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

Abstract

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.

• Authors: M 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
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 188 Issue 5 Pg. 877-86 (Sep 7 1998) ISSN: 0022-1007 [Print] UNITED STATES
• PMID: 9730889 (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

Topics

• 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)