The specificity of peptides bound to human histocompatibility leukocyte antigen (HLA)-B27 influences the prevalence of arthritis in HLA-B27 transgenic rats.

Human histocompatibility leukocyte antigen B27 is highly associated with the rheumatic diseases termed spondyloarthropathies, but the mechanism is not known. B27 transgenic rats develop a spontaneous disease resembling the human spondyloarthropathies that includes arthritis and colitis. To investigate whether this disease requires the binding of specific peptides to B27, we made a minigene construct in which a peptide from influenza nucleoprotein, NP383-391 (SRYWAIRTR), which binds B27 with high affinity, is targeted directly to the ER by the signal peptide of the adenovirus E3/gp19 protein. Rats transgenic for this minigene, NP1, were made and bred with B27 rats. The production of the NP383-391 peptide in B27(+)NP1(+) rats was confirmed immunologically and by mass spectrometry. The NP1 product displaced approximately 90% of the 3H-Arg-labeled endogenous peptide fraction in B27(+)NP1(+) spleen cells. Male B27(+)NP1(+) rats had a significantly reduced prevalence of arthritis, compared with B27(+)NP- males or B27(+) males with a control construct, NP2, whereas colitis was not significantly affected by the NP1 transgene. These findings support the hypothesis that B27-related arthritis requires binding of a specific peptide or set of peptides to B27, and they demonstrate a method for efficient transgenic targeting of peptides to the ER.
AuthorsM Zhou, A Sayad, W A Simmons, R C Jones, S D Maika, N Satumtira, M L Dorris, S J Gaskell, R S Bordoli, R B Sartor, C A Slaughter, J A Richardson, R E Hammer, J D Taurog
JournalThe Journal of experimental medicine (J Exp Med) Vol. 188 Issue 5 Pg. 877-86 (Sep 7 1998) ISSN: 0022-1007 [Print] UNITED STATES
PMID9730889 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • HLA-B27 Antigen
  • NP protein, Influenza A virus
  • Nucleoproteins
  • Peptide Fragments
  • RNA-Binding Proteins
  • Viral Core Proteins
  • Amino Acid Sequence
  • Animals
  • Animals, Genetically Modified
  • Arthritis (epidemiology, genetics, immunology)
  • Base Sequence
  • Chromatography, High Pressure Liquid
  • Cytotoxicity, Immunologic (genetics)
  • Female
  • Gene Expression Regulation (immunology)
  • HLA-B27 Antigen (genetics, metabolism)
  • Humans
  • Influenza A virus (genetics)
  • Male
  • Mass Spectrometry
  • Molecular Sequence Data
  • Nucleoproteins (biosynthesis, genetics, immunology)
  • Peptide Fragments (genetics, immunology, metabolism)
  • Prevalence
  • Protein Binding (genetics, immunology)
  • RNA-Binding Proteins
  • Rats
  • Rats, Inbred Lew
  • Rats, Sprague-Dawley
  • T-Lymphocytes, Cytotoxic (immunology)
  • Transgenes (immunology)
  • Viral Core Proteins (biosynthesis, genetics, immunology)

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