| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Transgenic Mice1
,||,¶,||
* Department of Rheumatology, Internal Medicine III, Medical University of Vienna, Vienna, Austria;
Ludwig Boltzmann Institute for Rheumatology and Balneology, Vienna, Austria;
Laboratory of Molecular Genetics, Hellenic Pasteur Institute, Athens, Greece;
Institute of Pathophysiology, Medical University of Vienna, Vienna, Austria;
¶ Institute of Medical Biochemistry, Medical University of Vienna, Vienna, Austria;
|| Center of Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria;
# Institute of Molecular and Cellular Biology, Centre National de la Recherche Scientifique, Strasbourg, France;
** Department of Cell Biology and Anatomy, Mount Sinai School of Medicine, New York, NY 10029; and
Institute of Immunology, Biomedical Sciences Research Center "Alexander Fleming," Vari, Greece
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 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- leads to aberrant expression of hnRNP-A2 in the rheumatoid joint and subsequently to autoimmune reactions, which may enhance the inflammatory and destructive process.
This article has been cited by other articles:
|
|
 |
|
  G Schett, H Dumortier, E Hoefler, S Muller, and G Steiner B cell epitopes of the heterogeneous nuclear ribonucleoprotein A2: identification of a new specific antibody marker for active lupus disease Ann Rheum Dis, May 1, 2009; 68(5): 729 - 735. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J S Smolen, D Aletaha, and G Steiner Does damage cause inflammation? Revisiting the link between joint damage and inflammation Ann Rheum Dis, February 1, 2009; 68(2): 159 - 162. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. H. Hoffmann, J. Tuncel, K. Skriner, M. Tohidast-Akrad, B. Turk, S. Pinol-Roma, G. Serre, G. Schett, J. S. Smolen, R. Holmdahl, et al. The Rheumatoid Arthritis-Associated Autoantigen hnRNP-A2 (RA33) Is a Major Stimulator of Autoimmunity in Rats with Pristane-Induced Arthritis J. Immunol., December 1, 2007; 179(11): 7568 - 7576. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
