Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1991 Oct;88(4):1370–1378. doi: 10.1172/JCI115443

LKM-1 autoantibodies recognize a short linear sequence in P450IID6, a cytochrome P-450 monooxygenase.

M P Manns 1, K J Griffin 1, K F Sullivan 1, E F Johnson 1
PMCID: PMC295608  PMID: 1717511

Abstract

LKM-1 autoantibodies, which are associated with autoimmune chronic active hepatitis, recognize P450IID6, a cytochrome P-450 monooxygenase. The reactivities of 26 LKM-1 antisera were tested with a panel of deletion mutants of P450IID6 expressed in Escherichia coli. 22 sera recognize a 33-amino acid segment of P450IID6, and 11 of these recognize a shorter segment, DPAQPPRD. PAQPPR is also found in IE175 of herpes simplex virus type 1 (HSV-1). Antibodies for HSV-1 proteins were detected by ELISA in 17 of 20 LKM-1 sera tested. An immobilized, synthetic peptide, DPAQPPRDC, was used to purify LKM-1 antibodies. Affinity purified LKM-1 autoantibodies react on immunoblots with a protein in BHK cells after infection with HSV-1. 11 of 24 LKM-1 sera, including 3 that recognize DPAQPPRD, also exhibit antibodies to the hepatitis C virus (HCV) protein, C100-3. Affinity purified LKM-1 antibodies did not recognize C100-3. However, partial sequence identity was evident between portions of the immunopositive 33-amino acid segment of P450IID6 and other portions of the putative HCV polyprotein. Immune cross-recognition of P450IID6 and HCV or HSV-1 proteins may contribute to the occurrence of LKM-1 autoantibodies.

