Skip to main content
SpringerLink
Log in

Adaptive Immunity and the Clinical Definition of Autoantibodies

  • Chapter
  • First Online:
Liver Immunology

  • 631 Accesses

Abstract

Detection of autoantibodies in the patient’s serum is a key diagnostic tool in autoimmune liver diseases, provided that the clinician is familiar with the laboratory methods and interprets correctly the results. Indirect immunofluorescence on triple rodent tissue should be used at a screening level, since it allows the simultaneous detection of the majority of liver-relevant autoantibodies, that is, anti-nuclear, anti-smooth muscle, anti-liver-kidney, anti-liver cytosol, and anti-mitochondrial antibody. Type 1 autoimmune hepatitis is characterized by anti-nuclear and/or anti-smooth muscle antibodies, whereas type 2 autoimmune hepatitis is characterized by anti-liver-kidney microsomal and/or anti-liver cytosolic type 1 antibodies. Anti-soluble liver antigen testing by a molecular-based assay should be included in the diagnostic work-up of liver disease of unknown origin, being highly specific for autoimmune hepatitis. Anti-mitochondrial antibody is the serological hallmark of primary biliary cholangitis and has high disease specificity. Rim-like and multiple nuclear dots anti-nuclear antibodies are also specific for primary biliary cholangitis and are of particular diagnostic value in anti-mitochondrial antibody negative patients. Atypical anti-neutrophil cytoplasmic antibody is detected by indirect immunofluorescence on human neutrophils and is associated with type 1 autoimmune hepatitis, primary/autoimmune sclerosing cholangitis, and inflammatory bowel disease.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 139.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Takeda K, Akira S. Toll-like receptors. Curr Protoc Immunol. 2015;109:14.12.1–10. https://doi.org/10.1002/0471142735.im1412s109.

    Article  Google Scholar 

  2. Dieu MC, Vanbervliet B, Vicari A, Bridon JM, Oldham E, Aït-Yahia S, et al. Selective recruitment of immature and mature dendritic cells by distinct chemokines expressed in different anatomic sites. J Exp Med. 1998;188:373–86. https://doi.org/10.1084/jem.188.2.373.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Sallusto F, Schaerl PI, Loetscher P, Schaniel C, Lenig D, Mackay CR, et al. Rapid and coordinated switch in chemokine receptor expression during dendritic cell maturation. Eur J Immunol. 1998;28:2760–9. https://doi.org/10.1002/(SICI)1521-4141(199809)28:09<2760::AID-IMMU2760>3.0.CO;2-N.

    Article  CAS  PubMed  Google Scholar 

  4. Fessas P, Possamai LA, Clark J, Daniels E, Gudd C, Mullish BH, et al. Immunotoxicity from checkpoint inhibitor therapy: clinical features and underlying mechanisms. Immunology. 2019; https://doi.org/10.1111/imm.13141.

  5. Sallusto F. Heterogeneity of human CD4(+) T cells against microbes. Annu Rev Immunol. 2016;34:317–34. https://doi.org/10.1146/annurev-immunol-032414-112056.

    Article  CAS  PubMed  Google Scholar 

  6. Ohkura N, Kitagawa Y, Sakaguchi S. Development and maintenance of regulatory T cells. Immunity. 2013;38:414–23. https://doi.org/10.1016/j.immuni.2013.03.002.

    Article  CAS  PubMed  Google Scholar 

  7. Nutt SL, Hodgkin PD, Tarlinton DM, Corcoran LM. The generation of antibody-secreting plasma cells. Nat Rev Immunol. 2015;15:160–71. https://doi.org/10.1038/nri3795.

    Article  CAS  PubMed  Google Scholar 

  8. Heath WR, Kato Y, Steiner TM, Caminschi I. Antigen presentation by dendritic cells for B cell activation. Curr Opin Immunol. 2019;58:44–52. https://doi.org/10.1016/j.coi.2019.04.003.

    Article  CAS  PubMed  Google Scholar 

  9. Ma Y, Okamoto M, Thomas MG, Bogdanos DP, Lopes AR, Portmann B, et al. Antibodies to conformational epitopes of soluble liver antigen define a severe form of autoimmune liver disease. Hepatol Baltim MD. 2002;35:658–64. https://doi.org/10.1053/jhep.2002.32092.

    Article  CAS  Google Scholar 

  10. Hov JR, Boberg KM, Karlsen TH. Autoantibodies in primary sclerosing cholangitis. World J Gastroenterol WJG. 2008;14:3781–91. https://doi.org/10.3748/wjg.14.3781.

    Article  CAS  PubMed  Google Scholar 

  11. Vergani D, Alvarez F, Bianchi FB, Cançado ELR, Mackay IR, Manns MP, et al. Liver autoimmune serology: a consensus statement from the committee for autoimmune serology of the International Autoimmune Hepatitis Group. J Hepatol. 2004;41:677–83. https://doi.org/10.1016/j.jhep.2004.08.002.

