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Transgenic Mice Α Autoantibodies In Aberrant Expression of the Autoantigen Heterogeneous Nuclear Ribonucleoprotein-A2 (RA33) and Spontaneous Formation of Rheumatoid This information is current as Arthritis-Associated Anti-RA33 of September 27, 2021. Autoantibodies in TNF- α Transgenic Mice Silvia Hayer, Makiyeh Tohidast-Akrad, Silva Haralambous, Beatrice Jahn-Schmid, Karl Skriner, Sylvie Trembleau, Hélène Dumortier, Serafin Pinol-Roma, Kurt Redlich, Georg Downloaded from Schett, Sylviane Muller, George Kollias, Josef Smolen and Günter Steiner J Immunol 2005; 175:8327-8336; ; doi: 10.4049/jimmunol.175.12.8327 http://www.jimmunol.org/content/175/12/8327 http://www.jimmunol.org/ References This article cites 74 articles, 14 of which you can access for free at: http://www.jimmunol.org/content/175/12/8327.full#ref-list-1 Why The JI? Submit online. by guest on September 27, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2005 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Aberrant Expression of the Autoantigen Heterogeneous Nuclear Ribonucleoprotein-A2 (RA33) and Spontaneous Formation of Rheumatoid Arthritis-Associated Anti-RA33 Autoantibodies in TNF-␣ Transgenic Mice1 Silvia Hayer,* Makiyeh Tohidast-Akrad,† Silva Haralambous,‡ Beatrice Jahn-Schmid,§ Karl Skriner,2*¶ Sylvie Trembleau,ʈ He´le`ne Dumortier,# Serafin Pinol-Roma,** Kurt Redlich,* Georg Schett,* Sylviane Muller,# George Kollias,†† Josef Smolen,*†ʈ and Gu¨nter Steiner3*†¶ʈ Human TNF-␣ transgenic (hTNFtg) mice develop erosive arthritis closely resembling rheumatoid arthritis (RA). To investigate mechanisms leading to pathological autoimmune reactions in RA, we examined hTNFtg animals for the presence of RA-associated Downloaded from autoantibodies including Abs to citrullinated epitopes (anti-cyclic citrullinated peptide), heterogeneous nuclear ribonucleoprotein (hnRNP)-A2 (anti-RA33), and heat shock proteins (hsp) (anti-hsp). Although IgM anti-hsp Abs were detected in 40% of hTNFtg and control mice, IgG anti-hsp Abs were rarely seen, and anti-cyclic citrullinated peptide Abs were not seen at all. In contrast, >50% of hTNFtg mice showed IgG anti-RA33 autoantibodies, which became detectable shortly after the onset of arthritis. These Abs were predominantly directed to a short epitope, which was identical with an epitope previously described in MRL/lpr mice. Incidence of anti-RA33 was significantly decreased in mice treated with the osteoclast inhibitor osteoprotegerin and also in http://www.jimmunol.org/ c-fos-deficient mice lacking osteoclasts. Pronounced expression of hnRNP-A2 and a smaller splice variant was seen in joints of hTNFtg mice, whereas expression was low in control animals. Although the closely related hnRNP-A1 was also overexpressed, autoantibodies to this protein were infrequently detected. Because expression of hnRNP-A2 in thymus, spleen, brain, and lung was similar in hTNFtg and control mice, aberrant expression appeared to be restricted to the inflamed joint. Finally, immunization of hTNFtg mice with recombinant hnRNP-A2 or a peptide harboring the major B cell epitope aggravated arthritis. These findings suggest that overproduction of TNF-␣ leads to aberrant expression of hnRNP-A2 in the rheumatoid joint and subsequently to autoimmune reactions, which may enhance the inflammatory and destructive process. The Journal of Immunology, 2005, 175: 8327–8336. by guest on September 27, 2021 he pathogenesis of rheumatoid arthritis (RA)4 is still un- class II genes, the frequent presence of autoantibodies, and the resolved. Although effects mediated by proinflammatory efficacy of T cell-directed therapies suggest involvement of T cytokines are pivotal in the development of this chronic the adaptive immune response, primarily in the initial phases of the destructive disorder (1), the strong association of RA with MHC disease but also in its subsequent course (2–4). With respect to autoimmune responses, apart from rheumatoid factor (RF), i.e., autoantibody to IgG, autoantibodies to a variety of Ags have been *Department of Rheumatology, Internal Medicine III, Medical University of Vienna, Vienna, Austria; †Ludwig Boltzmann Institute for Rheumatology and Balneology, Vi- described in recent years (5). In particular, the discovery of auto- enna, Austria; ‡Laboratory of Molecular Genetics, Hellenic Pasteur Institute, Athens, antibodies to citrullinated proteins such as fibrin or vimentin in