title: Characterization of autoreactive T cells to the autoantigens heterogeneous nuclear ribonucleoprotein A2 (RA33) and filaggrin in patients with rheumatoid arthritis.
abstract: The role of autoimmune reactions in the pathogenesis of rheumatoid arthritis (RA) is poorly understood. To address this issue we have investigated the spontaneous T cell response to two well-characterized humoral autoantigens in RA patients and controls: 1) the heterogeneous nuclear ribonucleoprotein A2, i.e., the RA33 Ag (A2/RA33), and 2) filaggrin in unmodified and citrullinated forms. In stimulation assays A2/RA33 induced proliferative responses in PBMC of almost 60% of the RA patients but in only 20% of the controls (patients with osteoarthritis or psoriatic arthritis and healthy individuals), with substantially stronger responses in RA patients (p < 0.00002). Furthermore, synovial T cells of seven RA patients investigated were also clearly responsive. In contrast, responses to filaggrin were rarely observed and did not differ between RA patients and controls. Analysis of A2/RA33-induced cytokine secretion revealed high IFN-gamma and low IL-4 production in both RA and control PBMC, whereas IL-2 production was mainly observed in RA PBMC (p < 0.03). Moreover, A2/RA33-specific T cell clones from RA patients showed a strong Th1 phenotype and secreted higher amounts of IFN-gamma than Th1 clones from controls (p < 0.04). Inhibition experiments performed with mAbs against MHC class II molecules showed A2/RA33-induced T cell responses to be largely HLA-DR restricted. Finally, immunohistochemical analyses revealed pronounced overexpression of A2/RA33 in synovial tissue of RA patients. Taken together, the presence of autoreactive Th1-like cells in RA patients in conjunction with synovial overexpression of A2/RA33 may indicate potential involvement of this autoantigen in the pathogenesis of RA.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine III, University of Vienna, Vienna, Austria.
authors.forename: Ruth
authors.initials: R
authors.lastname: Fritsch
authors.forename: Daniela
authors.initials: D
authors.lastname: Eselböck
authors.forename: Karl
authors.initials: K
authors.lastname: Skriner
authors.forename: Beatrice
authors.initials: B
authors.lastname: Jahn-Schmid
authors.forename: Clemens
authors.initials: C
authors.lastname: Scheinecker
authors.forename: Barbara
authors.initials: B
authors.lastname: Bohle
authors.forename: Makiyeh
authors.initials: M
authors.lastname: Tohidast-Akrad
authors.forename: Silvia
authors.initials: S
authors.lastname: Hayer
authors.forename: Josef
authors.initials: J
authors.lastname: Neumüller
authors.forename: Serafin
authors.initials: S
authors.lastname: Pinol-Roma
authors.forename: Josef S
authors.initials: JS
authors.lastname: Smolen
authors.forename: Günter
authors.initials: G
authors.lastname: Steiner
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D017951:Antigen Presentation; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000473:pathology; D001324:Autoantigens / Q000096:biosynthesis / Q000276:immunology*; D002999:Clone Cells; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D005260:Female; D000091344:Filaggrin Proteins; D006684:HLA-DR Antigens / Q000276:immunology / Q000378:metabolism; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D006801:Humans; D007381:Intermediate Filament Proteins / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D012332:RNA, Heterogeneous Nuclear / Q000276:immunology*; D012261:Ribonucleoproteins / Q000096:biosynthesis / Q000276:immunology*; D013583:Synovial Membrane / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*
chemical_list: D001324:Autoantigens; D016207:Cytokines; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D006684:HLA-DR Antigens; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D007381:Intermediate Filament Proteins; D012332:RNA, Heterogeneous Nuclear; D012261:Ribonucleoproteins; C439768:hnRNP A2