CoChat
Sign Up
Cited by 82Liver Diseases and ImmunityImmune Cell Function and InteractionPediatric Hepatobiliary Diseases and Treatments

Natural killer cells regulate T cell immune responses in primary biliary cirrhosis

Open access
Shimoda, Shinji, Hisamoto, Satomi, Harada, Kenichi, Iwasaka, Sho, Chong, Yong, Nakamura, Minoru, Bekki, Yuki, Yoshizumi, Tomoharu +6 more·2015·Hepatology
DOI 10.1002/hep.28122PMC PMC4681684
Open this paper in CoChat — free account

Abstract

The hallmark of primary biliary cirrhosis (PBC) is the presence of autoreactive T‐ and B‐cell responses that target biliary epithelial cells (BECs). Biliary cell cytotoxicity is dependent upon initiation of innate immune responses followed by chronic adaptive, as well as bystander, mechanisms. Critical to these mechanisms are interactions between natural killer (NK) cells and BECs. We have taken advantage of the ability to isolate relatively pure viable preparations of liver‐derived NK cells, BECs, and endothelial cells, and studied interactions between NK cells and BECs and focused on the mechanisms that activate autoreactive T cells, their dependence on interferon (IFN)‐γ, and expression of BEC major histocompatibility complex (MHC) class I and II molecules. Here we show that at a high NK/BEC ratio, NK cells are cytotoxic for autologous BECs, but are not dependent on autoantigen, yet still activate autoreactive CD4 + T cells in the presence of antigen presenting cells. In contrast, at a low NK/BEC ratio, BECs are not lysed, but IFN‐γ production is induced, which facilitates expression of MHC class I and II molecules on BEC and protects them from lysis upon subsequent exposure to autoreactive NK cells. Furthermore, IFN‐γ secreted from NK cells after exposure to autologous BECs is essential for this protective function and enables autoreactive CD4 + T cells to become cytopathic. Conclusions : NK cell‐mediated innate immune responses are likely critical at the initial stage of PBC, but also facilitate and maintain the chronic cytopathic effect of autoantigen‐specific T cells, essential for progression of disease. (H epatology 2015;62:1817‐1827)

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1002/hep.28122

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Expansion of innate immune cells, including natural killer cells and myeloid-derived suppressor cells, has been observed in patients with primary biliary cholangitis.

    “including natural killer cells and myeloid-derived suppressor cells, has been observed in patients with primary biliary cholangitis.[41][42][43][44]”

    From Primary biliary cholangitis. (2024) · cites this paper as [43]

    The Introduction and Results describe NK-cell involvement in primary biliary cirrhosis, but they do not report expansion of NK cells. The Discussion says the numbers of activated NK cells were similar across the study groups, and our copy does not report expansion of myeloid-derived suppressor cells. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • NKs are enriched around the diseased small bile ducts of patients with PBC.

    “NKs are enriched around the diseased small bile ducts of patients with PBC.”

    From The liver as a central "hub" of the immune system: pathophysiological implications (2025) · cites this paper as [266]

    The Discussion (page unavailable) speculates that NK cells surround biliary epithelial cells in PBC livers. It does not establish that NK cells are enriched around diseased small bile ducts; the citing sentence presents a proposed location as an observed enrichment. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