    Article  PubMed  Google Scholar 

  12. Terziroli Beretta-Piccoli B, Mieli-Vergani G, Vergani D. The clinical usage and definition of autoantibodies in immune-mediated liver disease: a comprehensive overview. J Autoimmun. 2018; https://doi.org/10.1016/j.jaut.2018.10.004.

  13. European Association for the Study of the Liver. EASL clinical practice guidelines: autoimmune hepatitis. J Hepatol. 2015;63:971–1004. https://doi.org/10.1016/j.jhep.2015.06.030.

    Article  Google Scholar 

  14. Mackay IR, Taft LI, Cowling DC. Lupoid hepatitis. Lancet. 1956;268:1323–6. https://doi.org/10.1016/S0140-6736(56)91483-0.

    Article  Google Scholar 

  15. Agmon-Levin N, Damoiseaux J, Kallenberg C, Sack U, Witte T, Herold M, et al. International recommendations for the assessment of autoantibodies to cellular antigens referred to as anti-nuclear antibodies. Ann Rheum Dis. 2014;73:17–23. https://doi.org/10.1136/annrheumdis-2013-203863.

    Article  CAS  PubMed  Google Scholar 

  16. Chan EKL, Damoiseaux J, Carballo OG, Conrad K, de Melo Cruvinel W, Francescantonio PLC, et al. Report of the first international consensus on standardized nomenclature of antinuclear antibody HEp-2 cell patterns 2014–2015. Front Immunol. 2015;6:412. https://doi.org/10.3389/fimmu.2015.00412.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Czaja AJ, Cassani F, Cataleta M, Valentini P, Bianchi FB. Antinuclear antibodies and patterns of nuclear immunofluorescence in type 1 autoimmune hepatitis. Dig Dis Sci. 1997;42:1688–96. https://doi.org/10.1023/a:1018809431189.

    Article  CAS  PubMed  Google Scholar 

  18. Invernizzi P, Selmi C, Ranftler C, Podda M, Wesierska-Gadek J. Antinuclear antibodies in primary biliary cirrhosis. Semin Liver Dis. 2005;25:298–310. https://doi.org/10.1055/s-2005-916321.

    Article  PubMed  Google Scholar 

  19. Granito A, Muratori P, Muratori L, Pappas G, Cassani F, Worthington J, et al. Antibodies to SS-A/Ro-52kD and centromere in autoimmune liver disease: a clue to diagnosis and prognosis of primary biliary cirrhosis. Aliment Pharmacol Ther. 2007;26:831–8. https://doi.org/10.1111/j.1365-2036.2007.03433.x.

    Article  CAS  PubMed  Google Scholar 

  20. Liberal R, Mieli-Vergani G, Vergani D. Clinical significance of autoantibodies in autoimmune hepatitis. J Autoimmun. 2013;46:17–24. https://doi.org/10.1016/j.jaut.2013.08.001.

    Article  CAS  PubMed  Google Scholar 

  21. Gregorio GV, Portmann B, Reid F, Donaldson PT, Doherty DG, McCartney M, et al. Autoimmune hepatitis in childhood: a 20-year experience. Hepatol Baltim MD. 1997;25:541–7. https://doi.org/10.1002/hep.510250308.

    Article  CAS  Google Scholar 

  22. Couto CA, Bittencourt PL, Porta G, Abrantes-Lemos CP, Carrilho FJ, Guardia BD, et al. Antismooth muscle and antiactin antibodies are indirect markers of histological and biochemical activity of autoimmune hepatitis. Hepatol Baltim MD. 2014;59:592–600. https://doi.org/10.1002/hep.26666.

    Article  CAS  Google Scholar 

  23. Gregorio GV, McFarlane B, Bracken P, Vergani D, Mieli-Vergani G. Organ and non-organ specific autoantibody titres and IgG levels as markers of disease activity: a longitudinal study in childhood autoimmune liver disease. Autoimmunity. 2002;35:515–9.

    Article  CAS  PubMed  Google Scholar 

  24. Muratori P, Granito A, Pappas G, Pendino GM, Quarneti C, Cicola R, et al. The serological profile of the autoimmune hepatitis/primary biliary cirrhosis overlap syndrome. Am J Gastroenterol. 2009;104:1420–5. https://doi.org/10.1038/ajg.2009.126.

    Article  PubMed  Google Scholar 

  25. Efe C, Wahlin S, Ozaslan E, Berlot AH, Purnak T, Muratori L, et al. Autoimmune hepatitis/primary biliary cirrhosis overlap syndrome and associated extrahepatic autoimmune diseases. Eur J Gastroenterol Hepatol. 2012;24:531–4. https://doi.org/10.1097/MEG.0b013e328350f95b.