Greece; §Institute of Pathophysiology, Medical University of Vienna, Vienna, Austria; ʈ patients with RA was one of the most important finding in rheu- ¶Institute of Medical Biochemistry, Medical University of Vienna, Vienna, Austria; Cen- ter of Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; #In- matology research, pointing to the potential importance of post- stitute of Molecular and Cellular Biology, Centre National de la Recherche Scientifique, translational modifications in the generation of autoepitopes (6, 7). Strasbourg, France; **Department of Cell Biology and Anatomy, Mount Sinai School of Medicine, New York, NY 10029; and ††Institute of Immunology, Biomedical Sciences Another well-characterized autoantigen of interest is the heteroge- Research Center “Alexander Fleming,” Vari, Greece neous nuclear ribonucleoprotein (hnRNP)-A2, also known as the Received for publication May 5, 2005. Accepted for publication October 3, 2005. RA33 Ag. Autoantibodies to this protein (anti-RA33) are detect- The costs of publication of this article were defrayed in part by the payment of page able in one third of RA patients and show similar specificity for charges. This article must therefore be hereby marked advertisement in accordance RA as RF (8, 9). Importantly, pronounced Th1-like reactivity to with 18 U.S.C. Section 1734 solely to indicate this fact. hnRNP-A2 has recently been described to occur in ϳ50% of RA 1 This work was supported by the Center of Molecular Medicine of the Austrian Academy of Sciences, Vienna. patients but not in disease controls, suggesting possible pathogenic 2 Current address: Department of Rheumatology and Clinical Immunology, Charite´ involvement of this autoreactivity (10). University Medicine, Humboldt University and Free University of Berlin, Berlin, Autoantibodies may be already present very early or even years Germany. before the onset of disease, as recently demonstrated for RF and 3 Address correspondence and reprint requests to Dr. Gu¨nter Steiner, Department of anti-cyclic citrullinated peptide (CCP) Abs (11, 12). This indicates Rheumatology, Internal Medicine III, Medical University of Vienna, Wa¨hringer Gu¨rtel 18-20, A-1090 Vienna, Austria. E-mail address: [email protected] a role of such autoimmune response in the pathogenesis of RA, but 4 Abbreviations used in this paper: RA, rheumatoid arthritis; RF, rheumatoid factor; a definitive proof for this is still lacking. In contrast, there is abun- hnRNP, heterogeneous nuclear ribonucleoprotein; CCP, cyclic citrullinated peptide; dant evidence for the role of cytokines in RA synovitis and the hsp, heat shock protein; hTNF, human TNF; tg, transgenic; OPG, osteoprotegerin; ␣ TRAP, tartrate resistant acid phosphatase; RRM, RNA recognition motif; snRNP, ensuing joint destruction. In particular, TNF- , IL-1, and IL-6 ap- small nuclear RNP; wt, wild type; SLE, systemic lupus erythematosus. pear to constitute the most important proinflammatory mediators Copyright © 2005 by The American Association of Immunologists, Inc. 0022-1767/05/$02.00 8328 DEVELOPMENT OF AUTOANTIBODIES IN TNF␣ TRANSGENIC MICE of the RA process. The role of TNF-␣ is undisputed, given its Histological analysis abundant presence in the joint and the successful therapeutic in- Serial paraffin sections (1–2 ␮m) of hind and front paws and knees were tervention with biological agents inhibiting TNF-␣ (1). Another stained with H&E for histological analyses of arthritis. Areas of inflam- important piece of evidence for the pivotal role of TNF-␣ in RA mation and bone erosion were counted in mm2. To investigate expression pathogenesis stems from the observation that mice carrying human of hnRNP-A2, paraffin sections were boiled in 0.01 M Na-citrate buffer (pH TNF-␣ as transgene develop a severe erosive inflammatory poly- 6) in a microwave oven for 2 min at 780 W and for 10 min at 180 W. After cooling to room temperature, sections were stained with the 10D1 mAb arthritis demonstrating typical features of human RA, such as sy- (0.7 mg/ml) directed to hnRNP-A2 diluted 1/100–1/200 (10, 21). For de- novial hypercellularity, inflammatory infiltrates, pannus formation, tection of osteoclasts, sections were stained for tartrate-resistant acid phos- cartilage destruction, bone erosions, and, finally, crippling of paws phatase (TRAP) using the Leukocyte Acid Phosphatase staining kit (Sig- (13). Other experimental models in which
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