The citation lists haven’t been fetched yet

References 52 · Cited by 82

Research works printed but not linked: 44

  1. [1]Gershwin ME Mackay IR The causes of primary biliary cirrhosis: Convenient and inconvenient truths Hepatology 2008 47 737 745 18098322
  2. [2]Hirschfield GM Gershwin ME The immunobiology and pathophysiology of primary biliary cirrhosis Annu Rev Pathol 2013 8 303 330 23347352
  3. [3]Nakanuma Y Sasaski M Harada K Autophagy and senescence in fibrosing cholangiopathies J Hepatol 2014 25435435
  4. [4]Selmi C Zuin M Gershwin ME The unfinished business of primary biliary cirrhosis J Hepatol 2008 49 451 460 18640737 PMC2555965
  5. [5]Kita H Lian ZX Van de Water J He XS Matsumura S Kaplan M Luketic V Identification of HLA-A2-restricted CD8(+) cytotoxic T cell responses in primary biliary cirrhosis: T cell activation is augmented by immune complexes cross-presented by dendritic cells J Exp Med 2002 195 113 123 11781370 PMC2196012
  6. [6]Matsui M Nakamura M Ishibashi H Koike K Kudo J Niho Y Human monoclonal antibodies from a patient with primary biliary cirrhosis that recognize two distinct autoepitopes in the E2 component of the pyruvate dehydrogenase complex Hepatology 1993 18 1069 1077 7693571
  7. [7]Shimoda S Van de Water J Ansari A Nakamura M Ishibashi H Coppel RL Lake J Identification and precursor frequency analysis of a common T cell epitope motif in mitochondrial autoantigens in primary biliary cirrhosis J Clin Invest 1998 102 1831 1840 9819369 PMC509133
  8. [8]Lleo A Zhang W McDonald WH Seeley EH Leung PS Coppel RL Ansari AA Shotgun proteomics: identification of unique protein profiles of apoptotic bodies from biliary epithelial cells Hepatology 2014 60 1314 1323 24841946 PMC4175017
  9. [10]Zhang J Zhang W Leung PS Bowlus CL Dhaliwal S Coppel RL Ansari AA Ongoing activation of autoantigen-specific B cells in primary biliary cirrhosis Hepatology 2014 60 1708 1716 25043065 PMC4211937
  10. [11]Wang L Qiu J Yu L Hu X Zhao P Jiang Y Increased numbers of CD5+CD19+CD1dhighIL-10+ Bregs, CD4+Foxp3+ Tregs, CD4+CXCR5+Foxp3+ follicular regulatory T (TFR) cells in CHB or CHC patients J Transl Med 2014 12 251 25199644 PMC4173099
  11. [12]Kamihira T Shimoda S Nakamura M Yokoyama T Takii Y Kawano A Handa M Biliary epithelial cells regulate autoreactive T cells: implications for biliary-specific diseases Hepatology 2005 41 151 159 15619239
  12. [13]Shimoda S Harada K Niiro H Shirabe K Taketomi A Maehara Y Tsuneyama K Interaction between Toll-like receptors and natural killer cells in the destruction of bile ducts in primary biliary cirrhosis Hepatology 2011 53 1270 1281 21400555 PMC3077894
  13. [14]Shimoda S Harada K Niiro H Taketomi A Maehara Y Tsuneyama K Kikuchi K CX3CL1 (fractalkine): a signpost for biliary inflammation in primary biliary cirrhosis Hepatology 2010 51 567 575 19908209 PMC2911959
  14. [15]Shimoda S Nakamura M Ishibashi H Hayashida K Niho Y HLA DRB4 0101-restricted immunodominant T cell autoepitope of pyruvate dehydrogenase complex in primary biliary cirrhosis: evidence of molecular mimicry in human autoimmune diseases J Exp Med 1995 181 1835 1845 7536796 PMC2191998
  15. [16]Shimoda S Tsuneyama K Kikuchi K Harada K Nakanuma Y Nakamura M Ishibashi H The role of natural killer (NK) and NK T cells in the loss of tolerance in murine primary biliary cirrhosis Clin Exp Immunol 2012 168 279 284 22519590 PMC3390479
  16. [17]Hudspeth K Pontarini E Tentorio P Cimino M Donadon M Torzilli G Lugli E The role of natural killer cells in autoimmune liver disease: a comprehensive review J Autoimmun 2013 46 55 65 23880068
  17. [20]Kikuchi K Lian ZX Yang GX Ansari AA Ikehara S Kaplan M Miyakawa H Bacterial CpG induces hyper-IgM production in CD27(+) memory B cells in primary biliary cirrhosis Gastroenterology 2005 128 304 312 15685542
  18. [21]Kita H Naidenko OV Kronenberg M Ansari AA Rogers P He XS Koning F Quantitation and phenotypic analysis of natural killer T cells in primary biliary cirrhosis using a human CD1d tetramer Gastroenterology 2002 123 1031 1043 12360465
  19. [22]Floreani A Franceschet I Cazzagon N Primary biliary cirrhosis: overlaps with other autoimmune disorders Semin Liver Dis 2014 34 352 360 25057958
  20. [23]Selmi C Lleo A Pasini S Zuin M Gershwin ME Innate immunity and primary biliary cirrhosis Curr Mol Med 2009 9 45 51 19199941
  21. [24]Allina J Hu B Sullivan DM Fiel MI Thung SN Bronk SF Huebert RC T cell targeting and phagocytosis of apoptotic biliary epithelial cells in primary biliary cirrhosis J Autoimmun 2006 27 232 241 17222534 PMC6200357
  22. [25]Lleo A Maroni L Glaser S Alpini G Marzioni M Role of cholangiocytes in primary biliary cirrhosis Semin Liver Dis 2014 34 273 284 25057951 PMC4182310
