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Hepatology
Original article
Mucosa-associated invariant T cells link intestinal immunity with antibacterial immune defects in alcoholic liver disease
  1. Antonio Riva1,2,
  2. Vishal Patel1,2,3,
  3. Ayako Kurioka4,
  4. Hannah C Jeffery5,
  5. Gavin Wright6,
  6. Sarah Tarff6,
  7. Debbie Shawcross2,3,
  8. Jennifer M Ryan3,
  9. Alexander Evans7,
  10. Sarah Azarian1,
  11. Jasmohan S Bajaj8,
  12. Andrew Fagan8,
  13. Vinood Patel9,
  14. Kosha Mehta9,
  15. Carlos Lopez9,
  16. Marieta Simonova10,
  17. Krum Katzarov10,
  18. Tanya Hadzhiolova10,
  19. Slava Pavlova10,
  20. Julia A Wendon3,
  21. Ye Htun Oo5,
  22. Paul Klenerman4,
  23. Roger Williams1,2,
  24. Shilpa Chokshi1,2
  1. 1 Institute of Hepatology London, Foundation for Liver Research, London, UK
  2. 2 Division of Transplantation, Immunology and Mucosal Biology, Faculty of Life Sciences and Medicine, King’s College London, London, UK
  3. 3 Institute of Liver Studies, King’s College London, London, UK
  4. 4 Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK
  5. 5 Centre for Liver Research and NIHR BRU in Liver Disease, University of Birmingham, Birmingham, UK
  6. 6 Department of Gastroenterology, Basildon University Hospital, Basildon, UK
  7. 7 Department of Gastroenterology, Royal Berkshire Hospital, Reading, UK
  8. 8 Department of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VAMC, Richmond, Virginia, USA
  9. 9 Department of Biomedical Sciences, University of Westminster, London, UK
  10. 10 Department of Gastroenterology, Military Medical Academy, Sofia, Bulgaria
  1. Correspondence to Dr Shilpa Chokshi, Institute of Hepatology, London Foundation for Liver Research, 111 Coldharbour Lane, London SE5 9NT, UK; s.chokshi{at}researchinliver.org.uk

Abstract

Background/aims Intestinal permeability with systemic distribution of bacterial products are central in the immunopathogenesis of alcoholic liver disease (ALD), yet links with intestinal immunity remain elusive. Mucosa-associated invariant T cells (MAIT) are found in liver, blood and intestinal mucosa and are a key component of antibacterial host defences. Their role in ALD is unknown.

Methods/design We analysed frequency, phenotype, transcriptional regulation and function of blood MAIT cells in severe alcoholic hepatitis (SAH), alcohol-related cirrhosis (ARC) and healthy controls (HC). We also examined direct impact of ethanol, bacterial products from faecal extracts and antigenic hyperstimulation on MAIT cell functionality. Presence of MAIT cells in colon and liver was assessed by quantitative PCR and immunohistochemistry/gene expression respectively.

Results In ARC and SAH, blood MAIT cells were dramatically depleted, hyperactivated and displayed defective antibacterial cytokine/cytotoxic responses. These correlated with suppression of lineage-specific transcription factors and hyperexpression of homing receptors in the liver with intrahepatic preservation of MAIT cells in ALD. These alterations were stronger in SAH, where surrogate markers of bacterial infection and microbial translocation were higher than ARC. Ethanol exposure in vitro, in vivo alcohol withdrawal and treatment with Escherichia coli had no effect on MAIT cell frequencies, whereas exposure to faecal bacteria/antigens induced functional impairments comparable with blood MAIT cells from ALD and significant MAIT cell depletion, which was not observed in other T cell compartments.

Conclusions In ALD, the antibacterial potency of MAIT cells is compromised as a consequence of contact with microbial products and microbiota, suggesting that the ‘leaky’ gut observed in ALD drives MAIT cell dysfunction and susceptibility to infection in these patients.

  • alcoholic liver disease
  • mucosal immunity
  • t lymphocytes
  • bacterial translocation
  • inflammation

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

https://doi.org/10.1136/gutjnl-2017-314458

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    Footnotes

    • Contributors AR: study design, experimental work, data acquisition and analysis, manuscript preparation. SC: study design and supervision, manuscript preparation and final approval. Experimental collaborators: AK, HCJ, PK and YO. Provision of samples: VinP, SA, JAW, ST, GW, JMR, DS, AE, AF, JSB, KM, CL, VisP, TH, SP, MS and KK. Critical evaluation of the manuscript for important intellectual content and study funding: RW. All authors reviewed and approved the final version of the manuscript.

    • Funding This study was funded by the Foundation for Liver Research.

    • Competing interests None declared.

    • Patient consent Detail has been removed from this case description/these case descriptions to ensure anonymity. The editors and reviewers have seen the detailed information available and are satisfied that the information backs up the case the authors are making.

    • Ethics approval All local recruiting centres had individual ethical approval: the North East London Research Ethics Committee (08/H0702/52); the National Research Ethics Service (NRES) Committees South West (13/SW/0219), Portsmouth South Central (12/SC/0359), London Riverside (135979), London Westminster (12/LO/1417); the Local Research Ethics Committee (LREC) South Birmingham (98/CA5192 and 06/Q2708/11); the Steroids or Pentoxifylline for Alcoholic Hepatitis trial (STOPAH) (09/MRE09/59); and the Richmond VA Medical Center IRB (bajaj004).

    • Provenance and peer review Not commissioned; externally peer reviewed.

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