Full text

PDF
1370

Images in this article

1372Image
on p.1372
1375Image
on p.1375
1375Image
on p.1375

Selected References

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

  1. Devereux J., Haeberli P., Smithies O. A comprehensive set of sequence analysis programs for the VAX. Nucleic Acids Res. 1984 Jan 11;12(1 Pt 1):387–395. doi: 10.1093/nar/12.1part1.387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. DiDonato J. A., Muller M. T. DNA binding and gene regulation by the herpes simplex virus type 1 protein ICP4 and involvement of the TATA element. J Virol. 1989 Sep;63(9):3737–3747. doi: 10.1128/jvi.63.9.3737-3747.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Earnshaw W. C., Sullivan K. F., Machlin P. S., Cooke C. A., Kaiser D. A., Pollard T. D., Rothfield N. F., Cleveland D. W. Molecular cloning of cDNA for CENP-B, the major human centromere autoantigen. J Cell Biol. 1987 Apr;104(4):817–829. doi: 10.1083/jcb.104.4.817. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Edwards R. J., Murray B. P., Boobis A. R., Davies D. S. Identification and location of alpha-helices in mammalian cytochromes P450. Biochemistry. 1989 May 2;28(9):3762–3770. doi: 10.1021/bi00435a021. [DOI] [PubMed] [Google Scholar]
  5. Fusconi M., Lenzi M., Ballardini G., Miniero R., Cassani F., Zauli D., Bianchi F. B. Anti-HCV testing in autoimmune hepatitis and primary biliary cirrhosis. Lancet. 1990 Sep 29;336(8718):823–823. doi: 10.1016/0140-6736(90)93297-3. [DOI] [PubMed] [Google Scholar]
  6. Gonzalez F. J., Matsunaga T., Nagata K., Meyer U. A., Nebert D. W., Pastewka J., Kozak C. A., Gillette J., Gelboin H. V., Hardwick J. P. Debrisoquine 4-hydroxylase: characterization of a new P450 gene subfamily, regulation, chromosomal mapping, and molecular analysis of the DA rat polymorphism. DNA. 1987 Apr;6(2):149–161. doi: 10.1089/dna.1987.6.149. [DOI] [PubMed] [Google Scholar]
  7. Gonzalez F. J., Skoda R. C., Kimura S., Umeno M., Zanger U. M., Nebert D. W., Gelboin H. V., Hardwick J. P., Meyer U. A. Characterization of the common genetic defect in humans deficient in debrisoquine metabolism. Nature. 1988 Feb 4;331(6155):442–446. doi: 10.1038/331442a0. [DOI] [PubMed] [Google Scholar]
  8. Gueguen M., Meunier-Rotival M., Bernard O., Alvarez F. Anti-liver kidney microsome antibody recognizes a cytochrome P450 from the IID subfamily. J Exp Med. 1988 Aug 1;168(2):801–806. doi: 10.1084/jem.168.2.801. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gueguen M., Yamamoto A. M., Bernard O., Alvarez F. Anti-liver-kidney microsome antibody type 1 recognizes human cytochrome P450 db1. Biochem Biophys Res Commun. 1989 Mar 15;159(2):542–547. doi: 10.1016/0006-291x(89)90027-2. [DOI] [PubMed] [Google Scholar]
  10. HUNTER W. M., GREENWOOD F. C. Preparation of iodine-131 labelled human growth hormone of high specific activity. Nature. 1962 May 5;194:495–496. doi: 10.1038/194495a0. [DOI] [PubMed] [Google Scholar]
  11. Helfman D. M., Feramisco J. R., Fiddes J. C., Thomas G. P., Hughes S. H. Identification of clones that encode chicken tropomyosin by direct immunological screening of a cDNA expression library. Proc Natl Acad Sci U S A. 1983 Jan;80(1):31–35. doi: 10.1073/pnas.80.1.31. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Ishida N., Tawaragi Y., Inuzuka C., Sugita O., Kubota I., Nakazato H., Noguchi T., Sassa S. Four species of cDNAs for cytochrome P450 isozymes immunorelated to P450C-M/F encode for members of P450IID subfamily, increasing the number of members within the subfamily. Biochem Biophys Res Commun. 1988 Oct 31;156(2):681–688. doi: 10.1016/s0006-291x(88)80896-9. [DOI] [PubMed] [Google Scholar]
  13. Kahlon J., Whitley R. J. Antibody response of the newborn after herpes simplex virus infection. J Infect Dis. 1988 Nov;158(5):925–933. doi: 10.1093/infdis/158.5.925. [DOI] [PubMed] [Google Scholar]
  14. Kato N., Hijikata M., Ootsuyama Y., Nakagawa M., Ohkoshi S., Sugimura T., Shimotohno K. Molecular cloning of the human hepatitis C virus genome from Japanese patients with non-A, non-B hepatitis. Proc Natl Acad Sci U S A. 1990 Dec;87(24):9524–9528. doi: 10.1073/pnas.87.24.9524. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kuo G., Choo Q. L., Alter H. J., Gitnick G. L., Redeker A. G., Purcell R. H., Miyamura T., Dienstag J. L., Alter M. J., Stevens C. E. An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science. 1989 Apr 21;244(4902):362–364. doi: 10.1126/science.2496467. [DOI] [PubMed] [Google Scholar]
  16. 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]
  17. 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]
  18. 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]
  19. Manns M. Autoantibodies and antigens in liver diseases--updated. J Hepatol. 1989 Sep;9(2):272–280. doi: 10.1016/0168-8278(89)90063-9. [DOI] [PubMed] [Google Scholar]
  20. Manns M., Meyer zum Büschenfelde K. H., Slusarczyk J., Dienes H. P. Detection of liver-kidney microsomal autoantibodies by radioimmunoassay and their relation to anti-mitochondrial antibodies in inflammatory liver diseases. Clin Exp Immunol. 1984 Sep;57(3):600–608. [PMC free article] [PubMed] [Google Scholar]
  21. McFarlane I. G., Smith H. M., Johnson P. J., Bray G. P., Vergani D., Williams R. Hepatitis C virus antibodies in chronic active hepatitis: pathogenetic factor or false-positive result? Lancet. 1990 Mar 31;335(8692):754–757. doi: 10.1016/0140-6736(90)90870-b. [DOI] [PubMed] [Google Scholar]
  22. McGeoch D. J., Dolan A., Donald S., Brauer D. H. Complete DNA sequence of the short repeat region in the genome of herpes simplex virus type 1. Nucleic Acids Res. 1986 Feb 25;14(4):1727–1745. doi: 10.1093/nar/14.4.1727. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Meyer U. A., Skoda R. C., Zanger U. M. The genetic polymorphism of debrisoquine/sparteine metabolism-molecular mechanisms. Pharmacol Ther. 1990;46(2):297–308. doi: 10.1016/0163-7258(90)90096-k. [DOI] [PubMed] [Google Scholar]
  24. Mishiro S., Hoshi Y., Takeda K., Yoshikawa A., Gotanda T., Takahashi K., Akahane Y., Yoshizawa H., Okamoto H., Tsuda F. Non-A, non-B hepatitis specific antibodies directed at host-derived epitope: implication for an autoimmune process. Lancet. 1990 Dec 8;336(8728):1400–1403. doi: 10.1016/0140-6736(90)93101-t. [DOI] [PubMed] [Google Scholar]
  25. Nebert D. W., Nelson D. R., Coon M. J., Estabrook R. W., Feyereisen R., Fujii-Kuriyama Y., Gonzalez F. J., Guengerich F. P., Gunsalus I. C., Johnson E. F. The P450 superfamily: update on new sequences, gene mapping, and recommended nomenclature. DNA Cell Biol. 1991 Jan-Feb;10(1):1–14. doi: 10.1089/dna.1991.10.1. [DOI] [PubMed] [Google Scholar]
  26. Nelson D. R., Strobel H. W. Secondary structure prediction of 52 membrane-bound cytochromes P450 shows a strong structural similarity to P450cam. Biochemistry. 1989 Jan 24;28(2):656–660. doi: 10.1021/bi00428a036. [DOI] [PubMed] [Google Scholar]
  27. Oldstone M. B. Molecular mimicry and autoimmune disease. Cell. 1987 Sep 11;50(6):819–820. doi: 10.1016/0092-8674(87)90507-1. [DOI] [PubMed] [Google Scholar]
  28. Parekh B. S., Schwimmbeck P. W., Buchmeier M. J. High efficiency immunoaffinity purification of anti-peptide antibodies on thiopropyl sepharose immunoadsorbants. Pept Res. 1989 May-Jun;2(3):249–252. [PubMed] [Google Scholar]
  29. Poulos T. L., Finzel B. C., Howard A. J. High-resolution crystal structure of cytochrome P450cam. J Mol Biol. 1987 Jun 5;195(3):687–700. doi: 10.1016/0022-2836(87)90190-2. [DOI] [PubMed] [Google Scholar]
  30. Schattner A., Rager-Zisman B. Virus-induced autoimmunity. Rev Infect Dis. 1990 Mar-Apr;12(2):204–222. doi: 10.1093/clinids/12.2.204. [DOI] [PubMed] [Google Scholar]
  31. Towbin H., Staehelin T., Gordon J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci U S A. 1979 Sep;76(9):4350–4354. doi: 10.1073/pnas.76.9.4350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Vento S., Di Perri G., Luzzati R., Garofano T., Concia E., Bassetti D. Type 2 autoimmune hepatitis and hepatitis C virus infection. Lancet. 1990 Apr 14;335(8694):921–922. doi: 10.1016/0140-6736(90)90524-9. [DOI] [PubMed] [Google Scholar]
  33. 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]
  34. 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 Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES