J. Exp. Med., Volume 188, Number 5, September 7, 1998 877-886

The Specificity of Peptides Bound to Human Histocompatibility Leukocyte Antigen (HLA)-B27 Influences the Prevalence of Arthritis in HLA-B27 Transgenic Rats

By Ming Zhou,^* Alain Sayad,^*§ William A. Simmons,^* Richard C. Jones,^¶ Shanna D. Maika, Nimman Satumtira,^* Martha L. Dorris,^* Simon J. Gaskell,^¶ Robert S. Bordoli,^** R. Balfour Sartor, Clive A. Slaughter, James A. Richardson, Robert E. Hammer, and Joel D. Taurog^*

From the ^* Harold C. Simmons Arthritis Research Center and Department of Internal Medicine;  Howard Hughes Medical Institute and Department of Biochemistry; ^§ Department of Pediatrics and  Department of Pathology, University of  Texas Southwestern Medical Center, Dallas, Texas 75235; ^¶ Department of Chemistry, UMIST, Manchester, United Kingdom; ^** Micromass Ltd, Wythenshawe, Manchester, United Kingdom; and the  Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599

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 ~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.

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