Immunodominant T-cell epitopes of hnRNP-A2 associated with disease activity in patients with rheumatoid arthritis.
The heterogeneous nuclear ribonucleoprotein A2 (hnRNP-A2) has been described as an important autoantigen in rheumatoid arthritis (RA) since it is targeted by autoantibodies, autoreactive T cells, and is aberrantly expressed in synovial cells in patients. To identify hnRNP-A2-specific T-cell epitopes possibly associated with pathogenicity, we used an innovative approach. We first scanned 280 overlapping hnRNP-A2 peptides for binding to the RA-associated class II molecules HLA-DR4 and HLA-DR1, leading to a comprehensive selection of binders. The selected peptides were tested in IFN-gamma-specific ELISPOT assay: PBMC from 18% of RA patients showed a significant IFN-gamma response to hnRNP-A2 peptides, 15% to the overlapping sequences 117-133 and/or 120-133, whereas PBMC from healthy individuals tested negative. We measured proliferative responses to these two peptides in another cohort of patients with RA or osteoarthritis: positive responses were found in 28% of RA, but also in 11% of osteoarthritis patients and these responses could be blocked by anti-MHC class II Ab. Remarkably, the presence of 117/120-133-specific T cells was significantly associated with active disease in RA patients, and bone erosion appeared to be more common in T-cell positive patients. These data suggest involvement of hnRNP-A2 specific cellular autoimmune responses in RA pathogenesis.
Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria. sylvie.trembleau@meduniwien.ac.at
Sylvie
S
Trembleau
Markus
M
Hoffmann
Brigitte
B
Meyer
Valerie
V
Nell
Helga
H
Radner
Wolfgang
W
Zauner
Juergen
J
Hammer
Gerald
G
Aichinger
Gottfried
G
Fischer
Josef
J
Smolen
Günter
G
Steiner
D001172:Arthritis, Rheumatoid / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D018985:Epitopes, B-Lymphocyte / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D008213:Lymphocyte Activation; D010446:Peptide Fragments / Q000276:immunology; D016133:Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology*
D001323:Autoantibodies; D001324:Autoantigens; D018985:Epitopes, B-Lymphocyte; D018984:Epitopes, T-Lymphocyte; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D016056:Immunodominant Epitopes; D010446:Peptide Fragments; D007371:Interferon-gamma