The Journal of Experimental Medicine
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*Arthritis
*Joint Disorders
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© The Rockefeller University Press, 0022-1007/1998/9/877/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 5, September 7, 1998 877-886

Articles

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

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

From the * Harold C. Simmons Arthritis Research Center and Department of Internal Medicine; {ddagger} 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 {dagger}{dagger} 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.

Key Words: human histocompatibility leukocyte antigen B27 • transgenic rat • antigenic peptide • arthritis • mass spectrometry

Address correspondence to Joel D. Taurog, M.D., Harold C. Simmons Arthritis Research Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75235-8884. Phone: (214) 648-6837; Fax: (214) 648-3783; E-mail: taurog{at}utsw.swmed.edu

The technical assistance of Graham Fox, Lisa Holt, and Julie Vorobiov is gratefully acknowledged. We thank Dr. William Biddison for the Q124 CTL line, and Dr. James Forman for providing the pHSE3' expression vector.

M. Zhou's current address is Brooklyn Hospital Center, 121 DeKalb Ave., Brooklyn, NY 11201.

A. Sayad's current address is Abon-Jaoude Hospital, Beirut, Lebanon.

W.A. Simmons' current address is Argonex Pharmaceuticals, 706 Forest St., Charlottesville, VA 22903.

S.D. Maika's current address is Institute for Cell and Molecular Biology, University of Texas, Austin, TX 78712.

Abbreviations used: LEW, Lewis; LN, lymph node; SD, Sprague Dawley.


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