THE SPECIFICITY OF PEPTIDES BOUND TO HUMAN HISTOCOMPATIBILITY LEUKOCYTE ANTIGEN (HLA)-B27 INFLUENCES THE PREVALENCE OF ARTHRITIS IN HLA-B27TRANSGENIC RATS

Human histocompatibility leukocyte antigen B27 is highly associated wi th the rheumatic diseases termed spondyloarthropathies, but the mechan ism is not known. B27 transgenic rats develop a spontaneous disease re sembling the human spondyloarthropathies that includes arthritis and c olitis. To investigate whether this disease requires the binding of sp ecific peptides to B27, we made a minigene construct in which a peptid e from influenza nucleoprotein, NP383-391 (SRYWAIRTR), which binds B27 with high affinity, is targeted directly to the ER by the signal pept ide of the adenovirus E3/gp19 protein. Rats transgenic for this minige ne, 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 similar to 90% of the H- 3-Arg-labeled endogenous peptide fraction in B27(+)NP1(+) spleen cells . Male B27(+)NP1(+) rats had a significantly reduced prevalence of art hritis, compared with B27(+)NP(-) males or B27(+) males with a control construct, NP2, whereas colitis was not significantly affected by the NP1 transgene. These finding; support the hypothesis that B27-related arthritis requires binding of a specific peptide or set of peptides t o B27, and they demonstrate a method for efficient transgenic targetin g of peptides to the ER.