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

• Published in: The Journal of experimental medicine Vol. 188; no. 5; pp. 877 - 886
• Main Authors: Zhou, M, Sayad, A, Simmons, W A, Jones, R C, Maika, S D, Satumtira, N, Dorris, M L, Gaskell, S J, Bordoli, R S, Sartor, R B, Slaughter, C A, Richardson, J A, Hammer, R E, Taurog, J D
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 07-09-1998
• Subjects: Amino Acid Sequence; Animals; Animals, Genetically Modified; Arthritis - epidemiology; Arthritis - genetics; Arthritis - immunology; Base Sequence; Chromatography, High Pressure Liquid; Cytotoxicity, Immunologic - genetics; Female; Gene Expression Regulation - immunology; HLA-B27 Antigen - genetics; HLA-B27 Antigen - metabolism; Humans; Influenza A virus - genetics; Male; Mass Spectrometry; Molecular Sequence Data; Nucleocapsid Proteins; Nucleoproteins - biosynthesis; Nucleoproteins - genetics; Nucleoproteins - immunology; Peptide Fragments - genetics; Peptide Fragments - immunology; Peptide Fragments - metabolism; Prevalence; Protein Binding - genetics; Protein Binding - immunology; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley; RNA-Binding Proteins; T-Lymphocytes, Cytotoxic - immunology; Transgenes - immunology; Viral Core Proteins - biosynthesis; Viral Core Proteins - genetics; Viral Core Proteins - immunology
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.188.5.877

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.