The specificity of peptides bound to human histocompatibility leukocyte antigen (HLA)-B27 influences the prevalence of arthritis in HLA-B27 transgenic rats.
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.
Zhou
M
M
Harold C. Simmons Arthritis Research Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75235, USA.
Sayad
A
A
Simmons
W A
WA
Jones
R C
RC
Maika
S D
SD
Satumtira
N
N
Dorris
M L
ML
Gaskell
S J
SJ
Bordoli
R S
RS
Sartor
R B
RB
Slaughter
C A
CA
Richardson
J A
JA
Hammer
R E
RE
Taurog
J D
JD
D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D001168:Arthritis / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology*; D001483:Base Sequence; D002851:Chromatography, High Pressure Liquid; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D015796:HLA-B27 Antigen / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D009980:Influenza A virus / Q000235:genetics; D008297:Male; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D019590:Nucleocapsid Proteins; D009698:Nucleoproteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D015995:Prevalence; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D016601:RNA-Binding Proteins; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D019076:Transgenes / Q000276:immunology; D014758:Viral Core Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology
D015796:HLA-B27 Antigen; C048842:NP protein, Influenza A virus; D019590:Nucleocapsid Proteins; D009698:Nucleoproteins; D010446:Peptide Fragments; D016601:RNA-Binding Proteins; D014758:Viral Core Proteins