  23. [27]Lleo A Bowlus CL Yang GX Invernizzi P Podda M Van de Water J Ansari AA Biliary apotopes and anti-mitochondrial antibodies activate innate immune responses in primary biliary cirrhosis Hepatology 2010 52 987 998 20568301 PMC2932809
  24. [28]Tsuneyama K Harada K Kono N Sasaki M Saito T Gershwin ME Ikemoto M Damaged interlobular bile ducts in primary biliary cirrhosis show reduced expression of glutathione-S-transferase-pi and aberrant expression of 4-hydroxynonenal J Hepatol 2002 37 176 183 12127421
  25. [31]Shimoda S Harada K Niiro H Yoshizumi T Soejima Y Taketomi A Maehara Y Biliary epithelial cells and primary biliary cirrhosis: the role of liver-infiltrating mononuclear cells Hepatology 2008 47 958 965 18181218
  26. [32]Kaplan MM Gershwin ME Primary biliary cirrhosis N Engl J Med 2005 353 1261 1273 16177252
  27. [33]Hashimoto N Shimoda S Kawanaka H Tsuneyama K Uehara H Akahoshi T Kinjo N Modulation of CD4(+) T cell responses following splenectomy in hepatitis C virus-related liver cirrhosis Clin Exp Immunol 2011 165 243 250 21615390 PMC3142649
  28. [34]Migliaccio C Nishio A Van de Water J Ansari AA Leung PS Nakanuma Y Coppel RL Monoclonal antibodies to mitochondrial E2 components define autoepitopes in primary biliary cirrhosis J Immunol 1998 161 5157 5163 9820485
  29. [35]Shimoda S Ishikawa F Kamihira T Komori A Niiro H Baba E Harada K Autoreactive T-cell responses in primary biliary cirrhosis are proinflammatory whereas those of controls are regulatory Gastroenterology 2006 131 606 618 16890612
  30. [36]Sallusto F Lanzavecchia A Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha J Exp Med 1994 179 1109 1118 8145033 PMC2191432
  31. [37]Maio M Altomonte M Tatake R Zeff RA Ferrone S Reduction in susceptibility to natural killer cell-mediated lysis of human FO-1 melanoma cells after induction of HLA class I antigen expression by transfection with B2m gene J Clin Invest 1991 88 282 289 1905328 PMC296030
  32. [38]Kamihira T Shimoda S Harada K Kawano A Handa M Baba E Tsuneyama K Distinct costimulation dependent and independent autoreactive T-cell clones in primary biliary cirrhosis Gastroenterology 2003 125 1379 1387 14598254
  33. [39]Tsuneyama K Van de Water J Leung PS Cha S Nakanuma Y Kaplan M De Lellis R Abnormal expression of the E2 component of the pyruvate dehydrogenase complex on the luminal surface of biliary epithelium occurs before major histocompatibility complex class II and BB1/B7 expression Hepatology 1995 21 1031 1037 7535733
  34. [40]Afford SC Ahmed-Choudhury J Randhawa S Russell C Youster J Crosby HA Eliopoulos A CD40 activation-induced, Fas-dependent apoptosis and NF-kappaB/AP-1 signaling in human intrahepatic biliary epithelial cells FASEB J 2001 15 2345 2354 11689460
  35. [42]Isse K Harada K Zen Y Kamihira T Shimoda S Harada M Nakanuma Y Fractalkine and CX3CR1 are involved in the recruitment of intraepithelial lymphocytes of intrahepatic bile ducts Hepatology 2005 41 506 516 15726664
  36. [43]Harada K Van de Water J Leung PS Coppel RL Ansari A Nakanuma Y Gershwin ME In situ nucleic acid hybridization of cytokines in primary biliary cirrhosis: predominance of the Th1 subset Hepatology 1997 25 791 796 9096578
  37. [44]Ganguly D Haak S Sisirak V Reizis B The role of dendritic cells in autoimmunity Nat Rev Immunol 2013 13 566 577 23827956 PMC4160805
  38. [45]Gutterman JU Cytokine therapeutics: lessons from interferon alpha Proc Natl Acad Sci U S A 1994 91 1198 1205 8108387 PMC43124
  39. [46]Ayres RC Neuberger JM Shaw J Joplin R Adams DH Intercellular adhesion molecule-1 and MHC antigens on human intrahepatic bile duct cells: effect of pro-inflammatory cytokines Gut 1993 34 1245 1249 8104850 PMC1375463
  40. [47]Cooper MA Elliott JM Keyel PA Yang L Carrero JA Yokoyama WM Cytokine-induced memory-like natural killer cells Proc Natl Acad Sci U S A 2009 106 1915 1919 19181844 PMC2644138
  41. [48]Sun JC Beilke JN Lanier LL Adaptive immune features of natural killer cells Nature 2009 457 557 561 19136945 PMC2674434
  42. [49]Paust S Gill HS Wang BZ Flynn MP Moseman EA Senman B Szczepanik M Critical role for the chemokine receptor CXCR6 in NK cell-mediated antigen-specific memory of haptens and viruses Nat Immunol 2010 11 1127 1135 20972432 PMC2982944
  43. [50]Leavenworth JW Wang X Wenander CS Spee P Cantor H Mobilization of natural killer cells inhibits development of collagen-induced arthritis Proc Natl Acad Sci U S A 2011 108 14584 14589 21873193 PMC3167502
  44. [51]Nielsen N Odum N Urso B Lanier LL Spee P Cytotoxicity of CD56(bright) NK cells towards autologous activated CD4+ T cells is mediated through NKG2D, LFA-1 and TRAIL and dampened via CD94/NKG2A PLoS One 2012 7 e31959 22384114 PMC3284517

