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* Department of Rheumatology, Medical University of Vienna, Vienna, Austria;
Center of Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria;
Department of Cell and Molecular Biology, Section for Medical Inflammation Research, Lund, Sweden;
Department of Rheumatology, Charité University Hospital, Berlin, Germany;
¶ Ludwig Boltzmann Institute for Rheumatology and Balneology, Second Department of Medicine, Hietzing Hospital, Vienna, Austria;
|| Department of Cell Biology and Anatomical Sciences, Sophie Davis School of Biomedical Education/City University of New York Medical School, New York, NY 10031; and
# Laboratory of Epidermis Differentiation and Rheumatoid Autoimmunity, Centre National de la Recherche Scientifique-Toulouse III University, Toulouse, France
A single intradermal injection of the mineral oil pristane in susceptible DA.1F rats induces erosive arthritis closely mimicking rheumatoid arthritis (RA). Pristane-induced arthritis (PIA) is driven by autoreactive T cells but no autoantigen has been identified to date. We therefore analyzed B and T cell responses to autoantigens potentially involved in the pathogenesis of RA, including IgG, citrullinated proteins, stress proteins, glucose-6-phosphate isomerase, and heterogeneous nuclear ribonucleoprotein (hnRNP)-A2 (RA33). IgG and IgM autoantibodies to hnRNP-A2 were detectable in sera of pristane-primed DA.1F rats already 1 wk before disease onset, reached maximum levels during the acute phase, and correlated with arthritis severity. Apart from rheumatoid factor, autoantibodies to other Ags were not observed. CD4+ lymph node cells isolated 10 days after pristane injection produced IFN-
but not IL-4 in response to stimulation with hnRNP-A2, whereas none of the other candidate Ags elicited cytokine secretion. Surprisingly, hnRNP-A2 also stimulated lymph node cells of naive animals to produce inflammatory cytokines in a MyD88-dependent manner. Furthermore, hnRNP-A2 was highly overexpressed in the joints of rats injected with pristane. Overexpression coincided with the appearance of anti-RA33 Abs and preceded the onset of clinical symptoms of PIA by several days. Taken together, these data suggest hnRNP-A2 to be among the primary inducers of autoimmunity in PIA. Therefore, this Ag might play a pivotal role in the pathogenesis of PIA and possibly also human RA.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Center of Molecular Medicine (CeMM) of the Austrian Academy of Sciences, the START Prize of the Austrian Science Fund (to G.S.), and Marie Curie Host Fellowship no. HPMT-CT-2000-00126 of the European Commission Research Directorate.
2 Current address: Clinic for Internal Medicine 3, University of Erlangen-Nurnberg, Erlangen, Germany.
3 Address correspondence and reprint requests to Dr. Günter Steiner, Department of Rheumatology, Medical University of Vienna, Waehringer Guertel 18, Vienna, Austria. E-mail address: guenter.steiner{at}meduniwien.ac.at
4 Abbreviations used in this paper: RA, rheumatoid arthritis; G6PI, glucose-6-phosphate isomerase; hnRNP, heterogeneous nuclear ribonucleoprotein; HSP, heat shock protein; PIA, pristane-induced arthritis; RF, rheumatoid factor; TRAP, tartrate-resistant acid phosphatase.
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