Skip to main content
NCBI home page
Clinical and Experimental Immunology logoLink to Clinical and Experimental Immunology
. 1994 Jul;97(1):94–99. doi: 10.1111/j.1365-2249.1994.tb06585.x

Differences in immune recognition of cytochrome P4502D6 by liver kidney microsomal (LKM) antibody in autoimmune hepatitis and chronic hepatitis C virus infection.

Y Ma 1, M Peakman 1, A Lobo-Yeo 1, L Wen 1, M Lenzi 1, J Gäken 1, F Farzaneh 1, G Mieli-Vergani 1, F B Bianchi 1, D Vergani 1
PMCID: PMC1534799  PMID: 8033426

Abstract

LKM-1 antibody, which characterizes a subtype of autoimmune hepatitis (AIH), is also found in some patients with chronic hepatitis C virus (HCV) infection. It has been suggested that HCV initiates autoimmunity through molecular mimicry, because there is partial identity between HCV and cytochrome P4502D6 (CYP2D6), the putative target of LKM-1. Whether CYP2D6 is the target of LKM-1 in HCV-related liver disease, however, is controversial. To clarify this issue, we have studied by phage plaque assay and Western blot the reactivity to recombinant CYP2D6, isolated from a human liver cDNA library, in 55 patients with LKM-1, 18 (14 females, median age 12 years) anti-HCV-negative, with classical AIH, and 37 (27 females, median age 52 years) anti-HCV-positive. Reactivity to CYP2D6 was found in 72% of the anti-HCV-negative, but only in 27% of the anti-HCV-positive patients (P < 0.001), although immunofluorescence LKM-1 titres were similar in the two groups. In addition, to investigate whether the antibody responsible for the LKM-1 fluorescent pattern also reacts with CYP2D6, we have determined the specificity of LKM-1 antibodies present in the supernatant of lymphoblastoid B cell lines obtained from two patients with LKM-1-positive AIH. An oligo/monoclonal antibody thus generated gave both the typical fluorescent pattern and reacted with CYP2D6. Our results show that whilst antibodies producing the characteristic LKM-1 fluorescent pattern can react with CYP2D6, not all LKM-1-positive sera do so, particularly if obtained from patients with chronic HCV infection. This suggests that LKM-1 in HCV infection recognizes epitopes or antigens different from those targeted in AIH.