Authors
Shimoda, S., Hisamoto, S., Harada, K., Iwasaka, S., Chong, Y., Nakamura, M., Bekki, Y., Yoshizumi, T., Shirabe, K., Ikegami, T., Maehara, Y., He, X., Gershwin, M. E., & Akashi, K.
Affiliations
  • Kyushu University (JP)
  • Kanazawa University (JP)
  • Nagasaki Medical Center (JP)
  • University of California, Davis (US)
Corresponding author
  • Shimoda, Shinji
  • Gershwin, M. Eric
ORCID
Venue
Hepatology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2015-10-16
Volume
62
Issue
6
Pages
1817-1827
ISSN
  • 0270-9139 (ISSN-L)
  • 1527-3350
DOI
10.1002/hep.28122
PMC
PMC4681684
OpenAlex
W1961434898
Cited by
82
References
52
Citations by year
2026: 4 · 2025: 6 · 2024: 5 · 2023: 11 · 2022: 7 · 2021: 9 · 2020: 9 · 2019: 8 · 2018: 4 · 2017: 7 · 2016: 11 · 2015: 1
FWCI
4.54
Type
journal article
Language
en
Open access
Licence
Locations
  • Hepatology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (DK 39588)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK 39588, R37DK039588, R01DK039588)
Topics
  • Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
  • Health Sciences › Medicine › Surgery › Pediatric Hepatobiliary Diseases and Treatments
Keywords
primary biliary cirrhosis, natural killer cells, cholangiocytes, autoreactive T cells, interferon-gamma, MHC class I and II expression, NK cell cytotoxicity, innate immune response, autoimmunity, CD4+ T cells, autoantigens
MeSH terms
Humans, Immunity, Cellular, Killer Cells, Natural, Liver Cirrhosis, Biliary, T-Lymphocytes

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review