    Article  PubMed  Google Scholar 

  26. Arbuckle MR, McClain MT, Rubertone MV, Scofield RH, Dennis GJ, James JA, et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med. 2003;349:1526–33. https://doi.org/10.1056/NEJMoa021933.

    Article  CAS  PubMed  Google Scholar 

  27. Andrade RJ, Robles-Díaz M. Diagnostic and prognostic assessment of suspected drug-induced liver injury in clinical practice. Liver Int. https://doi.org/10.1111/liv.14271.

  28. Wang C, Zheng X, Jiang P, Tang R, Gong Y, Dai Y, et al. Genome-wide association studies of specific antinuclear autoantibody subphenotypes in primary biliary cholangitis. Hepatol Baltim MD. 2019;70:294–307. https://doi.org/10.1002/hep.30604.

    Article  CAS  Google Scholar 

  29. Angulo P, Peter JB, Gershwin ME, DeSotel CK, Shoenfeld Y, Ahmed AE, et al. Serum autoantibodies in patients with primary sclerosing cholangitis. J Hepatol. 2000;32:182–7.

    Article  CAS  PubMed  Google Scholar 

  30. Zauli D, Schrumpf E, Crespi C, Cassani F, Fausa O, Aadland E. An autoantibody profile in primary sclerosing cholangitis. J Hepatol. 1987;5:14–8. https://doi.org/10.1016/s0168-8278(87)80055-7.

    Article  CAS  PubMed  Google Scholar 

  31. Johnson GD, Holborow EJ, Glynn LE. Antibody to smooth muscle in patients with liver disease. Lancet Lond Engl. 1965;2:878–9.

    Article  CAS  Google Scholar 

  32. Bottazzo GF, Florin-Christensen A, Fairfax A, Swana G, Doniach D, Groeschel-Stewart U. Classification of smooth muscle autoantibodies detected by immunofluorescence. J Clin Pathol. 1976;29:403–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bogdanos DP, Mieli-Vergani G, Vergani D. Autoantibodies and their antigens in autoimmune hepatitis. Semin Liver Dis. 2009;29:241–53. https://doi.org/10.1055/s-0029-1233533.

    Article  CAS  PubMed  Google Scholar 

  34. Mieli-Vergani G, Vergani D, Czaja AJ, Manns MP, Krawitt EL, Vierling JM, et al. Autoimmune hepatitis. Nat Rev Dis Primer. 2018;4:18017. https://doi.org/10.1038/nrdp.2018.17.

    Article  Google Scholar 

  35. Gregorio GV, Portmann B, Karani J, Harrison P, Donaldson PT, Vergani D, et al. Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study. Hepatol Baltim MD. 2001;33:544–53. https://doi.org/10.1053/jhep.2001.22131.

    Article  CAS  Google Scholar 

  36. Terziroli Beretta-Piccoli B, Vergani D, Mieli-Vergani G. Autoimmune sclerosing cholangitis: evidence and open questions. J Autoimmun. 2018; https://doi.org/10.1016/j.jaut.2018.10.008.

  37. Kerkar N, Vergani D. De novo autoimmune hepatitis -is this different in adults compared to children? J Autoimmun. 2018;95:26–33. https://doi.org/10.1016/j.jaut.2018.10.023.

    Article  PubMed  Google Scholar 

  38. Terziroli Beretta-Piccoli B, Di Bartolomeo C, Deleonardi G, Grondona AG, Silvestri T, Tesei C, et al. Swiss hepatitis C cohort study, autoimmune liver serology before and after successful treatment of chronic hepatitis C by direct acting antiviral agents. J Autoimmun. 2019;102:89–95. https://doi.org/10.1016/j.jaut.2019.04.019.

    Article  CAS  PubMed  Google Scholar 

  39. Muratori L, Cataleta M, Muratori P, Lenzi M, Bianchi FB. Liver/kidney microsomal antibody type 1 and liver cytosol antibody type 1 concentrations in type 2 autoimmune hepatitis. Gut. 1998;42:721–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Gelpi C, Sontheimer EJ, Rodriguez-Sanchez JL. Stranger things have happened autoantibodies against a serine tRNA-protein complex implicated in cotranslational selenocysteine insertion. Proc Natl Acad Sci U S A. 1992;89:9739–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Herkel J, Heidrich B, Nieraad N, Wies I, Rother M, Lohse AW. Fine specificity of autoantibodies to soluble liver antigen and liver/pancreas. Hepatol Baltim MD. 2002;35:403–8. https://doi.org/10.1053/jhep.2002.30699.

