title: Aberrant expression of the autoantigen heterogeneous nuclear ribonucleoprotein-A2 (RA33) and spontaneous formation of rheumatoid arthritis-associated anti-RA33 autoantibodies in TNF-alpha transgenic mice.
abstract: Human TNF-alpha 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 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 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-alpha leads to aberrant expression of hnRNP-A2 in the rheumatoid joint and subsequently to autoimmune reactions, which may enhance the inflammatory and destructive process.
authors.affiliation: Department of Rheumatology, Internal Medicine III, Medical University of Vienna, Vienna, Austria;
authors.forename: Silvia
authors.initials: S
authors.lastname: Hayer
authors.forename: Makiyeh
authors.initials: M
authors.lastname: Tohidast-Akrad
authors.forename: Silva
authors.initials: S
authors.lastname: Haralambous
authors.forename: Beatrice
authors.initials: B
authors.lastname: Jahn-Schmid
authors.forename: Karl
authors.initials: K
authors.lastname: Skriner
authors.forename: Sylvie
authors.initials: S
authors.lastname: Trembleau
authors.forename: Hélène
authors.initials: H
authors.lastname: Dumortier
authors.forename: Serafin
authors.initials: S
authors.lastname: Pinol-Roma
authors.forename: Kurt
authors.initials: K
authors.lastname: Redlich
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.forename: Sylviane
authors.initials: S
authors.lastname: Muller
authors.forename: George
authors.initials: G
authors.lastname: Kollias
authors.forename: Josef
authors.initials: J
authors.lastname: Smolen
authors.forename: Günter
authors.initials: G
authors.lastname: Steiner
mesh_terms: D000818:Animals; D000917:Antibody Formation; D001172:Arthritis, Rheumatoid / Q000209:etiology / Q000276:immunology*; D001323:Autoantibodies / Q000096:biosynthesis*; D001324:Autoantigens / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology*; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007596:Joints / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000494:pharmacology*
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D014409:Tumor Necrosis Factor-alpha; C439768:hnRNP A2