Full text

PDF
94

Images in this article

97Fig. 1
on p.97

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alvarez F., Bernard O., Homberg J. C., Kreibich G. Anti-liver-kidney microsome antibody recognizes a 50,000 molecular weight protein of the endoplasmic reticulum. J Exp Med. 1985 May 1;161(5):1231–1236. doi: 10.1084/jem.161.5.1231. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Farrant J., Bryant A. E., Lever A. M., Edwards A. J., Knight S. C., Webster A. D. Defective low-density cells of dendritic morphology from the blood of patients with common variable hypogammaglobulinaemia: low immunoglobulin production on stimulation of normal B cells. Clin Exp Immunol. 1985 Jul;61(1):189–194. [PMC free article] [PubMed] [Google Scholar]
  3. Homberg J. C., Abuaf N., Bernard O., Islam S., Alvarez F., Khalil S. H., Poupon R., Darnis F., Lévy V. G., Grippon P. Chronic active hepatitis associated with antiliver/kidney microsome antibody type 1: a second type of "autoimmune" hepatitis. Hepatology. 1987 Nov-Dec;7(6):1333–1339. doi: 10.1002/hep.1840070626. [DOI] [PubMed] [Google Scholar]
  4. Johnson P. J., McFarlane I. G., Eddleston A. L. The natural course and heterogeneity of autoimmune-type chronic active hepatitis. Semin Liver Dis. 1991 Aug;11(3):187–196. doi: 10.1055/s-2008-1040436. [DOI] [PubMed] [Google Scholar]
  5. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  6. Lenzi M., Ballardini G., Fusconi M., Cassani F., Selleri L., Volta U., Zauli D., Bianchi F. B. Type 2 autoimmune hepatitis and hepatitis C virus infection. Lancet. 1990 Feb 3;335(8684):258–259. doi: 10.1016/0140-6736(90)90070-l. [DOI] [PubMed] [Google Scholar]
  7. Lunel F., Abuaf N., Frangeul L., Grippon P., Perrin M., Le Coz Y., Valla D., Borotto E., Yamamoto A. M., Huraux J. M. Liver/kidney microsome antibody type 1 and hepatitis C virus infection. Hepatology. 1992 Sep;16(3):630–636. doi: 10.1002/hep.1840160304. [DOI] [PubMed] [Google Scholar]
  8. Ma Y., Peakman M., Lenzi M., Gäken J., Thomas M. G., Farzaneh F., Ballardini G., Cassani F., Mieli-Vergani G., Bianchi F. B. Case against subclassification of type II autoimmune chronic active hepatitis. Lancet. 1993 Jan 2;341(8836):60–60. doi: 10.1016/0140-6736(93)92541-z. [DOI] [PubMed] [Google Scholar]
  9. Magrin S., Craxì A., Fiorentino G., Fabiano C., Provenzano G., Pinzello G. B., Palazzo U., Almasio P., Pagliaro L. Is autoimmune chronic active hepatitis a HCV-related disease? J Hepatol. 1991 Jul;13(1):56–60. doi: 10.1016/0168-8278(91)90864-8. [DOI] [PubMed] [Google Scholar]
  10. Manns M. P., Griffin K. J., Sullivan K. F., Johnson E. F. LKM-1 autoantibodies recognize a short linear sequence in P450IID6, a cytochrome P-450 monooxygenase. J Clin Invest. 1991 Oct;88(4):1370–1378. doi: 10.1172/JCI115443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Manns M. P., Johnson E. F., Griffin K. J., Tan E. M., Sullivan K. F. Major antigen of liver kidney microsomal autoantibodies in idiopathic autoimmune hepatitis is cytochrome P450db1. J Clin Invest. 1989 Mar;83(3):1066–1072. doi: 10.1172/JCI113949. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Meyer zum Büschenfelde K. H., Lohse A. W., Manns M., Poralla T. Autoimmunity and liver disease. Hepatology. 1990 Aug;12(2):354–363. doi: 10.1002/hep.1840120225. [DOI] [PubMed] [Google Scholar]
  13. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Seelig R., Renz M., Bünger G., Schröter H., Seelig H. P. Anti-LKM-1 antibodies determined by use of recombinant P450 2D6 in ELISA and western blot and their association with anti-HCV and HCV-RNA. Clin Exp Immunol. 1993 Jun;92(3):373–380. doi: 10.1111/j.1365-2249.1993.tb03408.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Smith M. G., Williams R., Walker G., Rizzetto M., Doniach D. Hepatic disorders associated with liver-kidney microsomal antibodies. Br Med J. 1974 Apr 13;2(5910):80–84. doi: 10.1136/bmj.2.5910.80. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Southern E. M. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975 Nov 5;98(3):503–517. doi: 10.1016/s0022-2836(75)80083-0. [DOI] [PubMed] [Google Scholar]
  17. Todros L., Touscoz G., D'Urso N., Durazzo M., Albano E., Poli G., Baldi M., Rizzetto M. Hepatitis C virus-related chronic liver disease with autoantibodies to liver-kidney microsomes (LKM). Clinical characterization from idiopathic LKM-positive disorders. J Hepatol. 1991 Jul;13(1):128–131. doi: 10.1016/0168-8278(91)90874-b. [DOI] [PubMed] [Google Scholar]
  18. Weiner A. J., Kuo G., Bradley D. W., Bonino F., Saracco G., Lee C., Rosenblatt J., Choo Q. L., Houghton M. Detection of hepatitis C viral sequences in non-A, non-B hepatitis. Lancet. 1990 Jan 6;335(8680):1–3. doi: 10.1016/0140-6736(90)90134-q. [DOI] [PubMed] [Google Scholar]
  19. Yamamoto A. M., Cresteil D., Homberg J. C., Alvarez F. Characterization of anti-liver-kidney microsome antibody (anti-LKM1) from hepatitis C virus-positive and -negative sera. Gastroenterology. 1993 Jun;104(6):1762–1767. doi: 10.1016/0016-5085(93)90657-x. [DOI] [PubMed] [Google Scholar]
  20. Zanger U. M., Hauri H. P., Loeper J., Homberg J. C., Meyer U. A. Antibodies against human cytochrome P-450db1 in autoimmune hepatitis type II. Proc Natl Acad Sci U S A. 1988 Nov;85(21):8256–8260. doi: 10.1073/pnas.85.21.8256. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Clinical and Experimental Immunology are provided here courtesy of British Society for Immunology

RESOURCES