    Article  CAS  Google Scholar 

  42. Meda F, Wang P, Longhi MS, Bogdanos DP, Mieli-Vergani G, Vergani D, et al. Identification of HLA-DR3 restricted CD4 T-cell epitopes on soluble liver antigen in autoimmune hepatitis type 1. J Hepatol. 2007;46:S13. https://doi.org/10.1016/S0168-8278(07)61623-7.

    Article  Google Scholar 

  43. Zachou K, Weiler-Normann C, Muratori L, Muratori P, Lohse AW, Dalekos GN. Permanent immunosuppression in SLA/LP-positive autoimmune hepatitis is required although overall response and survival are similar. Liver Int Off J Int Assoc Study Liver. 2019; https://doi.org/10.1111/liv.14280.

  44. Hov JR, Boberg KM, Taraldsrud E, Vesterhus M, Boyadzhieva M, Solberg IC, et al. Antineutrophil antibodies define clinical and genetic subgroups in primary sclerosing cholangitis. Liver Int Off J Int Assoc Study Liver. 2017;37:458–65. https://doi.org/10.1111/liv.13238.

    Article  CAS  Google Scholar 

  45. Mackay IR. Primary biliary cirrhosis showing a high titer of autoantibody; report of a case. N Engl J Med. 1958;258:185–8. https://doi.org/10.1056/NEJM195801232580407.

    Article  CAS  PubMed  Google Scholar 

  46. Bogdanos D-P, Baum H, Vergani D. Antimitochondrial and other autoantibodies. Clin Liver Dis. 2003;7:759–77. vi

    Article  PubMed  Google Scholar 

  47. Liu H, Norman GL, Shums Z, Worman HJ, Krawitt EL, Bizzaro N, et al. PBC screen: an IgG/IgA dual isotype ELISA detecting multiple mitochondrial and nuclear autoantibodies specific for primary biliary cirrhosis. J Autoimmun. 2010;35:436–42. https://doi.org/10.1016/j.jaut.2010.09.005.

    Article  CAS  PubMed  Google Scholar 

  48. Tanaka A, Leung PSC, Young HA, Gershwin ME. Toward solving the etiological mystery of primary biliary cholangitis. Hepatol Commun. 2017;1:275–87. https://doi.org/10.1002/hep4.1044.

    Article  CAS  PubMed Central  Google Scholar 

  49. Sun C, Xiao X, Yan L, Sheng L, Wang Q, Jiang P, et al. Histologically proven AMA positive primary biliary cholangitis but normal serum alkaline phosphatase: is alkaline phosphatase truly a surrogate marker? J Autoimmun. 2019; https://doi.org/10.1016/j.jaut.2019.01.005.

  50. Terziroli Beretta-Piccoli B, Mieli-Vergani G, Vergani D. Serology in autoimmune hepatitis: a clinical-practice approach. Eur J Intern Med. 2017; https://doi.org/10.1016/j.ejim.2017.10.006.

  51. Mieli-Vergani G, Vergani D, Baumann U, Czubkowski P, Debray D, Dezsofi A, et al. Diagnosis and management of paediatric autoimmune liver disease: ESPGHAN hepatology committee position statement. J Pediatr Gastroenterol Nutr. 2017; https://doi.org/10.1097/MPG.0000000000001801.

Download references

Author information

Authors and Affiliations

  1. Epatocentro Ticino, Lugano, Switzerland

    Benedetta Terziroli Beretta-Piccoli

  2. Institute of Liver Studies, Mowat Labs, King’s College Hospital, London, UK

    Benedetta Terziroli Beretta-Piccoli & Diego Vergani

  3. King’s College Hospital, Paediatric Liver, GI and Nutrition Centre, Mowat Labs, London, UK

    Giorgina Mieli-Vergani

Authors
  1. Benedetta Terziroli Beretta-Piccoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Giorgina Mieli-Vergani
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Diego Vergani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Benedetta Terziroli Beretta-Piccoli .

Editor information

Editors and Affiliations

  1. Division of Rheumatology, Allergy and Clinical Immunology, The University of California School of Medicine, Davis, CA, USA

    M. Eric Gershwin

  2. Departments of Medicine and Surgery, Baylor College of Medicine, Houston, TX, USA

    John M. Vierling

  3. Department of Medicine, Teikyo University School of Medicine, Itabashi, Tokyo, Japan

    Atsushi Tanaka

  4. President, Hannover Medical School, Hannover, Germany

    Michael P. Manns

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Terziroli Beretta-Piccoli, B., Mieli-Vergani, G., Vergani, D. (2020). Adaptive Immunity and the Clinical Definition of Autoantibodies. In: Gershwin, M.E., M. Vierling, J., Tanaka, A., P. Manns, M. (eds) Liver Immunology . Springer, Cham. https://doi.org/10.1007/978-3-030-51709-0_4

Download citation

Publish with us

Policies and ethics

Search

Navigation