Identification of novel human aggrecan T cell epitopes in HLA-B27 transgenic mice associated with spondyloarthropathy.
The pathology of ankylosing spondylitis, reactive arthritis, and other spondyloarthropathies (SpA) is closely associated with the human leukocyte class I Ag HLA-B27. A characteristic finding in SpA is inflammation of cartilage structures of the joint, in particular at the site of ligament/tendon and bone junction (enthesitis). In this study, we investigated the role of CD8+ T cells in response to the cartilage proteoglycan aggrecan as a potential candidate autoantigen in BALB/c-B27 transgenic mice. We identified four new HLA-B27-restricted nonamer peptides, one of them (no. 67) with a particularly strong T cell immunogenicity. Peptide no. 67 immunization was capable of stimulating HLA-B27-restricted, CD8+ T cells in BALB/c-B27 transgenic animals, but not in wild-type BALB/c mice. The peptide was specifically recognized on P815-B27 transfectants by HLA-B27-restricted CTLs, which were also detectable by HLA tetramer staining ex vivo as well as in situ. Most importantly, analysis of the joints from peptide no. 67-immunized mice induced typical histological signs of SpA. Our data indicate that HLA-B27-restricted epitopes derived from human aggrecan are involved in the induction of inflammation (tenosynovitis), underlining the importance of HLA-B27 in the pathogenesis of SpA.
Kuon
Wolfgang
W
Department of Gastroenterology and Rheumatology, Charité-Universitätsmedizin, Berlin, Germany. kuon@medizin.fu-berlin.de
Kuhne
Maren
M
Busch
Dirk H
DH
Atagunduz
Pamir
P
Seipel
Martina
M
Wu
Peihua
P
Morawietz
Lars
L
Fernahl
Gabriele
G
Appel
Heiner
H
Weiss
Elisabeth H
EH
Krenn
Veit
V
Sieper
Joachim
J
D053674:Aggrecans; D000818:Animals; D016918:Arthritis, Reactive / Q000209:etiology; D001665:Binding Sites; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte; D016326:Extracellular Matrix Proteins / Q000276:immunology*; D005260:Female; D015796:HLA-B27 Antigen / Q000502:physiology*; D007114:Immunization; D037181:Lectins, C-Type; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D011509:Proteoglycans / Q000276:immunology*; D025242:Spondylarthropathies / Q000209:etiology*; D013167:Spondylitis, Ankylosing / Q000209:etiology; D013717:Tenosynovitis / Q000209:etiology
C508320:Acan protein, mouse; D053674:Aggrecans; D018984:Epitopes, T-Lymphocyte; D016326:Extracellular Matrix Proteins; D015796:HLA-B27 Antigen; D037181:Lectins, C-Type; D011509:Proteoglycans