatol 40:167–179PubMedCrossRef

39.

Kasela S, Kisand K, Tserel L, Kaleviste E, Remm A, Fischer K, Esko T, Westra HJ, Fairfax BP, Makino S, Knight JC, Franke L, Metspalu A, Peterson P, Milani L (2017) Pathogenic implications for autoimmune mechanisms derived by comparative eQTL analysis of CD4+ versus CD8+ T cells. PLoS Genet 13:e1006643PubMedPubMedCentralCrossRef

40.

Yu Y, Wu DM, Li J, Deng SH, Liu T, Zhang T, He M, Zhao YY, Xu Y (2020) Bixin attenuates experimental autoimmune encephalomyelitis by suppressing TXNIP/NLRP3 inflammasome activity and activating NRF2 signalling. Front Immunol 11:593368PubMedPubMedCentralCrossRef

41.

Wu H, Chen S, Li A, Shen K, Wang S, Wang S, Wu P, Luo W, Pan Q (2021) LncRNA expression profiles in systemic lupus erythematosus and rheumatoid arthritis: emerging biomarkers and therapeutic targets. Front Immunol 12:792884PubMedPubMedCentralCrossRef

42.

Guo T, Xing Y, Chen Z, Zhu H, Yang L, Xiao Y, Xu J (2022) Long non-coding RNA NEAT1 knockdown alleviates rheumatoid arthritis by reducing IL-18 through p300/CBP repression. Inflammation 45:100–115PubMedCrossRef

43.

Jeffery HC, Braitch MK, Bagnall C, Hodson J, Jeffery LE, Wawman RE, Wong LL, Birtwistle J, Bartlett H, Lohse AW, Hirschfield GM, Dyson J, Jones D, Hubscher SG, Klenerman P, Adams DH, Oo YH (2018) Changes in natural killer cells and exhausted memory regulatory T Cells with corticosteroid therapy in acute autoimmune hepatitis. Hepatol Commun 2:421–436PubMedPubMedCentralCrossRef

44.

Zhao Y, Zhang Y, Liu YM, Liu Y, Feng X, Liao HY, Vergani D, Ma Y, Yan HP (2011) Identification of T-cell epitopes on soluble liver antigen in Chinese patients with autoimmune hepatitis. Liver Int 31:721–729PubMedCrossRef

45.

Cookson S, Constantini PK, Clare M, Underhill JA, Bernal W, Czaja AJ, Donaldson PT (1999) Frequency and nature of cytokine gene polymorphisms in type 1 autoimmune hepatitis. Hepatology 30:851–856PubMedCrossRef

46.

Czaja AJ, Cookson S, Constantini PK, Clare M, Underhill JA, Donaldson PT (1999) Cytokine polymorphisms associated with clinical features and treatment outcome in type 1 autoimmune hepatitis. Gastroenterology 117:645–652PubMedCrossRef

47.

Grønbaek H, Kreutzfeldt M, Kazankov K, Jessen N, Sandahl T, Hamilton-Dutoit S, Vilstrup H, Møller JH (2016) Single-centre experience of the macrophage activation marker soluble (s)CD163—associations with disease activity and treatment response in patients with autoimmune hepatitis. Aliment Pharmacol Ther 44:1062–1070PubMedCrossRef

48.

Honda M, Kubes P (2018) Neutrophils and neutrophil extracellular traps in the liver and gastrointestinal system. Nat Rev Gastroenterol Hepatol 15:206–221PubMedCrossRef

49.

Domerecka W, Kowalska-Kępczyńska A, Michalak A, Homa-Mlak I, Mlak R, Cichoż-Lach H, Małecka-Massalska T (2021) Etiopathogenesis and diagnostic strategies in autoimmune hepatitis. Diagnostics (Basel) 11:1418PubMedCrossRef

50.

Domerecka W, Homa-Mlak I, Mlak R, Michalak A, Wilińska A, Kowalska-Kępczyńska A, Dreher P, Cichoż-Lach H, Małecka-Massalska T (2022) Indicator of inflammation and NETosis-low-density granulocytes as a biomarker of autoimmune hepatitis. J Clin Med 11:2174PubMedPubMedCentralCrossRef

51.

Denny MF, Yalavarthi S, Zhao W, Thacker SG, Anderson M, Sandy AR, McCune WJ, Kaplan MJ (2010) A distinct subset of proinflammatory neutrophils isolated from patients with systemic lupus erythematosus induces vascular damage and synthesizes type I IFNs. J Immunol 184:3284–3297PubMedCrossRef

52.

Villanueva E, Yalavarthi S, Berthier CC, Hodgin JB, Khandpur R, Lin AM, Rubin CJ, Zhao W, Olsen SH, Klinker M (2011) Netting neutrophils induce endothelial damage, infiltrate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus. J Immunol 187:538–552PubMedCrossRef

Titel: Characteristics of peripheral blood mononuclear cells and potential related molecular mechanisms in patients with autoimmune hepatitis: a single-cell RNA sequencing analysis
Publikationsdatum: 10.02.2024
Erschienen in: Medical Molecular Morphology
Print ISSN: 1860-1480
Elektronische ISSN: 1860-1499
DOI: https://doi.org/10.1007/s00795-024-00380-5

Springer Medizin

Characteristics of peripheral blood mononuclear cells and potential related molecular mechanisms in patients with autoimmune hepatitis: a single-cell RNA sequencing analysis

Abstract

Neu im Fachgebiet Pathologie

Molekularpathologische Untersuchungen im Wandel der Zeit

Vergleichende Pathologie in der onkologischen Forschung

Gastrointestinale Stromatumoren

Personalisierte Medizin in der Onkologie

Springer Medizin

Abstract

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Neu im Fachgebiet Pathologie

Molekularpathologische Untersuchungen im Wandel der Zeit

Vergleichende Pathologie in der onkologischen Forschung

Gastrointestinale Stromatumoren

Personalisierte Medizin in der Onkologie